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Objective: To investigate if there is a reduced risk of type 1 diabetes in children breastfed or exclusively breastfed by performing a pooled analysis with adjustment for recognized confounders.Research Design and Methods: Relevant studies were identified from literature searches using MEDLINE, Web of Science, and EMBASE. Authors of relevant studies were asked to provide individual participant data or conduct prespecified analyses. Meta-analysis techniques were used to combine odds ratios (ORs) and investigate heterogeneity between studies.Results: Data were available from 43 studies including 9,874 patients with type 1 diabetes. Overall, there was a reduction in the risk of diabetes after exclusive breast-feeding for >2 weeks (20 studies; OR = 0.75, 95% CI 0.64-0.88), the association after exclusive breast-feeding for >3 months was weaker (30 studies; OR = 0.87, 95% CI 0.75-1.00), and no association was observed after (nonexclusive) breast-feeding for >2 weeks (28 studies; OR = 0.93, 95% CI 0.81-1.07) or >3 months (29 studies; OR = 0.88, 95% CI 0.78-1.00). These associations were all subject to marked heterogeneity (I(2) = 58, 76, 54, and 68%, respectively). In studies with lower risk of bias, the reduced risk after exclusive breast-feeding for >2 weeks remained (12 studies; OR = 0.86, 95% CI 0.75-0.99), and heterogeneity was reduced (I(2) = 0%). Adjustments for potential confounders altered these estimates very little.Conclusions: The pooled analysis suggests weak protective associations between exclusive breast-feeding and type 1 diabetes risk. However, these findings are difficult to interpret because of the marked variation in effect and possible biases (particularly recall bias) inherent in the included studies. [ABSTRACT FROM AUTHOR]

Objective: To test whether the frequency of human enterovirus RNA in fecal samples collected monthly from early infancy was associated with development of multiple islet autoantibodies in children with the highest risk HLA genotype.Research Design and Methods: Individuals carrying the HLA DRB1*0401-DQA1*03-DQB1*0302/DRB1*03-DQA1*05-DQB1*02 genotype were identified at birth and followed with monthly stool samples from age 3 to 35 months. Blood samples taken at age 3, 6, 9, and 12 months and then annually were tested for autoantibodies to insulin, GAD 65 and IA-2. Among 911 children, 27 developed positivity for two or more islet autoantibodies in two or more consecutive samples (case subjects). Two control subjects per case subject were matched by follow-up time, date of birth, and county of residence. Stool samples were analyzed for enterovirus with a semiquantitative real-time RT-PCR.Results: The frequency of human enterovirus RNA in stool samples from case subjects before seroconversion (43 of 339, 12.7%) did not differ from the frequency in control subjects (94 of 692, 13.6%) (P = 0.97). Results remained essentially unchanged after adjustment for potential confounders, restriction to various time windows before seroconversion, or infections in the 1st year of life or after inclusion of samples collected after seroconversion. There was no difference in the average quantity of enterovirus RNA or in the frequency of repeatedly positive samples. The estimated relative risk for islet autoimmunity per enterovirus RNA-positive sample during follow-up (nested case-control analysis) was 1.12 (95% CI 0.66-1.91).Conclusions: There was no support for the hypothesis that fecal shedding of enteroviral RNA is a major predictor of advanced islet autoimmunity. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether enterovirus infections predict progression to type 1 diabetes in genetically predisposed children repeatedly positive for islet autoantibodies.Research Design and Methods: Since 1993, the Diabetes and Autoimmunity Study in the Young (DAISY) has followed 2,365 genetically predisposed children for islet autoimmunity and type 1 diabetes. Venous blood and rectal swabs were collected every 3-6 months after seroconversion for islet autoantibodies (against GAD, insulin, or insulinoma-associated antigen-2 [IA-2]) until diagnosis of diabetes. Enteroviral RNA in serum or rectal swabs was detected using reverse transcriptase PCR with primers specific for the conserved 5' noncoding region, detecting essentially all enterovirus serotypes.Results: Of 140 children who seroconverted to repeated positivity for islet autoantibodies at a median age of 4.0 years, 50 progressed to type 1 diabetes during a median follow-up of 4.2 years. The risk of progression to clinical type 1 diabetes in the sample interval following detection of enteroviral RNA in serum (three diabetes cases diagnosed among 17 intervals) was significantly increased compared with that in intervals following a negative serum enteroviral RNA test (33 cases diagnosed among 1,064 intervals; hazard ratio 7.02 [95% CI 1.95-25.3] after adjusting for number of autoantibodies). Results remained significant after adjustment for ZnT8-autoantibodies and after restriction to various subgroups. Enteroviral RNA in rectal swabs was not predictive of progression to type 1 diabetes. No evidence for viral persistence was found.Conclusions: This novel observation suggests that progression from islet autoimmunity to type 1 diabetes may increase after an enterovirus infection characterized by the presence of viral RNA in blood. [ABSTRACT FROM AUTHOR]

