Scope of epidemiology and daily practice in children with type 1 diabetes in the Netherlands
Hummelink, Engelina
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CHAPTEr 3
seasonality of diagnosis of type 1 diabetes
mellitus in the Netherlands (young dudes-2)
E.A.J.M. Spaans, P.R. van Dijk, K.H. Groenier, P.L.P. Brand, H.M. Reeser, H.J.G. Bilo, N. Kleefstra
AbStrAct
Background: The aim of this study was to investigate seasonality in the initial presentation
of type 1 diabetes mellitus (T1DM) among Dutch children.
Methods: Observational, nationwide study in the Netherlands. Using the national registry
for both healthcare reimbursement and pharmaceutical care, data of all Dutch children (aged 0-14 years) with a diagnosis of T1DM in the period 2009-2011 were obtained. results: During the study period (2009-2011) an average annual number of 2.909.537 chil-dren aged 0-14 lived in the Netherlands and 676 children were diagnosed with T1DM per year, translating into an annual incidence rate (IR) of T1DM of 23.2 per thousand children (ptc). The annual IR differed significantly (p=0.03) between seasons: 6.4 ptc in winter, 4.9 ptc in spring, 5.4 ptc in summer and 6.6 ptc in autumn. This pattern was present within both boys and girls. Conclusions: Among Dutch children aged 0-14 years, there is seasonality in the of T1DM with a peak incidence in autumn and winter.
iNTroduCTioN Type 1 diabetes mellitus (T1DM) results from an autoimmune response, directed against the beta cells of the pancreas. Besides genetic susceptibility, lifestyle and environmental factors that are largely unknown play a role in the pathogenesis of T1DM (1,2). A potential role of retrovirus and enterovirus infections has been proposed (3–5), as well as certain food products, pollutants, and vitamin D exposure (1). Studies examining the incidence of T1DM in relation to season of birth and season of disease onset may help to support associations with such environmental factors. If birth season is associated with T1DM incidence, this could imply that prenatal environmental etiologic factors affect the child in utero, whilst an association with season of onset would point towards seasonal environmental factors triggering the immune response leading to T1DM (6–9).
Most studies reported seasonality (7,10–14) with different patterns between different age groups (15–18), whereas only one study did not find seasonality (19). Recently, the Eurodiab study described seasonality with peak incidence in the winter in 21 of the 23 European countries included (20). As the Netherlands has not been participating in this register since 1999, seasonality patterns in diagnosis of T1DM in the Netherlands are unknown.
The aim of the present study was to investigate nationwide the seasonality in the initial presentation of T1DM among children aged 0-14 years. Furthermore, potential patterns in both sex and age subgroups were examined.
MATEriAl ANd METHods study design and aims
This retrospective cohort study covering a 3-year period (2009-2011) is part of the Young DUDEs initiative (DUtch Diabetes Estimates), a project aimed at investigating the magnitude and impact of diabetes mellitus and its complications among children and adolescents in the Netherlands. A detailed description has been published previously (21). We investigated the incidence of T1DM by season among children, aged 0-14 years, during the period 2009-2011 in the Netherlands. data collection
In the Netherlands, all children with T1DM are treated by hospital-based paediatricians. Over the time period 2009-2011, reimbursement of hospital care was handled nation-wide through the registration as Diagnosis Treatment Combination (Diagnose-Behandel Combinatie (DBC) in Dutch); physicians are required to record the appropriate codes in a computer system. Each DBC code contains information about the specialty of the attending
physician, the patient’s diagnosis and the type of care provided. All DBC codes are stored in a national database, managed by Vektis (Vektis, Zeist, the Netherlands). Vektis also man-ages other databases such as the Basic Health Insurance Information System, containing demographic information (like date of birth and sex) for all children registered as inhabitants in the Netherlands, and information on drug prescription. The coverage of this system is 98% (22). Claims records for pharmaceutical care with a coverage of 99%, were derived from the Pharmacy Information System, containing information on the date the drug was supplied, who prescribed the drug, the specific drug that was supplied (including Anatomical Thera-peutic Chemical (ATC) code), and the quantity supplied. Since all health care system records, including the Pharmacy