Scope of epidemiology and daily practice in children with type 1 diabetes in the Netherlands
Hummelink, Engelina
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date: 2019
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Hummelink, E. (2019). Scope of epidemiology and daily practice in children with type 1 diabetes in the Netherlands. Rijksuniversiteit Groningen.
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
in children with type 1 diabetes mellitus
in the Netherlands
Lay-out: Optima Grafische Communicatie (www.ogc.nl) Printed by: Optima Grafische Communicatie (www.ogc.nl)
All rights reserved. No part of this publication may be reported or transmitted in any form or by any means without prior written permission of the author
and daily practice in children with
type 1 diabetes mellitus in the Netherlands
Proefschrift
ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen op gezag van de rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op woensdag 15 mei 2019 om 12.45 uur doorEngelina Anna Johanna Maria Hummelink
geboren op 3 februari 1967 te Huizen
Prof. dr. P.L.P. Brand Copromotor Dr. N. Kleefstra Beoordelingscommissie Prof. dr. T.P. Links Prof. dr. A.A.E. Verhagen Prof. dr. J.M. Wit
Chapter 1 Introduction 7 PArT oNE: EPidEMiology of TyPE 1 diABETEs MElliTus iN CHildrEN
iN THE NETHErlANds Chapter 2 The incidence of type 1 diabetes mellitus is still increasing in the Netherlands, but has stabilised in children under five (Young DUDEs-1) 23 Chapter 3 Seasonality of diagnosis of type 1 diabetes mellitus in the Netherlands (Young Dudes-2) 33 Chapter 4 Thyroid disease and type 1 diabetes mellitus in Dutch children: a nationwide study (Young Dudes-3) 47 Chapter 5 Healthcare reimbursement costs of children with type 1 diabetes in the Netherlands, a nationwide study (Young Dudes-4) 59 PArT Two: AdHErENCE To oPTiMAl sElf-MANAgEMENT of CHildrEN
wiTH TyPE 1 diABETEs MElliTus usiNg AN iNsuliN PuMP Chapter 6 Mealtime insulin bolus adherence and glycaemic control in adolescents on insulin pump therapy 73 Chapter 7 Factors related to optimal insulin pump management in adolescents with type 1 diabetes mellitus 89 Chapter 8 General discussion 103 Chapter 9 Summary 121 Chapter 10 Dutch summary (Nederlandse samenvatting) 127 Dankwoord 137 About the author 143
CHAPTEr 1
wHAT THis THEsis is ABouT Job, a seven year old boy, was referred to the emergency department of our hospital. Since a few days his mother noticed that he had been drinking a lot and had been complaining of being very thirsty. He also had to pee frequently. Job wetted his bed occasionally, but in re-cent weeks his bed was already completely wet when his parents went to sleep. He had not eaten well last week, but he did eat a lot of yoghurt. According to his parents, Job seemed to have lost some weight. The family history did not show any relevant details. The whole family had had gastroenteritis two weeks earlier. On physical examination, we saw a very thin, skinny boy with sunken eyes. No further physical or behavioural abnormalities were noticed. The clinical suspicion of type 1 diabetes mellitus (based on the classical symptoms of polyuria and polydipsia) was supported by laboratory test results which showed a very high blood glucose level (48 mmol/L) without acidosis (blood that is acidified). The HbA1c value (a measure that reflects the blood glucose concentration of the preceding 2-3 months) was clearly elevated (83 mmol/mol). Glucose was also found in large quantities in the urine. A few weeks later, confirmation of the suspicion of autoimmune diabetes came from the results of autoantibody testing, which was positive for antibodies against the Langerhans islets in the pancreas which are responsible for the production of insulin in the human body. The inevitable conclusion of all this information is that Job has newly onset type 1 diabetes mellitus. From now on his life and that of his family will change dramatically, with daily blood glucose measurements, insulin injections, concerns about the glucose values, fear and real threat of hypoglycaemic episodes and the risk of long-term complications including eye and kidney problems. definition: diabetes mellitus (dM), commonly referred to as diabetes, is a group of metabolic disorders characterised by high blood glucose levels over a prolonged period of time. Type 1 diabetes mellitus (T1DM) is the type of diabetes mellitus in which insufficient and eventually no insulin is produced. T1DM is one of the most common chronic diseases in childhood. The incidence differs considerably between countries, with the highest recorded incidence in Finland with 64.2 per 100,000 person-years in 2005 (1). T1DM has a major impact on quality of life and daily functioning for the affected children and their family. The management of this disease poses substantial demands on the children and family, leading to work restrictions, negative financial impact, anxiety and worries (2). History
Between 1914 and 1916, the Romanian physiologist Nicolas Paulescu first extracted a pancreatic antidiabetic agent that he used to treat dogs, but his experiments remained unnoticed to the scientific world. His method to prepare pancreatic extract was similar to
