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Objectives: Previous reports indicate bone deficits in patients with Fontan circulation. However, the consequences of these deficits on bone strength and when these changes occur are unclear. Aim: To compare the tibial bone strength-strain index between young patients (6-19 years) with Fontan circulation and age- and sex-matched controls, and to determine strength-strain-index in subgroups of children (6-12 years) and adolescents (13-19 years) versus controls. Method: The tibia was examined with peripheral quantitative CT. Based on the assessed data, bone strength-strain index was calculated in the lateral and anterior-posterior directions. Results: Twenty patients with Fontan and twenty controls (mean age 13.0 ± 4.4 years; 50% females) were examined. Patients had a lower strength-strain index in the lateral direction compared to controls (808.4 ± 416.8mm3 versus 1162.5 ± 552.1mm3, p = 0.043). Subgroup analyses showed no differences regarding strength-strain index in children (6-12 years) with Fontan circulation compared to controls. However, the adolescents (13-19 years) with Fontan circulation had lower strength-strain indexes in both the lateral and anterior-posterior directions compared to controls (1041.4 ± 299.8mm3 versus 1596.4 ± 239.6mm3, p < 0.001, and 771.7 ± 192.4mm3 versus 1084.9 ± 215.0mm3, p = 0.004). When adjusted for height, there were differences between patients (6-19 years) and controls in strength-strain indexes in both the lateral and anterior-posterior directions. In subgroup analyses, the results remained robust. Conclusion: Young patients (6-19 years) with Fontan circulation have a lower strength-strain index in the tibia compared to controls. Subgroup analyses show that this deficit is mainly driven by the differences in adolescents (13-19 years), which might suggest that bone strength decreases with age.

Atrial septal defect secundum is a common type of congenital heart defect and even more common among children born premature. The aim of this study was to assess premature birth as a potential associated risk factors for cardiac morbidity in children with isolated ASD II. In this retrospective national registry-based case–control study all children born in Sweden between 2010 and 2015 with an isolated ASD II diagnosis were included. Association between premature birth and cardiac morbidity in children with isolated ASD II was assessed by different outcomes-models using conditional logistic regression and adjustments were made for confounding factors. Overall, 11% of children with an isolated ASD II received treatment for heart failure. Down syndrome was the only independent risk factors for associated with cardiac morbidity in children with ASD II (OR = 2.25 (95%CI 1.25–4.07). Preterm birth in children was not associated with an increased risk of ASD II cardiac morbidity.

Aim: To evaluate red flags as an instrument to distinguish other medical conditions from Functional Gastrointestinal Disorders (FGID) in children with long-term abdominal pain. Methods: In a retrospective follow-up, data were collected from 317 children who were referred for medical assessment due to long-term abdominal pain between the years 2011 and 2012 at three Swedish paediatric open clinic units in Sweden. Throughout the review of medical records, any documented red flags at the primary consultation and finally set diagnosis after 1 year were noted for all cases. Results: A non-FGID disease was diagnosed in 32 cases (10.1%). The sensitivity of red flags to predict inflammatory bowel disease (IBD) was 100% and the specificity 64.1%. The sensitivity of red flags to predict celiac disease was 45.5% and the specificity 63.7%. The sensitivity of red flags to predict any non-FGID disease was 59.4%, and the specificity was 65.6%. Conclusion: The use of red flags is a sensitive instrument to identify patients with IBD but less applicable when identifying celiac disease and other organic diseases. Specificity is generally low and future biomarkers for assessing children with long-term abdominal pain is needed.

Background: Mortality and severe morbidity remain high in extremely preterm infants. Human milk-based nutrient fortifiers may prevent serious complications and death. We aimed to investigate whether supplementation with human milk-based fortifier (HMBF), as compared to bovine milk-based fortifier (BMBF), reduced the incidence of the composite outcome of necrotising enterocolitis (NEC), sepsis, and mortality in extremely preterm infants exclusively fed human milk. Methods: In this multicentre, randomised controlled trial at 24 neonatal units in Sweden, extremely preterm infants born between gestational week 22 + 0 and 27 + 6 fed exclusively human breast milk (mother's own and/or donor milk), were randomly assigned (1:1) to receive targeted fortification with either HMBF or BMBF. Randomisation was conducted before the enteral feeds reached 100 mL/kg/day, and was stratified by enrolment site, gestational age, singleton/twin, and sex. The allocation was concealed before inclusion, but after randomisation the study was not blinded for the clinical staff. For the NEC diagnosis, the study group was masked to an independent radiologist, and the final assessment of NEC and culture-proven sepsis was done by a blinded consensus panel review. The primary outcome was the composite of NEC stage II–III, culture-proven sepsis, and mortality from inclusion to discharge, no longer than postmenstrual week 44 + 0, in the intention-to-treat population (ClinicalTrials.gov, NCT03797157). Findings: Between February 21st, 2019, and May 21st, 2021, 229 neonates were randomly assigned (115 HMBF, 114 BMBF). After exclusion of one infant due to parents’ withdrawal of consent, 228 infants were included in the intention-to-treat analysis. Of the 115 infants assigned to HMBF, 41 (35.7%) fulfilled the criteria of either NEC, sepsis, or death, compared with 39 (34.5%) of 113 infants assigned to BMBF (OR 1.05, 95% CI 0.61–1.81, p = 0.86). Adverse events did not differ significantly between groups. In

IMPORTANCE: Few studies have examined the incidence of long-term disabilities due to bacterial meningitis in childhood with extended follow-up time and a nationwide cohort. OBJECTIVE: To describe the long-term risks of disabilities following a childhood diagnosis of bacterial meningitis in Sweden. DESIGN, SETTING, AND PARTICIPANTS: This nationwide retrospective registry-based cohort study included individuals diagnosed with bacterial meningitis (younger than 18 years) and general population controls matched (1:9) by age, sex, and place of residence. Data were retrieved from the Swedish National Patient Register from January 1, 1987, to December 31, 2021. Data were analyzed from July 13, 2022, to November 30, 2023. EXPOSURE: A diagnosis of bacterial meningitis in childhood recorded in the National Patient Register between 1987 and 2021. MAIN OUTCOMES AND MEASURES: Cumulative incidence of 7 disabilities (cognitive disabilities, seizures, hearing loss, motor function disorders, visual disturbances, behavioral and emotional disorders, and intracranial structural injuries) after bacterial meningitis in childhood. RESULTS: The cohort included 3623 individuals diagnosed with bacterial meningitis during childhood and 32 607 controls from the general population (median age at diagnosis, 1.5 [IQR, 0.4-6.2] years; 44.2% female and 55.8% male, median follow-up time, 23.7 [IQR, 12.2-30.4] years). Individuals diagnosed with bacterial meningitis had higher cumulative incidence of all 7 disabilities, and 1052 (29.0%) had at least 1 disability. The highest absolute risk of disabilities was found for behavioral and emotional disorders, hearing loss, and visual disturbances. The estimated adjusted hazard ratios (HRs) showed a significant increased relative risk for cases compared with controls for all 7 disabilities, with the largest adjusted HRs for intracranial structural injuries (26.04 [95% CI, 15.50-43.74]), hearing loss (7.90 [95% CI, 6.68-9.33]), and motor function disorders (4

Objective: To explore the glucose-related hormone profile of very low birthweight (VLBW) infants and assess the association between neonatal hyperglycaemia and insulin resistance during the admission period. Design: A prospective observational study—the Very Low Birth Weight Infants, Glucose and Hormonal Profiles over Time study. Setting: A tertiary neonatal intensive care unit and four neonatal units in county hospitals in Sweden. Patients: 48 infants born <1500 g (VLBW) during 2016–2019. Outcome measures: Plasma concentrations of glucose-related hormones and proteins (C-peptide, insulin, ghrelin, glucagon-like peptide 1 (GLP-1), glucagon, leptin, resistin and proinsulin), insulin:C-peptide and proinsulin:insulin ratios, Homoeostatic Model Assessment 2 (HOMA2) and Quantitative Insulin Sensitivity Check (QUICKI) indices, measured on day of life (DOL) 7 and at postmenstrual age 36 weeks. Results: Lower gestational age was significantly associated with higher glucose, C-peptide, insulin, proinsulin, leptin, ghrelin, resistin and GLP-1 concentrations, increased HOMA2 index, and decreased QUICKI index and proinsulin:insulin ratio. Hyperglycaemic infants had significantly higher glucose, C-peptide, insulin, leptin and proinsulin concentrations, and lower QUICKI index, than normoglycaemic infants. Higher glucose and proinsulin concentrations and insulin:C-peptide ratio, and lower QUICKI index on DOL 7 were significantly associated with longer duration of hyperglycaemia during the admission period. Conclusions: VLBW infants seem to have a hormone profile consistent with insulin resistance. Lower gestational age and hyperglycaemia are associated with higher concentrations of insulin resistance markers.

