NutriBrain: protocol for a randomised, double-blind, controlled trial to evaluate the effects of a nutritional product on brain integrity in preterm infants.

BACKGROUND: The gut microbiota and the brain are connected through different mechanisms. Bacterial colonisation of the gut plays a substantial role in normal brain development, providing opportunities for nutritional neuroprotective interventions that target the gut microbiome. Preterm infants are at risk for brain injury, especially white matter injury, mediated by inflammation and infection. Probiotics, prebiotics and L-glutamine are nutritional components that have individually already demonstrated beneficial effects in preterm infants, mostly by reducing infections or modulating the inflammatory response. The NutriBrain study aims to evaluate the benefits of a combination of probiotics, prebiotics and L-glutamine on white matter microstructure integrity (i.e., development of white matter tracts) at term equivalent age in very and extremely preterm born infants. METHODS: This study is a double-blind, randomised, controlled, parallel-group, single-center study. Eighty-eight infants born between 24 + 0 and < 30 + 0 weeks gestational age and less than 72 h old will be randomised after parental informed consent to receive either active study product or placebo. Active study product consists of a combination of Bifidobacterium breve M-16V, short-chain galacto-oligosaccharides, long-chain fructo-oligosaccharides and L-glutamine and will be given enterally in addition to regular infant feeding from 48 to 72 h after birth until 36 weeks postmenstrual age. The primary study outcome of white matter microstructure integrity will be measured as fractional anisotropy, assessed using magnetic resonance diffusion tensor imaging at term equivalent age and analysed using Tract-Based Spatial Statistics. Secondary outcomes are white matter injury, brain tissue volumes and cortical morphology, serious neonatal infections, serum inflammatory markers and neurodevelopmental outcome. DISCUSSION: This study will be the first to evaluate the effect of a combination of probiotics, prebiotics and L-glutamine on brain development in preterm infants. It may give new insights in the development and function of the gut microbiota and immune system in relation to brain development and provide a new, safe treatment possibility to improve brain development in the care for preterm infants. TRIAL REGISTRATION: ISRCTN, ISRCTN96620855 . Date assigned: 10/10/2017.

The Influence of Meteorological Factors and Atmospheric Pollutants on the Risk of Preterm Birth.

Atmospheric pollutants and meteorological conditions are suspected to be causes of preterm birth. We aimed to characterize their possible association with the risk of preterm birth (defined as birth occurring before 37 completed gestational weeks). We pooled individual data from 13 birth cohorts in 11 European countries (71,493 births from the period 1994-2011, European Study of Cohorts for Air Pollution Effects (ESCAPE)). City-specific meteorological data from routine monitors were averaged over time windows spanning from 1 week to the whole pregnancy. Atmospheric pollution measurements (nitrogen oxides and particulate matter) were combined with data from permanent monitors and land-use data into seasonally adjusted land-use regression models. Preterm birth risks associated with air pollution and meteorological factors were estimated using adjusted discrete-time Cox models. The frequency of preterm birth was 5.0%. Preterm birth risk tended to increase with first-trimester average atmospheric pressure (odds ratio per 5-mbar increase = 1.06, 95% confidence interval: 1.01, 1.11), which could not be distinguished from altitude. There was also some evidence of an increase in preterm birth risk with first-trimester average temperature in the -5°C to 15°C range, with a plateau afterwards (spline coding, P = 0.08). No evidence of adverse association with atmospheric pollutants was observed. Our study lends support for an increase in preterm birth risk with atmospheric pressure.

Dietary Intake of Protein in Early Childhood Is Associated with Growth Trajectories between 1 and 9 Years of Age.

