Intake of B vitamins and the risk of developing islet autoimmunity and type 1 diabetes in the TEDDY study.

PURPOSE: The aim was to study the association between dietary intake of B vitamins in childhood and the risk of islet autoimmunity (IA) and progression to type 1 diabetes (T1D) by the age of 10 years. METHODS: We followed 8500 T1D-susceptible children born in the U.S., Finland, Sweden, and Germany in 2004 -2010 from the Environmental Determinants of Diabetes in the Young (TEDDY) study, which is a prospective observational birth cohort. Dietary intake of seven B vitamins was calculated from foods and dietary supplements based on 24-h recall at 3 months and 3-day food records collected regularly from 6 months to 10 years of age. Cox proportional hazard models were adjusted for energy, HLA-genotype, first-degree relative with T1D, sex, and country. RESULTS: A total of 778 (9.2) children developed at least one autoantibody (any IA), and 335 (3.9%) developed multiple autoantibodies. 280 (3.3%) children had IAA and 319 (3.8%) GADA as the first autoantibody. 344 (44%) children with IA progressed to T1D. We observed that higher intake of niacin was associated with a decreased risk of developing multiple autoantibodies (HR 0.95; 95% CI 0.92, 0.98) per 1 mg/1000 kcal in niacin intake. Higher intake of pyridoxine (HR 0.66; 95% CI 0.46, 0.96) and vitamin B12 (HR 0.87; 95% CI 0.77, 0.97) was associated with a decreased risk of IAA-first autoimmunity. Higher intake of riboflavin (HR 1.38; 95% CI 1.05, 1.80) was associated with an increased risk of GADA-first autoimmunity. There were no associations between any of the B vitamins and the outcomes "any IA" and progression from IA to T1D.  CONCLUSION: In this multinational, prospective birth cohort of children with genetic susceptibility to T1D, we observed some direct and inverse associations between different B vitamins and risk of IA.

Detecting potential outliers in longitudinal data with time-dependent covariates.

BACKGROUND: Outliers can influence regression model parameters and change the direction of the estimated effect, over-estimating or under-estimating the strength of the association between a response variable and an exposure of interest. Identifying visit-level outliers from longitudinal data with continuous time-dependent covariates is important when the distribution of such variable is highly skewed. OBJECTIVES: The primary objective was to identify potential outliers at follow-up visits using interquartile range (IQR) statistic and assess their influence on estimated Cox regression parameters. METHODS: Study was motivated by a large TEDDY dietary longitudinal and time-to-event data with a continuous time-varying vitamin B12 intake as the exposure of interest and development of Islet Autoimmunity (IA) as the response variable. An IQR algorithm was applied to the TEDDY dataset to detect potential outliers at each visit. To assess the impact of detected outliers, data were analyzed using the extended time-dependent Cox model with robust sandwich estimator. Partial residual diagnostic plots were examined for highly influential outliers. RESULTS: Extreme vitamin B12 observations that were cases of IA had a stronger influence on the Cox regression model than non-cases. Identified outliers changed the direction of hazard ratios, standard errors, or the strength of association with the risk of developing IA. CONCLUSION: At the exploratory data analysis stage, the IQR algorithm can be used as a data quality control tool to identify potential outliers at the visit level, which can be further investigated.

Associations of dietary patterns between age 9 and 24 months with risk of celiac disease autoimmunity and celiac disease among children at increased risk.

