The Relationship Between Vitamin D Intake and Serum 25-hydroxyvitamin D in Young Children: A Meta-Regression to Inform WHO/FAO Vitamin D Intake Recommendations.

BACKGROUND: This work was commissioned by the World Health Organization and Food and Agriculture Organization to inform their update on the vitamin D requirements for children aged <4 y. OBJECTIVES: The objective of this work was to undertake multilevel and multivariable dose-response modeling of serum 25-hydroxyvitamin D (25OHD) to total vitamin D intake in children aged <4 y with the goal of deriving updated vitamin D requirements for young children. METHODS: Systematically identified randomized controlled trials among healthy children from 2 wk up to 3.9 y of age provided with daily vitamin D supplements or vitamin D-fortified foods were included. Linear and nonlinear random effects multilevel meta-regression models with and without covariates were fitted and compared. Interindividual variability was included by simulating the individual serum 25OHD responses. The percentage of individuals reaching set minimal and maximal serum 25OHD thresholds was calculated and used to derive vitamin D requirements. RESULTS: A total of 31 trials with 186 data points from North America, Europe, Asia, and Australasia/Oceania, with latitudes ranging from 61°N to 38°S, and with participants of likely mostly light or medium skin pigmentation, were included. In 29 studies the children received vitamin D supplements and in 2 studies the children received vitamin D-fortified milk with or without supplements. The dose-response relationship between vitamin D intake and serum 25OHD was best fitted with the unadjusted quadratic model. Adding additional covariates, such as age, did not significantly improve the model. At a vitamin D intake of 10 µg/d, 97.3% of the individuals were predicted to achieve a minimal serum 25OHD threshold of 28 nmol/L. At a vitamin D intake of 35 µg/d, 1.4% of the individuals predicted to reach a maximal serum 25OHD threshold of 200 nmol/L. CONCLUSIONS: In conclusion, this paper details the methodological steps taken to derive vitamin D requirements in children aged <4 y, including the addition of an interindividual variability component.

Serum 25-hydroxyvitamin D threshold and risk of rickets in young children: a systematic review and individual participant data meta-analysis to inform the development of dietary requirements for vitamin D.

PURPOSE: The objective of this systematic review was to determine a minimum serum 25-hydroxyvitamin D (25OHD) threshold based on the risk of having rickets in young children. This work was commissioned by the WHO and FAO within the framework of the update of the vitamin D requirements for children 0-3 years old. METHODS: A systematic search of Embase was conducted to identify studies involving children below  4 years of age with serum 25OHD levels and radiologically confirmed rickets, without any restriction related to the geographical location or language. Study-level and individual participant data (IPD)-level random effects multi-level meta-analyses were conducted. The odds, sensitivity and specificity for rickets at different serum 25OHD thresholds were calculated for all children as well as for children with adequate calcium intakes only. RESULTS: A total of 120 studies with 5412 participants were included. At the study-level, children with rickets had a mean serum 25OHD of 23 nmol/L (95% CI 19-27). At the IPD level, children with rickets had a median and mean serum 25OHD of 23 and 29 nmol/L, respectively. More than half (55%) of the children with rickets had serum 25OHD below 25 nmol/L, 62% below 30 nmol/L, and 79% below 40 nmol/L. Analysis of odds, sensitivities and specificities for nutritional rickets at different serum 25OHD thresholds suggested a minimal risk threshold of around 28 nmol/L for children with adequate calcium intakes and 40 nmol/L for children with low calcium intakes. CONCLUSION: This systematic review and IPD meta-analysis suggests that from a public health perspective and to inform the development of dietary requirements for vitamin D, a minimum serum 25OHD threshold of around 28 nmol/L and above would represent a low risk of nutritional rickets for the majority of children with an adequate calcium intake.

Calcium, zinc, and vitamin D in breast milk: a systematic review and meta-analysis.