Background: The prevalence of atopic dermatitis (AD) has increased over several decades and now affects about one-fifth of all children in high-income countries (HICs). While the increase continues in lower-income countries, the prevalence of AD might have reached a plateau in HICs. Objectives: To investigate trends in the prevalence of AD and atopic comorbidity in schoolchildren in Sweden. Methods: The study population consisted of three cohorts of children (median age 8 years) in Norrbotten, Sweden, for 1996 (n = 3430), 2006 (n = 2585) and 2017 (n = 2785). An identical questionnaire that included questions from the International Study of Asthma and Allergies in Childhood (ISAAC) protocol was used in all three cohorts. Trends in AD prevalence were estimated, as well as trends in atopic comorbidity. AD prevalence was estimated both according to the ISAAC definition of AD and by adding the reported diagnosis by a physician (D-AD). Results: The prevalence of AD decreased in the last decade, from 22.8% (1996) and 21.3% (2006) to 16.3% (2017; P < 0.001). The prevalence of D-AD was lower, but the same pattern of decrease was seen, from 9.3% (1996) and 9.4% (2006) to 5.7% (2017; P < 0.001). In all three cohorts, AD was more common among girls than boys (18.9% vs. 13.8% in 2017; P < 0.001). Children from the mountain inlands had a higher prevalence of AD than children from coastal cities (22.0% vs. 15.1% in 2017; P < 0.001). In comparing D-AD, there were no significant differences between the sexes or between inland or coastal living. Concomitant asthma increased over the years from 12.2% (1996) to 15.8% (2006) to 23.0% (2017; P < 0.001). Concomitant allergic rhinitis and allergic sensitization increased from 1996 (15.0% and 27.5%) to 2006 (24.7% and 49.5%) but then levelled off until 2017 (21.0% and 46.7%). Conclusions: The prevalence of AD among schoolchildren in Sweden decreased over the study period, whereas atopic comorbidity among children with AD incr

OBJECTIVE: To investigate potential risk factors behind the increased incidence of necrotising enterocolitis (NEC) in Swedish extremely preterm infants. DESIGN: Registry data from two population-based national cohorts were studied. NEC diagnoses (Bell stage ≥II) were validated against hospital records. PATIENTS: All liveborn infants <27 weeks of gestation 2004-2007 (n=704) and 2014-2016 (n=895) in Sweden. MAIN OUTCOME MEASURES: NEC incidence. RESULTS: The validation process resulted in a 28% reduction of NEC cases but still confirmed a higher NEC incidence in the later epoch compared with the earlier (73/895 (8.2%) vs 27/704 (3.8%), p=0.001), while the composite of NEC or death was lower (244/895 (27.3%) vs 229/704 (32.5%), p=0.022). In a multivariable Cox regression model, censored for mortality, there was no significant difference in early NEC (0-7 days of life) between epochs (HR=0.9 (95% CI 0.5 to 1.9), p=0.9), but being born in the later epoch remained an independent risk factor for late NEC (>7 days) (HR=2.7 (95% CI 1.5 to 5.0), p=0.001). In propensity score analysis, a significant epoch difference in NEC incidence (12% vs 2.8%, p<0.001) was observed only in the tertile of infants at highest risk of NEC, where the 28-day mortality was lower in the later epoch (35% vs 50%, p=0.001). More NEC cases were diagnosed with intramural gas in the later epoch (33/73 (45.2%) vs 6/26 (23.1%), p=0.047). CONCLUSIONS: The increase in NEC incidence between epochs was limited to cases occurring after 7 days of life and was partly explained by increased survival in the most extremely preterm infants. Misclassification of NEC is common.

Background: Arachidonic acid (ARA) and docosahexaenoic acid (DHA) are important structural components of neural cellular membranes and possess anti-inflammatory properties. Very preterm infants are deprived of the enhanced placental supply of these fatty acids, but the benefit of postnatal supplementation on brain development is uncertain. The aim of this study was to test the hypothesis that early enteral supplementation with ARA and DHA in preterm infants improves white matter (WM) microstructure assessed by diffusion-weighted MRI at term equivalent age. Methods: In this double-blind, randomized controlled trial, infants born before 29 weeks gestational age were allocated to either 100 mg/kg ARA and 50 mg/kg DHA (ARA:DHA group) or medium chain triglycerides (control). Supplements were started on the second day of life and provided until 36 weeks postmenstrual age. The primary outcome was brain maturation assessed by diffusion tensor imaging (DTI) using Tract-Based Spatial Statistics (TBSS) analysis. Results: We included 120 infants (60 per group) in the trial; mean (range) gestational age was 26+3 (22+6 - 28+6) weeks and postmenstrual age at scan was 41+3 (39+1 - 47+0) weeks. Ninety-two infants underwent MRI imaging, and of these, 90 had successful T1/T2 weighted MR images and 74 had DTI data of acceptable quality. TBSS did not show significant differences in mean or axial diffusivity between the groups, but demonstrated significantly higher fractional anisotropy in several large WM tracts in the ARA:DHA group, including corpus callosum, the anterior and posterior limb of the internal capsula, inferior occipitofrontal fasciculus, uncinate fasciculus, and the inferior longitudinal fasciculus. Radial diffusivity was also significantly lower in several of the same WM tracts in the ARA:DHA group. Conclusion: This study suggests that supplementation with ARA and DHA at doses matching estimated fetal accretion rates improves WM maturation compared to control treatment

Objective: To examine how the effect of disadvantaged socioeconomic circumstances on the risk of paediatric infections is mediated by pregnancy smoking, excess weight during pregnancy and breast feeding in children under 5 years of age. Design: A population-level, retrospective cohort study. The Swedish Medical Birth Register was combined with the National Patient Register, the longitudinal integration database for health insurance and labour market studies, the Cause of Death Register and a local register held by the Child Health Care Unit in Uppsala Region. Setting: Uppsala Region, Sweden. Patients: 63 216 term and post-term singletons born to women who resided in Uppsala Region, Sweden between 1997 and 2015. Main outcome measures: Number of hospital admissions for infectious diseases. Secondary outcomes were the number of hospitalisations for respiratory and enteric infections, respectively. Results: The effect of disadvantaged socioeconomic circumstances, that is, low maternal education on the overall risk of paediatric infections was mediated to a considerable (33%-64%) proportion by pregnancy smoking, excess weight during pregnancy and breast feeding. Conclusions: Pregnancy smoking, excess weight during pregnancy and breast feeding mediate a considerable proportion of the association between deprived socioeconomic circumstances and paediatric infectious diseases. Therefore, inequalities in paediatric infectious diseases may be reduced by public health policies addressing these health-related behaviours.

Aim: We evaluated the effect on body mass index standard deviation score (BMI-SDS) of a combined treatment (Web-COP) for children with obesity, including a web-based component targeting their parents. Methods: This randomised controlled trial recruited children 5–12 years of age with obesity (International Obesity Task Force BMI [IOTF-BMI] ≥30 kg/m2) from school health care and outpatient paediatric clinics in in Northern Sweden from 1 June 2019 to 21 June 2020. The children were randomised to Web-COP, an intervention with group sessions and a 12-week web-based component, or standard care. The primary outcome was the change in IOTF BMI-SDS after 6 months. Results: In total, 75 children (33 girls), mean age 9.5 years, were randomised, and 65/75 (87%) children and their parents completed the study, 35/39 (90%) in the Web-COP intervention and 30/36 (83%) in the standard care group. BMI-SDS at 6 months was changed from 3.08 to 2.81 in the intervention group compared to an increase from 3.07 to 3.16 in the standard care group, representing a significant difference between groups (p < 0.001). In the intervention group, 14/30 (47%) reduced their BMI-SDS ≥0.25, compared to none in the standard care group. Conclusion: The parent-focused intervention significantly improved BMI-SDS in children with obesity as compared to children in standard care.