BACKGROUND: Higher gluten intake in childhood is associated with increased incidence of celiac disease autoimmunity (CDA) and celiac disease. It remains to be studied whether different dietary patterns independent of gluten intake contribute to the incidence. OBJECTIVES: This study aimed to explore associations of dietary patterns by age 2 y with risk of CDA and celiac disease in genetically susceptible children. METHODS: Data was used from 6726 participants at genetic risk of type 1 diabetes and celiac disease enrolled in the observational cohort, The Environmental Determinants of Diabetes in the Young (TEDDY) study. Children were annually screened for tissue transglutaminase autoantibodies (tTGAs) from age 2 y. Principal component analysis extracted dietary patterns, based on intake of 27 food groups assessed by 3-d food records at age 9 to 24 mo. The primary outcome was CDA (i.e., persistently tTGA-positive in at least 2 consecutive samples), and the secondary outcome was celiac disease. During follow-up to mean age 11.0 (standard deviation 3.6) y, 1296 (19.3%) children developed CDA, and 529 (7.9%) were diagnosed with celiac disease. Associations of adherence to dietary patterns (per 5-unit increase) with the study outcomes were estimated by Cox regression models adjusted for risk factors including gluten intake. RESULTS: At age 9 mo, a dietary pattern higher in the food groups vegetable fats and milk was associated with reduced risk of CDA (hazard ratio [HR]: 0.88; 95% confidence interval [CI]: 0.79, 0.98; P = 0.02). At 24 mo, a dietary pattern higher in the food groups wheat, vegetable fats, and juices, and lower in milk, meat, and oats at age 24 mo was associated with increased risk of CDA (HR: 1.18; 95% CI: 1.05, 1.33; P < 0.001) and celiac disease (HR: 1.24; 95% CI: 1.03, 1.50; P = 0.03). CONCLUSIONS: Dietary patterns in early childhood are associated with risk of CDA and celiac disease in genetically predisposed children, independent of gluten intake.

HLA Genotype and Probiotics Modify the Association Between Timing of Solid Food Introduction and Islet Autoimmunity in the TEDDY Study.

OBJECTIVE: To study the interaction among HLA genotype, early probiotic exposure, and timing of complementary foods in relation to risk of islet autoimmunity (IA). RESEARCH DESIGN AND METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,676 children with increased genetic risk of type 1 diabetes. We used a Cox proportional hazards regression model adjusting for potential confounders to study early feeding and the risk of IA in a sample of 7,770 children. RESULTS: Any solid food introduced early (<6 months) was associated with increased risk of IA if the child had the HLA DR3/4 genotype and no probiotic exposure during the 1st year of life. Rice introduced at 4-5.9 months compared with later in the U.S. was associated with an increased risk of IA. CONCLUSIONS: Timing of solid food introduction, including rice, may be associated with IA in children with the HLA DR3/4 genotype not exposed to probiotics. The microbiome composition under these exposure combinations requires further study.

Dietary Intake and Body Mass Index Influence the Risk of Islet Autoimmunity in Genetically At-Risk Children: A Mediation Analysis Using the TEDDY Cohort.

Background/Objective: Growth and obesity have been associated with increased risk of islet autoimmunity (IA) and progression to type 1 diabetes. We aimed to estimate the effect of energy-yielding macronutrient intake on the development of IA through BMI. Research Design and Methods: Genetically at-risk children (n = 5,084) in Finland, Germany, Sweden, and the USA, who were autoantibody negative at 2 years of age, were followed to the age of 8 years, with anthropometric measurements and 3-day food records collected biannually. Of these, 495 (9.7%) children developed IA. Mediation analysis for time-varying covariates (BMI z-score) and exposure (energy intake) was conducted. Cox proportional hazard method was used in sensitivity analysis. Results: We found an indirect effect of total energy intake (estimates: indirect effect 0.13 [0.05, 0.21]) and energy from protein (estimates: indirect effect 0.06 [0.02, 0.11]), fat (estimates: indirect effect 0.03 [0.01, 0.05]), and carbohydrates (estimates: indirect effect 0.02 [0.00, 0.04]) (kcal/day) on the development of IA. A direct effect was found for protein, expressed both as kcal/day (estimates: direct effect 1.09 [0.35, 1.56]) and energy percentage (estimates: direct effect 72.8 [3.0, 98.0]) and the development of GAD autoantibodies (GADA). In the sensitivity analysis, energy from protein (kcal/day) was associated with increased risk for GADA, hazard ratio 1.24 (95% CI: 1.09, 1.53), p = 0.042. Conclusions: This study confirms that higher total energy intake is associated with higher BMI, which leads to higher risk of the development of IA. A diet with larger proportion of energy from protein has a direct effect on the development of GADA.

Interaction Between Dietary Iron Intake and Genetically Determined Iron Overload: Risk of Islet Autoimmunity and Progression to Type 1 Diabetes in the TEDDY Study.

