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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.)

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.)

Background: Infections in early life have been linked to type 1 diabetes (T1D) risk, but no previous study has comprehensively analysed exposure to antibiotics, acetaminophen and infections during pregnancy and early childhood in relation to offspring risk of T1D., Methods: Participants in the Norwegian Mother and Child Cohort Study (n = 114 215 children, of whom 403 children were diagnosed with T1D) reported infections and medication use through repeated questionnaires from pregnancy until the children were 18 months old. Adjusted hazard ratios (aHR) for offspring T1D were estimated through Cox regression adjusted for child's sex, maternal age and parity, maternal T1D, smoking in pregnancy, education level, pre-pregnancy body mass index (BMI) and birthweight. Antibiotic use was also analysed in a population-based register cohort of 541 036 children of whom 836 developed T1D., Results: Hospitalization for gastroenteritis during the first 18 months of life was associated with increased risk (aHR 2.27, 95% CI 1.21 - 4.29, P = 0.01) of T1D. Childhood infections not requiring hospitalization, or any kind of maternal infection during pregnancy, did not predict offspring risk of T1D. Antibiotic or acetaminophen use in pregnancy, or child`s use in early childhood, was not associated with risk of T1D., Conclusions: Our study, which is population-based and the largest of its kind, did not find support for general early life infections, infection frequency or use of antibiotics or acetaminophen to play a major role in childhood T1D. Hospital admission for gastroenteritis was associated with T1D risk, but must be interpreted cautiously due to scarcity of cases.

Studies on vitamin D status during pregnancy and risk of type 1 diabetes mellitus (T1D) lack consistency and are limited by small sample sizes or single measures of 25-hydroxyvitamin D (25(OH)D). We investigated whether average maternal 25(OH)D plasma concentrations during pregnancy are associated with risk of childhood T1D. In a case-cohort design, we identified 459 children with T1D and a random sample (n = 1,561) from the Danish National Birth Cohort (n = 97,127) and Norwegian Mother and Child Cohort Study (n = 113,053). Participants were born between 1996 and 2009. The primary exposure was the estimated average 25(OH)D concentration, based on serial samples from the first trimester until delivery and on umbilical cord plasma. We estimated hazard ratios using weighted Cox regression adjusting for multiple confounders. The adjusted hazard ratio for T1D per 10-nmol/L increase in the estimated average 25(OH)D concentration was 1.00 (95% confidence interval: 0.90, 1.10). Results were consistent in both cohorts, in multiple sensitivity analyses, and when we analyzed mid-pregnancy or cord blood separately. In conclusion, our large study demonstrated that normal variation in maternal or neonatal 25(OH)D is unlikely to have a clinically important effect on risk of childhood T1D.

Background: Our objective was to examine the associations of parental body mass index (BMI) and maternal gestational weight gain with childhood-onset type 1 diabetes. Comparing the associations of maternal and paternal BMI with type 1 diabetes in the offspring will provide further insight into the role of unmeasured confounding by characteristics linked to BMI in both parents., Methods: We studied 132 331 children participating in the Norwegian Mother and Child Cohort Study (MoBa) and the Danish National Birth Cohort (DNBC) who were born between February 1998 and July 2009. Exposures of interest included parental BMI and maternal gestational weight gain obtained by maternal report. We used Cox-proportional hazards regression to examine the risk of type 1 diabetes (n=499 cases), which was ascertained by national childhood diabetes registers., Results: The incidence of type 1 diabetes was 32.7 per 100 000 person-years in MoBa and 28.5 per 100 000 person-years in DNBC. Both maternal pre-pregnancy obesity, adjusted hazard ratio (HR) 1.41 [95% confidence interval (CI): 1.06, 1.89] and paternal obesity, adjusted HR 1.51 (95% CI: 1.11, 2.04), were associated with childhood-onset type 1 diabetes. The associations were similar after mutual adjustment. In contrast, maternal total gestational weight gain was not associated with childhood-onset type 1 diabetes, adjusted HR 1.00 (95% CI: 0.99, 1.02) per kilogram increase., Conclusions: Our study suggests that the association between maternal obesity and childhood-onset type 1 diabetes is not likely explained by intrauterine mechanisms, but possibly rather by unknown environmental factors influencing BMI in the family.

Objective: Several genetic polymorphisms determine vitamin D status. We aimed to estimate the strength of association of established 25-hydroyxvitamin D (25OHD)-associated variants in the mother and in the fetus, with 25OHD concentration in newborn umbilical cord plasma., Methods: We randomly selected 578 mother and child dyads from the prospective Norwegian Mother and Child Cohort study. 25OHD was assayed in maternal samples taken shortly after delivery and in cord samples. We genotyped the mother and child for single nucleotide polymorphisms in or near GC, DHCR7, CYP2R1, and CYP24A1, previously confirmed to be associated with 25OHD, and computed genetic risk score (GRS). The genetic associations were replicated in an independent sample of 594 subjects., Results: Although both fetal and maternal GRS were associated with cord 25OHD, only fetal GRS remained significantly associated with cord 25OHD in a regression model with maternal and fetal GRS simultaneously (1.6 nmol/L per fetal 25OHD-increasing allele; 95% confidence interval, 0.6 to 2.5, P = 0.0001). Two fetal single nucleotide polymorphisms in the GC gene (rs2282679 and rs222040) were the strongest genetic predictors of cord 25OHD [4.0 (2.1 to 5.9) and 3.0 (1.3 to 4.8) nmol/L per fetal allele, P < 0.001], followed by rs12785878 in DHCR7 [2.0 (0.1 to 3.8) nmol/L, P = 0.037]. The independent replication sample gave similar results. With fetal genotype included in a regression model with environmental factors, R2 for cord 25OHD was 0.28., Conclusions: We show that fetal 25OHD-modifying genotype was a stronger predictor of cord 25OHD than corresponding maternal genotype. This raises interesting questions about fetal acquisition and placental transfer of 25OHD., (Copyright © 2017 Endocrine Society)