OBJECTIVE: We have previously described an association between use of cod liver oil (a dietary n-3 fatty acid supplement) and reduced risk of type 1 diabetes. n-3 fatty acids are ligands for the peroxisome proliferator-activated receptor-gamma (PPARG), which has recently been implicated in the control of inflammation and possibly autoimmunity. We aimed to estimate the association between the common Pro12Ala polymorphism of PPARG2 and risk of type 1 diabetes, and to test whether there is gene-environment interaction with use of cod liver oil in the first year of life or gene-gene interaction with the established insulin gene (INS) and human leukocyte antigen DQ (HLA-DQ) genetic susceptibility loci. METHODS: We designed a population-based case-control study of childhood-onset type 1 diabetes in Norway with information on use of cod liver oil in the first year of life from questionnaires and PPARG2 genotype data for 483 cases and 1520 control subjects. We used logistic regression for analysis. RESULTS: The odds ratio for the PPARG2 Ala/Ala or Pro/Ala vs. Pro/Pro genotype and type 1 diabetes was 0.89 (95% CI: 0.69-1.13, p = 0.33). There was no significant interaction with cod liver oil in the first year of life [P (interaction) = 0.35] or with the INS polymorphism [P(interaction) = 0.42]. CONCLUSIONS: Although the association between PPARG2 and type 1 diabetes was not significant, the observed odds ratio was almost identical to that observed in two previous studies and can contribute to meta-analysis indicating a weak but significant association. Our hypothesized interaction between cod liver oil and PPARG2 in reducing type 1 diabetes risk was not supported. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The aim of this study was to assess the utility of hemoglobin A1c (HbA1c) measurements in the early detection of clinical type 1 diabetes during prospective follow-up of children with islet autoimmunity. METHODS: The Diabetes Autoimmunity Study in the Young (DAISY) has followed for development of islet autoimmunity and diabetes general population newborns carrying human leukocyte antigen (HLA) genotypes conferring risk for type 1 diabetes and young siblings or offspring of people with type 1 diabetes. Testing for autoantibodies was performed at least once in 2234 and twice or more in 1887 children. Among the latter, 100 children tested positive on at least two consecutive visits. To date, 92 children have developed persistent islet autoantibodies to glutamic acid decarboxylase 65 (GAD65), insulin, or insulinoma associated antigen-2 (IA-2) and had at least two subsequent clinic visits. These children had study visits with point-of-care testing for HbA1c and random glucose every 3-6 months and those with random plasma glucose above 11.1 mmol/L or HbA1c above 6.3% were evaluated by a pediatric endocrinologist for clinical diabetes. RESULTS: During a mean follow-up of 3.4 yr from onset of autoimmunity, 28 children developed type 1 diabetes, at mean age of 6.5 yr. Mean prediagnostic HbA1c was 5.1% [standard deviation (SD) = 0.4%]. In a Cox regression model accounting for changes in values in individuals over time, increase in HbA1c predicted increased risk of progression to type 1 diabetes, hazard ratio = 4.8 (95% confidence interval 3.0-7.7) for each SD of 0.4%, independent of random glucose and number of autoantibodies. Increase in random plasma glucose levels only marginally predicted risk of progression (hazard ratio = 1.4, 95% confidence interval 1.02-1.8, per SD of 1.1 mmol/L). CONCLUSIONS: Normal but increasing Hb1Ac may be useful in early detection of type 1 diabetes, whereas random plasma glucose levels were less predictive. [ABSTRACT FROM AUTHOR]

Objective: An increasing incidence rate of childhood-onset type 1 diabetes has been described in several countries, particularly among the youngest children, and the Nordic countries have consistently been shown to have the highest incidence rates. An increasing incidence had previously been reported in Norway for 1973-1982, together with regional variation within the country. The aim of this study was to test whether there has been an increasing incidence of type 1 diabetes and a continued regional variation among children aged <15 years in Norway during 1989-1998.Research Design and Methods: As a part of the activities of the National Childhood Diabetes Registry of Norway and the EURODIAB study, a 10-year prospective, nationwide case registration of type 1 diabetes was done among children aged <15 years.Results: A total of 1867 new case subjects (1009 boys and 858 girls) were identified. The total incidence rate was 22.4 per 100000 person-years (95% CI 21.5-23.5). The incidence was 13.1, 26.3, and 28.8 per 100000 in the age-groups 0-4.9, 5-9.9, and 10-14.9 years, respectively. No increase or decrease over time was detected in any of the age-groups during the 10-year period. We found significant variation between the 19 counties, which only partly reflected the pattern previously described for 1973-1982.Conclusions: We found a significant regional variation within Norway. After a previous period of increase, the incidence has been stable in all age-groups <15 years during 1989-1998. [ABSTRACT FROM AUTHOR]

The objective of this study was to test whether maternal age at delivery, child's birth order, cesarean section, complicated delivery, maternal smoking during pregnancy, or neonatal jaundice predict islet autoimmunity in children at genetically increased risk of type 1 diabetes in a birth cohort with blood draws at ages 9, 15, and 24 months and yearly thereafter. Newborns with diabetes-associated human leukocyte antigen genotypes (n = 938) and offspring or siblings of persons with type 1 diabetes (n = 428) from the Denver, Colorado, metropolitan area were examined from January 1994 to February 2003. Information on perinatal factors was collected by using questionnaires soon after the birth. Islet autoimmunity was defined as positivity for > or = 1 autoantibody to glutamic acid decarboxylase65, insulin, or protein tyrosine phosphatase-2/ICA512 at > or = 2 consecutive visits (n = 52; mean follow-up, 3.9 years). Complicated delivery (breech, forceps, vacuum extraction) predicted a higher risk of islet autoimmunity (hazard ratio = 2.10, 95% confidence interval: 1.09, 4.05). Increasing maternal age was related to risk of islet autoimmunity among first-degree relatives of persons with type 1 diabetes (hazard ratios = 3.96 and 8.88 for maternal ages 25-34 and > or = 35 years, respectively, compared with < 25 years; p for trend = 0.008. Other factors evaluated were not related to risk of islet autoimmunity. In conclusion, influences in utero or during delivery may affect the fetal immune system. [ABSTRACT FROM AUTHOR]