OBJECTIVE: To examine whether iron intake and genetically determined iron overload interact in predisposing to the development of childhood islet autoimmunity (IA) and type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS: In The Environmental Determinants of Diabetes in the Young (TEDDY) study, 7,770 genetically high-risk children were followed from birth until the development of IA and progression to T1D. Exposures included energy-adjusted iron intake in the first 3 years of life and a genetic risk score (GRS) for increased circulating iron. RESULTS: We found a U-shaped association between iron intake and risk of GAD antibody as the first autoantibody. In children with GRS ≥2 iron risk alleles, high iron intake was associated with an increased risk of IA, with insulin as first autoantibody (adjusted hazard ratio 1.71 [95% CI 1.14; 2.58]) compared with moderate iron intake. CONCLUSIONS: Iron intake may alter the risk of IA in children with high-risk HLA haplogenotypes.

Gluten-free diet adherence in children with screening-detected celiac disease using a prospective birth cohort study.

BACKGROUND: Celiac disease has an increasing incidence worldwide and is treated with lifelong adherence to a gluten-free diet. We aimed to describe gluten-free diet adherence rates in children with screening-identified celiac disease, determine adherence-related factors, and compare adherence to food records in a multinational prospective birth cohort study. METHODS: Children in The Environmental Determinants of Diabetes in the Young study with celiac disease were included. Subjects had at least annual measurement of adherence (parent-report) and completed 3-day food records. Descriptive statistics, t-tests, Kruskal-Wallis tests and multivariable logistic and linear regression were employed. RESULTS: Two hundred ninety (73%) and 199 (67%) of subjects were always adherent to a gluten-free diet at 2 and 5 years post celiac disease diagnosis respectively. The percentage of children with variable adherence increased from 1% at 2 years to 15% at 5 years. Children with a first-degree relative with celiac disease were more likely to be adherent to the gluten-free diet. Gluten intake on food records could not differentiate adherent from nonadherent subjects. Adherent children from the United States had more gluten intake based on food records than European children (P < .001 and P = .007 at 2 and 5 years respectively). CONCLUSION: Approximately three-quarters of children with screening-identified celiac disease remain strictly adherent to a gluten-free diet over time. There are no identifiable features associated with adherence aside from having a first-degree relative with celiac disease. Despite good parent-reported adherence, children from the United States have more gluten intake when assessed by food records. Studies on markers of gluten-free diet adherence, sources of gluten exposure (particularly in the United States), and effects of adherence on mucosal healing are needed.

Sources of dietary gluten in the first 2 years of life and associations with celiac disease autoimmunity and celiac disease in Swedish genetically predisposed children: The Environmental Determinants of Diabetes in the Young (TEDDY) study.

BACKGROUND: High gluten intake is associated with increased risk of celiac disease (CD) in children at genetic risk. OBJECTIVES: We aimed to investigate if different dietary gluten sources up to age 2 y confer different risks of celiac disease autoimmunity (CDA) and CD in children at genetic risk. METHODS: Three-day food records were collected at ages 6, 9, 12, 18, and 24 mo from 2088 Swedish genetically at-risk children participating in a 15-y follow-up cohort study on type 1 diabetes and CD. Screening for CD was performed with tissue transglutaminase autoantibodies (tTGA). The primary outcome was CDA, defined as persistent tTGA positivity. The secondary outcome was CD, defined as having a biopsy specimen showing Marsh score ≥ 2 or an averaged tTGA level ≥ 100 Units. Cox regression adjusted for total gluten intake estimated HRs with 95% CIs for daily intake of gluten sources. RESULTS: During follow-up, 487 (23.3%) children developed CDA and 242 (11.6%) developed CD. Daily intake of ≤158 g porridge at age 9 mo was associated with increased risk of CDA (HR: 1.53; 95% CI: 1.05, 2.23; P = 0.026) compared with no intake. A high daily bread intake (>18.3 g) at age 12 mo was associated with increased risk of both CDA (HR: 1.47; 95% CI: 1.05, 2.05; P = 0.023) and CD (HR: 1.79; 95% CI: 1.10, 2.91; P = 0.019) compared with no intake. At age 18 mo, milk cereal drink was associated with an increased risk of CD (HR: 1.16; 95% CI: 1.00, 1.33; P = 0.047) per 200-g/d increased intake. No association was found for other gluten sources up to age 24 mo and risk of CDA or CD. CONCLUSIONS: High daily intakes of bread at age 12 mo and of milk cereal drink during the second year of life are associated with increased risk of both CDA and CD in genetically at-risk children.

