Low-Protein Infant Formula Enriched with Alpha-Lactalbumin during Early Infancy May Reduce Insulin Resistance at 12 Months: A Follow-Up of a Randomized Controlled Trial.

High protein intake during infancy results in accelerated early weight gain and potentially later obesity. The aim of this follow-up study at 12 months was to evaluate if modified low-protein formulas fed during early infancy have long-term effects on growth and metabolism. In a double-blinded RCT, the ALFoNS study, 245 healthy-term infants received low-protein formulas with either alpha-lactalbumin-enriched whey (α-lac-EW; 1.75 g protein/100 kcal), casein glycomacropeptide-reduced whey (CGMP-RW; 1.76 g protein/100 kcal), or standard infant formula (SF; 2.2 g protein/100 kcal) between 2 and 6 months of age. Breastfed (BF) infants served as a reference. At 12 months, anthropometrics and dietary intake were assessed, and serum was analyzed for insulin, C-peptide, and insulin-like growth factor 1 (IGF-1). Weight gain between 6 and 12 months and BMI at 12 months were higher in the SF than in the BF infants (p = 0.019; p < 0.001, respectively), but were not significantly different between the low-protein formula groups and the BF group. S-insulin and C-peptide were higher in the SF than in the BF group (p < 0.001; p = 0.003, respectively), but more alike in the low-protein formula groups and the BF group. Serum IGF-1 at 12 months was similar in all study groups. Conclusion: Feeding modified low-protein formula during early infancy seems to reduce insulin resistance, resulting in more similar growth, serum insulin, and C-peptide concentrations to BF infants at 6-months post intervention. Feeding modified low-protein formula during early infancy results in more similar growth, serum insulin, and C-peptide concentrations to BF infants 6-months post intervention, probably due to reduced insulin resistance in the low-protein groups.

Low-Protein Formulas with Alpha-Lactalbumin-Enriched or Glycomacropeptide-Reduced Whey: Effects on Growth, Nutrient Intake and Protein Metabolism during Early Infancy: A Randomized, Double-Blinded Controlled Trial.

Protein intake is higher in formula-fed than in breast-fed infants during infancy, which may lead to an increased risk of being overweight. Applying alpha-lactalbumin (α-lac)-enriched whey or casein glycomacropeptide (CGMP)-reduced whey to infant formula may enable further reduction of formula protein by improving the amino acid profile. Growth, nutrient intake, and protein metabolites were evaluated in a randomized, prospective, double-blinded intervention trial where term infants received standard formula (SF:2.2 g protein/100 kcal; n = 83) or low-protein formulas with α-lac-enriched whey (α-lac-EW;1.75 g protein/100 kcal; n = 82) or CGMP-reduced whey (CGMP-RW;1.76 g protein/100 kcal; n = 80) from 2 to 6 months. Breast-fed infants (BF; n = 83) served as reference. Except between 4 and 6 months, when weight gain did not differ between α-lac-EW and BF (p = 0.16), weight gain was higher in all formula groups compared to BF. Blood urea nitrogen did not differ between low-protein formula groups and BF during intervention, but was lower than in SF. Essential amino acids were similar or higher in α-lac-EW and CGMP-RW compared to BF. Conclusion: Low-protein formulas enriched with α-lac-enriched or CGMP-reduced whey supports adequate growth, with more similar weight gain in α-lac-enriched formula group and BF, and with metabolic profiles closer to that of BF infants.

Individual participant data (IPD)-level meta-analysis of randomised controlled trials with vitamin D-fortified foods to estimate Dietary Reference Values for vitamin D.