Aim: To describe glucose homeostasis disturbances (dysglycaemia) in very low-birthweight infants (<1500 g) during the admission period and explore associated risk factors. Methods: The LIGHT (very low-birthweight infants - glucose and hormonal profile over time) study was a prospective observational cohort study that included 49 very low-birthweight infants admitted to the tertiary neonatal intensive care unit in Umeå, Sweden, during 2016–2019. All glucose concentrations (n = 3515) sampled during the admission period were registered. Results: Hyperglycaemia >10 mmol/L and hypoglycaemia <2.6 mmol/L were registered in 63% and 55% of the infants, respectively. Onset of dysglycaemia occurred almost exclusively in the first postnatal week. Hyperglycaemia followed 15% of corticosteroid doses given; all were preceded by pre-existing hyperglycaemia. Pre-existing hyperglycaemia was found in 66.7% of hyperglycaemic infants who received inotrope treatment. Upon commencement, 72.5% of antimicrobial treatments given were neither preceded nor followed by hyperglycaemia. Conclusion: Dysglycaemia was common in very low-birthweight infants. Daily means of glucose concentrations seemed to follow a postmenstrual age-dependent pattern, decreasing towards term age suggesting a postmenstrual age-dependent developmental mechanism. The primary mechanism causing hyperglycaemia was independent of sepsis, and corticosteroid and inotrope treatments. No hypoglycaemia was registered during ongoing insulin treatment.

Introduction: Since the majority of hospitalisations due to RSV occur in young children, the illness profoundly influences the entire family. However, comprehensive evidence regarding its overall effects remains limited. The ResQ Family study aims to investigate the burden of RSV-induced pediatric hospitalisation on affected families. Methods: Spanning the 2022–2023 RSV season, an interdisciplinary, observational study was conducted in Germany, France, Italy and Sweden. Using an online questionnaire, parents and caregivers of children (< 24 months of age) with an RSV-induced hospitalisation were recruited. Information was gathered on topics related to RSV and parental health-related quality of life (HRQoL) during the acute infection phase (t0) and 6 weeks later (t1). Descriptive evaluations of the data set were performed during t0 and regarding a potential change over the observation period (t0 vs. t1). Subgroup analysis aimed to further identify differences across the countries. Results: A total set of 138 affected parents/caregivers were included in the study, with 59 participants responding to the follow-up survey (t1). Particularly during the acute infection phase, parental HRQoL was shown to be negatively influenced by the child’s RSV infection [total score (p < 0.001, d = 0.54), parent HRQoL summary score (p < 0.001, d = 0.67) and family functioning summary score (p = 0.007, d = 0.33)]. Significant disparities in disease awareness and support structures were observed across Europe, with France and Sweden showing notably higher levels. Conclusion: The ResQ Family study provides convincing evidence that RSV-associated hospitalisations in young children across Europe generate a multifaced burden for the entire family, partly even beyond the acute infection phase. Standardised approaches for disease prevention at societal, educational and policy levels are needed to guarantee every newborn the best possible start into life.

Introduction: The diagnosis and management of cow's milk allergy (CMA) is a topic of debate and controversy. Our aim was to compare the opinions of expert groups from the Middle East (n = 14) and the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) (n = 13). Methods: These Expert groups voted on statements that were developed by the ESPGHAN group and published in a recent position paper. The voting outcome was compared. Results: Overall, there was consensus amongst both groups of experts. Experts agreed that symptoms of crying, irritability and colic, as single manifestation, are not suggestive of CMA. They agreed that amino-acid based formula (AAF) should be reserved for severe cases (e.g., malnutrition and anaphylaxis) and that there is insufficient evidence to recommend a step-down approach. There was no unanimous consensus on the statement that a cow's milk based extensively hydrolysed formula (eHF) should be the first choice as a diagnostic elimination diet in mild/moderate cases. Although the statements regarding the role for hydrolysed rice formula as a diagnostic and therapeutic elimination diet were accepted, 3/27 disagreed. The votes regarding soy formula highlight the differences in opinion in the role of soy protein in CMA dietary treatment. Generally, soy-based formula is seldom available in the Middle-East region. All ESPGHAN experts agreed that there is insufficient evidence that the addition of probiotics, prebiotics and synbiotics increase the efficacy of elimination diets regarding CMA symptoms (despite other benefits such as decrease of infections and antibiotic intake), whereas 3/14 of the Middle East group thought there was sufficient evidence. Discussion: Differences in voting are related to geographical, cultural and other conditions, such as cost and availability. This emphasizes the need to develop region-specific guidelines considering social and cultural conditions, and to perform further research in this

A comprehensive international consensus on the cytogenetic risk-group stratification of KMT2A-rearranged (KMT2A-r) pediatric acute myeloid leukemia (AML) is lacking. This retrospective (2005-2016) International Berlin-Frankfurt-Münster Study Group study on 1256 children with KMT2A-r AML aims to validate the prognostic value of established recurring KMT2A fusions and additional cytogenetic aberrations (ACAs) and to define additional, recurring KMT2A fusions and ACAs, evaluating their prognostic relevance. Compared with our previous study, 3 additional, recurring KMT2A-r groups were defined: Xq24/KMT2A::SEPT6, 1p32/KMT2A::EPS15, and 17q12/t(11;17)(q23;q12). Across 13 KMT2A-r groups, 5-year event-free survival probabilities varied significantly (21.8%-76.2%; P < .01). ACAs occurred in 46.8% of 1200 patients with complete karyotypes, correlating with inferior overall survival (56.8% vs 67.9%; P < .01). Multivariable analyses confirmed independent associations of 4q21/KMT2A::AFF1, 6q27/KMT2A::AFDN, 10p12/KMT2A::MLLT10, 10p11.2/KMT2A::ABI1, and 19p13.3/KMT2A::MLLT1 with adverse outcomes, but not those of 1q21/KMT2A::MLLT11 and trisomy 19 with favorable and adverse outcomes, respectively. Newly identified ACAs with independent adverse prognoses were monosomy 10, trisomies 1, 6, 16, and X, add(12p), and del(9q). Among patients with 9p22/KMT2A::MLLT3, the independent association of French-American-British-type M5 with favorable outcomes was confirmed, and those of trisomy 6 and measurable residual disease at end of induction with adverse outcomes were identified. We provide evidence to incorporate 5 adverse-risk KMT2A fusions into the cytogenetic risk-group stratification of KMT2A-r pediatric AML, to revise the favorable-risk classification of 1q21/KMT2A::MLLT11 to intermediate risk, and to refine the risk-stratification of 9p22/KMT2A::MLLT3 AML. Future studies should validate the associations between the newly identified ACAs and outcomes and unravel the underlying bi

Introduction: Despite advances in neonatal care, late-onset sepsis remains an important cause of preventable morbidity and mortality. Neonatal late-onset sepsis rates have decreased in some countries, while in others they have not. Our objective was to compare trends in late-onset sepsis rates in 9 population-based networks from 10 countries and to assess the associated mortality within 7 days of late-onset sepsis. Methods: We performed a retrospective populationbased cohort study. Infants born at 24-28 weeks' gestation between 2007 and 2019 were eligible for inclusion. Lateonset sepsis was defined as a positive blood or cerebrospinal fluid culture. Late-onset sepsis rates were calculated for 3 epochs (2007-11, 2012-15, and 2016-19). Adjusted risk ratios (aRRs) for late-onset sepsis were calculated for each network. Results: Of a total of 82,850 infants, 16,914 (20.4%) had late-onset sepsis, with Japan having the lowest rate (7.1%) and Spain the highest (44.6%). Late-onset sepsis rates decreased in most networks and remained unchanged in a few. Israel, Sweden, and Finland showed the largest decrease in late-onset sepsis rates. The aRRs for late-onset sepsis showed wide variations between networks. The rate of mortality temporally related to late-onset sepsis was 10.9%. The adjusted mean length of stay for infants with late-onset sepsis was increased by 5-18 days compared to infants with no late-onset sepsis. Conclusions: One in 5 neonates of 24-28 weeks' gestation develops late-onset sepsis. Wide variability in late-onset sepsis rates exists between networks with most networks exhibiting improvement. Late-onset sepsis was associated with increased mortality and length of stay.

Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta-analyzed epigenome-wide associations of parental age with offspring blood DNAm of over 9500 newborns and 2000 children (5–10 years old) from the Pregnancy and Childhood Epigenetics consortium. In newborns, we identified 33 CpG sites in 13 loci with DNAm associated with maternal age (PFDR < 0.05). Eight of these CpGs were located near/in the MTNR1B gene, coding for a melatonin receptor. Regional analysis identified them together as a differentially methylated region consisting of 9 CpGs in/near MTNR1B, at which higher DNAm was associated with greater maternal age (PFDR = 6.92 × 10−8) in newborns. In childhood blood samples, these differences in blood DNAm of MTNR1B CpGs were nominally significant (p < 0.05) and retained the same positive direction, suggesting persistence of associations. Maternal age was also positively associated with higher DNA methylation at three CpGs in RTEL1-TNFRSF6B at birth (PFDR < 0.05) and nominally in childhood (p < 0.0001). Of the remaining 10 CpGs also persistent in childhood, methylation at cg26709300 in YPEL3/BOLA2B in external data was associated with expression of ITGAL, an immune regulator. While further study is needed to establish causality, particularly due to the small effect sizes observed, our results potentially support offspring DNAm as a mechanism underlying associations of maternal age with child health.

Human milk, due to its unique composition, is the optimal standard for infant nutrition. Osteopontin (OPN) is abundant in human milk but not bovine milk. The addition of bovine milk osteopontin (bmOPN) to formula may replicate OPN’s concentration and function in human milk. To address safety concerns, we convened an expert panel to assess the adequacy of safety data and physiological roles of dietary bmOPN in infancy. The exposure of breastfed infants to human milk OPN (hmOPN) has been well-characterized and decreases markedly over the first 6 months of lactation. Dietary bmOPN is resistant to gastric and intestinal digestion, absorbed and cleared from circulation within 8–24 h, and represents a small portion (<5%) of total plasma OPN. Label studies on hmOPN suggest that after 3 h, intact or digested OPN is absorbed into carcass (62%), small intestine (23%), stomach (5%), and small intestinal perfusate (4%), with <2% each found in the cecum, liver, brain, heart, and spleen. Although the results are heterogenous with respect to bmOPN’s physiologic impact, no adverse impacts have been reported across growth, gastrointestinal, immune, or brain-related outcomes. Recombinant bovine and human forms demonstrate similar absorption in plasma as bmOPN, as well as effects on cognition and immunity. The panel recommended prioritization of trials measuring a comprehensive set of clinically relevant outcomes on immunity and cognition to confirm the safety of bmOPN over that of further research on its absorption, distribution, metabolism, and excretion. This review offers expert consensus on the adequacy of data available to assess the safety of bmOPN for use in infant formula, aiding evidence-based decisions on the formulation of infant formula.

Background: Nutrition and growth in the preterm infant are fundamentally intertwined. Nutrition plays an important role in the care of the preterm infant, and especially so in the extremely preterm (EPT) infant. EPT infants have a high risk of malnutrition and poor growth, known to be associated with adverse outcomes. It is therefore important to study the nutrient intakes, factors affecting growth and other outcomes in this population of infants. Infants born preterm are at risk for developing iron overload due to erythrocyte transfusions. It is established that infants born preterm are at an increased risk of developing feeding difficulties in later childhood, but the underlying mechanisms remain unclear. Methods: Three cohorts of infants born preterm were studied in this thesis. In Paper I (macronutrient intakes), data from a cohort of EPT infants born at two Swedish hospitals between 2011 and 2021 were collected. Paper II (transfusion and iron overload) used data from a cohort of very low birth weight infants (WLBW; <1500 g) treated at Umeå University Hospital born between 2010 and 2013. Papers III (catch-up growth) and IV (feeding problems after discharge) used data from the national EXtremely PREterm infants in Sweden Study (EXPRESS) between 2004 and 2007. Data collection for the three study populations included parenteral and enteral nutritional intakes, all anthropometric measurements during the hospitalisation, results of laboratory analyses, perinatal data, and neonatal morbidity. Results: Paper I: Energy intakes between gestational weeks (GA) 29+0 and 33+6 were significantly different between the two studied hospitals. There were no differences regarding the intake of protein or carbohydrates, but intake of fat from lipid supplements was significantly higher at the hospital with higher energy intake, where a lower proportion of mother’s own milk was noted as well. There were no differences in growth between the two hospitals during the study period. Pa

Aim: The burden of respiratory disease is great among children. This study aimed to examine the temporal relationship between hospitalisation for respiratory syncytial virus (RSV) and bacterial pneumonia. Methods: A Swedish population-based cohort was created by combining data from the Swedish Medical Birth Register, the National Inpatient Register, the Cause of Death Register, the Total Population Register, and the Longitudinal Integration Database for Health Insurance and Labour Market Studies. Children born between 1998 and 2015 were included and followed for 2 years. We examined the temporal relationship between RSV hospitalisation and bacterial pneumonia using piecewise exponential models. Results: The final cohort comprised 1 641 747 children, 48.5% were females. There were 23 632 RSV and 4722 bacterial pneumonia hospitalisations, with mean age of 137.8 and 424.2 days, respectively. RSV hospitalisation was associated with bacterial pneumonia with an adjusted incidence rate ratio (aIRR) of 3.18. The risk was highest in the first month after RSV hospitalisation, aIRR 11.19. The risk of bacterial pneumonia was elevated for 4 months after RSV hospitalisation and before RSV hospitalisation. Conclusion: We found an increased risk for bacterial pneumonia hospitalisation in children hospitalised for RSV both before and after RSV hospitalisation, indicating a bidirectional relationship.

The recent advisory issued by the United States Food and Drug Administration, cautioning against the routine administration of probiotics in preterm neonates, has sparked a lively debate within the scientific community. This commentary presents a perspective from members of the Special Interest Group on Gut Microbiota and Modifications within the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and other authors who contributed to the ESPGHAN position paper on probiotics for preterm infants, as well as representatives from the European Foundation for the Care of Newborn Infants. We advocate for a more nuanced and supportive approach to the use of certain probiotics in this vulnerable population, balancing the demonstrated benefits and risks.

Background: It is well known that socially deprived children are more likely to be hospitalised for infections. Less is known about how different social disadvantages interact. Therefore, we examine intersectional inequalities in overall, upper respiratory, lower respiratory, enteric and genitourinary infections in the first 5 years of life. Methods: We conducted a population-based retrospective cohort study of Swedish children born between 1998 and 2015. Inequalities were examined using analysis of individual heterogeneity and discriminatory accuracy as the analytical framework. A variable with 60 intersectional strata was created by combining information on maternal education, household income, sex/gender and maternal migration status. We estimated the incidence rates of infectious disease hospitalisation for each intersectional strata and the associations between intersectional strata and infectious disease hospitalisations using logistic regression models. We furthermore quantified the discriminatory ability of the intersectional strata with respect to infectious disease hospitalisation. Results: The study included 1785 588 children and 318 080 hospital admissions. The highest overall incidence of hospitalisations for infections was found in boys born to low-educated mothers who lived in families with the lowest household income. The overall incidence of infections was unrelated to household income in children born to highly educated mothers. The ability of the intersectional strata to discriminate between children with and without infections was poor. Conclusion: We found that inequalities in paediatric infectious diseases were shaped by the intersections of different social disadvantages. These inequalities should be addressed by public health policies that reach all children.

Aim: Psychotropic medication can contribute to arrhythmia and identifying individuals at risk is crucial. This Swedish study compared the corrected QT (QTc) intervals of adolescents on psychotropic medication with unmedicated controls, when supine and after rising rapidly. Methods: The study was carried out at Östersund County Hospital in March 2022 and February to March 2023. It comprised 16 cases, aged 10–17 years and 28 controls. QTc intervals were measured with electrocardiography and calculated using Bazett's and Fridericia's formulas. Univariate and multiple linear regressions were used to assess differences in QTc intervals between the cases and controls and across sex, age and body mass index. Results: The mean QTc interval when supine, calculated with Bazett's formula, was longer for the adolescents on psychotropic medication than the controls (p = 0.046). The same was true for the mean QTc interval after rising rapidly from the supine position, calculated with both Bazett's formula (p = 0.009) and Fridericia's formula (p = 0.007). Mean QTc intervals varied by sex and age groups. Psychotropic medication prolonged QTc intervals, particularly in girls. Conclusion: Longer QTc intervals were found in adolescents on psychotropic medication, particularly after rising rapidly from the supine position.

