A majority of the children were diagnosed in autumn or winter (n=1353/27.1% and n=1286/25.8 %) vs. in spring or summer (n=1135/22.7% and n=1219/24.4%) (p=0.001). Spring was the season with the lowest number of new cases compared to the other seasons (p=0.006). Analyses by month revealed significant seasonality, with a peak frequency of diagnoses in January followed by August and September, the lowest frequency being observed in May (p<0.001) (Fig. S1). The observed frequency of new diagnosis in the cold season (52.9%) is in line with a report from Sweden (⁓53%) [5] while in general, comparisons with previous studies are challenging because of differences in the research designs and methods. We did not observe any difference in the seasonality of diabetes manifestation between the sexes. There is a male-to-female excess in patients with type 1 diabetes [7], and the reason for pronounced seasonality in males observed in some reports might reflect stronger statistical power.
To exclude potential changes in the environment over the years possibly contaminating the results, we looked for the difference in seasonality between those diagnosed during ≤2009 and >2009 but found no significant differences. The season of birth was not related to the time of disease manifestation.
We further divided the study population into two groups by age at diagnosis (0.5-4 years and 5˗14 years) and observed significant seasonality in the group of older children but not among the younger children (additional information is given in Online Resource Results). A previous report by Weets et al. agree with that finding [6]. Between-group analysis showed a clear difference as the youngest children had a peak of disease presentation in autumn and, surprisingly, a nadir in winter contrary to the older children with peaks both in autumn and in winter (Fig. 1). Furthermore, this observation was significant in boys but not in girls. A link between certain enteroviruses and progression to clinical type 1 diabetes has been implicated (reviewed in [8]). Enteroviruses more often affect younger children, and in Finland, more than 80% of enterovirus infections are diagnosed between August and December [9]. This may explain the peak of type 1 diabetes during autumn and the low frequency of disease presentation in winter among the younger children. Some seasonal cycling exists also in the 25(OH)D concentrations, as in Finnish children, they are observed to be decreased in winter in parallel with the decreased amount of sunlight [10]. Moreover, decreased 25(OH)D concentrations were associated with multipositivity for diabetes-related autoantibodies. Compared to the older children, the vitamin D intake in the younger children might be more closely controlled by the parents and the health care professionals due to more frequent contacts in the child health clinic during early childhood. Our results together with the current observation about the decreasing trend in the incidence rate of the disease only among younger children [11] suggest different environmental factors triggering the disease in children of different age.
All the analyses were then adjusted for age at diagnosis and sex. Contrary to our hypothesis, those diagnosed in spring or summer suffered from ketoacidosis more often than those diagnosed in autumn (Table 1). Furthermore, weight loss at diagnoses was highest in summer. Hanberger et al. reported similar findings of HbA1c as the levels were the highest in late spring and summer when the number of children diagnosed with type 1 diabetes was the lowest [5]. The results might be due to the higher risk for dehydration in the seasons with higher temperature leading to more severe metabolic decompensation, or due to the delay of diagnosis during summer holidays and poorer availability of health services. Interestingly, a few studies have reported a positive correlation between high-incidence seasons and C-peptide levels at diagnosis, suggesting variation in the secretory capability of remaining beta cells by season [12, 13]. As classical symptoms and weight loss present less often in children with higher C-peptide concentrations at diagnosis [13], possibly this could explain our observation of better clinical condition in autumn/winter. Unfortunately, we were unable to test this hypothesis as the FPDR does not provide information on the C-peptide concentrations at diagnosis. Nevertheless, the above-mentioned observations might let us to expect that there should be milder signs of autoimmunity during the high-incidence seasons reflecting heterogeneity on the pathogenic process according to the season of diagnosis.
However, we failed to show seasonality in the number of positive autoantibodies at diagnosis and the only notable relationship between season of disease presentation and autoantibodies was higher ICA titers observed in autumn (Table S2). In a small Slovakian study, IA-2A positivity at diagnosis showed seasonal cycling with a peak in autumn [14]. Similar seasonality has not been observed in IAA [14] or GADA at diagnosis [14, 15]. In a Belgian cohort, seasonality in the diagnosis of type 1 diabetes was restricted to HLA DR3/DR4-negative males [6]. However, we did not find any differences in the HLA genetics between the seasons (Table S3).
A strength of this cross-sectional observational study is the large sample derived from the nationwide register including more than 90% of all children diagnosed with diabetes. The retrospective nature of this study is a limitation. There is a possibility of selection bias as 1747 children were excluded because of the lack of samples for analyses [7]. However, the frequencies of seasons of disease presentation did not differ between the included and the excluded children.
In conclusion, our results from the country with the highest incidence of type 1 diabetes confirmed the seasonality of type 1 diabetes manifestation with peaks in autumn and winter. Seasonality of disease presentation was similar in both sexes. Younger children were most seldom diagnosed in winter whereas the peak of the diagnoses continued from autumn to winter in older children, suggesting heterogeneity in environmental factors contributing to the development of type 1 diabetes in children of different ages. Signs of a poorer metabolic status was observed during the seasons with fewer diagnoses, in spring and summer. However, based on the results from this and previous studies, no clear link can be discerned between seasonality, metabolic decompensation and beta cell autoimmunity at diagnosis.