CONTEXT AND PURPOSE: Individual participant data-level meta-regression (IPD) analysis is superior to meta-regression based on aggregate data in determining Dietary Reference Values (DRV) for vitamin D. Using data from randomized controlled trials (RCTs) with vitamin D3-fortified foods, we undertook an IPD analysis of the response of winter serum 25-hydroxyvitamin (25(OH)D) to total vitamin D intake among children and adults and derived DRV for vitamin D. METHODS: IPD analysis using data from 1429 participants (ages 2-89 years) in 11 RCTs with vitamin D-fortified foods identified via a systematic review and predefined eligibility criteria. Outcome measures were vitamin D DRV estimates across a range of serum 25(OH)D thresholds using unadjusted and adjusted models. RESULTS: Our IPD-derived estimates of vitamin D intakes required to maintain 97.5% of winter 25(OH)D concentrations ≥ 25 and ≥ 30 nmol/L are 6 and 12 µg/day, respectively (unadjusted model). The intake estimates to maintain 90%, 95% and 97.5% of concentrations ≥ 50 nmol/L are 33.4, 57.5 and 92.3 µg/day, respectively (unadjusted) and 17.0, 28.1 and 43.6 µg/day, respectively (adjusted for mean values for baseline serum 25(OH)D, age and BMI). CONCLUSIONS: IPD-derived vitamin D intakes required to maintain 90%, 95% and 97.5% of winter 25(OH)D concentrations ≥ 50 nmol/L are much higher than those derived from standard meta-regression based on aggregate data, due to the inability of the latter to capture between person-variability. Our IPD provides further evidence that using food-based approaches to achieve an intake of 12 µg/day could prevent vitamin D deficiency (i.e., serum 25(OH)D < 30 nmol/L) in the general population.

Soluble Transferrin Receptor during infancy and reference intervals for the Roche Cobas platform.

INTRODUCTION: Infant iron status assessments may be difficult to interpret due to infections. The soluble transferrin receptor (sTfR) has been suggested as a biomarker mainly unaffected by the acute phase response. Reference intervals reflecting dynamics of infant growth first year in life are not well established. METHODS: The sTfR and CRP concentrations were measured in samples from 451 term infants with the Roche Cobas platform in umbilical cord, at 48-96 hours, 4 and 12 months. Reference values were constructed as the 2.5th and 97.5th percentiles. The relationship between CRP concentrations >1 mg/L and sTfR was tested by Kendall correlation. RESULTS: Reference intervals for girls and boys were 2.4-9.5 mg/L at birth, 2.9-8.4 mg/L at 48-96 hours, 2.6-5.7 mg/L at 4 months and 3.0-6.3 mg/L at 12 months. No differences between sexes were observed except for at 4 months. sTfR did not covariate with CRP concentrations >1 mg/L except in 48-96 hours samples. CONCLUSION: This study reports reference intervals for sTfR from birth to 12 months of age in a large group of infants in a low-risk area for iron deficiency. sTfR might add value to infant iron status diagnostics since no covariation with CRP was found at birth, at 4 months or at 12 months.

Adjacent Primary Care May Reduce Less Urgent Pediatric Emergency Department Visits.

Aims: Pediatric emergency department (ED) overcrowding is a challenge. This study was designed to evaluate if a hospital-integrated primary care unit (HPCU) reduces less urgent visits at a pediatric ED. Methods: This retrospective cross-sectional study was carried out at a university hospital in Sweden, where the HPCU, open outside office hours, had been integrated next to the ED. Children seeking ED care during 4-week high- and low-load study periods before (2012) and after (2015) implementation of the HPCU were included. Information on patient characteristics, ED management, and length of ED stay was obtained from hospital data registers. Results: In total, 3216 and 3074 ED patient visits were recorded in 2012 and 2015, respectively. During opening hours of the HPCU, the proportions of pediatric ED visits (28% lower; P < .001), visits in the lowest triage group (36% lower; P < .001), patients presenting with fever (P = .001) or ear pain (P < .001), and nonadmitted ED patients (P = .033), were significantly lower in 2015 than in 2012, whereas the proportion of infants ≤3 months was higher in 2015 (P < .001). Conclusions: By enabling adjacent management of less urgent pediatric patients at adequate lower levels of medical care, implementation of a HPCU outside office hours may contribute to fewer and more appropriate pediatric ED visits.