Information System, use the same unique identifying number for each patient (the “Citizen Service Number”), it is possible to link all claims for any individual together and thereby track each individual through all domains of health care and over time. To investigate the seasonality the data were provided per year, per month and per sex. Before starting addressing the research questions, all claims and personal data were stripped from identifying characteristics to ensure anonymity: the Citizen Service Number was encrypted, date of birth converted into the person’s age, and the postal code recoded to limit its identifying properties to neighborhood level. Patients Children aged 14 years or younger on the first of July were selected for every single year of the study period (2009-2011). In this group, individuals with at least one DBC claim for diabetes (paediatrics code [0316] and diabetes diagnosis code [7104], or internal medicine code [0313] and diabetes diagnosis code [221, 222 or 223]) were included. Patients were only classified as T1DM if pharmaceutical claims showed prescription and pick-up of insulin (at least twice over a 4 year period 2008-2011). Patients with a diagnosis code of diabetes for whom no records of diabetes medication were found or only records of medication except insulin were excluded from further analysis in this study. The seasons were defined as fol-lows: winter - included the months December, January and February; spring - the months March, April and May; summer - the months June, July and August; autumn - the months September, October, November. Diagnosis of T1DM was defined as the month and year of the first DBC that was recorded for each patient. statistical analysis To examine whether T1DM diagnosis seasonality differed between age groups, we classified children into the age categories of 0-4 years, 5-9, and 10-14 years, and compared these to population statistics obtained from the national Central Bureau of Statistics which registers nationwide demographical data (23). The incidence of T1DM was assessed in each age cat-egory, both for all children and for boys and girls separately. We used the chi squared test to analyse seasonality in the diagnosis of diabetes. Statistical analyses were carried out using
SPSS (IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp.). As retrospec-tive studies using anonymized data are exempt from ethical review under Dutch law, medical ethics approval was not required for this study. rEsulTs Patients From 2009 to 2011 an average annual number of 2,909,537 children, 1,488,482 (51%) boys and 1,421,055 (49%) girls, were included. Of these children, 924,044 (32%) were aged 0-4 years, 993,356 (34%) were aged 5-9 years and 992,138 (34%) were aged 10-14 years. Among these patients, the average number of new cases of T1DM was 676 per year. This translated into an annual incidence rate (IR) of T1DM during the study period of 23.2 per thousand children (ptc).
Primary outcome - seasonality in the initial presentation of T1dM
The incidence of T1DM among children aged 0-14 years per season is presented in Table 1. Within each separate year of the study period, a lower IR was observed in the summer and spring while a higher IR was observed in the winter and autumn. On average, the annual IR was 6.4 ptc in winter, 4.9 in spring, 5.4 in summer, and 6.6 in autumn, indicating seasonality (p= 0.03). Table 1. Incidence rates of T1DM among children 0-14 years during the study period in the different seasons. 2009 2010 2011 Average T1DM
incidenceTotal populationIR(ptc) T1DM incidenceTotal populationIR(ptc) T1DM incidenceTotal populationIR(ptc) T1DM incidenceTotal populationIR(ptc)
winter 195 2,919,398 6.7 162 2,910,257 5.6 199 2,903,990 6.9 183 2,911,215 6.4 Spring 161 2,919,507 5.5 122 2,909,470 4.2 143 2,904,787 4.9 142 2,911,254 4.9 summer 144 2,915,342 4.9 145 2,907,100 5.0 186 2,902,524 6.4 158 2,908,322 5.4 Autumn 184 2,914,617 6.3 196 2,906,672 6.7 192 2,900,760 6.6 191 2,907,350 6.6 Total 684 2,917,216 28.5 625 2,908,375 21.5 720 2,903,015 24.8 676 2,909,535 23.2 Abbreviations: IR, incidence rate; ptc, per hundred thousand children; T1DM, type 1 diabetes mellitus.
secondary outcome - seasonality among boys and girls
The IR of T1DM per season among children aged 0-14 years, for boys and girls separately, is presented in Table 2. The average annual IR of T1DM during the study period was 23.3 ptc for boys and 23.2 ptc for girls. Although the same pattern in seasonality was apparent in both boys and girls as in the total group, with lowest IR in summer and spring and highest IR in winter and autumn, the IR between seasons were neither significant amongst boys (p=0.16) nor amongst girls (p=0.24).