BACKGROUND: In Norway, cod liver oil is an important source of dietary vitamin D and the long-chain n-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid, all of which have biological properties of potential relevance for the prevention of type 1 diabetes. OBJECTIVE: The main objective was to investigate whether the use of dietary cod liver oil or other vitamin D supplements, either by the mother during pregnancy or by the child during the first year of life, is associated with a lower risk of type 1 diabetes among children. DESIGN: We designed a nationwide case-control study in Norway with 545 cases of childhood-onset type 1 diabetes and 1668 population control subjects. Families were contacted by mail, and they completed a questionnaire on the frequency of use of cod liver oil and other vitamin D supplements and other relevant factors. RESULTS: Use of cod liver oil in the first year of life was associated with a significantly lower risk of type 1 diabetes (adjusted odds ratio: 0.74; 95% CI: 0.56, 0.99). Use of other vitamin D supplements during the first year of life and maternal use of cod liver oil or other vitamin D supplements during pregnancy were not associated with type 1 diabetes. CONCLUSION: Cod liver oil may reduce the risk of type 1 diabetes, perhaps through the antiinflammatory effects of long-chain n-3 fatty acids. Copyright © 2003 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

Objective: To assess whether maternal BMI before pregnancy and weight gain during pregnancy predicted the risk of islet autoimmunity in genetically susceptible children.Research Design and Methods: Of 46,939 newborns screened for the high-risk HLA genotype DR4-DQ8/DR3-DQ2, 1,003 were positive and 885 were followed with serial blood samples tested for autoantibodies to insulin, GAD, and insulinoma-associated protein 2 (IA2). The end point was defined as repeated positivity for two or three autoantibodies or the onset of type 1 diabetes (islet autoimmunity).Results: Thirty-six children developed islet autoimmunity, of whom 10 developed type 1 diabetes. Both maternal BMI > or =30 kg/m(2) before pregnancy and maternal weight gain > or =15 kg predicted the increased risk of islet autoimmunity (hazard ratio [HR] 2.5, P = 0.023, and HR 2.5, P = 0.015, respectively), independent of maternal diabetes.Conclusions: Maternal weight may predict risk of islet autoimmunity in offspring with a high genetic susceptibility for type 1 diabetes. [ABSTRACT FROM AUTHOR]

Background: High gluten and low dietary fiber in pregnancy intake is associated with an increased risk of celiac disease (CeD) in the child. Early life higher dietary quality is suggested to reduce the subsequent risk of CeD., Objectives: The aim was to investigate associations of pregnancy dietary quality and diversity with child risk of CeD., Methods: In The Norwegian Mother, Father and Child Cohort Study, 85,122 mother-child pairs had available data from a validated pregnancy food frequency questionnaire. Pregnancy dietary quality and diversity were estimated by a Pregnancy Healthy Eating Index [mean 99.3, standard deviation (SD) 9.9, range 48.8-128.3], and a Diet Diversity Score (mean 7.0, SD 1.0, range 1.6-9.8), respectively. Child CeD was captured by ≥2 diagnostic codes in the Norwegian Patient Registry. Logistic regression was used to estimate associations between pregnancy dietary quality, diversity and child CeD, adjusted for socioeconomic factors, and parents CeD [adjusted odds ratio (aOR), 95% confidence intervals (CI)]. CeD-susceptible human leukocyte antigen haplotypes (DQ2/DQ8) were present in 30,718 (45.5%)., Results: Up to mean age 16.0 (SD 1.8, 12.4-19.8) y, 1363 (1.6%) children were diagnosed with CeD. Lower as well as higher pregnancy dietary quality associated with a reduced risk of CeD in the child (<5th percentile aOR = 0.67, 95% CI: 0.48, 0.93, >95th percentile aOR = 0.71, 95% CI: 0.52, 0.98, respectively, nonlinear squared term P = 0.011). Analyses on genetically susceptible children, adjustments for pregnancy iron supplementation, gluten, and dietary fiber intake, and child early life dietary quality, gluten intake and iron supplementation, supported the finding. Pregnancy dietary diversity was not associated with child CeD (aOR = 1.00, 95% CI: 0.94, 1.07/score)., Conclusions: In this population-based study, lower as well as higher pregnancy dietary quality associated with a reduced risk of CeD diagnosis in the child. In contrast, no such association was observed with maternal dietary diversity., Competing Interests: Conflict of interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: I received funding from the European Union's Horizon 2020 research and innovation programme (grant number 864764 HEDIMED) and was supported by the Norwegian Institute of Public Health. I declare no competing interests.

