Background Type 1 diabetes (T1D) is an autoimmune disease characterized by progressive loss of the insulin producing pancreatic β-cells. The disease process starts years before the clinical diagnosis. The cause of T1D is unknown, but it is believed to be a combination of genetic and environmental factors. Around 50% of the genetic risk is attributed to the human leucocyte antigen (HLA) genes and the strongest associations are with the HLA-DR3-DQ2 and HLA-DR4-DQ8 haplotypes. The highest risk genotype is the heterozygote form of the two, the HLA-DQ2/8 genotype. It may be that certain environmental factors pose a risk to individuals with a particular genetic susceptibility but not to others. In the last few decades T1D incidence has risen very quickly and due to the rate of the increase, it is believed to depend on environmental factors rather than genetic. In parallel with this increase, the incidence of several environmental factors has also risen i.e., the incidence of cesarean section (CS), overweight/obesity in the general population and birthweight. These environmental factors have been implicated as risk factors for T1D, but studies have had conflicting results.

Objective The overall aim of this thesis was to increase knowledge regarding factors during pregnancy and the perinatal period that could increase or decrease the risk of T1D among children and adolescents. The environmental risk factors studied were mode of childbirth (study I), maternal BMI and gestational weight gain (GWG) (study II) and the child’s size for gestational age and birthweight (study III). In the last study the environmental risk factors were compared between children with different genetic risks of T1D.

Material and methods The studies included in this thesis are population-based register studies, three case-control studies and one cohort study, using prospectively collected material from the Swedish medical birth registry (MBR) and the Swedish pediatric diabetes quality registry (SWEDIABKIDS), as well as information from the Swedish national cohort study Better Diabetes Diagnosis (BDD). The study population consists of children and adolescents (0–18/19 years) diagnosed with T1D Jan 2000-Oct 2012 and registered in SWEDIABKIDS (n=9,376). All children with T1D were matched with four control children from the MBR with the same year and day of birth, same sex, and born in the same region of Sweden (n=37,504). In study I, the entire study population was used but in study III twins were excluded (n=552). In study II, children for whom data on their mother’s BMI in early pregnancy and GWG were available were included (3,231 children with T1D and 12,948 control children). In study IV, children with T1D who also participated in the BDD study were included (4,533 children).

Results and conclusions Maternal overweight and obesity were associated with an increased risk of T1D in the offspring but were not more common among children with high or low genetic risk. Maternal BMI was also inversely associated with the age at onset of T1D in children with HLADQ8/ X and/or HLA-DQ2/X. Neither GWG nor mode of childbirth had any obvious impact on the risk of developing T1D. Being born large for gestational age or with a birthweight ≥4000 g (macrosomia) was associated with an increased risk of T1D and being born small for gestational age or with a low birthweight (<2500 g) was associated with a decreased risk of T1D, irrespective of maternal BMI and diabetes. Comparing children with T1D and different HLA genotypes revealed a slight difference in birthweight between the genotype groups. Children with HLA-DQ2/8 were more often born with macrosomia compared to children with HLA-DQ8/X. Children without either HLA-DQ2 or HLADQ8 (HLA-DQX/X) were more often born with a low birthweight compared to those with HLADQ2/ 8 and HLA-DQ8/X. Size for gestational age did not differ between the genotype groups, and the effect of size for gestational age and birthweight on age at onset of T1D was ambiguous.

The effects of the environmental risk factors identified in this thesis are generally weak and no clear conclusion on whether they are causative can be drawn. Yet since overweight/obesity and a high birthweight are common in the population, even a small increase in risk can result in many cases of T1D. Overweight/obesity and a high birthweight are also associated with other adverse health outcomes and they are, at least partly, modifiable. This motivates additional research regarding their involvement in T1D etiology as well as preventive actions against overweight and obesity in the population.