Table 2. Incidence of DM. separated for boys and girls 0-14 years during the study period in the different seasons.
2009 2010 2011 Average
T1DM
incidenceTotal population IR T1DM incidenceTotal population IR T1DM incidenceTotal population IR T1DM incidenceTotal population IR
Boys winter 99 1,493,748 6.6 78 1,488,867 5.2 107 1,485,492 7.2 95 1,489,369 6.4 Spring 79 1,493,843 5.3 65 1,488,577 4.4 71 1,485,908 4.8 72 1,489,443 4.8 summer 75 1,491,568 5.0 75 1,487,279 5.0 95 1,484,670 6.4 82 1,487,839 5.5 Autumn 103 1,491,156 6.9 103 1,486,967 6.9 89 1,483,712 6.0 98 1,487,278 6.6 Total 356 1,492,579 23.9 321 1,487,923 21.6 362 1,484,946 24.4 347 1,488,482 23.3 girls winter 96 1,425,650 6.7 84 1,421,390 5.9 92 1,418,498 6.5 91 1,421,846 6.4 Spring 82 1,425,664 5.8 57 1,420,892 4.0 72 1,418,879 5.1 70 1,421,812 4.9 summer 69 1,423,774 4.8 70 1,419,821 4.9 91 1,417,854 6.4 77 1,420,483 5.4 Autumn 81 1,423,461 5.7 93 1,419,733 6.6 103 1,417,048 7.3 92 1,420,081 6.5 Total 328 1,424,637 23.0 304 1,420,459 21.4 358 1,418,070 25.2 330 1,421,055 23.2 Abbreviations: IR, incidence rate; ptc, per hundred thousand children; T1DM, type 1 diabetes mellitus.
secondary outcome - seasonality among different age categories
The IR among children 0-4 years was 2.8 ptc in the winter, 2.4 ptc in the spring, 3.1 ptc in the summer and 4.1 ptc in the autumn (p= 0.20) while among children aged 5-9/10-14 years the IRs were 6.9/9.1 pct in the winter, 7.2/8.2 pct in the autumn, 5.0/7.1 pct in the spring and 5.8/7.3 in the summer (p= 0.17/0.33). Further details with regard to the IR of T1DM per season among the different age categories is presented in Appendix 1, also separately for boys (Appendix 2) and girls (Appendix 3). No significant differences between seasons within the different age categories were found. disCussioN This study shows seasonality of T1DM diagnosis among Dutch children aged 14 years and younger with peak incidences in autumn and winter. This finding is in accordance with most previous studies on the seasonality of the diagnosis of T1DM (7,12,14,15,19,20). Although an initial study from 2001 found no relationship between the incidence of T1DM diagnosis and the season among several countries in Europe, a recent study within Europe based on accumulated data from 23 European registries over a 20-year observation period reported seasonal variation in T1DM diagnosis with highest IR in November to February among all patients and in both sexes in most countries (20). The largest study at present, a world-wide survey from 53 countries among children aged 0-14 years, also found seasonal variance with winter peaks and summer troughs in the ma-jority of the countries. Interestingly, this study reported a relation between the geographical
position and the presence of seasonal variation, with a more pronounced seasonality effect in countries further from the equator: highest IR on the Northern hemisphere were observed in October to January (lowest June to August) while on the Southern hemisphere highest IR were present from July to September (lowest January to March) (12). The exact seasonal variation in diagnosis of T1DM seems to change on a year to year basis, with a high IR in the winter but in different months (10,13). The amplitude of seasonal variation appears to be smallest in girls and in children younger than 5 years of age. Our results add to these observations by describing seasonality of diagnosis T1DM with the presence of a winter peak. Furthermore, although not statistically significant, there was a trend towards a difference between children aged 0-4 years, with a higher IR in the summer and spring, and the older age groups, with a lower IR seen in the winter and autumn. A previous study in Greece found higher IR in the summer among children aged 3 years and younger (19). In a study in Germany in children under five the higher IR was in the summer and fall whilst the lowest IR was found in the spring (24). Various reasons have been suggested for the apparent seasonality of T1DM onset in chil-dren including