Vitamin D status and cardiometabolic risk markers in young Swedish children: a double-blind randomized clinical trial comparing different doses of vitamin D supplements.

BACKGROUND: Observational studies have linked low vitamin D status to unfavorable cardiometabolic risk markers, but double-blinded vitamin D intervention studies in children are scarce. OBJECTIVES: The aim was to evaluate the effect of different doses of a vitamin D supplement on cardiometabolic risk markers in young healthy Swedish children with fair and dark skin. METHODS: Cardiometabolic risk markers were analyzed as secondary outcomes of a double-blind, randomized, milk-based vitamin D intervention trial conducted during late fall and winter in 2 areas of Sweden (latitude 63°N and 55°N, respectively) in both fair- and dark-skinned 5- to 7-y-old children. During the 3-mo intervention, 206 children were randomly assigned to a daily milk-based vitamin D3 supplement of either 10 or 25 µg or placebo (2 µg; only at 55°N). Anthropometric measures, blood pressure, serum 25-hydroxyvitamin D [25(OH)D], total cholesterol, HDL cholesterol, apoA-I, apoB, and C-reactive protein (CRP) were analyzed and non-HDL cholesterol calculated at baseline and after the intervention. RESULTS: At baseline, serum 25(OH)D was negatively associated with systolic and diastolic blood pressure (ß = -0.194; 95% CI: -0.153, -0.013; and ß = -0.187; 95% CI: -0.150, -0.011, respectively). At follow-up, there was no statistically significant difference in any of the cardiometabolic markers between groups. CONCLUSIONS: We could not confirm any effect of vitamin D supplementation on serum lipids, blood pressure, or CRP in healthy 5- to 7-y-old children. The study was registered at clinicaltrials.gov (NCT01741324).

Effectiveness of vitamin D supplementation in Swedish children may be negatively impacted by BMI and serum fructose.

In regions where sunlight exposure is limited, dietary vitamin D intake becomes important for maintaining status. However, Swedish children have been shown to have deficient or marginal status during the winter months even if the recommended dietary intake is met. Since low vitamin D status has been associated with several disease states, this study investigated the metabolic changes associated with improved vitamin D status due to supplementation. During the 3 winter months, 5-7-year-old children (n=170) in northern (Umeå, 63° N) and southern (Malmö, 55° N) Sweden were supplemented daily with 2 (placebo), 10 or 25 µg of vitamin D. BMI-for-age z-scores (BAZ), S-25(OH)D concentrations, insulin concentrations and the serum metabolome were assessed at baseline and follow-up. S-25(OH)D concentrations increased significantly in both supplementation groups (P<.001). Only arginine and isopropanol concentrations exhibited significant associations with improvements in S-25(OH)D. Furthermore, the extent to which S-25(OH)D increased was correlated with a combination of baseline BAZ and the change in serum fructose concentrations from baseline to follow up (P=.012). In particular, the change in S-25(OH)D concentrations was negatively correlated (P=.030) with the change in fructose concentrations for subjects with BAZ ≥0 and consuming at least 20 µg vitamin D daily. These results suggest that although the metabolic changes associated with improved vitamin D status are small, the effectiveness of dietary supplementation may be influenced by serum fructose concentrations.

Influence of social characteristics on use of paediatric emergency care in Sweden - a questionnaire based study.