Background & Aims: Maternal gluten intake in relation to child's risk of type 1 diabetes has been studied in few prospective studies considering the diet during pregnancy but none during lactation. Our aim was to study whether gluten, cereals, or dietary fiber in maternal diet during pregnancy and lactation is associated with the risk of islet autoimmunity or type 1 diabetes in the offspring., Methods: We included 4943 children with genetic susceptibility to type 1 diabetes from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study, born between 1996 and 2004. Maternal intake of gluten, different types of cereals, and dietary fiber were derived from a semi-quantitative validated food frequency questionnaire covering the eighth month of pregnancy and the third month of lactation. Children were monitored for islet autoantibodies up to age of 15 years and type 1 diabetes until year 2017. Risk of islet autoimmunity and clinical type 1 diabetes were estimated using Cox regression model, adjusted for energy intake, child's sex, HLA genotype, and familial diabetes., Results: Altogether 312 children (6.4%) developed islet autoimmunity at median age of 3.5 (IQR 1.7, 6.6) years and 178 children (3.6%) developed type 1 diabetes at median age of 7.1 (IQR 4.3, 10.6) years. Gluten intake during pregnancy was not associated with islet autoimmunity (HR 0.96; 95% CI 0.68, 1.35), per 1 g/MJ increase in intake nor type 1 diabetes (HR 0.96; 95% CI 0.62, 1.50) in the offspring. Higher barley consumption during lactation was associated with increased risk of type 1 diabetes (HR 3.25; 95% CI 1.21, 8.70) per 1 g/MJ increase in intake. Maternal intake of other cereals or dietary fiber was not associated with the offspring outcomes., Conclusions: We observed no association between maternal intake of gluten, most consumed cereals, or dietary fiber during pregnancy or lactation and the risk of islet autoimmunity or type 1 diabetes in children from a high-risk population., Competing Interests: Declaration of competing interest Authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims/hypothesis: The aim of this study was to investigate whether higher dietary intake of marine n-3 fatty acids during pregnancy is associated with a lower risk of type 1 diabetes in children., Methods: The Danish National Birth Cohort (DNBC) and the Norwegian Mother, Father and Child Cohort Study (MoBa) together include 153,843 mother-child pairs with prospectively collected data on eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intake during pregnancy from validated food frequency questionnaires. Type 1 diabetes diagnosis in children (n=634) was ascertained from national diabetes registries., Results: There was no association between the sum of EPA and DHA intake during pregnancy and risk of type 1 diabetes in offspring (pooled HR per g/day of intake: 1.00, 95% CI 0.88, 1.14), with consistent results for both the MoBa and the DNBC. Robustness analyses gave very similar results., Conclusions/interpretation: Initiation of a trial of EPA and DHA during pregnancy to prevent type 1 diabetes in offspring should not be prioritised., (© 2024. The Author(s).)

BackgroundSocioeconomic status in the risk of developing type 1 diabetes seems inconsistent. We investigated whether risk of childhood-onset type 1 diabetes differed by parental education or occupation in a nationwide cohort., Methods: This cohort study included all children born in Norway from 1974 to 2013. In individually linked data from nationwide population registries following children born in Norway up to 15 years of age, we identified 4647 with newly diagnosed type 1 diabetes during 15 381 923 person-years of follow-up., Results: Children of mothers with a master's degree had lower risk of type 1 diabetes than children of mothers with completed upper secondary education only (adjusted incidence rate ratio, aIRR=0.82 95% CI: 0.70 to 0.95). There was no difference between upper secondary and lower secondary maternal education (aIRR=0.98, 95% CI: 0.89 to 1.08). Paternal education was not significantly associated with type 1 diabetes, lower secondary compared with upper secondary aIRR 0.96 (0.88-1.05) and master compared with upper secondary aIRR 0.93 (0.83-1.05). While maternal elementary occupation was associated with a lower risk of type 1 diabetes, specific maternal or paternal occupations were not., Conclusions: Our results suggested inverse U-shaped associations between maternal socioeconomic status and risk of type 1 diabetes. Non-linear associations may be part of the reason why previous literature has been inconsistent., Competing Interests: Competing interests: PL-DR reports participation in a research project funded by LEO Pharma, all regulator mandated phase IV studies, all with funds paid to her institution (no personal fees) and with no relation to the work reported in this paper. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Infections in early childhood have been associated with risk of celiac disease (CD) and type 1 diabetes (T1D). We investigated whether this is driven by susceptibility genes for autoimmune disease by comparing infection frequency by genetic susceptibility variants for CD or T1D., Methods: We genotyped 373 controls and 384 children who developed CD or T1D in the population-based Norwegian Mother, Father and Child Cohort study (MoBa) study for human leukocyte antigen (HLA)-DQ, FUT2, SH2B3, and PTPN22, and calculated a weighted non-HLA genetic risk score (GRS) for CD and T1D based on over 40 SNPs. Parents reported infections in questionnaires when children were 6 and 18 months old. We used negative binomial regression to estimate incidence rate ratio (IRR) for infections by genotype., Results: HLA genotypes for CD and T1D or non-HLA GRS for T1D were not associated with infections. The non-HLA GRS for CD was associated with a nonsignificantly lower frequency of infections (aIRR: 0.95, 95% CI: 0.87-1.03 per weighted allele score), and significantly so when restricting to healthy controls (aIRR: 0.89, 0.81-0.99). Participants homozygous for rs601338(A;A) at FUT2, often referred to as nonsecretors, had a nonsignificantly lower risk of infections (aIRR: 0.91, 95% CI: 0.83-1.01). SH2B3 and PTPN22 genotypes were not associated with infections. The association between infections and risk of CD (OR: 1.15 per five infections) was strengthened after adjustment for HLA genotype and non-HLA GRS (OR: 1.24)., Conclusions: HLA variants and non-HLA GRS conferring susceptibility for CD were not associated with increased risk of infections in early childhood and is unlikely to drive the observed association between infections and risk of CD or T1D in many studies., (© 2023 The Authors. Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Aims: Studies of social inequality and risk of developing type 1 diabetes are inconsistent. The present review aimed to comprehensively review relevant literature and describe what has been reported on socio-economic status or parental occupation and risk of type 1 diabetes in children., Methods: We searched for publications between 1 January 1970 and 30 November 2021. We focused on the most recent and/or informative publication in cases of multiple publications from the same data source and referred to these as primary studies., Results: Our search identified 69 publications with relevant data. We identified eight primary cohort studies with individual-level data, which we considered the highest quality of evidence. Furthermore, we identified 13 primary case-control studies and 14 semi-ecological studies with area-level socio-economic status variables which provided a weaker quality of evidence. Four of eight primary cohort studies contained data on maternal education, showing non-linear associations with type 1 diabetes that were not consistent across studies. There was no consistent pattern on the association of parental occupation and childhood-onset type 1 diabetes., Conclusions: There is a need for more high-quality studies, but the existing literature does not suggest a major and consistent role of socio-economic status in the risk of type 1 diabetes., (© 2023 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Purpose: To investigate incidence of end-stage renal disease (ESRD), and the association of education and coronary heart disease (CHD) with ESRD, in subjects throughout Norway followed from the diagnosis of childhood-onset type 1 diabetes., Methods: All new onset cases of type 1 diabetes 1973-2016 were followed for CHD and ESRD in nation-wide registries through 2017. Ten matched controls per case were selected from the National Population Register. Cox regression was used to estimate hazard ratios, and probabilities were estimated by the cumulative incidence function accounting for competing risk., Results: Among 9311 patients with type 1 diabetes, 130 developed ESRD with a probability of ESRD after 40 years of 5.5%. The rate was 35-fold higher than in controls (aHR = 35.5, 95% CI 23.1 - 54.6). Higher education was associated with lower risk of ESRD compared to low education (aHR = 0.14, 95% CI 0.07 - 0.27). Diagnosed CHD was associated with 14-fold increased rate of ESRD (aHR = 14.3, 95% CI 9.2 - 22.2)., Conclusions: The hazard rate of ESRD was 35-fold higher in cases compared to controls. CHD was associated with a 14-fold increased rate of subsequent ESRD, while higher education was associated with substantially lower rate of ESRD., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: LCS received funding from the European Union's Horizon 2020 research and innovation programme (grant number 864764 HEDIMED) and was supported by the Norwegian Institute of Public Health. We declare no competing interests.