Acute lymphoblastic leukemia (ALL) is the most prevalent cancer in children, and despite considerable progress in treatment outcomes, relapses still pose significant risks of mortality and long-term complications. To address this challenge, we employed a supervised machine learning technique, specifically random survival forests, to predict the risk of relapse and mortality using array-based DNA methylation data from a cohort of 763 pediatric ALL patients treated in Nordic countries. The relapse risk predictor (RRP) was constructed based on 16 CpG sites, demonstrating c-indexes of 0.667 and 0.677 in the training and test sets, respectively. The mortality risk predictor (MRP), comprising 53 CpG sites, exhibited c-indexes of 0.751 and 0.754 in the training and test sets, respectively. To validate the prognostic value of the predictors, we further analyzed two independent cohorts of Canadian (n = 42) and Nordic (n = 384) ALL patients. The external validation confirmed our findings, with the RRP achieving a c-index of 0.667 in the Canadian cohort, and the RRP and MRP achieving c-indexes of 0.529 and 0.621, respectively, in an independent Nordic cohort. The precision of the RRP and MRP models improved when incorporating traditional risk group data, underscoring the potential for synergistic integration of clinical prognostic factors. The MRP model also enabled the definition of a risk group with high rates of relapse and mortality. Our results demonstrate the potential of DNA methylation as a prognostic factor and a tool to refine risk stratification in pediatric ALL. This may lead to personalized treatment strategies based on epigenetic profiling.

Background: Long QT syndrome (LQTS), Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), Brugada syndrome (BrS), and short QT syndrome are hereditary diseases caused by mutations in genes coding for cardiac ion channels. Patients carrying these mutations may be at risk of symptoms such as syncope and sudden cardiac death (SCD). To prevent symptoms, patients need to be managed properly and this management may include prophylactic medical treatment, and the use of an implantable cardioverter defibrillator (ICD) for high-risk patients. ICD treatment has previously been shown to prevent SCD, but it also carries a risk of complications and inappropriate shocks. In these studies, we investigated ICD treatment in patients with inherited arrhythmogenic channelopathies with a focus on individual risk assessment and ICD harm. Methods: Studies I–III are observational studies that use registries to identify patients and medical records to collect data. Studies I and III are performed with a descriptive approach that focus on phenotype, genotype, and medical treatment (Study I) and the diagnostic process and treatment over time (Study III). In Study II, we use Kaplan Meier analyses and incidence rates to assess risk scores and ICD harm. Study IV is a systematic review based on a systematic search and screening process. The data, which are synthesized without meta-analysis, are from published original works. Results: In Studies I and II, we present data on 109 Swedish LQTS patients with a first ICD implantation between 1992 and 2013 at a median age of 39 years (range, 5–78 years). Most patients received ICD treatment after aborted cardiac arrest (n=45, 41%) and after syncope despite receiving prophylactic medical treatment, i.e., beta-blockers (n=31, 29%). However, 10 patients (9%) received ICD treatment despite being asymptomatic and 17 patients (16%) after syncope without ongoing beta-blocker treatment. The incidence rate of a first appropriate shock was 4.3 per 100 p

Consumption of acidic fruit pouches in infancy may damage the epithelial barrier in the gastrointestinal tract and is suggested to increase allergy risk. We aimed to explore if a high fruit pouch consumption is associated with a higher incidence of early allergic manifestations. We included 2959 parent–child dyads from the Swedish prospective, population-based NorthPop birth cohort study with parentally reported data on frequency of fruit pouch consumption at 9 months of age, as well as parentally reported eczema, wheeze, physician-diagnosed asthma, and food allergy in the first 18 months of life. Immunoglobulin E levels (IgE) in serum (n = 1792), as response to a food mix and an inhalant mix, were determined at age 18 months. Compared with no consumption, daily consumption of one or more pouches at 9 months of age was associated with inhalant sensitization (odds ratio (OR) 2.27, 95% confidence interval (CI) 1.06–4.87, n = 1792) but did not remain significant in the multivariable adjusted model (aOR 2.08, 95% CI 0.95–4.53, n = 1679). There were no associations between fruit pouch consumption and allergic manifestations at this young age. This study suggests that fruit pouch consumption is not associated with allergic phenotypes or IgE sensitization in early childhood.

Background & aims: A balanced supply of arachidonic acid (ARA) and docosahexaenoic acid (DHA) may be crucial for quality of growth in preterm infants. This secondary analysis of a randomized controlled trial aimed to determine the effect of enhanced ARA and DHA supplementation on growth and body composition in infants born before 29 weeks of gestation. Furthermore, we aimed to study associations between human milk feeding, growth patterns and body composition. Methods: The ImNuT-trial randomized 121 infants to receive a daily supplement with medium chain triglycerides (control) or 100 mg/kg ARA and 50 mg/kg DHA (ARA:DHA group) from the second day of life until 36 weeks postmenstrual age. Growth and body composition were evaluated up to 3 months corrected age. Results: The ARA:DHA group showed better linear growth from birth to term equivalent age compared to the control group; mean difference in z score change from birth for length was 0.74 ([95% CI, 0.17–1.3]; p = 0.010). There were no differences in growth and body composition outcomes at 3 months corrected age between the groups. An increase in z score for weight after 36 weeks postmenstrual age and breastfeeding at 3 months corrected age were the strongest positive predictors of fat mass% at 3 months corrected age (both, p < 0.001). Conclusion: Early enhanced supplementation of ARA and DHA may be beneficial with respect to somatic growth in very preterm infants. Clinical trial registration: The trial has been registered on www.clinicaltrials.gov, ID: NCT03555019.

Introduction and objective: Human milk contains all the nutrients and bioactive components required for the optimal growth and development of newborns. It is also an optimal source of nutrition in premature infants, however it does not fully meet their nutritional demands. Studies have shown that infants fed exclusively human milk have better enteral nutrition tolerance, lower risk of necrotising enterocolitis, and improved neurodevelopmental outcomes. The aim of the study was to analyse preterm content of human milk collected from women as part of a randomised controlled trial assessing tailored nutrition. Materials and methods: We studied 726 samples from 39 mothers of premature infants during their first postnatal four weeks. Infants were assigned to standard or tailored enteral nutrition, but all mothers were asked to pool milk samples from full breast expression at each feed across a 24-hour period twice a week. Glucose, fat, protein, and energy levels were measured using the Miris Human Milk Analyser and compared to published values. We assessed the relationship between postnatal week and human milk content. Results: Protein content decreased over time. Median protein at four weeks of postnatal age was 1.37 and 1.32 per 100 mL (tailored vs. standard group, respectively). Lipid content increased over time. Median lipid content at four weeks of postnatal age was 4.06 and 3.82 per 100 mL (tailored vs. standard group). Glucose remained stable. Energy content increased over time only in the tailored group. Median energy at four weeks of postnatal age was 73.35 per 100 mL. Conclusions: Variations in human milk content exist between populations and should be considered when prescribing enteral nutrition in preterm infants.