BACKGROUND: Parental social characteristics influence the use of emergency departments (ED) in the USA, but less is known about paediatric ED care-seeking in countries with national health insurance. This prospective study was designed to evaluate associations between parental care-seeking and social characteristics, with emphasis on impact of non-native origin, at a paediatric ED in Sweden, a European country providing paediatric healthcare free of charge. METHODS: Parents attending a paediatric ED at a large urban university hospital filled out a questionnaire on social characteristics and reasons for care-seeking. Information on patient characteristics and initial management was obtained from ED registers and patient records. Paediatric ED physicians assessed the medical appropriateness of each patient visit triaged for ED care. RESULTS: In total, 962 patient visits were included. Telephone healthline service before the paediatric ED visit was less often used by non-native parents (63/345 vs. 249/544, p < 0.001). Low-aquity visits, triaged away from the ED, were more common among non-native parents (80/368 vs. 67/555, OR = 1.66; p = 0.018), and among those reporting lower abilities in the Swedish language (23/82 vs. 120/837, OR = 2.66; p = 0.003). Children of non-native parents were more often assessed by physicians not to require ED care (122/335 vs. 261/512, OR = 0.70; p = 0.028). CONCLUSIONS: This study confirms more direct and less urgent use of paediatric ED care by parents of non-native origin or with limited abilities in the Swedish language, proposing that parental social characteristics influence paediatric ED care-seeking, also in a country with healthcare free of charge, and that specific needs of these groups should be better met by prehospital medical services.

Vitamin D Intervention and Bone: A Randomized Clinical Trial in Fair- and Dark-skinned Children at Northern Latitudes.

OBJECTIVES: The aim of the study was to evaluate vitamin D status and effects of vitamin D intervention on bone mineral density (BMD) and content (BMC) in children with fair and dark skin in Sweden during winter. METHODS: In a 2-center prospective double-blinded randomized intervention study 5- to 7-year-old children (n = 206) with fair and dark skin in Sweden (55°N-63°N) received daily vitamin D supplements of 25 µg, 10 µg, or placebo (2 µg) during 3 winter months. We measured BMD and BMC for total body (TB), total body less head (TBLH), femoral neck (FN), and spine at baseline and 4 months later. Intake of vitamin D and calcium, serum 25-hydroxy vitamin D (S-25[OH]D), and related parameters were analyzed. RESULTS: Despite lower S-25(OH)D in dark than fair-skinned children, BMD of TB (P = 0.012) and TBLH (P = 0.002) and BMC of TBLH (P = 0.04) were higher at baseline and follow-up in those with dark skin. Delta (Δ) BMD and BMC of TB and TBLH did not differ between intervention and placebo groups, but FN-BMC increased more among dark-skinned children in the 25 µg (P = 0.038) and 10 µg (P = 0.027) groups compared to placebo. We found no associations between Δ S-25(OH)D, P-parathyroid hormone, P-alkaline phosphatase, and Δ BMD and BMC, respectively. CONCLUSIONS: BMD and BMC remained higher in dark- than fair-skinned children despite lower vitamin D status. Even though no difference in general was found in BMD or BMC after vitamin D intervention, the increase in FN-BMC in dark-skinned children may suggest an influence on bone in those with initially insufficient vitamin D status.

Vitamin D status and dental caries in healthy Swedish children.

Background: Vitamin D is crucial for mineralized tissue formation and immunological functions. The purpose of this study was to evaluate the association between vitamin D status and dental status in healthy children with vitamin D supplementation in infancy and at 6 years of age. Method: Eight-year-old children who had participated in a vitamin D intervention project when they were 6 years old were invited to participate in a dental follow-up study. They had fair or darker skin complexion and represented two geographically distant parts of Sweden. 25-hydroxy vitamin D in serum had been measured at 6 years of age and after a 3-month intervention with 25, 10 or 2 (placebo) µg of vitamin D3 per day. Two years later, caries and enamel defects were scored, self-reported information on e.g., oral behavior, dietary habits and intake of vitamin D supplements was collected, and innate immunity peptide LL37 levels in saliva and cariogenic mutant streptococci in tooth biofilm were analyzed. The outcome variables were caries and tooth enamel defects. Results: Dental status was evaluated in 85 of the 206 children in the basic intervention study. Low vitamin D levels were found in 28% at baseline compared to 11% after the intervention, and 34% reported continued intake of vitamin D supplements. Logistic regression supported a weak inverse association between vitamin D status at 6 years of age and caries 2 years later (odds ratio 0.96; p = 0.024) with minor attenuation after an adjustment for potential confounders. Multivariate projection regression confirmed that insufficient vitamin D levels correlated with caries and higher vitamin D levels correlated with being caries-free. Vitamin D status at 6 years of age was unrelated to enamel defects but was positively associated with saliva LL37 levels. Conclusion: An association between vitamin D status and caries was supported, but it was not completely consistent. Vitamin D status at 6 years of age was unrelated to enamel defects but was positively associated with LL37 expression. Trial registration: The basic intervention study was registered at ClinicalTrials.gov with register number NCT01741324 www.clinicaltrials.gov/ct2/show/NCT02347293 on November 26, 2012.