BACKGROUND: High protein intake in infancy might lead to a higher body mass index (BMI) in childhood. However, whether these associations differ between different sources of protein is unclear. OBJECTIVE: We investigated associations between the intake of total protein, protein from different sources, and individual amino acids in early childhood and repeatedly measured height, weight, and BMI up to the age of 9 y. METHODS: This study was performed in 3564 children participating in the Generation R Study, a population-based prospective cohort study in Rotterdam, Netherlands. Intakes of total protein, animal protein, vegetable protein, and individual amino acids (including methionine, arginine, lysine, threonine, valine, leucine, isoleucine, phenylalanine, tryptophan, histidine, cysteine, tyrosine, alanine, asparagine, glutamine, glycine, proline, and serine) at 1 y were assessed by using a food-frequency questionnaire. Height and weight were measured at the approximate ages of 14, 18, 24, 30, 36, and 45 mo and at 6 and 9 y, and BMI was calculated. RESULTS: After adjustment for confounders, linear mixed models showed that a 10-g higher total protein intake/d at 1 y was significantly associated with a 0.03-SD greater height (95% CI: 0.00, 0.06), a 0.06-SD higher weight (95% CI: 0.03, 0.09), and a 0.05-SD higher BMI (95% CI: 0.03, 0.08) up to the age of 9 y. Associations were stronger for animal than for vegetable protein intake but did not differ between dairy and nondairy animal protein or between specific amino acids. CONCLUSIONS: A higher intake of protein, especially animal protein, at 1 y of age was associated with a greater height, weight, and BMI in childhood up to 9 y of age. Future studies should explore the role of growth hormones and investigate whether protein intake in early childhood affects health later in life.

Macronutrient Intakes in Infancy Are Associated with Sleep Duration in Toddlerhood.

BACKGROUND: Dietary composition has been associated with sleep indexes. However, most of the evidence is based on cross-sectional data, and studies in young children are lacking. OBJECTIVE: The aim of this study was to explore the longitudinal associations of macronutrient composition of the diet with sleep duration and consolidation (number of awakenings) in infancy and early childhood. METHODS: The study was performed in 3465 children from the Generation R Study, a population-based cohort study in the Netherlands. Mothers reported their child's food intake at 13 mo of age by using a validated food-frequency questionnaire and their child's sleep patterns at 2 and 3 y of age. We used nutrient substitution models to assess the associations of relative macronutrient intakes with sleep indexes and adjusted the models for sociodemographic and lifestyle factors. RESULTS: Isocaloric substitution of fat intake by protein or carbohydrate in infancy was associated with longer total sleep duration at 2 but not 3 y of age. For each 5% increase in energy intake of either protein or carbohydrate at the expense of fat, sleep duration at 2 y of age was longer by 6 min (95% CI: 0.4, 12 min) and 4 min (95% CI: 2, 6 min), respectively. Further exploration of macronutrient subtypes indicated no consistent differences between saturated or unsaturated fat and that intake of plant compared with animal protein or Trp did not explain the association of higher total protein intake with longer sleep duration at 2 y of age. Replacing unsaturated with saturated fat was associated with 7 min (95% CI: -13, -1 min) shorter total sleep duration at 3 y of age. Macronutrient intakes were not associated with sleep consolidation. CONCLUSIONS: Our results suggest that the macronutrient composition of the diet is associated with sleep duration in young children. Future research should further study the causality of this association and explore the underlying mechanisms.

Associations of breast-feeding patterns and introduction of solid foods with childhood bone mass: The Generation R Study.

Breast-feeding has been associated with later bone health, but results from previous studies are inconsistent. We examined the associations of breast-feeding patterns and timing of introduction of solids with bone mass at the age of 6 years in a prospective cohort study among 4919 children. We collected information about duration and exclusiveness of breast-feeding and timing of introduction of any solids with postnatal questionnaires. A total body dual-energy X-ray absorptiometry scan was performed at 6 years of age, and bone mineral density (BMD), bone mineral content (BMC), area-adjusted BMC (aBMC) and bone area (BA) were analysed. Compared with children who were ever breast-fed, those never breast-fed had lower BMD (-4·62 mg/cm2; 95 % CI -8·28, -0·97), BMC (-8·08 g; 95 % CI -12·45, -3·71) and BA (-7·03 cm2; 95 % CI -12·55, -1·52) at 6 years of age. Among all breast-fed children, those who were breast-fed non-exclusively in the first 4 months had higher BMD (2·91 mg/cm2; 95 % CI 0·41, 5·41) and aBMC (3·97 g; 95 % CI 1·30, 6·64) and lower BA (-4·45 cm2; 95 % CI -8·28, -0·61) compared with children breast-fed exclusively for at least 4 months. Compared with introduction of solids between 4 and 5 months, introduction <4 months was associated with higher BMD and aBMC, whereas introduction between 5 and 6 months was associated with lower aBMC and higher BA. Additional adjustment for infant vitamin D supplementation did not change the results. In conclusion, results from the present study suggest that ever breast-feeding compared with never breast-feeding is associated with higher bone mass in 6-year-old children, but exclusive breast-feeding for 4 months or longer was not positively associated with bone outcomes.