BACKGROUND: We aimed to characterize breast milk microbiota and define associations with saliva and fecal microbiota and selected diseases in preschool children. METHODS: In a longitudinal cohort study, the microbiotas from breast milk, mouth, and fecal samples were characterized by 16S rRNA gene sequencing. Questionnaires and medical records provided information on demographics, medical, and dental data. RESULTS: The phylogeny in breast milk, saliva swabs, and feces differed at all levels (p < 0.0003), though all harbored species in Streptococcus, Veillonella, and Haemophilus. Species richness was highest in breast milk with increasing resemblance with the oral swab microbiota by increasing age. Caries-affected children at age 5 had been fed breast milk with tenfold higher abundance of caries-associated bacteria, e.g., Streptococcus mutans, than caries-free children (p < 0.002). At that age, taxa, e.g., Neisseria sicca were overrepresented in saliva swabs of children with otitis media (LDA score >2, p < 0.05). Gut symbionts, e.g., Bacteroides, were underrepresented in 3-month fecal samples in children later diagnosed with allergic disease (LDA score >2, p < 0.05). CONCLUSIONS: Distinct microbiotas for the three sources were confirmed, though resemblance between milk and oral swab microbiota increased by age. Future studies should evaluate if the observed associations with disease outcomes are causal. IMPACT: Few studies have studied the association between breast milk microbiota and gastrointestinal microbiota beyond early infancy. The present study confirms distinct microbiota profiles in breast milk, saliva swabs, and feces in infancy and indicates increasing resemblance between breast milk and the oral microbiota by increasing age. The fecal microbiota at 3 months was associated with later allergic disease; the saliva microbiota by age 5 differed between children with and without otitis media at the same age; and children with caries by age 5 h

Social-emotional problems occurring early in life can place children at future risk of adverse health, social and economic outcomes. Determinants of social-emotional problems are multi-layered and originate from different contexts surrounding children, though few studies consider them simultaneously. We adopted a holistic approach by using Bronfenbrenner's process-person-context-time model as a structuring device. We aimed to assess what characteristics of families and children from pregnancy, over birth, and up to 3 years of age are associated with social-emotional problems in boys and girls. This study used regional data from the Salut Programme, a universal health promotion programme implemented in Antenatal and Child Health Care, and data from national Swedish registers. The study population included 6033 3-year-olds and their parents during the period 2010–2018. Distinct logistic regression models for boys and girls were used to assess associations between the family social context, parents' lifestyle, parent's mental health, children's birth characteristics, and indicators of proximal processes (the independent variables); and children's social-emotional problems as measured by the parent-completed Ages and Stages Questionnaire: Social-Emotional between 33 and 41 months of age (the outcome). Overall, a less favourable family social context, detrimental lifestyle of the parents during pregnancy, and parents' mental illness from pregnancy onwards were associated with higher odds of social-emotional problems in 3-year-olds. Higher screentime and infrequent shared book-reading were associated with higher odds of social-emotional problems. The multifaceted determinants of children's social-emotional problems imply that many diverse targets for intervention exist. Additionally, this study suggests that Bronfenbrenner's process-person-context-time theoretical framework could be relevant for public health research and policy.

A significant proportion of events in paediatric acute myeloid leukaemia (AML) are caused by resistant disease (RD). We investigated clinical and biological characteristics in 66 patients with RD from 1013 children with AML registered and treated according to the NOPHO-AML 93, NOPHO-AML 2004, DB AML-01 and NOPHO-DBH AML 2012 protocols. Risk factors for RD were age10 years or older and a white-blood-cell count (WBC) of 100 × 109/L or more at diagnosis. The five-year overall survival (OS) was 38% (95% confidence interval [CI]: 28%–52%). Of the 63 children that received salvage therapy with chemotherapy, 59% (N = 37) achieved complete remission (CR) with OS 57% (95% CI: 42%–75%) compared to 12% (95% CI: 4%–35%) for children that did not achieve CR. Giving more than two salvage chemotherapy courses did not increase CR rates. OS for all 43 patients receiving allogeneic haematopoietic stem cell transplantation (HSCT) was 49% (95% CI: 36%–66%). Those achieving CR and proceeding to HSCT had an OS of 56% (95% CI: 41%–77%, N = 30). This study showed that almost 40% of children with primary resistant AML can be cured with salvage therapy followed by HSCT. Children that did not achieve CR after two salvage courses with chemotherapy did not benefit from additional chemotherapy.

BACKGROUND: Social-emotional ability is important for overall health and wellbeing in early childhood. Recognizing preschool children in need of extra support, especially those living in unfavourable conditions, can have immediate positive effects on their health and benefit their wellbeing in the long-term. OBJECTIVES: The aim of this study is to investigate whether there are social inequalities in preschool children's social-emotional problems, and whether inequalities differ between boys and girls. METHOD: This study utilized repeated measures from cross-sectional population-based surveys of three-year old children (2014-2018). The final study population comprised of 9,099 children which was 61% of all the eligible children in Västerbotten County during the study period. The Ages and Stages Questionnaires: Social-Emotional (ASQ:SE) 36-month interval was used to measure children's social-emotional ability. Social inequalities were studied with respect to parents' income, education, and place of birth, for which data was obtained from Statistics Sweden. Multiple logistic and ordered regressions were used. RESULTS: Among 3-year-olds, social-emotional problems were more common in the most vulnerable social groups, i.e. parents in the lowest income quintile (OR: 1.45, p < 0.001), parents with education not more than high school (OR: 1.51, p < 0.001), and both parents born outside Sweden (OR: 2.54, p < 0.001). Notably, there was a larger difference in social-emotional problems between the lowest and highest social categories for girls compared to boys. Higher odds of social-emotional problems were associated with boys not living with both parents and girls living in the areas of Skellefteå and Umeå, i.e. more populated geographical areas. CONCLUSION: Already at 3-years of age social-emotional problems were more common in children with parents in the most vulnerable social groups. This does not fulfil the ambition of an equitable start in life for every child a

Vitamin A has a key role in lung development and its deficiency is associated with an increased risk of bronchopulmonary dysplasia. This secondary cohort analysis of the ImNuT trial (Immature, Nutrition Therapy NCT03555019) aimed to (1) explore vitamin A status in preterm infants <29 weeks gestation and (2) assess the influence of inflammation and postnatal dexamethasone exposure on vitamin A concentrations in blood. We report detailed information on vitamin A biochemistry, vitamin A intake, markers of inflammation and dexamethasone exposure. After four weeks of age, infants exposed to dexamethasone (n = 39) showed higher vitamin A concentrations compared to unexposed infants (n = 41); median (IQR) retinol was 1.0 (0.74, 1.5) vs. 0.56 (0.41, 0.74) µmol/L, p < 0.001. Pretreatment retinol concentrations were lower in the dexamethasone group compared to non-exposed infants (p < 0.001); 88% vs. 60% of the infants were considered deficient in vitamin A (retinol < 0.7 µmol/L) at one week of age. Small size for gestational age, mechanical ventilation and elevated levels of interleukin-6 were factors negatively associated with first-week retinol concentrations. In conclusion, preterm infants <29 weeks gestation are at risk of vitamin A deficiency despite intakes that accommodate current recommendations. The presence of inflammation and dexamethasone exposure should be considered when interpreting vitamin A status.

Background: Swedish child health services (CHS) is a free-of-charge healthcare system that reaches almost all children under the age of 6. The aim for the CHS is to improve children's physical, psychological and social health by promoting health and development, preventing illness and detecting emerging problems early in the child's life. The services are defined in a national programme divided into three parts: universal interventions, targeted interventions and indicated interventions. The Swedish Child Health Services Register (BHVQ) is a national Quality Register developed in 2013. The register extracts data from the child's health record and automatically presents current data in real time. At present, the register includes 21 variables. Aim: We aim to describe data available in the BHVQ and the completeness of data in BHVQ across variables. Methods: Child-specific data were exported from the register, and data for children born in the regions were retrieved from Statistics Sweden to calculate coverage. Results: The register includes over 110 000 children born between 2011 and 2022 from 221 child healthcare centres in eight of Sweden's 21 regions. In seven of the eight regions, 100% of centres report data. The completeness of data differs between participating regions and birth cohorts. The average coverage for children born in 2021 is 71%. Conclusions: The BHVQ is a valuable resource for evaluating Child Health Services nationally, with high coverage for the youngest children. As a result of continuous improvement of the services, the possibility to follow the development of children's health in Sweden is possible through the register. When fully expanded, the register will be a natural and essential part of developing preventive services, improving healthcare for children below 6 years of age and a tool for developing evidence-based child health interventions.

Introduction: A detailed understanding of respiratory support patterns in preterm infants is lacking. The aim was to explore and visualize this practice in Sweden. Methods: Preterm infants with gestational ages of 22-31 weeks, admitted to neonatal units reporting daily to the Swedish Neonatal Quality Register and discharged alive in November 2015-April 2022, were included in this descriptive cohort study. Proportions receiving mechanical ventilation, noninvasive support, or supplemental oxygen were calculated and graphically displayed for each gestational week and postnatal day (range 0-97) up to hospital discharge or 36 weeks of postmenstrual age. Results: Respiratory support in 148,515 days of care (3,368 infants; 54% males; median [interquartile range] birthweight = 1,215 [900-1,525] g) was evaluated. Trajectories showed distinct nonlinear patterns for each category of respiratory support, but differences in respiratory support over the gestational age range were linear: the proportion of infants on mechanical ventilation decreased by -11.7 to -7.3% (variability in estimates related to the postnatal day chosen for regression analysis) for each week higher gestational age (r = -0.99 to -0.87, p ≤ 0.001). The corresponding proportions of infants with supplemental oxygen decreased by -12.4% to -4.5% for each week higher gestational age (r = -0.98 to -0.94, p < 0.001). At 36 weeks of postmenstrual age, dependencies on mechanical ventilation, noninvasive support, and supplemental oxygen varied from 3%, 84%, and 94% at 22 weeks to 0%, 3%, and 5% at 31 weeks of gestational age, respectively. Conclusions: Respiratory support patterns in very preterm infants follow nonlinear, gestational age-specific postnatal trajectories in a dose-response-related fashion.