the procedure described in 1919 by the American scientist Israel Kleiner (3). The discovery of insulin in 1921 by Banting and Best was a lifesaver, allowing for the first time a proper treatment for people with T1DM. These Canadian researchers were awarded the Nobel Prize for Medicine and Physiology in 1923 (4). In January 1922, a 14-year old boy named Leonard Thompson received the first injection of isletin, as the pancreas extract containing insulin was initially named. He suffered a severe allergic reaction, which on hindsight was not entirely unexpected due to the rather poor purification of the injected substance. The second injection 12 days later was successful (5). Until that time, T1DM was a fatal disease, which it still is in areas of the world where insulin is unavailable. Prevalence The estimated worldwide prevalence of T1DM in children younger than 15 years of age was almost 500,000 in 2013 (6). The average annual increase of incidence of T1DM worldwide was 2.8% per year during the period 1990-1999, with up to 79,000 new cases worldwide per year in children aged 0-15 years (7). In the USA, the incidence rate increased by 1.4% per annum (19.5 cases per 100,000 youth a year in 2002-2003 to 21.7 cases per 100,000 person-years in 2011-2012) (8,9). As mentioned, the highest recorded incidence rate of T1DM in children was in Finland (64.2 per 100,000 person-years (2005)) (10). By contrast, the incidence in China and Venezuela is only around 0.1 cases of T1DM per 100,000 person-years (7,11). Recent studies showed a stabilization of the incidence rate in Finland in the period 2005-2011 (1); similar trends were found in Norway and Sweden (12). Most well-designed and larger incidence studies are from the USA and Scandinavia. Un-fortunately, reliable information is lacking concerning the prevalence and incidence in many developing countries. The International Diabetes Federation atlas estimates of worldwide prevalence of T1DM in children younger than 15 years of age are presented in Figure 1. Data from the Netherlands were available in three time periods, the most recent being from 1996 to 1999 (6). Table 1: The estimated prevalence in 1978–1980 and 1996-1999 was 70 per 100,000 person-years (13) and 80 per 100,000 person-years, respectively (14). Although all paediatricians caring for children with T1DM in the Netherlands have the clinical experience that the incidence of the disease has continued to increase since 1999, recent incidence and prevalence data on T1DM prevalence in children are unavailable.
figure 1: Type 1 diabetes mellitus in children and adolescents >> number of new cases of type 1 diabetes mellitus per 100.000 children and adolescents (0-14) per year (2017) http://www.diabetesatlas.org/across-the-globe.html Table 1: Incidence (95% CI) of T1DM in the Netherlands 1978–1980 1978–1980 1996–1999 0 – 4 years 6.8 (6.6 – 7.1) 6.4 (6.2– 6.7) 12.9 (12.0 – 13.9) 5 – 9 years 10.9 (10.3 – 11.6) 12.4 (12.0 – 12.7) 19.3 (18.0 – 20.7) 10 – 14 years 14.3 (13.4 – 15.3) 18.1 (17.6 – 18.6) 24.2 (21.9 – 26.6) Total (0 – 14 years) 11.1 (10.5 – 11.7) 12.4 (12.0 – 12.8) No data
12 Pathogenesis of T1dM In the pathogenesis of T1DM, a loss of pancreatic islet β cells leads to a progressive and eventually complete loss of insulin producing capacity in the individual (15). The autoim-mune mechanisms leading to initiation of damage and complete destruction of β cells are only partly understood. The pathogenesis of this disease is complex and influenced by many factors (figure 2). Figuur 2 Figuur 3 figure 2: The natural history of type 1 diabetes – a 25-year-old concept revised A re-creation of the model of type 1 diabetes, originally proposed in 1986, is shown in black. Additions and conjectures based on recent knowledge gains are shown in purple. www.lancet.com Vol 383 January 4, 2014 Most children presenting with T1DM have autoantibodies against pancreatic β cells or autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA), insulinoma-associated autoantigen (IA2A) and zinc transporter 8 (ZnT8A) (16,17). These autoantibodies are often already present years before the clinical onset of T1DM (17). Some genetic factors associated with an increased susceptibility to develop T1DM have been identified. Individuals with haplotypes HLA-DR3-DQ2 or HLA-DR4-DQ8 are more prone to develop β cell autoimmunity (18). What eventually triggers this autoimmunity is only par-tially known; genetic susceptibility is a definite factor, both in itself, but also by influencing the severity of response to environmental triggers (19). At the moment, it is generally accepted that an environmental trigger is needed to activate the autoimmune destruction of pancreatic β cells (21). Several environmental factors have
been proposed in studies, including infections, especially viral infections with e.g. retrovirus and enterovirus (17). 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 fac- tors (20,21). An association with season of onset would point towards seasonal environmen-tal factors triggering the immune response leading to T1DM. The Eurodiab study described seasonality with peak incidence in the winter in 21 of the 23 participating European countries (22). As the Netherlands has not been participating in this register since 1999, seasonality patterns in diagnosis of T1DM in the Netherlands are unknown.