A priori and a posteriori dietary patterns at the age of 1 year and body composition at the age of 6 years: the Generation R Study.

Dietary patterns have been linked to obesity in adults, however, not much is known about this association in early childhood. We examined associations of different types of dietary patterns in 1-year-old children with body composition at school age in 2026 children participating in a population-based cohort study. Dietary intake at the age of 1 year was assessed with a food-frequency questionnaire. At the children's age of 6 years we measured their body composition with dual-energy X-ray absorptiometry and we calculated body mass index, fat mass index (FMI), and fat-free mass index (FFMI). Three dietary pattern approaches were used: (1) An a priori-defined diet quality score; (2) dietary patterns based on variation in food intake, derived from principal-component-analysis (PCA); and (3) dietary patterns based on variations in FMI and FFMI, derived with reduced-rank-regression (RRR). Both the a priori-defined diet score and a 'Health-conscious' PCA-pattern were characterized by a high intake of fruit, vegetables, grains, and vegetable oils, and, after adjustment for confounders, children with higher adherence to these patterns had a higher FFMI at 6 years [0.19 SD (95 % CI 0.08;0.30) per SD increase in diet score], but had no different FMI. One of the two RRR-patterns was also positively associated with FFMI and was characterized by intake of whole grains, pasta and rice, and vegetable oils. Our results suggest that different a priori- and a posteriori-derived health-conscious dietary patterns in early childhood are associated with a higher fat-free mass, but not with fat mass, in later childhood.

Protein intake in early childhood and cardiometabolic health at school age: the Generation R Study.

PURPOSE: High protein intake in infancy has been linked to obesity. We aimed to examine the associations of protein intake in early childhood with cardiovascular and metabolic outcomes at school age. METHODS: This study was performed in 2965 children participating in a population-based prospective cohort study. Protein intake at 1 year was assessed with a food frequency questionnaire and was adjusted for energy intake. At the children's age of 6 years, we measured their body fat percentage (BF%), blood pressure (BP), and insulin, HDL cholesterol, and triglyceride serum levels. These measures were incorporated into a cardiometabolic risk factor score, using age- and sex-specific SD scores. RESULTS: In covariate-adjusted models, higher protein intake was associated with a higher BF%, lower diastolic BP, and lower triglyceride levels. We observed a significant interaction of protein intake with child sex on metabolic outcomes. Stratified analyses showed that protein intake was positively associated with BF% [0.07 SD (95 % CI 0.02; 0.13) per 10 g/day] and insulin levels in girls, but not in boys. In boys, but not in girls, higher protein intake was associated with lower triglyceride levels [-0.12 SD (95 % CI -0.20; -0.04) per 10 g/day] and a lower cardiometabolic risk factor score. Protein intake was not consistently associated with systolic BP or HDL cholesterol levels. CONCLUSION: Protein intake in early childhood was associated with a higher BF% and higher insulin levels at 6 years in girls and with lower triglyceride levels in boys. Further studies are needed to explore these sex differences and to investigate whether the observed changes persist into adulthood.

Vitamin D deficiency in school-age children is associated with sociodemographic and lifestyle factors.

BACKGROUND: There is concern about a reemergence of vitamin D deficiency in children in developed countries. OBJECTIVES: The aims of this study were to describe vitamin D status in the Generation R study, a large multiethnic cohort of 6-y-old children in The Netherlands, and to examine sociodemographic, lifestyle, and dietary determinants of vitamin D deficiency. METHODS: We measured serum 25-hydroxyvitamin D [25(OH)D] concentrations in 4167 children aged 6 y and defined deficiency following recommended cutoffs. We examined the associations between subject characteristics and vitamin D deficiency with the use of multivariable logistic regression analyses. RESULTS: Serum 25(OH)D concentrations ranged from 4 to 211 nmol/L (median: 64 nmol/L), with 6.2% of the children having severely deficient (<25 nmol/L), 23.6% deficient (25 to <50 nmol/L), 36.5% sufficient (50 to <75 nmol/L), and 33.7% optimal (≥75 nmol/L) 25(OH)D concentrations. The prevalence of vitamin D deficiency [25(OH)D <50 nmol/L] was higher in winter (51.3%) than in summer (10.3%); and higher in African, Asian, Turkish, and Moroccan children (54.5%) than in those with a Dutch or other Western ethnic background (17.6%). In multivariable models, several factors were associated with vitamin D deficiency, including household income (OR: 1.74; 95% CI: 1.34, 2.27 for low vs. high income), child age (OR: 1.39; 95% CI: 1.20, 1.62 per year), child television watching (OR: 1.32; 95% CI: 1.06, 1.64 for ≥2 vs. <2 h/d), and playing outside (OR: 0.71; 95% CI: 0.57, 0.89 for ≥1 vs. <1 h/d). In a subgroup with dietary data (n = 1915), vitamin D deficiency was associated with a lower diet quality, but not with vitamin D intake or supplement use in early childhood. CONCLUSIONS: Suboptimal vitamin D status is common among 6-y-old children in The Netherlands, especially among non-Western children and in winter and spring. Important modifiable factors associated with vitamin D deficiency were overall diet quality, sedentary behavior, and playing outside.