25(OH)D Levels in Infancy Is Associated With Celiac Disease Autoimmunity in At-Risk Children: A Case-Control Study.

Objectives: An observed variation in the risk of celiac disease, according to the season of birth, suggests that vitamin D may affect the development of the disease. The aim of this study was to investigate if vitamin D concentration is associated with the risk of celiac disease autoimmunity (CDA) in genetically at-risk children. Study Design: Children prospectively followed in the multinational The Environmental Determinants of Diabetes in the Young study, conducted at six centers in Europe and the US, were selected for a 1-to-3 nested case-control study. In total, 281 case-control sets were identified. CDA was defined as positivity for tissue transglutaminase autoantibodies (tTGA) on two or more consecutive visits. Vitamin D was measured as 25-hydroxyvitamin D [25(OH)D] concentrations in all plasma samples prior to, and including, the first tTGA positive visit. Conditional logistic regression was used to examine the association between 25(OH)D and risk of CDA. Results: No significant association was seen between 25(OH)D concentrations (per 5 nmol/L increase) and risk for CDA development during early infancy (odds ratio [OR] 0.99, 95% confidence interval [CI] 0.95-1.04) or childhood (OR 1.02, 95% CI 0.97-1.07). When categorizing 25(OH)D concentrations, there was an increased risk of CDA with 25(OH)D concentrations <30 nmol/L (OR 2.23, 95% CI 1.29, 3.84) and >75 nmol/L (OR 2.10, 95% CI 1.28-3.44) in early infancy, as compared with 50-75 nmol/L. Conclusion: This study indicates that 25(OH)D concentrations <30 nmol/L and >75 nmol/L during early infancy were associated with an increased risk of developing CDA in genetically at-risk children. The non-linear relationship raises the need for more studies on the possible role of 25(OH)D in the relation to celiac disease onset.

Associations of breastfeeding with childhood autoimmunity, allergies, and overweight: The Environmental Determinants of Diabetes in the Young (TEDDY) study.

BACKGROUND: Breastfeeding has beneficial effects on numerous health outcomes. OBJECTIVES: We investigated whether breastfeeding duration is associated with the development of early childhood autoimmunity, allergies, or obesity in a multinational prospective birth cohort. METHODS: Infants with genetic susceptibility for type 1 diabetes (n = 8676) were followed for the development of autoantibodies to islet autoantigens or transglutaminase, allergies, and for anthropometric measurements to a median age of 8.3 y (IQR: 2.8-10.2 y). Information on breastfeeding was collected at 3 mo of age and prospectively thereafter. A propensity score for longer breastfeeding was calculated from the variables that were likely to influence any or exclusive breastfeeding. The risks of developing autoimmunity or allergy were assessed using Cox proportional hazards models, and the risk of obesity at 5.5 y of age was assessed using logistic regression with adjustment by the propensity score. RESULTS: Breastfeeding duration was not associated with a lower risk of either islet or transglutaminase autoimmunity (any breastfeeding >6 mo, adjusted HR: 1.07; 95% CI: 0.96, 1.19; exclusive breastfeeding >3 mo, adjusted HR: 1.03; 95% CI: 0.92, 1.15). Exclusive breastfeeding >3 mo was associated with a decreased risk of seasonal allergic rhinitis (adjusted HR: 0.70; 95% CI: 0.53, 0.92; P < 0.01). Any breastfeeding >6 mo and exclusive breastfeeding >3 mo were associated with decreased risk of obesity (adjusted OR: 0.62; 95% CI: 0.47, 0.81; P < 0.001; and adjusted OR: 0.68; 95% CI: 0.47, 0.95; P < 0.05, respectively). CONCLUSIONS: Longer breastfeeding was not associated with a lower risk of childhood (islet or transglutaminase) autoimmunity in genetically at-risk children but was associated with decreased risk of seasonal allergic rhinitis and obesity at 5.5 y of age.

Maternal food consumption during late pregnancy and offspring risk of islet autoimmunity and type 1 diabetes.

