Caesarean section and risk of type 1 diabetes.

AIMS/HYPOTHESIS: Delivery by Caesarean section continues to rise globally and has been associated with the risk of developing type 1 diabetes and the rate of progression from pre-symptomatic stage 1 or 2 type 1 diabetes to symptomatic stage 3 disease. The aim of this study was to examine the association between Caesarean delivery and progression to stage 3 type 1 diabetes in children with pre-symptomatic early-stage type 1 diabetes. METHODS: Caesarean section was examined in 8135 children from the TEDDY study who had an increased genetic risk for type 1 diabetes and were followed from birth for the development of islet autoantibodies and type 1 diabetes. RESULTS: The likelihood of delivery by Caesarean section was higher in children born to mothers with type 1 diabetes (adjusted OR 4.61, 95% CI 3.60, 5.90, p<0.0001), in non-singleton births (adjusted OR 4.35, 95% CI 3.21, 5.88, p<0.0001), in premature births (adjusted OR 1.91, 95% CI 1.53, 2.39, p<0.0001), in children born in the USA (adjusted OR 2.71, 95% CI 2.43, 3.02, p<0.0001) and in children born to older mothers (age group >28-33 years: adjusted OR 1.19, 95% CI 1.04, 1.35, p=0.01; age group >33 years: adjusted OR 1.80, 95% CI 1.58, 2.06, p<0.0001). Caesarean section was not associated with an increased risk of developing pre-symptomatic early-stage type 1 diabetes (risk by age 10 years 5.7% [95% CI 4.6%, 6.7%] for Caesarean delivery vs 6.6% [95% CI 6.0%, 7.3%] for vaginal delivery, p=0.07). Delivery by Caesarean section was associated with a modestly increased rate of progression to stage 3 type 1 diabetes in children who had developed multiple islet autoantibody-positive pre-symptomatic early-stage type 1 diabetes (adjusted HR 1.36, 95% CI 1.03, 1.79, p=0.02). No interaction was observed between Caesarean section and non-HLA SNPs conferring susceptibility for type 1 diabetes. CONCLUSIONS/INTERPRETATION: Caesarean section increased the rate of progression to stage 3 type 1 diabetes in children with pre-symptomatic early-stage type 1 diabetes. DATA AVAILABILITY: Data from the TEDDY study ( https://doi.org/10.58020/y3jk-x087 ) reported here will be made available for request at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Central Repository (NIDDK-CR) Resources for Research (R4R) ( https://repository.niddk.nih.gov/ ).

The Influence of Pubertal Development on Autoantibody Appearance and Progression to Type 1 Diabetes in the TEDDY Study.

Context: The 2 peaks of type 1 diabetes incidence occur during early childhood and puberty. Objective: We sought to better understand the relationship between puberty, islet autoimmunity, and type 1 diabetes. Methods: The relationships between puberty, islet autoimmunity, and progression to type 1 diabetes were investigated prospectively in children followed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Onset of puberty was determined by subject self-assessment of Tanner stages. Associations between speed of pubertal progression, pubertal growth, weight gain, homeostasis model assessment of insulin resistance (HOMA-IR), islet autoimmunity, and progression to type 1 diabetes were assessed. The influence of individual factors was analyzed using Cox proportional hazard ratios. Results: Out of 5677 children who were still in the study at age 8 years, 95% reported at least 1 Tanner Stage score and were included in the study. Children at puberty (Tanner Stage ≥2) had a lower risk (HR 0.65, 95% CI 0.45-0.93; P = .019) for incident autoimmunity than prepubertal children (Tanner Stage 1). An increase of body mass index Z-score was associated with a higher risk (HR 2.88, 95% CI 1.61-5.15; P < .001) of incident insulin autoantibodies. In children with multiple autoantibodies, neither HOMA-IR nor rate of progression to Tanner Stage 4 were associated with progression to type 1 diabetes. Conclusion: Rapid weight gain during puberty is associated with development of islet autoimmunity. Puberty itself had no significant influence on the appearance of autoantibodies or type 1 diabetes. Further studies are needed to better understand the underlying mechanisms.

Early appearance of thyroid autoimmunity in children followed from birth for type 1 diabetes risk.

PURPOSE: Autoantibodies to thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) define pre-clinical autoimmune thyroid disease (AITD) which can progress to either clinical hypo- or hyperthyroidism. We determined the age at seroconversion in children genetically at risk for type 1 diabetes. METHODS: TPOAb and TgAb seropositivity were determined in 5066 healthy children with HLA DR3 or DR4 containing haplogenotypes from The Environmental Determinants of Diabetes in the Young (TEDDY) Study. Children seropositive on the cross-sectional initial screen at 8-13 years of age had longitudinally collected samples (from 3.5 months of age) screened retrospectively and prospectively for thyroid autoantibodies to identify the age at seroconversion. First-appearing autoantibody was related to sex, HLA genotype, family history of AITD, and subsequent thyroid dysfunction and disease. RESULTS: The youngest appearance of TPOAb and TgAb was 10 and 15 months of age, respectively. Girls had higher incidence rates of both autoantibodies. Family history of AITD was associated with a higher risk of TPOAb hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.17, 3.08; and TgAb HR 2.55, 95% CI 1.91, 3.41. The risk of progressing to hypo- or hyperthyroidism was not different between TgAb and TPOAb, but children with both autoantibodies appearing at the same visit had a higher risk compared to TPOAb appearing first (HR 6.34, 95% CI 2.72, 14.76). MAIN CONCLUSION: Thyroid autoantibodies may appear during the first years of life, especially in girls, and in children with a family history of AITD. Simultaneous appearance of both autoantibodies increases the risk for hypo- or hyperthyroidism.