Dietary Intakes of Folic Acid and Methionine in Early Childhood Are Associated with Body Composition at School Age.

BACKGROUND: Deficiency of vitamin B-6, vitamin B-12, folate, folic acid, or methionine may lead to dysregulation of DNA methylation, which might lead to disturbed energy and lipid metabolism. OBJECTIVE: We aimed to explore whether intakes of vitamin B-6, vitamin B-12, folate, folic acid, and methionine at 1 y are associated with measures of growth and body composition at the age of 6 y. METHODS: This study was performed in 2922 children participating in The Generation R Study, a population-based prospective cohort study. Dietary intakes of vitamins B-6 and B-12, folate, folic acid, and methionine were assessed at a median age of 12.9 mo by using a validated food-frequency questionnaire. At the age of 6 y, height and weight were measured, and body mass index (BMI; in kg/m(2)) was calculated. Body fat was measured with dual-energy X-ray absorptiometry, and body fat percentage and the ratio of android fat mass to gynoid fat mass (android:gynoid) were calculated. RESULTS: In models adjusted for maternal and child characteristics, children with folic acid intakes in the highest tertile had a 0.16 SD score (SDS) lower weight (95% CI: -0.31, -0.02 SDS) and a 0.14 SDS lower BMI (95% CI: -0.26, -0.01 SDS) than children in the lowest tertile. Children with vitamin B-12 intakes in the highest tertile had a 0.13 SDS higher android:gynoid (95% CI: 0.00, 0.25 SDS) than children in the lowest tertile. In addition, children with intakes in the highest tertile of methionine had a 0.09 SDS higher BMI (95% CI: 0.01, 0.17) and a 0.12 SDS higher android:gynoid (95% CI: 0.02, 0.22) than children in the lowest tertile. Vitamin B-6 and folate intakes were not associated with any of the body composition outcomes measured. CONCLUSIONS: In this population of children, early high folic acid intakes were associated with a lower body weight and BMI at the age of 6 y. In contrast, early higher methionine intakes were associated with unfavorable body composition at the age of 6 y. Future studies should investigate long-term consequences of these outcomes on health.

The development of a diet quality score for preschool children and its validation and determinants in the Generation R Study.

BACKGROUND: Although many studies have examined health effects of infant feeding, studies on diet quality shortly after the weaning and lactation period are scarce. OBJECTIVES: Our aims were to develop and evaluate a diet score that measures overall diet quality in preschool children and to examine the sociodemographic and lifestyle determinants of this score. METHODS: On the basis of national and international dietary guidelines for young children, we developed a diet score containing 10 components: intake of vegetables; fruit; bread and cereals; rice, pasta, potatoes, and legumes; dairy; meat and eggs; fish; oils and fats; candy and snacks; and sugar-sweetened beverages. The total score ranged from 0 to 10 on a continuous scale and was standardized to an energy intake of 1200 kcal/d with the residual method. The score was evaluated in 3629 children participating in the Generation R Study, a population-based prospective cohort study. Food consumption was assessed with a food-frequency questionnaire (FFQ) at a median age of 13 mo. RESULTS: The mean ± SD diet score was 4.1 ± 1.3. The food-based diet score was positively associated with intakes of many nutrients, including n-3 (ω-3) fatty acids [FAs; 0.25 SD increase (95% CI: 0.22, 0.27) per 1 point increase in the diet score], dietary fiber [0.32 (95% CI: 0.30, 0.34)], and calcium [0.13 (95% CI: 0.11, 0.16)], and was inversely associated with intakes of sugars [-0.28 (95% CI: -0.31, -0.26)] and saturated fat [-0.03 (95% CI: -0.05, -0.01)]. A higher diet score was associated with several health-conscious behaviors, such as maternal folic acid supplement use during pregnancy, no smoking during pregnancy, and children watching less television. CONCLUSION: We developed a novel food-based diet score for preschool children that could be applied in future studies to compare diet quality in early childhood and to investigate associations between diet in early childhood and growth, health, and development.