AIMS/HYPOTHESIS: We aimed to investigate the association between maternal consumption of gluten-containing foods and other selected foods during late pregnancy and offspring risk of islet autoimmunity (IA) and type 1 diabetes in The Environmental Determinants of Diabetes in the Young (TEDDY) study. METHODS: The TEDDY study recruited children at high genetic risk for type 1 diabetes at birth, and prospectively follows them for the development of IA and type 1 diabetes (n = 8556). A questionnaire on the mother's diet in late pregnancy was completed by 3-4 months postpartum. The maternal daily intake was estimated from a food frequency questionnaire for eight food groups: gluten-containing foods, non-gluten cereals, fresh milk, sour milk, cheese products, soy products, lean/medium-fat fish and fatty fish. For each food, we described the distribution of maternal intake among the four participating countries in the TEDDY study and tested the association of tertile of maternal food consumption with risk of IA and type 1 diabetes using forward selection time-to-event Cox regression. RESULTS: By 28 February 2019, 791 cases of IA and 328 cases of type 1 diabetes developed in TEDDY. There was no association between maternal late-pregnancy consumption of gluten-containing foods or any of the other selected foods and risk of IA, type 1 diabetes, insulin autoantibody-first IA or GAD autoantibody-first IA (all p ≥ 0.01). Maternal gluten-containing food consumption in late pregnancy was higher in Sweden (242 g/day), Germany (247 g/day) and Finland (221 g/day) than in the USA (199 g/day) (pairwise p < 0.05). CONCLUSIONS/INTERPRETATION: Maternal food consumption during late pregnancy was not associated with offspring risk for IA or type 1 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00279318.

Children's erythrocyte fatty acids are associated with the risk of islet autoimmunity.

Our aim was to investigate the associations between erythrocyte fatty acids and the risk of islet autoimmunity in children. The Environmental Determinants of Diabetes in the Young Study (TEDDY) is a longitudinal cohort study of children at high genetic risk for type 1 diabetes (n = 8676) born between 2004 and 2010 in the U.S., Finland, Sweden, and Germany. A nested case-control design comprised 398 cases with islet autoimmunity and 1178 sero-negative controls matched for clinical site, family history, and gender. Fatty acids composition was measured in erythrocytes collected at the age of 3, 6, and 12 months and then annually up to 6 years of age. Conditional logistic regression models were adjusted for HLA risk genotype, ancestry, and weight z-score. Higher eicosapentaenoic and docosapentaenoic acid (n - 3 polyunsaturated fatty acids) levels during infancy and conjugated linoleic acid after infancy were associated with a lower risk of islet autoimmunity. Furthermore, higher levels of some even-chain saturated (SFA) and monounsaturated fatty acids (MUFA) were associated with increased risk. Fatty acid status in early life may signal the risk for islet autoimmunity, especially n - 3 fatty acids may be protective, while increased levels of some SFAs and MUFAs may precede islet autoimmunity.

Metabolomics-related nutrient patterns at seroconversion and risk of progression to type 1 diabetes.

OBJECTIVE: Our aim was to elucidate the role of diet in type 1 diabetes (T1D) by examining combinations of nutrient intake in the progression from islet autoimmunity (IA) to T1D. METHODS: We measured 2457 metabolites and dietary intake at the time of seroconversion in 132 IA-positive children in the prospective Diabetes Autoimmunity Study in the Young. IA was defined as the first of two consecutive visits positive for at least one autoantibody (insulin, GAD, IA-2, or ZnT8). By December 2018, 40 children progressed to T1D. Intakes of 38 nutrients were estimated from semiquantitative food frequency questionnaires. We tested the association of each metabolite with progression to T1D using multivariable Cox regression. Nutrient patterns that best explained variation in candidate metabolites were identified using reduced rank regression (RRR), and their association with progression to T1D was tested using Cox regression adjusting for age at seroconversion and high-risk HLA genotype. RESULTS: In stepwise selection, 22 nutrients significantly predicted at least two of the 13 most significant metabolites associated with progression to T1D, and were included in RRR. A nutrient pattern corresponding to intake lower in linoleic acid, niacin, and riboflavin, and higher in total sugars, explained 18% of metabolite variability. Children scoring higher on this metabolite-related nutrient pattern at seroconversion had increased risk for progressing to T1D (HR = 3.17, 95%CI = 1.42-7.05). CONCLUSIONS: Combinations of nutrient intake reflecting candidate metabolites are associated with increased risk of T1D, and may help focus dietary prevention efforts.