Influence of awareness and availability of medical alternatives on parents seeking paediatric emergency care.

AIMS: Direct seeking of care at paediatric emergency departments may result from an inadequate awareness or a short supply of medical alternatives. We therefore evaluated the care-seeking patterns, availability of medical options and initial medical assessments - with overall reference to socioeconomic status - of parents at an urban paediatric emergency department in a Scandinavian country providing free paediatric healthcare. METHODS: The parents of children assessed by paediatric emergency department physicians at a Swedish university hospital over a 25-day winter period completed a questionnaire on recent medical contacts and their reasons for attendance. Additional information was obtained from ledgers, patient records and population demographics. RESULTS: In total, 657 of 713 eligible patients (92%) were included. Seventy-nine per cent of their parents either failed to or managed to establish medical contact before the emergency department visit, whereas 21% sought care with no attempt at recent medical contact. Visits with a failed telephone or primary care contact (18%) were more common outside office hours ( p=0.014) and were scored as less urgent ( p=0.014). A perceived emergency was the main reason for no attempt at medical contact before the visit. Direct emergency department care-seeking was more common from the city district with the lowest socioeconomic status ( p=0.027). CONCLUSIONS: Although most parents in this Swedish study tried to seek medical advice before attending a paediatric emergency department, perceived emergency, a short supply of telephone health line or primary care facilities and lower socioeconomic status contributed to direct care-seeking by almost 40% of parents. Pre-hospital awareness and the availability of medical alternatives with an emphasis on major differences in socioeconomic status should therefore be considered to further optimize care-seeking in paediatric emergency departments.

A Validation Study of an Interviewer-Administered Short Food Frequency Questionnaire in Assessing Dietary Vitamin D and Calcium Intake in Swedish Children.

Vitamin D and calcium are essential nutrients with a range of biological effects of public health relevance. This study aimed to validate a short food frequency questionnaire (SFFQ) against a three-day food record (3D record), assessing the intake of vitamin D and calcium in Swedish children during wintertime. In a double-blinded, randomized food-based intervention study on the effect of feeding different daily doses of vitamin D supplement to 5-7-year-old children (n = 85), 79 (93%) participants completed SFFQ1 at baseline and SFFQ2 after the intervention, and 72 were informed to fill in a 3D record. The 28 (39%) children who completed the 3D record were included in this validation study. The baseline level of serum-25 hydroxy vitamin D [S-25(OH)D] was used as a biomarker. The correlation between all three instruments were moderate to strong. SFFQ2 and the 3D record correlated moderately to S-25(OH)D. Bland-Altman analysis showed that SFFQ2 overestimated vitamin D intake by on average 0.6 µg/day, (limits of agreement (LOA) 5.7 and -4.6 µg/day), whereas the intake of calcium was underestimated by on average 29 mg/day, (LOA 808 and -865 mg/day). Finally, the validity coefficient calculated for vitamin D using the method of triad was high (0.75). In conclusion, this SFFQ, assessed by a dietician, is a valid tool to assess dietary vitamin D and calcium intake in groups of young children.