Effects of protein intake on blood pressure, insulin sensitivity and blood lipids in children: a systematic review.

High protein intake in early childhood is associated with obesity, suggesting possible adverse effects on other cardiometabolic outcomes. However, studies in adults have suggested beneficial effects of protein intake on blood pressure (BP) and lipid profile. Whether dietary protein intake is associated with cardiovascular and metabolic health in children is unclear. Therefore, we aimed to systematically review the evidence on the associations of protein intake with BP, insulin sensitivity and blood lipids in children. We searched the databases Medline, Embase, Cochrane Central and PubMed for interventional and observational studies in healthy children up to the age of 18 years, in which associations of total, animal and/or vegetable protein intake with one or more of the following outcomes were reported: BP; measures of insulin sensitivity; cholesterol levels; or TAG levels. In the search, we identified 6636 abstracts, of which fifty-six studies met all selection criteria. In general, the quality of the included studies was low. Most studies were cross-sectional, and many did not control for potential confounders. No overall associations were observed between protein intake and insulin sensitivity or blood lipids. A few studies suggested an inverse association between dietary protein intake and BP, but evidence was inconclusive. Only four studies examined the effects of vegetable or animal protein intake, but with inconsistent results. In conclusion, the literature, to date provides insufficient evidence for effects of protein intake on BP, insulin sensitivity or blood lipids in children. Future studies could be improved by adequately adjusting for key confounders such as energy intake and obesity.

Protein intake in infancy and kidney size and function at the age of 6 years: The Generation R Study.

BACKGROUND: High protein intake has been linked to kidney growth and function. Whether protein intake is related to kidney outcomes in healthy children is unclear. METHODS: We examined the associations between protein intake in infancy and kidney outcomes at age 6 years in 2968 children participating in a population-based cohort study. Protein intake at 1 year was assessed using a food-frequency questionnaire and was adjusted for energy intake. At age 6 years we measured the kidney volume and urinary albumin/creatinine ratio (ACR) of all participating children, and we estimated glomerular filtration rate (eGFR) using serum creatinine and cystatin C levels. RESULTS: In models adjusted for age, sex, body surface area, and sociodemographic factors, a higher protein intake was associated with a lower ACR and a higher eGFR but was not consistently associated with kidney volume. However, after further adjustment for additional dietary and lifestyle factors, such as sodium intake, diet quality, and television watching, higher protein intake was no longer associated with kidney function. No differences in associations were observed between animal and vegetable protein intake. CONCLUSIONS: Our findings show that protein intake in early childhood is not independently associated with kidney size or function at the age of 6 years. Further study is needed on other early life predictors of kidney size and function in later life.

Adherence to a healthy diet according to the World Health Organization guidelines and all-cause mortality in elderly adults from Europe and the United States.

The World Health Organization (WHO) has formulated guidelines for a healthy diet to prevent chronic diseases and postpone death worldwide. Our objective was to investigate the association between the WHO guidelines, measured using the Healthy Diet Indicator (HDI), and all-cause mortality in elderly men and women from Europe and the United States. We analyzed data from 396,391 participants (42% women) in 11 prospective cohort studies who were 60 years of age or older at enrollment (in 1988-2005). HDI scores were based on 6 nutrients and 1 food group and ranged from 0 (least healthy diet) to 70 (healthiest diet). Adjusted cohort-specific hazard ratios were derived by using Cox proportional hazards regression and subsequently pooled using random-effects meta-analysis. During 4,497,957 person-years of follow-up, 84,978 deaths occurred. Median HDI scores ranged from 40 to 54 points across cohorts. For a 10-point increase in HDI score (representing adherence to an additional WHO guideline), the pooled adjusted hazard ratios were 0.90 (95% confidence interval (CI): 0.87, 0.93) for men and women combined, 0.89 (95% CI: 0.85, 0.92) for men, and 0.90 (95% CI: 0.85, 0.95) for women. These estimates translate to an increased life expectancy of 2 years at the age of 60 years. Greater adherence to the WHO guidelines is associated with greater longevity in elderly men and women in Europe and the United States.