Maternal antibiotic use during pregnancy has been linked to asthma risk in children, but the role of underlying infections remains unclear. We investigated the association of maternal antibiotic use and infections during pregnancy with offspring risk of asthma. We used two population-based cohorts: the Norwegian Mother, Father and Child Cohort Study (MoBa) (n = 53 417) and a register-based cohort (n = 417 548). Asthma was defined based on dispensed asthma medications at 7 and 13 years from the Norwegian Prescription Database. Self-reported information on antibiotic use and infections during pregnancy was available in MoBa, while registrations of dispensed prescriptions were used to classify use of antibiotics in the register-based cohort. Maternal antibiotic use during pregnancy was associated with asthma at 7 in both cohorts (adjusted risk ratio (aRR) 1.23, 95% CI 1.11-1.37 in MoBa and 1.21, 1.16-1.25 in the register cohort) and asthma at 13 in the register cohort (1.13, 1.03-1.23) after adjusting for maternal characteristics. In MoBa, the estimate was attenuated after adjusting for infections during pregnancy. Maternal lower and upper respiratory tract infections (aRR 1.30, 95% CI 1.07-1.57 and 1.19, 1.09-1.30, respectively) and urinary tract infections (1.26, 1.11-1.42) showed associations with asthma at 7. Register cohort also showed an increased risk of asthma in relation to maternal antibiotics before and after pregnancy. Our findings suggest that both maternal antibiotics and infections during pregnancy have a role in the risk of offspring asthma. However, results from the register cohort suggest that the effect of antibiotics may reflect the shared underlying susceptibility., (© 2022. The Author(s).)

Background: Maternal diabetes is a well-known risk factor for pregnancy complications. Possible links between long-term maternal blood sugar in the normal range and pregnancy complications are less well described., Methods: We assayed glycated haemoglobin (HbA1c) in blood samples collected around the 18th week of pregnancy for 2937 singleton pregnancies in the Norwegian Mother, Father and Child Cohort Study (2000-09). Perinatal outcomes (gestational length, birthweight, birth length and head circumference, large-for-gestational age, small-for-gestational age, congenital malformations, preterm delivery and preeclampsia) were obtained from medical records. We tested associations using linear and log-binomial regression, adjusting for maternal age, body mass index (BMI) and smoking., Results: Size at birth increased modestly but linearly with HbA1c. Birthweight rose 0.10 standard deviations [95% confidence interval (CI): 0.03, 0.16], for each 5-mmol/mol unit increase in HbA1c, corresponding to about 40 g at 40 weeks of gestation. Large-for-gestational age rose 23% (95% CI: 1%, 50%) per five-unit increase. Other pregnancy complications increased in non-linear fashion, with strongest associations within the top quartile of HbA1c (>35 mmol/mol or >5.4%). Per unit HbA1c within the top quartile, preterm delivery increased by 14% (95% CI: 1%, 31%), preeclampsia increased by 20% (95% CI: 5%, 37%) and gestational duration decreased by 0.7 days (95% CI: -1.0, -0.3)., Conclusions: Among women with no recorded diabetes, higher HbA1c levels at 18 gestational weeks were associated with important perinatal outcomes independent of mother's age, smoking or BMI., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Aims: We investigated the current extent of undiagnosed diabetes and prediabetes and their associated cardiovascular risk profile in a population-based study., Methods: All residents aged ≥20 years in the Nord-Trøndelag region, Norway, were invited to the HUNT4 Survey in 2017-2019, and 54% attended. Diagnosed diabetes was self-reported, and in those reporting no diabetes HbA1c was used to classify undiagnosed diabetes (≥48 mmol/mol [6.5%]) and prediabetes (39-47 mmol/mol [5.7%-6.4%]). We estimated the age- and sex-standardized prevalence of these conditions and their age- and sex-adjusted associations with other cardiovascular risk factors., Results: Among 52,856 participants, the prevalence of diabetes was 6.0% (95% CI 5.8, 6.2), of which 11.1% were previously undiagnosed (95% CI 10.1, 12.2). The prevalence of prediabetes was 6.4% (95% CI 6.2, 6.6). Among participants with undiagnosed diabetes, 58% had HbA1c of 48-53 mmol/mol (6.5%-7.0%), and only 14% (i.e., 0.1% of the total study population) had HbA1c >64 mmol/mol (8.0%). Compared with normoglycaemic participants, those with undiagnosed diabetes or prediabetes had higher body mass index, waist circumference, systolic blood pressure, triglycerides and C-reactive protein but lower low-density lipoprotein cholesterol (all p < 0.001). Participants with undiagnosed diabetes had less favourable values for every measured risk factor compared with those with diagnosed diabetes., Conclusions: The low prevalence of undiagnosed diabetes suggests that the current case-finding-based diagnostic practice is well-functioning. Few participants with undiagnosed diabetes had very high HbA1c levels indicating severe hyperglycaemia. Nonetheless, participants with undiagnosed diabetes had a poorer cardiovascular risk profile compared with participants with known or no diabetes., (© 2022 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Background: We aimed to study the cumulative incidence and risk factors (sex, age, calendar year of diabetes onset, country of origin and educational level) of acute myocardial infarction (AMI) in subjects with type 1 diabetes and matched controls., Methods: A nationwide cohort of subjects with type 1 diabetes diagnosed at age < 15 years in Norway during 1973-2000 was followed until the first AMI event, emigration, death or 31st of December 2017. The Norwegian Childhood Diabetes Registry was linked to five nationwide registries, and up to ten sex- and age-matched controls per case were included., Results: Among 7086 subjects with type 1 diabetes, 170 (2.4%) were identified with incident AMI, compared to 193 (0.3%) of 69,356 controls. Mean age and diabetes duration at first AMI was 40.8 years and 30.6 years, respectively. The probability of AMI after 40 years of follow-up was 8.0% in subjects with type 1 diabetes and 1.1% in controls, aHR 9.05 (95% CI 7.18-11.41). In type 1 diabetes, male sex (aHR 1.45), higher age at onset of diabetes and lower education (higher compared to lower, aHR 0.38) were significantly associated with higher risk of AMI. There was no significant time trend in AMI by calendar year of diabetes onset., Conclusions: We found nine-fold excess risk of AMI in subjects with type 1 diabetes, and three-fold higher risk in subjects with low versus high education. These results highlight a strengthened focus on prevention of cardiovascular disease, and diabetes education tailored to the subjects' educational background., (© 2022. The Author(s).)