BACKGROUND: Global estimates of calcium, zinc and vitamin D content in breastmilk are lacking. The objective of this systematic review was to determine the calcium, zinc, and vitamin D content in breast milk. METHODS: A systematic search of the online databases Embase, MEDLINE, and CENTRAL was conducted in November 2022 and complemented by searches of the African Journals Online database and the LILACS database, and reference lists. Studies reporting the calcium, zinc and vitamin D content in breast milk of apparently healthy mothers and infants were included. Random effects meta-analyses were conducted. The effect of influencing factors were investigated with sub-group analyses and meta-regressions. RESULTS: A total of 154 studies reporting on breast milk calcium were identified, with a mean calcium concentration in breast milk of 261 mg/L (95% CI: 238, 284). Calcium concentration was influenced by maternal health and decreased linearly over the duration of lactation. Calcium concentration at a specific time during lactation could be estimated with the equation: calcium concentration [mg/L] = 282 - 0.2331 ✕ number of days since birth. A total of 242 studies reporting on breast milk zinc were identified, with a mean zinc concentration of 2.57 mg/L (95% CI: 2.50, 2.65). Zinc concentration was influenced by several factors, such as maternal age, gestational age, and maternal diet. Zinc concentration started high in the first weeks post-partum followed by a rapid decrease over the first months. Zinc concentration at a specific time during lactation could be estimated with the equation: zinc concentration [mg/L] = 6 + 0.0005 ✕ days - 2.0266 ✕ log(days). A total of 43 studies reporting on breast milk vitamin D were identified, with a mean total antirachitic activity of breast milk of 58 IU/L (95% CI: 45, 70), which consisted mostly of 25OHD3, and smaller amounts of vitamin D3, 25OHD2 and vitamin D2. Vitamin D concentration showed wide variations between studies and was influenced by vitamin D supplementation, continent and season. CONCLUSIONS: This review provides global estimates of calcium, zinc and vitamin D content in breast milk, as well as indications on changes over time and depending on influencing factors.

The Volume of Breast Milk Intake in Infants and Young Children: A Systematic Review and Meta-Analysis.

Objective: The objective of this study was to provide global breast milk intake estimates for infants and children from 0 to 3 years old. Materials and Methods: A systematic search of online databases (Embase, MEDLINE, and CENTRAL) was conducted and complemented with a manual search of additional databases (African Journals Online and LILACS), reference lists, and unpublished data. Studies with apparently healthy mothers and their children 0-3 years old worldwide were included. Random effects meta-analyses, subgroup analyses, and meta-regressions were conducted. Results: A total of 167 studies on breast milk intake were identified. The mean daily breast milk intake among all the studies included was 670 mL per day and 117 mL/kg per day. Breast milk intake was influenced by infant age, infant body weight, and breastfeeding practices. The deuterium dilution method tended to yield higher estimates than test-weighing methods. Breast milk intake over time was modeled with a nonlinear meta-regression: breast milk intake (mL/day) = 51-1.4 × days +180 × log(days). When restricting to studies involving healthy term infants exclusively breastfed up to 6 months, breast milk intake was 624 mL per day and 135 mL/kg per day at 1 month, 735 mL per day and 126 mL/kg per day at 3 months, 729 mL per day and 107 mL/kg per day at 6 months, and 593 mL per day and 61 mL/kg per day at 12 months. Conclusions: This review provides global breast milk intake estimates for infants and young children. It demonstrates differences in intakes according to region and measurement method, as well as longitudinal changes over the first year of life.

Reliability of Self-Reported Height and Weight in Children: A School-Based Cross-Sectional Study and a Review.

Since anthropometric measurements are not always feasible in large surveys, self-reported values are an alternative. Our objective was to assess the reliability of self-reported weight and height values compared to measured values in children with (1) a cross-sectional study in Switzerland and (2) a comprehensive review with a meta-analysis. We conducted a secondary analysis of data from a school-based study in Switzerland of 2616 children and a review of 63 published studies including 122,629 children. In the cross-sectional study, self-reported and measured values were highly correlated (weight: r = 0.96; height: r = 0.92; body mass index (BMI) r = 0.88), although self-reported values tended to underestimate measured values (weight: -1.4 kg; height: -0.9 cm; BMI: -0.4 kg/m2). Prevalence of underweight was overestimated and prevalence of overweight was underestimated using self-reported values. In the meta-analysis, high correlations were found between self-reported and measured values (weight: r = 0.94; height: r = 0.87; BMI: r = 0.88). Weight (-1.4 kg) and BMI (-0.7 kg/m2) were underestimated, and height was slightly overestimated (+0.1 cm) with self-reported values. Self-reported values tended to be more reliable in children above 11 years old. Self-reported weight and height in children can be a reliable alternative to measurements, but should be used with caution to estimate over- or underweight prevalence.

Risk factors during first 1,000 days of life for carotid intima-media thickness in infants, children, and adolescents: A systematic review with meta-analyses.