Infant macronutrient composition is associated with differences in cardiovascular structures and function in childhood.

Early-life nutrition may influence cardiovascular development. Not much is known about the associations between dietary composition and cardiovascular risk factors in childhood. We examined the associations of infant macronutrient intake with cardiovascular structures and function in 2882 children participating in a prospective, population-based cohort study. Information on macronutrient intake at the age of 14 mo was obtained from food-frequency questionnaires completed by a parent. Systolic and diastolic blood pressure, carotid-femoral pulse wave velocity (PWV), fractional shortening, and left cardiac structures (left atrial diameter, aortic root diameter, and left ventricular mass) were measured at the age of 6 y. Linear regression analyses were performed by using energy-adjusted macronutrient intakes, adjusted for maternal, child, and other dietary factors. Higher total fat intake was associated with higher carotid-femoral PWV (P-trend = 0.03), whereas higher intakes of total carbohydrate and mono- and disaccharides were associated with lower carotid-femoral PWV. No consistent associations were observed for macronutrient intake with systolic blood pressure, diastolic blood pressure, fractional shortening, and aortic root diameter. Higher intakes of total, saturated, monounsaturated, and polyunsaturated fat were associated with lower left atrial diameter (all P-trend ≤ 0.01), and higher total carbohydrate and mono- and disaccharide intakes were associated with higher left atrial diameter (P-trend < 0.01 and 0.02, respectively). Furthermore, the third tertile of mono- and disaccharide intake was associated with a higher left ventricular mass (difference: 1.01 g; 95% CI: 0.18, 1.85 g; P = 0.02). Dietary macronutrient composition in infancy may lead to developmental differences in cardiovascular structures and function in childhood. Further studies are needed to investigate whether these differences have consequences for the risk of future cardiovascular disease.

Air pollution exposure estimation using dispersion modelling and continuous monitoring data in a prospective birth cohort study in The Netherlands.

Previous studies suggest that pregnant women and children are particularly vulnerable to the adverse effects of air pollution. A prospective cohort study in pregnant women and their children enables identification of the specific effects and critical periods. This paper describes the design of air pollution exposure assessment for participants of the Generation R Study, a population-based prospective cohort study from early pregnancy onwards in 9778 women in The Netherlands. Individual exposures to PM10 and NO2 levels at the home address were estimated for mothers and children, using a combination of advanced dispersion modelling and continuous monitoring data, taking into account the spatial and temporal variation in air pollution concentrations. Full residential history was considered. We observed substantial spatial and temporal variation in air pollution exposure levels. The Generation R Study provides unique possibilities to examine effects of short- and long-term air pollution exposure on various maternal and childhood outcomes and to identify potential critical windows of exposure.

Residential traffic exposure and pregnancy-related outcomes: a prospective birth cohort study.

BACKGROUND: The effects of ambient air pollution on pregnancy outcomes are under debate. Previous studies have used different air pollution exposure assessment methods. The considerable traffic-related intra-urban spatial variation needs to be considered in exposure assessment. Residential proximity to traffic is a proxy for traffic-related exposures that takes into account within-city contrasts. METHODS: We investigated the association between residential proximity to traffic and various birth and pregnancy outcomes in 7,339 pregnant women and their children participating in a population-based cohort study. Residential proximity to traffic was defined as 1) distance-weighted traffic density in a 150 meter radius, and 2) proximity to a major road. We estimated associations of these exposures with birth weight, and with the risks of preterm birth and small size for gestational age at birth. Additionally, we examined associations with pregnancy-induced hypertension, (pre)eclampsia, and gestational diabetes. RESULTS: There was considerable variation in distance-weighted traffic density. Almost fifteen percent of the participants lived within 50 m of a major road. Residential proximity to traffic was not associated with birth and pregnancy outcomes in the main analysis and in various sensitivity analyses. CONCLUSIONS: Mothers exposed to residential traffic had no higher risk of adverse birth outcomes or pregnancy complications in this study. Future studies may be refined by taking both temporal and spatial variation in air pollution exposure into account.