Additional autoimmune diseases in T1dM
Patients having T1DM are more prone to develop other autoimmune diseases, the most com-mon being autoimmune thyroid disease and coeliac disease. Less common are autoimmune gastric disease, Addison’s disease, autoimmune hepatitis, myasthenia gravis, pernicious anaemia, vitiligo, non-organ specific autoimmune disease and multiple autoimmune diseases (such as juvenile idiopathic arthritis, Sjögren syndrome, psoriasis and sarcoidosis) (24).
The prevalence of autoimmune thyroid disease (AITD) in a combined population of children and adults in Europe is estimated to be 3% for hypothyroidism and 0.75% for hy-perthyroidism (23). In children with T1DM, detectable antithyroid antibodies were reported in 15%-19% of patients (25,26). Unfortunately, it is at present unknown what proportion of children with thyroid autoantibodies will develop AITD, with estimates ranging from 3% to 60% (24–26). The prevalence of overt thyroid disease in children in the Netherlands with and without T1DM is unknown. Clinical presentation Although T1DM can have its début in adulthood, the peak incidence age is in childhood and adolescence (27). Classical clinical features include polydipsia, polyuria, weight loss due to hyperglycaemia and sometimes polyphagia and blurred vision (28). Other types of diabetes in children and adolescents include type 2 diabetes mellitus (T2DM), maturity onset diabetes of the young (MODY), Kir 6.2 diabetes, diabetes associated with cystic fibrosis and steroid induced diabetes. T2DM is characterized by increasing insulin demand caused by increased insulin resistance resulting in a relative insulin shortage (instead of the absolute shortage in T1DM). However, this relative shortage occurs mostly in adults (29,30). Most T2DM cases become manifest when β cells are incapable of meeting this increased demand. A combination of hereditary, social, behavioural and environmental factors play a role in the aetiology of this disease (31). It is estimated that 8-45% of children with diabetes in the USA have T2DM, compared to approximately 2% in the Netherlands. This higher prevalence of T2DM in the USA is largely
explained by the much higher prevalence of overweight and obesity in the USA compared to the Netherlands, especially in minority populati ons (32). MODY is a monogeneti c autosomal dominant defect in β cell functi on representi ng 1-2% of children with diabetes. MODY is characterized by hyperglycaemia starti ng at an age below 25 caused by impaired insulin secreti on with minimal or no defects in insulin acti on (33). Finally, any process that diff usely injures the pancreas can lead to diabetes, such as pancre-ati ti s and trauma, endocrinopathies, drug or chemically induced glucose metabolism disorders, infecti on, geneti c syndromes such as cysti c fi brosis, and geneti c defects in insulin acti on (32). In this thesis, only children with T1DM will be studied. Treatment opti ons for glycaemic control
The mainstay of T1DM treatment is the exogenous replacement of insulin to compensate for the loss of endogenous insulin producti on. Achieving good glycaemic control (with blood glucose concentrati ons between 4.5 and 9 mmol/l) remains a major challenge in and for most pati ents, however. Ideally, insulin replacement therapy should mimic the physiologi-cal insulin secreti on response as much as possible. In daily practi ce, however, fi nding and maintaining the balance between short-term complicati ons (i.e. hypoglycaemic events, the risk of which increases with strict insulin management) and long-term adverse sequelae (microvascular complicati ons such as reti nopathy, renal failure and neuropathy, which are less likely with strict glucose management) is a struggle for pati ents and their families. A variety of treatment methods and schemes have been developed to improve and maintain opti mal glycaemic control, mostly by subcutaneous insulin administrati on. The two most commonly used treatment strategies are multi ple daily injecti ons (MDI) (Figure 3), combining a long acti ng insulin covering a basal need during the day with short acti ng insulin injecti ons administered before the meals, and conti nuous subcutaneous in-sulin infusion (CSII) (26). CSII involves wearing a device (comprising an insulin pump and an infusion set, including a cannula for subcutaneous inserti on and a tubing system to connect the insulin reservoir to the cannula) which provides a steady fl ow of short acti ng insulin into the body. The “basal fl ow” delivers insulin between the meals and at night, and bolus doses are administered to cover the food eaten and correct high blood glucose levels.