BACKGROUND: The first 1,000 days of life, i.e., from conception to age 2 years, could be a critical period for cardiovascular health. Increased carotid intima-media thickness (CIMT) is a surrogate marker of atherosclerosis. We performed a systematic review with meta-analyses to assess (1) the relationship between exposures or interventions in the first 1,000 days of life and CIMT in infants, children, and adolescents; and (2) the CIMT measurement methods. METHODS AND FINDINGS: Systematic searches of Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), and Cochrane Central Register of Controlled Trials (CENTRAL) were performed from inception to March 2019. Observational and interventional studies evaluating factors at the individual, familial, or environmental levels, for instance, size at birth, gestational age, breastfeeding, mode of conception, gestational diabetes, or smoking, were included. Quality was evaluated based on study methodological validity (adjusted Newcastle-Ottawa Scale if observational; Cochrane collaboration risk of bias tool if interventional) and CIMT measurement reliability. Estimates from bivariate or partial associations that were least adjusted for sex were used for pooling data across studies, when appropriate, using random-effects meta-analyses. The research protocol was published and registered on the International Prospective Register of Systematic Reviews (PROSPERO; CRD42017075169). Of 6,221 reports screened, 50 full-text articles from 36 studies (34 observational, 2 interventional) totaling 7,977 participants (0 to 18 years at CIMT assessment) were retained. Children born small for gestational age had increased CIMT (16 studies, 2,570 participants, pooled standardized mean difference (SMD): 0.40 (95% confidence interval (CI): 0.15 to 0.64, p: 0.001), I2: 83%). When restricted to studies of higher quality of CIMT measurement, this relationship was stronger (3 studies, 461 participants, pooled SMD: 0.64 (95% CI: 0.09 to 1.19, p: 0.024), I2: 86%). Only 1 study evaluating small size for gestational age was rated as high quality for all methodological domains. Children conceived through assisted reproductive technologies (ART) (3 studies, 323 participants, pooled SMD: 0.78 (95% CI: -0.20 to 1.75, p: 0.120), I2: 94%) or exposed to maternal smoking during pregnancy (3 studies, 909 participants, pooled SMD: 0.12 (95% CI: -0.06 to 0.30, p: 0.205), I2: 0%) had increased CIMT, but the imprecision around the estimates was high. None of the studies evaluating these 2 factors was rated as high quality for all methodological domains. Two studies evaluating the effect of nutritional interventions starting at birth did not show an effect on CIMT. Only 12 (33%) studies were at higher quality across all domains of CIMT reliability. The degree of confidence in results is limited by the low number of high-quality studies, the relatively small sample sizes, and the high between-study heterogeneity. CONCLUSIONS: In our meta-analyses, we found several risk factors in the first 1,000 days of life that may be associated with increased CIMT during childhood. Small size for gestational age had the most consistent relationship with increased CIMT. The associations with conception through ART or with smoking during pregnancy were not statistically significant, with a high imprecision around the estimates. Due to the large uncertainty in effect sizes and the limited quality of CIMT measurements, further high-quality studies are needed to justify intervention for primordial prevention of cardiovascular disease (CVD).

Spot urine samples to estimate 24-hour urinary calcium excretion in school-age children.

Urinary calcium/creatinine ratio (UCa/Cr) on a single spot urine sample is frequently used in children to evaluate calciuria, but its accuracy to estimate 24-h urinary calcium excretion (24hUCa) has not been properly assessed. We analyzed the correlation between UCa/Cr in various spot samples and 24hUCa among healthy children. A 24-h urine specimen and three spot urine samples (evening, first, and second morning) were collected in a convenience sample of children aged 6 to 16 years (n = 101). Measured 24hUCa was compared with UCa/Cr in each of the three spot samples. The ability of UCa/Cr to discriminate between children with and without hypercalciuria (calciuria > 4 mg/kg/24 h, 1 mmol/kg/24 h) and optimal timing of the spot sample were determined. Eighty-five children completed an adequate 24-h urine collection. Pearson correlation coefficients between the UCa/Cr on the spot sample and 24hUCa were 0.64, 0.71, and 0.52 for the evening, first, and second morning spot samples, respectively. Areas under the ROC curve were 0.90, 0.82, and 0.75, respectively, for the corresponding spot samples.Conclusion: The relatively strong correlation between 24hUCa and UCa/Cr in evening and first morning spot urine samples suggests that these spots could be preferred in clinical practice.Trial registration: ClinicalTrials.gov , NCT02900261, date of trial registration 14 September 2016. What is Known: •Urinary calcium/creatinine ratio on a single spot urine sample is frequently used as a proxy for 24-h urinary calcium excretion. •Correlation of these indicators, including the best timing for spot urine sampling, has not been properly assessed. What is New: •Relatively strong correlations were found between the calcium/creatinine ratio on a single spot urine sample and 24-h urinary calcium excretion in healthy children. •Evening and first morning spot samples had the highest correlation.