A priori and a posteriori derived dietary patterns in infancy and cardiometabolic health in childhood: The role of body composition.

BACKGROUND & AIMS: Cardiometabolic risk has its origins in early life. However, it is unclear whether diet during early childhood is associated with cardiometabolic health, and what the role is of obesity. We aimed to study whether overall diet during early childhood is associated with cardiometabolic health and to examine if difference in body composition explain this association. METHODS: We examined associations of different types of dietary patterns in infancy with cardiometabolic health at school age among 2026 Dutch children participating in a population-based cohort in the Netherlands. Food intake at the age of 1 year was assessed with a food-frequency questionnaire. Three dietary pattern approaches were used: 1) An a priori-defined diet quality score; 2) dietary patterns based on variation in food intake, derived from principal component analysis (PCA); and 3) dietary patterns based on variations in fat and fat-free mass index, derived with reduced-rank regression (RRR). At the children's age of 6 years, we measured their body composition, systolic and diastolic blood pressure, and serum concentrations of insulin, triglycerides, and HDL-cholesterol, which we combined in a cardiometabolic risk-factor score. RESULTS: We observed that, after adjustment for confounders, children with higher adherence to a 'Health-conscious' PCA-derived pattern had a lower cardiometabolic risk-factor score (-0.07 SD (95%CI -0.12; -0.02) per SD). This association did not change after adjustment for fat and fat-free mass index. The RRR-derived dietary patterns based on variations in body composition were not associated with the cardiometabolic risk-factor score. CONCLUSIONS: Our results suggest that diet in early childhood may affect cardiometabolic health independent of differences in body composition.

25-Hydroxyvitamin D concentrations, asthma and eczema in childhood: The generation R study.

BACKGROUND & AIMS: A role of vitamin D in the development of respiratory and allergic disease in children remains unclear. It may be likely that vitamin D has an effect on airway inflammation, but only few studies examined the effect in children. We aimed to examine whether serum 25-hydroxyvitamin D (25(OH) vitamin D) concentrations are associated with the fraction of exhaled nitric oxide (FeNO), airway interrupter resistance (Rint), physician diagnosed asthma ever, wheezing and eczema in a population-based cohort study in 6 year old children. METHODS: Serum 25(OH) vitamin D concentration was assessed in 3815 children. 25(OH) vitamin D concentrations ≥75 nmol/L were considered as sufficient, between 50 and 75 nmol/L as insufficient, and <50 nmol/L as deficient. FeNO and Rint were measured at the research center. Data on physician diagnosed asthma, wheezing, and eczema were obtained by parent-reported questionnaires. RESULTS: In comparison with sufficient 25(OH) vitamin D concentration, deficient concentrations were associated with elevated FeNO of ≥25 ppb (OR: 2.54; 95% CI: 1.34-4.80). In addition, deficient and insufficient 25(OH) vitamin D concentrations were associated with a lower Rint (Z-score: -1.26; 95% CI: -1.66 to -0.85) (ß: -0.75; 95% CI: -1.08 to -0.42), and increased risks of eczema (OR: 1.65; 95% CI: 1.13-2.41) (OR: 1.44; 95% CI: 1.06-1.95). Insufficient 25(OH) vitamin D concentration were associated with a decreased risk of physician diagnosed asthma ever (OR: 0.59; 95% CI: 0.38-0.94). CONCLUSIONS: Our results indicate that lower 25(OH) vitamin D levels are associated with elevated FeNO levels, but lower Rint values. Lower 25(OH) vitamin D levels are also associated with a decreased risk for asthma diagnoses but an increased risk for eczema.

Plasma fatty acid patterns during pregnancy and child's growth, body composition, and cardiometabolic health: The Generation R Study.