the aforementioned geographical position and (subsequent) climatological factors which (might) influence the amount of exposure to sunshine and vitamin D status. Furthermore, temperature, exposure to antigens, (enterovirus or Coxsackie virus) infections, pollution, hormones, physical activity and nutrition have been proposed (11,12,16,25–27). However, causality between these (related) factors and seasonality of T1DM diagnosis has not been proven and results are conflicting (20,28–31). Although speculative we could hypothesize that the higher IR in the summer in the children aged 0-4 years could be caused by differences in pathogenic mechanisms and differences in exposure in different ages might lead to differences in time from exposure to the potential trigger to the moment of overt diabetes (32) This is a nationwide study to report the presence of seasonality in the diagnosis of T1DM in the Netherlands. Some limitations should be taken into consideration when interpreting the results of our study. First, we used data from two separate independent databases (healthcare insurance and pharmacy). Although a previous study has shown that these databases yield a 98-99% coverage (22), misclassification of type 1 diabetes mellitus, for example through incorrect registration of diagnosis codes, cannot be completely excluded. Possibly, some children with type 2 diabetes mellitus with (short-term) insulin treatment may have been incorrectly classified as T1DM, but this will have occurred rarely below the age of 14 years. Second, the observation period in the present study was relatively short and subgroup analysis was limited by the relative small amount of children. The diagnosis code system we used may not
always be completely up-to-date, in that in some cases the registration of the DBC code may have taken place somewhat later than the month of diagnosis. We found a slightly higher incidence rate in this study compared to our previous study (ICR 23.2 vs. 21.4)(21). Patients moving from one to another hospital can have two ‘first’ DBC registrations within a year, and this may have accounted for the difference in ICR between this and our previous study in which we selected for DBC codes over the entire year. CoNClusioN Among Dutch children, aged 0-14 years, there is seasonality in the diagnosis of T1DM with a peak of incidence in autumn and winter and a significantly lower incidence in the summer and spring. These finding may be of relevance for identifying aetiologic factors for T1DM.
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Appendix 1. Incidence of DM, separated for the age categories 0-4, 5-9 and 10-14 years among children during the
study period in the different seasons
2009 2010 2011 Average
T1DM
incidenceTotal population IR T1DM incidenceTotal population IR T1DM incidenceTotal population IR T1DM incidenceTotal population IR
0-4 years winter 27 929,020 2.9 24 923,927 2.6 26 921,769 2.8 26 924,906 2.8 Spring 21 928,708 2.3 22 923,122 2.4 24 922,357 2.6 22 924,729 2.4 summer 15 927,254 1.6 28 922,080 3.0 43 921,637 4.7 29 923,657 3.1 Autumn 38 925,924 4.1 43 921,812 4.7 32 920,918 3.5 38 922,884 4.1 Total 101 927,726 10.9 117 922,735 12.7 125 921,670 13.6 114 924,044 12.4 5-9 years winter 77 1,008,437 7.6 55 997,388 5.5 75 979,565 7.7 69 995,130 6.9 Spring 62 1,009,981 6.1 40 998,378 4.0 47 981,174 4.8 50 996,511 5.0 summer 60 1,007,292 6.0 49 994,121 4.9 64 976,135 6.6 58 992,516 5.8 Autumn 68 1,005,112 6.8 74 990,355 7.5 72 972,330 7.4 71 989,266 7.2 Total 267 1,007,705 26.5 218 995,061 21.9 258 977,301 26.4 248 993,356 24.9 10-14 years winter 91 981,940 9.3 83 988,941 8.4 98 1,002,656 9.8 91 991,179 9.1 Spring 78 980,818 8.0 60 987,970 6.1 72 1,001,256 7.2 70 990,014 7.1 summer 69 980,796 7.0 68 990,899 6.9 79 1,004,753 7.9 72 992,149 7.3 Autumn 78 983,581 7.9 79 994,533 7.9 88 1,007,513 8.7 82 995,209 8.2 Total 316 981,784 32.2 290 990,586 29.3 337 1,004,044 33.6 314 992,138 31.7 Abbreviations: IR, incidence rate; ptc, per hundred thousand children; T1DM, type 1 diabetes mellitus.