Introduction: We aimed to investigate whether the proportion of undiagnosed diabetes varies by socioeconomic status and healthcare consumption, in a Norwegian population screened with glycated hemoglobin (HbA 1c )., Research Design and Methods: In this cohort study, we studied age-standardized diabetes prevalence using data from men and women aged 40-89 years participating in four surveys of the Tromsø Study with available data on HbA 1c and self-reported diabetes: 1994-1995 (n=6720), 2001 (n=5831), 2007-2008 (n=11 987), and 2015-2016 (n=20 170). We defined undiagnosed diabetes as HbA 1c ≥6.5% (48 mmol/mol) and no self-reported diabetes. We studied the association of education, income and contact with a general practitioner on undiagnosed diabetes and estimated adjusted prevalence ratio (aPR) from multivariable adjusted (age, sex, body mass index) log-binomial regression., Results: Higher education was associated with lower prevalence of diagnosed and undiagnosed diabetes. Those with secondary and tertiary education had lower prevalence of undiagnosed diabetes (aPR for tertiary vs primary: 0.54, 95% CI: 0.44 to 0.66). Undiagnosed as a proportion of all diabetes was also significantly lower in those with tertiary education (aPR:0.78, 95% CI: 0.65 to 0.93). Household income was also negatively associated with prevalence of undiagnosed diabetes. Across the surveys, approximately 80% of those with undiagnosed diabetes had been in contact with a general practitioner the last year, similar to those without diabetes., Conclusions: Undiagnosed diabetes was lower among participants with higher education. The hypothesis that those with undiagnosed diabetes had been less in contact with a general practitioner was not supported., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aim: Genetic markers are established as predictive of type 1 diabetes, but unknown early life environment is believed to be involved. Umbilical cord blood may reflect perinatal metabolism and exposures. We studied whether selected polar metabolites in cord blood contribute to prediction of type 1 diabetes., Methods: Using a targeted UHPLC-QQQ-MS platform, we quantified 27 low-molecular-weight metabolites (including amino acids, small organic acids, and bile acids) in 166 children, who later developed type 1 diabetes, and 177 random control children in the Norwegian Mother, Father, and Child cohort. We analyzed the data using logistic regression (estimating odds ratios per SD [adjusted odds ratio (aOR)]), area under the receiver operating characteristic curve (AUC), and k-means clustering. Metabolites were compared to a genetic risk score based on 51 established non-HLA single-nucleotide polymorphisms, and a 4-category HLA risk group., Results: The strongest associations for metabolites were aminoadipic acid (aOR = 1.23; 95% CI, 0.97-1.55), indoxyl sulfate (aOR = 1.15; 95% CI, 0.87-1.51), and tryptophan (aOR = 0.84; 95% CI, 0.65-1.10), with other aORs close to 1.0, and none significantly associated with type 1 diabetes. K-means clustering identified 6 clusters, none of which were associated with type 1 diabetes. Cross-validated AUC showed no predictive value of metabolites (AUC 0.49), whereas the non-HLA genetic risk score AUC was 0.56 and the HLA risk group AUC was 0.78., Conclusions: In this large study, we found no support of a predictive role of cord blood concentrations of selected bile acids and other small polar metabolites in the development of type 1 diabetes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Introduction: To test whether parechovirus and anellovirus, frequent enteric viruses, were associated with subsequent celiac disease (CD). We hypothesized that children who later developed CD would have increased frequency of parechovirus infections before transglutaminase 2 (TG2) antibody development. Anellovirus testing was exploratory, as a potential marker of immune status., Methods: Matched case-control design nested within a longitudinal birth cohort (the MIDIA study) of children at genetic risk of CD (carrying the human leukocyte antigen genotype DR4-DQ8/DR3-DQ2, recruited throughout Norway during 2001-2007). We retrospectively tested blood samples taken at age 3, 6, 9, and 12 months, and then annually, to determine when TG2 antibodies developed. Of 220 genetically at-risk children tested, 25 were diagnosed with CD (cases; ESPGHAN 2012 criteria) and matched for follow-up time, birthdate, and county of residence with 2 randomly selected children free from CD (controls) from the cohort. Viruses were quantified in monthly stool samples (collected from 3 through 35 months of age) using real-time polymerase chain reaction methods., Results: Parechovirus was detected in 222 of 2,005 stool samples (11.1%) and was more frequent in samples from cases before developing TG2 antibodies (adjusted odds ratio 1.67, 95% confidence interval 1.14-2.45, P = 0.01). The odds ratio was higher when a sample was positive for both parechovirus and enterovirus (adjusted odds ratio 4.73, 95% confidence interval 1.26-17.67, P = 0.02). Anellovirus was detected in 1,540 of 1,829 samples (84.2%), but did not differ significantly between case and control subjects., Discussion: Early-life parechovirus infections were associated with development of CD in genetically at-risk children.