Aim: The use of pulmonary vasodilator therapy in children born preterm is largely unknown. Our aim was to map prescription patterns in children with bronchopulmonary dysplasia in Sweden. Methods: This was a descriptive national registry-based study of children <7 years who had been prescribed a pulmonary vasodilator during 2007–2017, were born preterm and classified as having bronchopulmonary dysplasia. Information on prescriptions, patient characteristics and comorbidities were retrieved from the Swedish Prescribed Drug Register and linked to other national registers. Results: The study included 74 children, 54 (73%) born at 22–27 weeks' gestation and 20 (27%) at 28–36 weeks. Single therapy was most common, n = 64 (86.5%), and sildenafil was prescribed most frequently, n = 69 (93%). Bosentan, iloprost, macitentan and/or treprostinil were used mainly for combination therapies, n = 10 (13.5%). Patent ductus arteriosus or atrial septal defect were present in 29 (39%) and 25 (34%) children, respectively, and 20 (69%) versus 3 (12%) underwent closure. Cardiac catheterisation was performed in 19 (26%) patients. Median duration of therapy was 4.6 (1.9-6.8, 95% CI) months. Mortality was 9%. Conclusion: Preterm children with bronchopulmonary dysplasia were prescribed pulmonary vasodilators, often without prior catheterisation. Sildenafil was most commonly used. Diagnostic tools, effects, and drug safety need further evaluation.

BACKGROUND: Probiotics, defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host, are widely used despite uncertainty regarding their efficacy and discordant recommendations about their use. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Special Interest Group on Gut Microbiota and Modifications provides updated recommendations for the use of probiotics for the management of selected pediatric gastrointestinal disorders. METHODS: All systematic reviews and/or meta-analyses, as well as subsequently published randomized controlled trials (RCTs) (until December 2021), that compared the use of probiotics in all delivery vehicles and formulations, at any dose, with no probiotic (ie, placebo or no treatment), were eligible for inclusion. The recommendations were formulated only if at least 2 RCTs on a similar well-defined probiotic strain were available. The modified Delphi process was used to establish consensus on the recommendations. RESULTS: Recommendations for the use of specific probiotic strains were made for the management of acute gastroenteritis, prevention of antibiotic-associated diarrhea, nosocomial diarrhea and necrotizing enterocolitis, management of Helicobacter pylori infection, and management of functional abdominal pain disorders and infant colic. CONCLUSIONS: Despite evidence to support the use of specific probiotics in some clinical situations, further studies confirming the effect(s) and defining the type, dose, and timing of probiotics are still often required. The use of probiotics with no documented health benefits should be discouraged.

Introduction: The risk for brain injury manifested as cerebral palsy is higher in very preterm born children than in term. Prenatal administration of magnesium sulfate (MgSO4) has been shown to be neuroprotective and reduces the proportion of very preterm born children later diagnosed with cerebral palsy. A Swedish national clinical practice guideline was implemented in March 2020, stipulating the administration of a single intravenous dose of 6 g MgSO4 1–24 h prior to delivery before gestational age 32+0, aiming for 90% treatment coverage. The aim of this study was to evaluate the feasibility of this new clinical practice guideline in the first year of its implementation. Material and methods: Data on MgSO4 treatment were collected by reviewing the medical charts of women who gave birth to live born children in gestational age 22+0–31+6 during the period of March 1, 2020 to February 28, 2021, at five Swedish university hospitals. Women with pre-eclampsia, eclampsia, or high elevated liver enzymes low platelets (HELLP) were excluded. Results: A total of 388 women were eligible and 79% received treatment with MgSO4. Of the 21% not receiving treatment, 9% did not receive treatment due to lack of knowledge about the clinical practice guideline, 9% were not possible to treat and 3% had missing data. The proportion treated increased from 72% to 87% from the first to the last 3 months. Of those treated, 81% received the drug within the stipulated timeframe (mean 8.7 h, median 3.4 h). Conclusions: There was a positive trend over time in the proportion of women receiving MgSO4 treatment, but the a priori target of 90% was not reached during the first year of implementation. Our findings indicate that this target could be reached with additional information to clinicians.

Background: Child health and development can be promoted by strengthening and supporting parents. Research on parental support programs based on positive psychology and a health-promoting approach aimed at all parents, and in particular parents of infants is limited. All Children in Focus (ACF) is a parental support program that has been evaluated in a randomized trial in parents of children 3–12 years. The ACF is based on health promotion aiming to increase parents’ confidence and child’s well-being. In the current study, we will study the effects of a revised version of the ACF called Little ACF adapted to parents with children aged 1–2 years. Methods: The study includes a randomized controlled trial (RCT) taking place at several Child Health Centers (CHCs) in Sweden. The RCT will evaluate the efficacy of Little ACF (intervention) in comparison with four digital lectures about child development and parenting (active control). Parents are recruited at the 10-, 12-, or 18-month visits to CHC by CHC-nurses. Data to assess changes in parental competencies and child socio-emotional development are collected through online questionnaires completed by parents at five time points: baseline, post-intervention, after 6 and 12 months, and when the child is 3 years old. Discussion: The paper describes a study protocol of a randomized controlled trial evaluating the effects of a parental support program during infancy. Several issues related to the methodology and implementation are discussed. Trial registration: ClinicalTrials.gov NCT05445141. Registered on 6 July 2022.

Hypodiploidy, defined as modal numbers (MNs) 45 or lower, has not been independently investigated in pediatric acute myeloid leukemia (AML) but is a well-described high-risk factor in pediatric acute lymphoblastic leukemia. We aimed to characterize and study the prognostic impact of hypodiploidy in pediatric AML. In this retrospective cohort study, we included children below 18 years of age with de novo AML and a hypodiploid karyotype diagnosed from 2000 to 2015 in 14 childhood AML groups from the International Berlin-Frankfurt-Münster (I-BFM) framework. Exclusion criteria comprised constitutional hypodiploidy, monosomy 7, composite karyotype, and t(8;21) with concurring sex chromosome loss. Hypodiploidy occurred in 81 patients (1.3%) with MNs, 45 (n = 66); 44 (n = 10) and 43 (n = 5). The most frequently lost chromosomes were chromosome 9 and sex chromosomes. Five-year event-free survival (EFS) and overall survival (OS) were 34% and 52%, respectively, for the hypodiploid cohort. Children with MN≤44 (n = 15) had inferior EFS (21%) and OS (33%) compared with children with MN = 45 (n = 66; EFS, 37%; OS, 56%). Adjusted hazard ratios (HRs) were 4.9 (P = .001) and 6.1 (P = .003). Monosomal karyotype or monosomy 9 had particular poor OS (43% and 15%, respectively). Allogeneic stem cell transplantation (SCT) in first complete remission (CR1) (n = 18) did not mitigate the unfavorable outcome of hypodiploidy (adjusted HR for OS was 1.5; P = .42). We identified pediatric hypodiploid AML as a rare subgroup with an inferior prognosis even in the patients treated with SCT in CR1.