Increased vitamin D intake differentiated according to skin color is needed to meet requirements in young Swedish children during winter: a double-blind randomized clinical trial.

Background: Dark skin and low exposure to sunlight increase the risk of vitamin D insufficiency in children.Objective: The aim of the study was to evaluate the amount of vitamin D needed to ascertain that most children >4 y of age attain sufficient serum 25-hydroxyvitamin D [S-25(OH)D; i.e., ≥50 nmol/L] during winter regardless of latitude and skin color.Design: In a longitudinal, double-blind, randomized, food-based intervention study, 5- to 7-y-old children from northern (63°N) and southern (55°N) Sweden with fair (n = 108) and dark (n = 98) skin were included. Children, stratified by skin color by using Fitzpatrick's definition, were randomly assigned to receive milk-based vitamin D3 supplements that provided 2 (placebo), 10, or 25 µg/d during 3 winter months.Results: Mean daily vitamin D intake increased from 6 to 17 µg and 26 µg in the intervention groups supplemented with 10 and 25 µg, respectively. In the intention-to-treat analysis, 90.2% (95% CI: 81.1%, 99.3%) of fair-skinned children randomly assigned to supplementation of 10 µg/d attained sufficient concentrations, whereas 25 µg/d was needed in dark-skinned children to reach sufficiency in 95.1% (95% CI: 88.5%, 100%). In children adherent to the study product, 97% (95% CI: 91.3%, 100%) and 87.9% (95% CI: 76.8%, 99%) of fair- and dark-skinned children, respectively, achieved sufficient concentrations if supplemented with 10 µg/d. By using 95% prediction intervals for 30 and 50 nmol S-25(OH)D/L, intakes of 6 and 20 µg/d are required in fair-skinned children, whereas 14 and 28 µg/d are required in children with dark skin.Conclusion: Children with fair and dark skin require vitamin D intakes of 20 and 28 µg/d, respectively, to maintain S-25(OH)D ≥50 nmol/L, whereas intakes of 6 and 14 µg/d, respectively, are required to maintain concentrations ≥30 nmol/L during winter. This trial was registered at clinicaltrials.gov as NCT01741324.

Sedation with ketamine and low-dose midazolam for short-term procedures requiring pharyngeal manipulation in young children.

BACKGROUND: Pediatric intestinal biopsy procedures including considerable transpharyngeal manipulation of a wire-guided metal capsule require adequate sedation or anesthesia. This retrospective cohort study was designed to evaluate intravenous sedation with ketamine and low-dose midazolam in young children undergoing these procedures before and also after discharge from the hospital. METHODS: A total of 244 biopsy procedures in 217 children under the age of 16 years were evaluated. All anesthesia records were reviewed according to a defined study protocol and in 145 cases the parents were also interviewed by telephone to obtain further information on possible adverse effects before and after discharge. RESULTS: Ketamine and low-dose midazolam were carefully titrated by an experienced anesthesia team at an approximate dose ratio of 40 : 1 (total doses 2.3 and 0.05 mg.kg(-1)) in continuously monitored spontaneously breathing children. Possibly associated problems before discharge were salivation (5.7%), vomiting (4.9%), oxygen desaturation (3.3%), laryngospasm (2.5%) and rash (1.2%) according to the patient records and blurred vision (27%), nausea and vomiting (19%), vertigo (13%) and hallucinations or nightmares (3.5%) according to telephone interviews. Few, mild and transient problems remained after discharge from the hospital. CONCLUSIONS: Careful titration of ketamine and low-dose midazolam provides adequate sedation for nonsurgical pediatric short-term procedures also requiring considerable pharyngeal manipulation, particularly considering the low number of serious airway problems such as laryngospasm. The high incidence of late postoperative problems suggests that prospective studies should be designed for long-term follow-up of young children subjected to sedation or anesthesia.