Objective: To study whether serum galectin-3 and other biomarkers of inflammation predict coronary heart disease (CHD) in subjects with long-standing childhood-onset type 1 diabetes., Research Design and Methods: A population-based nationwide cohort of 299 subjects with type 1 diabetes diagnosed in Norway at <15 years of age during 1973-1982 was examined in 2002-2003 at a mean age of 33 years (range 21-44), with mean diabetes duration of 24 years (range 19-30). Subjects were followed through 31 December 2017 for their first CHD event registered by a hospitalization or cause of death using nationwide registries. Stored serum samples were available for 296 subjects and analyzed for interleukin-6 (IL-6), IL-6 receptor, IL-18, hs-CRP, matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), galectin-3, and high-sensitivity troponin T. Adjusted hazard ratios (aHRs) for CHD per SD increase in biomarker were estimated using Cox regression., Results: Of 295 subjects, 40 (13.6%) had a documented CHD event during a mean follow-up of 14.4 years (range 0.5-16). IL-6 (aHR 1.32 [95% CI 1.07-1.63]), galectin-3 (aHR 1.44 [95% CI 1.09-1.80]), and TIMP-1 (aHR 1.37 [95% CI 1.04-1.81]) were significant predictors of CHD after adjustment for conventional risk factors., Conclusions: Galectin-3 was significantly associated with future CHD in subjects with type 1 diabetes, and if the results are replicated in larger studies, it may aid in prediction together with conventional risk factors for CHD., (© 2021 by the American Diabetes Association.)

Background: Coeliac disease is an immune-mediated intestinal disease characterised by lifelong intolerance to dietary gluten in genetically predisposed individuals. Microbial factors including infections or bacterial microbiota have long been suspected to be involved in the aetiology, but the scientific literature on the topic is scattered and heterogeneous., Aims: To review human observational studies on microbes and coeliac disease METHODS: We identified 135 publications judged relevant. Most studies were cross-sectional, and prone to reverse causation and other biases. Only a few were prospective. Cohort studies and longitudinal studies that have sampled biological specimens before disease onset are emphasised in the review., Results: Infections during early childhood were associated with an increased risk of subsequent coeliac disease in nine studies , whereas maternal infections during pregnancy did not show a clear association. For the most frequently studied microbial factors, some evidence for an association was found, including Helicobacter pylori (four out of 16 studies), adenovirus (two out of nine studies) and enterovirus (two out of six studies). Rotavirus infections have been associated with disease development, and rotavirus vaccination may reduce the risk. Among the many studies of gut microbiota, most were cross-sectional and, therefore, potentially influenced by reverse causation. Only two smaller prospective case-control studies with sampling before disease onset were identified; they reported inconsistent findings regarding the faecal microbiome., Conclusions: Several microbes are potentially linked to coeliac disease. As microbial factors are amenable to interventions, larger prospective studies are still warranted., (© 2020 John Wiley & Sons Ltd.)

Objectives: To determine the association between childhood growth prior to the development of celiac disease (CD) and CD autoimmunity (CDA) identified by periodic serological screening., Study Design: The Diabetes Autoimmunity Study in the Young cohort includes 1979 genetically at-risk children from Denver, Colorado, with annual growth measurements from age nine months until ten years. Between 1993 and February 2019, 120 children developed CDA defined by persistent positive tissue transglutaminase autoantibodies (TGA); among these, 71 met our criteria for CD based on histopathological findings or high TGA levels. Age- and sex-specific z -scores of weight, body mass index (BMI), and height prior to seroconversion were derived using US reference charts as standards. Joint modeling of serial growth measurements was used to estimate adjusted hazard ratios (aHRs) accounting for celiac-associated human leukocyte antigens, early-life feeding practices, and socio-demographics., Results: In the first 10 years of life, there were no significant associations between the child's current weight, BMI and height and the risk of screening-detected CDA or CD, neither was the weight nor BMI velocity associated with CDA or CD as identified by screening (all aHRs approximated 1). Increased height velocity was associated with later CD, but not CDA, development (aHR per 0.01- z score/year, 1.28; 95% confidence interval [CI] 1.18-1.38 and 1.03; 0.97-1.09, respectively)., Conclusions: In the first 10 years of life, from prospectively collected serial growth measurements, we found no evidence of impaired childhood growth before CD and CDA development as identified through early and periodic screening.