Context: The effect of vitamin D on muscle strength in adults is not established., Objective: Our objective was to test whether vitamin D supplementation increases muscle strength and power compared with placebo., Design: We conducted a randomized, double-blind, placebo-controlled trial., Setting: The setting was immigrants' activity centers., Participants: Two hundred fifty-one healthy adult males and females aged 18-50 years with non-Western immigrant background performed the baseline test and 86% returned to the follow-up test., Interventions: Sixteen weeks of daily supplementation with 25 μg (1000 IU) vitamin D3, 10 μg (400 IU) vitamin D3, or placebo., Main Outcome Measures: Difference in jump height between pre- and postintervention. Secondary outcomes were differences in handgrip strength and chair-rising test., Results: Percentage change in jump height did not differ between those receiving vitamin D (25 or 10 μg vitamin D3) and those receiving placebo (mean difference -1.4%, 95% confidence interval: -4.9% to 2.2%, P=.44). No significant effect was detected in the subgroup randomized to 25 μg vitamin D or in other preplanned subgroup analyses nor were there any significant differences in handgrip strength or the chair-rising test. Mean serum 25-hydroxyvitamin D3 concentration increased from 27 to 52 nmol/L and from 27 to 43 nmol/L in the 25 and 10 μg supplementation groups, respectively, whereas serum 25-hydroxyvitamin D3 did not change in the placebo group., Conclusions: Daily supplementation with 25 or 10 μg vitamin D3 for 16 weeks did not improve muscle strength or power measured by the jump test, handgrip test, or chair-rising test in this population with low baseline vitamin D status.

The hypothesis that under some circumstances enteroviral infections can lead to type 1 diabetes (T1D) was proposed several decades ago, based initially on evidence from animal studies and sero-epidemiology. Subsequently, enterovirus RNA has been detected more frequently in serum of patients than in control subjects, but such studies are susceptible to selection bias and reverse causality. Here, we review critically recent evidence from human studies, focusing on longitudinal studies with potential to demonstrate temporal association. Among seven longitudinal birth cohort studies, the evidence that enterovirus infections predict islet autoimmunity is quite inconsistent in our interpretation, due partially, perhaps, to heterogeneity in study design and a limited number of subjects studied. An association between enterovirus and rapid progression from autoimmunity to T1D was reported by one longitudinal study, but although consistent with evidence from animal models, this novel observation awaits replication. It is possible that a potential association with initiation and/or progression of islet autoimmunity can be ascribed to a subgroup of the many enterovirus serotypes, but this has still not been investigated properly. There is a need for larger studies with frequent sample intervals and collection of specimens of sufficient quality and quantity for detailed characterization of enterovirus. More research into the molecular epidemiology of enteroviruses and enterovirus immunity in human populations is also warranted. Ultimately, this knowledge may be used to devise strategies to reduce the risk of T1D in humans., (© 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for Immunology.)

Background: The incidence rates of childhood onset type 1 diabetes are almost universally increasing across the globe but the aetiology of the disease remains largely unknown. We investigated whether birth order is associated with the risk of childhood diabetes by performing a pooled analysis of previous studies., Methods: Relevant studies published before January 2010 were identified from MEDLINE, Web of Science and EMBASE. Authors of studies provided individual patient data or conducted pre-specified analyses. Meta-analysis techniques were used to derive combined odds ratios (ORs), before and after adjustment for confounders, and investigate heterogeneity., Results: Data were available for 6 cohort and 25 case-control studies, including 11,955 cases of type 1 diabetes. Overall, there was no evidence of an association prior to adjustment for confounders. After adjustment for maternal age at birth and other confounders, a reduction in the risk of diabetes in second- or later born children became apparent [fully adjusted OR = 0.90 95% confidence interval (CI) 0.83-0.98; P = 0.02] but this association varied markedly between studies (I² = 67%). An a priori subgroup analysis showed that the association was stronger and more consistent in children < 5 years of age (n = 25 studies, maternal age adjusted OR = 0.84 95% CI 0.75, 0.93; I² = 23%)., Conclusion: Although the association varied between studies, there was some evidence of a lower risk of childhood onset type 1 diabetes with increasing birth order, particularly in children aged < 5 years. This finding could reflect increased exposure to infections in early life in later born children.

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., (Copyright 2004 Johns Hopkins Bloomberg School of Public Health)