Plasma ascorbic acid and the risk of islet autoimmunity and type 1 diabetes: the TEDDY study.

AIMS/HYPOTHESIS: We studied the association of plasma ascorbic acid with the risk of developing islet autoimmunity and type 1 diabetes and examined whether SNPs in vitamin C transport genes modify these associations. Furthermore, we aimed to determine whether the SNPs themselves are associated with the risk of islet autoimmunity or type 1 diabetes. METHODS: We used a risk set sampled nested case-control design within an ongoing international multicentre observational study: The Environmental Determinants of Diabetes in the Young (TEDDY). The TEDDY study followed children with increased genetic risk from birth to endpoints of islet autoantibodies (350 cases, 974 controls) and type 1 diabetes (102 cases, 282 controls) in six clinical centres. Control participants were matched for family history of type 1 diabetes, clinical centre and sex. Plasma ascorbic acid concentration was measured at ages 6 and 12 months and then annually up to age 6 years. SNPs in vitamin C transport genes were genotyped using the ImmunoChip custom microarray. Comparisons were adjusted for HLA genotypes and for background population stratification. RESULTS: Childhood plasma ascorbic acid (mean ± SD 10.76 ± 3.54 mg/l in controls) was inversely associated with islet autoimmunity risk (adjusted OR 0.96 [95% CI 0.92, 0.99] per +1 mg/l), particularly islet autoimmunity, starting with insulin autoantibodies (OR 0.94 [95% CI 0.88, 0.99]), but not with type 1 diabetes risk (OR 0.93 [95% Cl 0.86, 1.02]). The SLC2A2 rs5400 SNP was associated with increased risk of type 1 diabetes (OR 1.77 [95% CI 1.12, 2.80]), independent of plasma ascorbic acid (OR 0.92 [95% CI 0.84, 1.00]). CONCLUSIONS/INTERPRETATION: Higher plasma ascorbic acid levels may protect against islet autoimmunity in children genetically at risk for type 1 diabetes. Further studies are warranted to confirm these findings. DATA AVAILABILITY: The datasets generated and analysed during the current study will be made available in the NIDDK Central Repository at https://www.niddkrepository.org/studies/teddy.

Metabolite-related dietary patterns and the development of islet autoimmunity.

The role of diet in type 1 diabetes development is poorly understood. Metabolites, which reflect dietary response, may help elucidate this role. We explored metabolomics and lipidomics differences between 352 cases of islet autoimmunity (IA) and controls in the TEDDY (The Environmental Determinants of Diabetes in the Young) study. We created dietary patterns reflecting pre-IA metabolite differences between groups and examined their association with IA. Secondary outcomes included IA cases positive for multiple autoantibodies (mAb+). The association of 853 plasma metabolites with outcomes was tested at seroconversion to IA, just prior to seroconversion, and during infancy. Key compounds in enriched metabolite sets were used to create dietary patterns reflecting metabolite composition, which were then tested for association with outcomes in the nested case-control subset and the full TEDDY cohort. Unsaturated phosphatidylcholines, sphingomyelins, phosphatidylethanolamines, glucosylceramides, and phospholipid ethers in infancy were inversely associated with mAb+ risk, while dicarboxylic acids were associated with an increased risk. An infancy dietary pattern representing higher levels of unsaturated phosphatidylcholines and phospholipid ethers, and lower sphingomyelins was protective for mAb+ in the nested case-control study only. Characterization of this high-risk infant metabolomics profile may help shape the future of early diagnosis or prevention efforts.

The relationship between breastfeeding and reported respiratory and gastrointestinal infection rates in young children.