Objectives: Preterm infants have a high risk of post discharge feeding problems, but there is a lack of population-based studies in infants born extremely preterm and little is known about underlying mechanisms.The objectives were to assess the incidence of post discharge feeding problems and underweight in a population-based cohort of infants born extremely preterm in Sweden (EXPRESS) and identify perinatal risk factors. Methods: Perinatal health data and prenatal/postnatal growth data was prospectively collected in the cohort. Data on clinical diagnoses related to feeding problems were obtained from the Swedish Patient Register, population prevalence data was also obtained. The main outcome was a composite of post discharge feeding problem diagnosis and/or underweight at 2.5 years of age. Results: In total, 66 children (19%) had post discharge feeding problems diagnosed before 2 years and/or underweight at 2.5 years of age. The risk of feeding problems when compared to the general population was significantly higher, with an odds ratio (OR) of 193 (95% CI 137.6-270.9). The strongest risk factors for feeding problems were the number of days on mechanical ventilation during the first eight postnatal weeks, OR of 1.59 (CI 95% 1.29-1.98), and the Clinical Risk Index for Babies-score, OR of 1.14 (CI 95% 1.03-1.26). Conclusions: Post discharge feeding problems and underweight are common in children born extremely preterm. The strongest perinatal risk factor for later feeding problems was early treatment with mechanical ventilation. Identifying infants at risk of post discharge feeding problems might be useful for targeting of nutritional support.

Aim: Organisation of care, perinatal and neonatal management of very preterm infants in the Nordic regions were hypothesised to vary significantly. The aim of this observational study was to test this hypothesis. Methods: Information on preterm infants in the 21 greater healthcare regions of Denmark, Finland, Iceland, Norway and Sweden was gathered from national registers in 2021. Preterm birth rates, case-mix, perinatal interventions, neonatal morbidity and survival to hospital discharge in very (<32 weeks) and extremely preterm infants (<28 weeks of gestational age) were compared. Results: Out of 287 642 infants born alive, 16 567 (5.8%) were preterm, 2389 (0.83%) very preterm and 800 (0.28%) were extremely preterm. In very preterm infants, exposure to antenatal corticosteroids varied from 85% to 98%, live births occurring at regional centres from 48% to 100%, surfactant treatment from 28% to 69% and use of mechanical ventilation varied from 13% to 77% (p < 0.05 for all comparisons). Significant regional variations within and between countries were also seen in capacity in neonatal care, case-mix and number of admissions, whereas there were no statistically significant differences in survival or major neonatal morbidities. Conclusion: Management of very preterm infants exhibited significant regional variations in the Nordic countries.

Purpose: Adolescents with congenital heart disease transition from childhood to adulthood and transfer from pediatric-oriented to adult-oriented care. High-level empirical evidence on the effectiveness of transitional care is scarce. This study investigated the empowering effect (primary outcome) of a structured person-centered transition program for adolescents with congenital heart disease and studied its effectiveness on transition readiness, patient-reported health, quality of life, health behaviors, disease-related knowledge, and parental outcomes e.g., parental uncertainty, readiness for transition as perceived by the parents (secondary outcomes). Methods: The STEPSTONES-trial comprised a hybrid experimental design whereby a randomized controlled trial was embedded in a longitudinal observational study. The trial was conducted in seven centers in Sweden. Two centers were allocated to the randomized controlled trial-arm, randomizing participants to intervention or control group. The other five centers were intervention-naïve centers and served as contamination check control group. Outcomes were measured at the age of 16 years (baseline), 17 years, and 18.5 years. Results: The change in empowerment from 16 years to 18.5 years differed significantly between the intervention group and control group (mean difference = 3.44; 95% confidence interval = 0.27–6.65; p = .036) in favor of intervention group. For the secondary outcomes, significant differences in change over time were found in parental involvement (p = .008), disease-related knowledge (p = .0002), and satisfaction with physical appearance (p = .039). No differences in primary or secondary outcomes were detected between the control group and contamination check control group, indicating that there was no contamination in the control group. Discussion: The STEPSTONES transition program was effective in increasing patient empowerment, reducing parental involvement, improving satisfaction with physical appeara

Aim: To describe clinical presentation and development of tolerance among children with Food protein-induced enterocolitis syndrome (FPIES) in a population in northern Sweden. Methods: A retrospective review of medical records of children presenting with FPIES symptoms from 1 January 2004, to 31 May 2018. Results: Sixty children (65% boys) with FPIES were included. The estimated incidence gradually increased to 0.45% in 2016–2017. The most common food triggers were cow's milk (40%), fish (37%) and oat (23%). Symptoms presented in 31 (60%) children before 6 months and in 57 (95%) before 1 year of age. The median age for FPIES diagnosis was 7 (range 3–134) months and for fish FPIES 13 (range 7–134) months. By 3 years of age, 67% of children with FPIES to milk and oat but none of the children with fish FPIES had developed tolerance. Allergic conditions like eczema and asthma were reported in 52% of the children. Conclusion: The cumulative FPIES incidence was 0.45% in 2016–2017. Most children presented with symptoms before 1 year of age, but the diagnosis was often delayed, especially for FPIES to fish. Tolerance development occurred at an earlier age when FPIES was triggered by milk and oat compared to fish.

Purpose: A previous study by the International Berlin-Frankfurt-Münster Study Group (I-BFM-SG) on childhood KMT2A-rearranged (KMT2A-r) AML demonstrated the prognostic value of the fusion partner. This I-BFM-SG study investigated the value of flow cytometry-based measurable residual disease (flow-MRD) and evaluated the benefit of allogeneic stem-cell transplantation (allo-SCT) in first complete remission (CR1) in this disease. Methods: A total of 1,130 children with KMT2A-r AML, diagnosed between January 2005 and December 2016, were assigned to high-risk (n = 402; 35.6%) or non-high-risk (n = 728; 64.4%) fusion partner-based groups. Flow-MRD levels at both end of induction 1 (EOI1) and 2 (EOI2) were available for 456 patients and were considered negative (<0.1%) or positive (≥0.1%). End points were 5-year event-free survival (EFS), cumulative incidence of relapse (CIR), and overall survival (OS). Results: The high-risk group had inferior EFS (30.3% high risk v 54.0% non-high risk; P < .0001), CIR (59.7% v 35.2%; P < .0001), and OS (49.2% v 70.5%; P < .0001). EOI2 MRD negativity was associated with superior EFS (n = 413; 47.6% MRD negativity v n = 43; 16.3% MRD positivity; P < .0001) and OS (n = 413; 66.0% v n = 43; 27.9%; P < .0001), and showed a trend toward lower CIR (n = 392; 46.1% v n = 26; 65.4%; P = .016). Similar results were obtained for patients with EOI2 MRD negativity within both risk groups, except that within the non-high-risk group, CIR was comparable with that of patients with EOI2 MRD positivity. Allo-SCT in CR1 only reduced CIR (hazard ratio, 0.5 [95% CI, 0.4 to 0.8]; P = .00096) within the high-risk group but did not improve OS. In multivariable analyses, EOI2 MRD positivity and high-risk group were independently associated with inferior EFS, CIR, and OS. Conclusion: EOI2 flow-MRD is an independent prognostic factor and should be included as risk stratification factor in childhood KMT2A-r AML. Treatment approaches other than allo-S

Background: Erythroferrone (ERFE) has been identified as a hepcidin-regulating hormone synthetized by erythroblasts correlating to the erythropoietic activity and the needs for iron substrate in bone marrow of adults. The present study aimed to assess the ERFE serum concentrations and its predictors in infants. Methods: ERFE was explored at 4 time points during the first year of life in 45 healthy, breastfed, normal birth weight (NBW) infants, and 136 marginally low birth weight infants (LBW, 2000–2500 g) receiving iron (N = 58) or placebo (N = 78) between 6 weeks and 6 months of age. Results: ERFE concentrations were low at birth, increasing gradually during the first year of life. In NBW infants, reference ranges (5th to 95th percentile) were at 6 weeks <0.005–0.99 ng/mL and at 12 months <0.005–33.7 ng/mL. ERFE was higher in LBW infants at 6 weeks but lower at 12 months compared to NBW and minimally affected by iron supplementation among LBW infants. Correlations of ERFE with erythropoietic and iron status markers were weak and inconsistent. Conclusions: The role of ERFE in the crosstalk of erythropoiesis and iron homeostasis remains unclear in infants and further studies on ERFE in infants and older children are warranted within the framework of the erythropoietin–ERFE–hepcidin axis. Impact: Normal range of erythroferrone in healthy infants is described for the first time. Erythroferrone in infants lacks correlation to iron status and markers of erythropoiesis. The findings indicate differences in infant regulation of iron homeostasis as compared to adults. The findings point to a need to study infant erythropoiesis separately from its adult counterpart. The findings may have clinical impact on management strategies of iron-loading anemia in infancy.