Appendix 2. Incidence of DM, separated for the age categories 0-4, 5-9 and 10-14 years among boys during the study
period in the different seasons
2009 2010 2011 Average
T1DM
incidenceTotal population IR T1DM incidenceTotal population IR T1DM incidenceTotal population IR T1DM incidenceTotal population IR
0-4 years winter 15 475,444 3.2 11 472,790 2.3 12 471,700 2.5 13 473,312 2.7 Spring 10 475,233 2.1 14 472,489 3.0 15 472,050 3.2 13 473,257 2.7 summer 9 474,474 2.9 14 471,893 3.0 17 471,683 3.6 13 472,683 2.8 Autumn 25 473,880 5.3 21 471,607 4.5 18 471,295 3.8 21 472,261 4.5 Total 59 474,758 12.4 60 472,195 12.7 62 471,682 13.1 60 472,878 12.8 5-9 years winter 36 515,724 7.0 24 509,920 4.7 41 501,056 8.2 34 508,900 6.6 Spring 33 516,622 6.4 24 510,555 4.7 23 501,689 4.6 27 509,622 5.2 summer 33 515,150 6.4 25 508,378 4.9 34 499,240 6.8 31 507,589 6.0 Autumn 36 513,871 7.0 34 506,497 6.7 33 497,524 6.6 34 505,964 6.8 Total 138 515,342 26.8 107 508,837 21.0 131 499,877 26.2 125 508,019 24.7 10-14 years winter 48 502,580 9.6 43 506,157 8.5 54 512,736 10.5 48 507,158 9.5 Spring 36 501,989 7.2 27 505,533 5.3 33 512,170 6.4 32 506,564 6.3 summer 33 501,944 6.6 36 507,008 7.1 44 513,747 8.6 38 507,567 7.4 Autumn 42 502,405 8.3 48 508,863 9.4 38 514,892 7.4 43 509,053 8.4 Total 159 502,480 31.6 154 506,891 30.4 169 513,386 32.9 161 507,585 31.7 Abbreviations: IR, incidence rate; ptc, per hundred thousand children; T1DM, type 1 diabetes mellitus.
Appendix 3. Incidence of DM, separated for the age categories 0-4, 5-9 and 10-14 years among girls during the study
period in the different seasons
2009 2010 2011 Average
T1DM
incidenceTotal population IR T1DM incidenceTotal population IR T1DM incidenceTotal population IR T1DM incidenceTotal population IR
0-4 years winter 12 453,576 2.6 13 451,137 2.9 14 450,069 3.1 13 451,594 2.9 Spring 11 453,475 2.4 8 450,633 1.8 9 450,307 2.0 9 451,472 2.1 summer 6 452,780 1.3 14 450,187 3.1 26 449,953 5.8 15 450,974 3.4 Autumn 13 452,044 2.9 22 450,205 4.9 14 449,622 3.1 16 450,624 3.6 Total 42 452,969 9.3 57 450,541 12.7 63 449,988 14.0 54 451,166 12.0 5-9 years winter 41 492,714 8.3 31 487,468 6.4 34 478,509 7.1 35 486,230 7.3 Spring 29 493,359 5.9 16 487,823 3.3 24 479,486 5.0 23 486,889 4.7 summer 27 492,142 5.5 24 485,743 4.9 30 476,895 6.3 27 484,927 5.6 Autumn 32 491,241 6.5 40 483,858 8.3 39 474,805 8.2 37 483,301 7.7 Total 129 492,364 26.2 111 486,223 22.8 127 477,424 26.6 122 485,337 25.2 10-14 years winter 43 479,360 9.0 40 482,784 8.3 44 489,921 9.0 42 484,022 8.7 Spring 42 478,829 8.8 33 482,436 6.8 39 489,086 8.0 38 483,450 7.9 summer 36 479,852 7.5 32 483,890 6.6 35 491,006 7.1 34 482,583 7.1 Autumn 36 480,177 7.5 31 485,670 6.4 50 492,620 10.1 39 486,156 8.0 Total 157 479,305 32.8 136 483,695 28.1 168 490,658 34.2 154 484,553 31.7 Abbreviations: IR, incidence rate; ptc, per thousand children; T1DM, type 1 diabetes mellitus.