Maternal diet can influence the developing immune system of the offspring. We hypothesized that maternal fibre and gluten intake during pregnancy were associated with the risk of celiac disease in the child. In the Norwegian Mother, Father and Child Cohort Study (MoBa, n = 85,898) higher maternal fibre intake (median 29.5 g/day) was associated with a lower risk of celiac disease in the offspring (adjusted relative risk 0.90, 95% CI 0.83 to 0.98 per 10 g/d increase). Gluten intake during pregnancy (median 13.0 g/d) was associated with a higher risk of childhood CD (adjusted relative risk = 1.21, 95% CI 1.02 to 1.43 per 10 g/d increase). These results were largely unaffected by adjustment for the child's gluten intake at 18 months. In an independent study of 149 mother/child dyads, maternal fibre intake did not predict concentrations of total or sub-types of short-chain fatty acids in repeated infant stool samples, or fecal microbiome diversity in the mother or child. Our results suggest that high fibre and low gluten intake during pregnancy could be protective factors for celiac disease, although the mechanism is unknown.

Objectives: During pregnancy, small quantities of maternal cells are naturally transmitted to the fetus. This transmission, termed maternal microchimerism (MMc), has been implicated in autoimmune diseases but its potential role is unclear. We aimed to investigate if MMc at birth predicted childhood celiac disease (CD) risk, a common immune-mediated enteropathy often presenting in childhood., Methods: We designed a case-control study, nested in the Norwegian Mother, Father and Child Cohort. Participants were HLA class II typed to determine noninherited, nonshared maternal alleles (NIMA). Droplet digital (dd) PCR assays specific for common HLA class II NIMAs (HLA-DQB103:01, 04:02 and 06:02/03) were used to estimate the quantity of maternal DNA, as a marker of maternal cells, in cord blood DNA from 124 children who later developed clinically diagnosed CD (median age at end of study 7.4 years, range 3.6-12.9) and 124 random controls. We tested whether presence of MMc was associated with CD using logistic regression, and compared ranks between cases and controls., Results: MMc, for example, maternal HLA antigens not inherited by the child, was found in 42% of cases and 43% of controls, and not associated with CD (odds ratio [OR] 0.97, 95% confidence interval [CI] 0.58-1.60). The ranks of MMc quantities in cases and controls were also similar (Mann-Whitney U-test, P = 0.71). The subgroup with HLA-DQB1:03*01 as their NIMA had a potential association with MMc, where levels greater than median was associated with CD (OR 3.78, 95% CI 1.28-11.18)., Conclusion: MMc measured in cord blood was not associated with later risk of CD.

Background: The relationship between maternal gluten intake in pregnancy, offspring intake in childhood, and offspring risk of type 1 diabetes has not been examined jointly in any studies. Our aim was to study the relationship between maternal and child intake of gluten and risk of type 1 diabetes in children., Methods and Findings: We included 86,306 children in an observational nationwide cohort study, the Norwegian Mother and Child Cohort Study (MoBa), with recruitment from 1999 to 2008 and with follow-up time to April 15, 2018. We used registration of type 1 diabetes in the Norwegian childhood diabetes registry as the outcome. We used Cox proportional hazard regression to estimate hazard ratios (HRs) for the mother's intake of gluten up to week 22 of pregnancy and offspring gluten intake when the child was 18 months old. The average time followed was 12.3 years (0.70-16.0). A total of 346 children (0.4%) children were diagnosed with type 1 diabetes, resulting in an incidence rate of 32.6/100,000 person-years. Mean gluten intake per day was 13.6 g for mothers and 8.8 g for children. There was no association between the mother's intake of gluten in pregnancy and offspring type 1 diabetes, with an adjusted HR (aHR) of 1.02 (95% confidence interval [CI] 0.73-1.43, p = 0.91) for each 10-g-per-day increment. There was an association between offspring intake of gluten and a higher risk of type 1 diabetes, with an aHR of 1.46 (95% CI 1.06-2.01, p = 0.02) for each 10-g-per-day increment. Among the limitations are the likely imprecision in estimation of gluten intake and that we only had information regarding gluten intake at 2 time points in early life., Conclusions: Our results show that, while the mother's intake of gluten in pregnancy was not associated with type 1 diabetes, a higher intake of gluten by the child at an early age may give a higher risk of type 1 diabetes., Competing Interests: The authors have declared that no competing interests exist.

Epidemiological data on pediatric type 1 diabetes (T1D), mainly incidence, have become increasingly available since the second half of the 20th century. Comparative incidence data across populations were only obtained since the 1980s. The 2019 IDF Atlas provides T1D incidence, prevalence and mortality estimates for children < 15 years for all 211 countries, but actual data were available for only 94 countries (only 3 low-income). The estimated prevalent cases were 600,900 and incident cases 98,200. Incidence remains highest in Finland (60/100,000/ year), Sardinia and Sweden, followed by Kuwait, some other northern European countries, Saudi Arabia, Algeria, Australia, New Zealand, USA and Canada. The lowest incidence is seen across East and South-East Asia. Globally, the average increase in incidence has been 3-4%/year over past decades, being steeper in low-incidence countries. Although T1D mortality has drastically decreased, there is still a higher risk compared with the non-diabetic population, especially in people with diabetic nephropathy., (Copyright© of YS Medical Media ltd.)