BACKGROUND: Exposure to different concentrations of fatty acids during fetal life may affect growth and metabolism. However, most studies examined individual fatty acids, whereas concentrations highly correlate and may interact with each other. We aimed to evaluate patterns of plasma fatty acids during pregnancy and their associations with growth, body composition, and cardiometabolic health of the 6-year-old offspring. METHODS: This study was performed in 4830 mother-child pairs participating in a population-based cohort in the Netherlands. Around 20 weeks of gestation, we measured plasma phospholipid concentrations of 22 fatty acids, in which we identified three fatty acid patterns using principal component analysis: a 'high n-6 polyunsaturated fatty acid (PUFA)' pattern, a 'monounsaturated and saturated fatty acid (MUFA and SFA)' pattern, and a 'high n-3 PUFA' pattern. When the children were 6 years old, we measured their anthropometrics and detailed body composition (using dual-energy X-ray absorptiometry), and we calculated their body mass index (BMI), fat mass index (FMI), fat-free mass index (FFMI). At the same age, children's blood pressure, and serum insulin, HDL-cholesterol, and triacylglycerol were measured. RESULTS: After adjustment for confounders and the other patterns, a higher score for the 'high n-6 PUFA' pattern during pregnancy was associated with a higher height, BMI, and FFMI in the offspring at 6 years, but not independently with cardiometabolic outcomes. The 'MUFA and SFA' pattern was not consistently associated with child body composition or cardiometabolic health. A higher score for the 'high n-3 PUFA' pattern was associated with a lower FMI, higher FFMI, higher HDL-cholesterol, and lower triacylglycerol. CONCLUSIONS: Our results suggest that plasma fatty acid patterns during pregnancy may affect offspring's body composition and cardiometabolic health. Specifically, a pattern characterized by high n-3 PUFA levels was associated with a more favorable body composition and blood lipid profile.

25-hydroxyvitamin D concentrations during fetal life and bone health in children aged 6 years: a population-based prospective cohort study.

BACKGROUND: 25-hydroxyvitamin D (25[OH]D) concentrations during fetal life might have long-lasting effects on skeletal development, but results from previous studies are inconsistent. We investigated the associations of maternal and fetal 25(OH)D concentrations with childhood bone health. METHODS: In a prospective multiethnic population-based cohort study, embedded within the Generation R Study (Rotterdam, Netherlands), pregnant women living in the study area with an expected delivery date between April 1, 2002, and Jan 1, 2006, were eligible for participation in the study at our research centre in the Erasmus MC-Sophia Children's Hospital. We measured maternal 25(OH)D concentrations during mid-pregnancy (at a median of 20·4 weeks gestation [IQR 19·9-21·1]) and fetal 25(OH)D concentrations at birth (at a median of 40·1 weeks gestation [39·3-41·0]). We measured total-body bone mineral density, bone mineral content (BMC), area-adjusted BMC, and bone area using dual-energy X-ray absorptiometry (DXA) in offspring at 6 years of age. We examined associations using multivariable linear regression models, adjusted for several sociodemographic and lifestyle variables, and for child's height. FINDINGS: We enrolled 9901 mother-and-child pairs and obtained both mid-pregnancy maternal 25(OH)D concentrations and offspring DXA scans at age 6 years in 4815 pairs. Severe maternal 25(OH)D deficiency (<25 nmol/L) during mid-pregnancy was associated with higher offspring BMC (4·71 g, 95% CI 1·09 to 8·33; p=0·011) and larger bone area (7·54 cm2, 2·99 to 12·11; p=0·001) at age 6 years, compared with maternal 25(OH)D sufficiency (≥50 nmol/L) during mid-pregnancy. However, in a subgroup of children with available data on 25(OH)D concentrations at 6 years (n=3034), such associations for BMC (4·67 g, -0·05 to 9·39; p=0·052) and bone area (5·25 cm2, -0·41 to 10·91; p=0·069) were no longer significant after adjustment for the child's own 25(OH)D concentrations. No associations were seen between maternal 25(OH)D concentrations in mid-pregnancy and offspring bone mineral density (1·07 mg/cm2, -1·84 to 3·99; p=0·47) or area-adjusted BMC (-1·58 g, -4·72 to 1·61; p=0·32), and the association with skeletal parameters at 6 years did not differ by maternal BMI, maternal calcium intake, child sex, or weight status. Similar associations were seen with fetal 25(OH)D concentrations at birth. INTERPRETATION: We found inverse associations between 25(OH)D concentrations during fetal life with BMC and bone area in childhood, but these associations were no longer significant after adjustment for childhood 25(OH)D status. Our data suggest that 25(OH)D concentrations during childhood might be more relevant for bone outcomes than than 25(OH)D concentrations during fetal life. FUNDING: Erasmus University Medical Center, Organization for Health Research and Development (ZonMw), Organization for Scientific Research (NWO), the Ministry of Health, Welfare and Sport.