BACKGROUND: Although breastfeeding is touted as providing many health benefits to infants, some aspects of this relationship remain poorly understood. METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) is a prospective longitudinal study that follows children from birth through childhood, and collects data on illness events, breastfeeding duration, and time to introduction of formula or foods at 3 month intervals up until 4 years of age and at 6 months intervals thereafter. Exclusive and non-exclusive breastfeeding is examined in relation to the 3-month odds of a respiratory or gastrointestinal infection for 6861 children between the ages of 3-18 months, and 5666 children up to the age of 4 years. Analysis was performed using logistic regression models with generalized estimating equation methodology. All models were adjusted for potential confounding variables. RESULTS: At 3-6 months of age, breastfeeding was found to be inversely associated with the odds of respiratory infections with fever (OR = 0.82, 95% CI = 0.70-0.95), otitis media (OR = 0.76, 95% CI = 0.62-0.94), and infective gastroenteritis (OR = 0.55, 95% CI = 0.46-0.70), although the inverse association with respiratory illnesses was observed only for girls during the winter months. Between 6 and 18 months of age, breastfeeding within any 3 month period continued to be inversely associated with the odds of ear infection and infective gastroenteritis, and additionally with the odds of conjunctivitis, and laryngitis and tracheitis, over the same 3 month period within this age range. However, breastfeeding in this group was associated with increased reports of common cold. Duration of exclusive breastfeeding was inversely associated with the odds of otitis media up to 48 months of age (OR = 0.97, 95% CI = 0.95-0.99) after breastfeeding had stopped. CONCLUSIONS: This study demonstrates that breastfeeding can be protective against multiple respiratory and gastrointestinal acute illnesses in some children up to at least 6 months of age, with duration of exclusive breastfeeding being somewhat protective of otitis media even after breastfeeding has stopped. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00279318 . Date of registration: January 17, 2006 (proactively registered). First Posted: January 19, 2006.

Early Probiotic Supplementation and the Risk of Celiac Disease in Children at Genetic Risk.

Probiotics are linked to positive regulatory effects on the immune system. The aim of the study was to examine the association between the exposure of probiotics via dietary supplements or via infant formula by the age of 1 year and the development of celiac disease autoimmunity (CDA) and celiac disease among a cohort of 6520 genetically susceptible children. Use of probiotics during the first year of life was reported by 1460 children. Time-to-event analysis was used to examine the associations. Overall exposure of probiotics during the first year of life was not associated with either CDA (n = 1212) (HR 1.15; 95%CI 0.99, 1.35; p = 0.07) or celiac disease (n = 455) (HR 1.11; 95%CI 0.86, 1.43; p = 0.43) when adjusting for known risk factors. Intake of probiotic dietary supplements, however, was associated with a slightly increased risk of CDA (HR 1.18; 95%CI 1.00, 1.40; p = 0.043) compared to children who did not get probiotics. It was concluded that the overall exposure of probiotics during the first year of life was not associated with CDA or celiac disease in children at genetic risk.

Association of Gluten Intake During the First 5 Years of Life With Incidence of Celiac Disease Autoimmunity and Celiac Disease Among Children at Increased Risk.

Importance: High gluten intake during childhood may confer risk of celiac disease. Objectives: To investigate if the amount of gluten intake is associated with celiac disease autoimmunity and celiac disease in genetically at-risk children. Design, Setting, and Participants: The participants in The Environmental Determinants of Diabetes in the Young (TEDDY), a prospective observational birth cohort study designed to identify environmental triggers of type 1 diabetes and celiac disease, were followed up at 6 clinical centers in Finland, Germany, Sweden, and the United States. Between 2004 and 2010, 8676 newborns carrying HLA antigen genotypes associated with type 1 diabetes and celiac disease were enrolled. Screening for celiac disease with tissue transglutaminase autoantibodies was performed annually in 6757 children from the age of 2 years. Data on gluten intake were available in 6605 children (98%) by September 30, 2017. Exposures: Gluten intake was estimated from 3-day food records collected at ages 6, 9, and 12 months and biannually thereafter until the age of 5 years. Main Outcomes and Measures: The primary outcome was celiac disease autoimmunity, defined as positive tissue transglutaminase autoantibodies found in 2 consecutive serum samples. The secondary outcome was celiac disease confirmed by intestinal biopsy or persistently high tissue transglutaminase autoantibody levels. Results: Of the 6605 children (49% females; median follow-up: 9.0 years [interquartile range, 8.0-10.0 years]), 1216 (18%) developed celiac disease autoimmunity and 447 (7%) developed celiac disease. The incidence for both outcomes peaked at the age of 2 to 3 years. Daily gluten intake was associated with higher risk of celiac disease autoimmunity for every 1-g/d increase in gluten consumption (hazard ratio [HR], 1.30 [95% CI, 1.22-1.38]; absolute risk by the age of 3 years if the reference amount of gluten was consumed, 28.1%; absolute risk if gluten intake was 1-g/d higher than the reference amount, 34.2%; absolute risk difference, 6.1% [95% CI, 4.5%-7.7%]). Daily gluten intake was associated with higher risk of celiac disease for every 1-g/d increase in gluten consumption (HR, 1.50 [95% CI, 1.35-1.66]; absolute risk by age of 3 years if the reference amount of gluten was consumed, 20.7%; absolute risk if gluten intake was 1-g/d higher than the reference amount, 27.9%; absolute risk difference, 7.2% [95% CI, 6.1%-8.3%]). Conclusions and Relevance: Higher gluten intake during the first 5 years of life was associated with increased risk of celiac disease autoimmunity and celiac disease among genetically predisposed children.