Monitoring caffeine intake in children with a questionnaire and urine collection: a cross-sectional study in a convenience sample in Switzerland.

PURPOSE: The objectives of this study were (1) to estimate caffeine intake and identify the main sources of intake using a dietary questionnaire, (2) to assess 24-h urinary excretion of caffeine and its metabolites, and (3) to assess how self-reported intake estimates correlates with urinary excretion among children in Switzerland. METHODS: We conducted a cross-sectional study of children between 6 and 16 years of age in one region of Switzerland. The participants filled in a dietary questionnaire and collected a 24-h urine sample. Caffeine intake was estimated with the questionnaire. Caffeine, paraxanthine, theophylline, and theobromine excretions were measured in the urine sample. Correlations between questionnaire-based intake and urinary excretion estimates were assessed using Spearman correlation coefficients. RESULTS: Ninety-one children were included in the analysis (mean age 10.6 years; 43% female). The mean daily caffeine intake estimate derived from the diet questionnaire was 39 mg (range 0-237), corresponding, when related to body weight, to 1.2 mg/kg (range 0.0-6.3). Seven children (8%) had a caffeine intake above the upper recommended level of 3 mg/kg per day. The main sources of caffeine intake were cocoa milk (29%), chocolate (25%), soft drinks (11%), mocha yogurt (10%), tea (8%), and energy drinks (8%). The 24-h urinary excretion of caffeine was 0.3 mg (range 0.0-1.5), paraxanthine 1.4 mg (range 0.0-7.1), theophylline 0.1 mg (range 0.0-0.6), and theobromine 14.8 mg (range 0.3-59.9). The correlations between estimates of caffeine intake and the 24-h urinary excretion of caffeine was modest (ρ = 0.21, p = 0.046) and with the metabolites of caffeine were weak (ρ = 0.09-0.11, p = 0.288-0.423). CONCLUSIONS: Caffeine intake in a sample of children in a region of Switzerland was relatively low. The major sources of intake were cocoa milk, chocolate and soft drinks. Self-reported caffeine intake correlated weakly with urinary excretion of caffeine and some of its main metabolites. TRIAL REGISTRATION NUMBER: NCT02900261.

Population biomonitoring of micronutrient intakes in children using urinary spot samples.

PURPOSE: Urinary spot samples are a promising method for the biomonitoring of micronutrient intake in children. Our aim was to assess whether urinary spot samples could be used to estimate the 24-h urinary excretion of potassium, phosphate, and iodine at the population level. METHODS: A cross-sectional study of 101 children between 6 and 16 years of age was conducted. Each child collected a 24-h urine collection and three urinary spot samples (evening, overnight, and morning). Several equations were used to estimate 24-h excretion based on the urinary concentrations of each micronutrient in the three spot samples. Various equations and spot combinations were compared using several statistics and plots. RESULTS: Ninety-four children were included in the analysis (mean age: 10.5 years). The mean measured 24-h urinary excretions of potassium, phosphate, and iodine were 1.76 g, 0.61 g, and 95 µg, respectively. For potassium, the best 24-h estimates were obtained with the Mage equation and morning spot (mean bias: 0.2 g, correlation: 0.27, precision: 56%, and misclassification: 10%). For phosphate, the best 24-h estimates were obtained with the Mage equation and overnight spot (mean bias: - 0.03 g, correlation: 0.54, precision: 72%, and misclassification: 10%). For iodine, the best 24-h estimates were obtained with the Remer equation and overnight spot (mean bias: - 8 µg, correlation: 0.58, precision: 86%, misclassification: 16%). CONCLUSIONS: Urinary spot samples could be a good alternative to 24-h urine collection for the population biomonitoring of iodine and phosphate intakes in children. For potassium, spot samples were less reliable.

Sodium intake and blood pressure in children with clinical conditions: A systematic review with meta-analysis.