Maternal dietary supplement use and development of islet autoimmunity in the offspring: TEDDY study.

OBJECTIVE: We investigated the association between maternal use of vitamin D and omega-3 fatty acids (n-3 FAs) supplements during pregnancy and risk of islet autoimmunity (IA) in the offspring. METHODS: The Environmental Determinants of Diabetes in the Young (TEDDY) Study is prospectively following 8676 children with increased genetic risk for type 1 diabetes in Finland, Germany, Sweden, and the United States. Blood samples were collected every 3 months between 3 and 48 months of age then every 6 months thereafter to determine persistent IA. Duration, frequency, and supplement dose during pregnancy were recalled by mothers at 3 to 4 months postpartum. Cumulative intakes of supplemental vitamin D and n-3 FAs were analyzed as continuous or binary variables. We applied time-to-event analysis to study the association between maternal supplement use and IA, adjusting for country, human leukocyte antigen-DR-DQ genotype, family history of type 1 diabetes and sex. Secondary outcomes included insulin autoantibodies (IAA) or glutamic acid decarboxylase (GADA) as the first appearing autoantibody. RESULTS: As of February 2018, there were 747 (9.0%) children with IA. Vitamin D supplement intake during pregnancy (any vs none) was not associated with risk for IA (hazard ratio [HR] 1.11; 95% confidence interval [CI] 0.94, 1.31); neither was cumulative vitamin D supplement intake. Supplemental n-3 FA intake was similarly not associated with IA risk (HR: 1.19, 95% CI 0.98, 1.45). Similar lack of association was observed for either IAA or GADA as the first appearing autoantibody. CONCLUSIONS: The TEDDY cohort showed no evidence of benefit regarding IA risk for vitamin D or n-3 FA supplementation during pregnancy.

Associations of Maternal Diabetes During Pregnancy with Overweight in Offspring: Results from the Prospective TEDDY Study.

OBJECTIVE: This study aimed to determine the relationship between different forms of, and potential pathways between, maternal diabetes and childhood obesity at different ages. METHODS: Prospective cohort data from The Environmental Determinants of Diabetes in the Young (TEDDY) study, which was composed of 5,324 children examined from 0.25 to 6 years of age, were analyzed. Cross-sectional and longitudinal analyses taking into account potential confounders and effect modifiers such as maternal prepregnancy BMI and birth weight z scores were performed. RESULTS: Offspring of mothers with gestational diabetes mellitus (GDM) or type 1 diabetes mellitus (T1DM) showed a higher BMI standard deviation score and increased risk for overweight and obesity at 5.5 years of age than offspring of mothers without diabetes. While these associations could be substantially explained by maternal prepregnancy BMI in offspring of mothers with GDM, significant associations disappeared after adjustment for birth weight z scores in offspring of T1DM mothers. Furthermore, overweight risk became stronger with increasing age in offspring of mothers with diabetes compared with offspring of mothers without diabetes. CONCLUSIONS: Maternal diabetes is associated with increased risk of offspring overweight, and the association appears to get stronger as children grow older. Indeed, intrauterine exposure to maternal T1DM may predispose children to later obesity through increased birth weight, while maternal BMI is more important in children exposed to GDM.