Little is known on the effect of sodium intake on BP of children with clinical conditions. Our objective was therefore to review systematically studies that have assessed the association between sodium intake and BP in children with various clinical conditions. A systematic search of several databases was conducted and supplemented by a manual search of bibliographies and unpublished studies. Experimental and observational studies assessing the association between sodium intake and BP and involving children or adolescents between 0 and 18 years of age with any clinical condition were included. Out of the 6861 records identified, 51 full texts were reviewed, and 16 studies (10 experimental and 6 observational), involving overall 2902 children and adolescents, were included. Ten studies were conducted in children with elevated BP without identifiable cause, two in children with familial hypertension, one in children with at least one cardiovascular risk factor, one in children with chronic renal insufficiency, one in children with urolithiasis, and one in premature infants. A positive association between sodium intake and BP was found in all studies, except one. The meta-analysis of six studies among children with elevated BP without identifiable cause revealed a difference of 6.3 mm Hg (95% CI 2.9-9.6) and 3.5 mm Hg (95% CI 1.2-5.7) in systolic and diastolic BP, respectively, for every additional gram of sodium intake per day. In conclusion, our results indicate that the BP response to salt is greater in children with clinical conditions, mainly hypertension, than in those without associated clinical conditions.

Estimation of salt intake and excretion in children in one region of Switzerland: a cross-sectional study.

PURPOSE: Salt intake among children in Switzerland is unknown. The objectives of this study were to determine salt excretion and to identify the main dietary sources of salt intake among children in one region of Switzerland. METHODS: We conducted a cross-sectional study using a convenient sample of children 6-16 years of age in Valais, Switzerland, between 2016 and 2018. All children visiting several regional health care providers and without any clinical condition that could affect sodium intake or excretion were eligible. Each child completed a 24-h urine collection to assess salt excretion and two dietary questionnaires to assess dietary sources of salt intake. Weight and height were measured. RESULTS: Data were available on 94 children (55 boys and 39 girls; mean age 10.5 years; age range 6-16 years). The mean 24-h salt urinary excretion was 5.9 g [SD 2.8; range 0.8-16.0; 95% confidence interval (CI) 5.3-6.5]. Two-thirds (62%) of the children had salt excretions above recommendations of maximum intake (i.e., ≥ 2 g per day for children up to 6 years of age and ≥ 5 g per day for children 7-16 years of age). The salt excretion tended to be higher during the week-end (6.0 g, 95% CI 5.4-6.6) than during the week (5.4 g, 95% CI 4.3-6.7). The main sources of salt intake were pastas, potatoes, and rice (23% of total salt intake), pastries (16%), bread (16%), and cured meats (10%). One child out of three (34%) added salt to their plate at the table. CONCLUSIONS: Salt intake in children in one region of Switzerland was high. Our findings suggest that salt intake in children could be reduced by lowering salt content in commonly eaten foods. TRIAL REGISTRATION NUMBER: NCT02900261.

Urine Spot Samples Can Be Used to Estimate 24-Hour Urinary Sodium Excretion in Children.

Background: The gold standard to assess salt intake is 24-h urine collections. Use of a urine spot sample can be a simpler alternative, especially when the goal is to assess sodium intake at the population level. Several equations to estimate 24-h urinary sodium excretion from urine spot samples have been tested in adults, but not in children. Objective: The objective of this study was to assess the ability of several equations and urine spot samples to estimate 24-h urinary sodium excretion in children. Methods: A cross-sectional study of children between 6 and 16 y of age was conducted. Each child collected one 24-h urine sample and 3 timed urine spot samples, i.e., evening (last void before going to bed), overnight (first void in the morning), and morning (second void in the morning). Eight equations (i.e., Kawasaki, Tanaka, Remer, Mage, Brown with and without potassium, Toft, and Meng) were used to estimate 24-h urinary sodium excretion. The estimates from the different spot samples and equations were compared with the measured excretion through the use of several statistics. Results: Among the 101 children recruited, 86 had a complete 24-h urine collection and were included in the analysis (mean age: 10.5 y). The mean measured 24-h urinary sodium excretion was 2.5 g (range: 0.8-6.4 g). The different spot samples and equations provided highly heterogeneous estimates of the 24-h urinary sodium excretion. The overnight spot samples with the Tanaka and Brown equations provided the most accurate estimates (mean bias: -0.20 to -0.12 g; correlation: 0.48-0.53; precision: 69.7-76.5%; sensitivity: 76.9-81.6%; specificity: 66.7%; and misclassification: 23.0-27.7%). The other equations, irrespective of the timing of the spot, provided less accurate estimates. Conclusions: Urine spot samples, with selected equations, might provide accurate estimates of the 24-h sodium excretion in children at a population level. At an individual level, they could be used to identify children with high sodium excretion. This study was registered at clinicaltrials.gov as NCT02900261.