B
L
D
BS
figure 3: principle of multi ple daily injecti ons (MDI): the basal fl ow (grey horizontal bar) covers the insulin requirement overnight and between meals, the boluses (yellow humps) represent the extra insulin required to process glucose intake during breakfast (B), lunch (L) and dinner (D). Before sleep (BS)Striving for optimal glycaemic control requires repeated or ongoing measurement of blood glucose levels, either by using a blood glucose meter (self-monitoring of blood glucose, SMBG) or with a real-time continuous glucose monitoring sensor subcutaneously (rtCGM).
Technological advances aimed at progressive integration of CSII and rtCGM are being made, especially in developed countries. Sensor-augmented pump systems are already be-ing used in clinical practice, allowing automated stops of insulin delivery when glucose levels drop below a specified cut-off point (34). An even more sophisticated closed loop system with both lowering or stopping of insulin delivery in case of hypoglycaemia and increased insulin delivery in case of hyperglycaemia (thus increasingly mimicking the physiological function of the pancreas automatically) is expected within the next few years (35). Besides these technical developments, there is the possibility of islet-cell transplantation or pancreatic transplantation, for example in patients with severe, life threating hypoglycaemia, severe glycaemic variability and progressive diabetic complications. Improvements of trans- plant procedures and immunosuppressive regimens have led to better long-term results. In se-lected centres of pancreas-alone transplantation, five-year insulin independence rates of more than 50% have been described (36). Remaining challenges for larger scale implementation of this treatment include the shortage of human donor pancreases, the need for immunosuppres-sion and the inadequacy of the islet isolation process (37). In the Netherlands, all children with T1DM are being treated with insulin using CSII or MDI so this thesis focused on this treatment. Treatment goals in children with T1dM
According to the International Society of Paediatric and Adolescent Diabetes (ISPAD), the main goals of treatment of children with T1DM are to normalize growth and development and to reduce the risks of short- and long-term complications by optimal glycaemic control (table 2) (38). The long-term microvascular complications of T1DM are related to the degree of long-term metabolic dysregulation: the higher the HbA1c over a long period of time, the higher the microvascular complication risk. T1DM is also associated with an increased risk of macrovascular complications. This is only partly dependent on the degree of long-term metabolic control (38,39). Table 2: complications of T1DM short term complications - hypoglycaemia - hyperglycaemia - ketoacidosis Long term complications
Microvascular - - retinopathynephropathy - peripheral neuropathy - autonomic neuropathy Long term complications
Macrovascular - - cardiovascular diseaseperipheral arterial disease - cerebrovascular diseases
Another goal of T1DM treatment is to facilitate the patient in leading a life as normally as possible without limitations, or as few as possible, in daily activity. Good glycaemic control allows children to go to school without interruptions in their education due to their T1DM, and to participate in sports and other social activities to the same extent as children without T1DM.
Achieving good glycaemic control requires properly developed self-management skills, including a correct use of insulin with MDI or CSII, and frequent daily SMBG or rtCGM. Developing these complex and sophisticated self-management skills requires extensive and ongoing education, and a mutually trusting relationship between patients, parents, and medical team. Diabetes self-management will of course have to take into account differences between children of various ages and differences in understanding and (coping) possibilities of both patients and caregivers (32). Despite the critical importance of teaching and learning proper T1DM self-management skills for long-term glycaemic control, there is hardly any evidence on the key factors related to successful self-management education in diabetes. Unfortunately, in daily practice, it is hard to achieve and maintain treatment goals as recommended in the ISPAD guidelines, especially during puberty (40). Administering insulin boluses and performing SMBG just before or during meals is particularly challenging in ado-lescents. Adolescents usually manage their T1DM increasingly independently, with waning supervision from their parents or caregivers. However, many adolescents lack the coping and problem-solving skills to adequately self-manage their disease, and poor adherence to insulin treatment is particularly common in this age range (42,43). Most children and adolescents with T1DM do not reach their HbA1c targets, especially adolescent girls with longstanding disease (44–46). Although it is generally assumed that adherence to insulin management is of key importance for the short- and long-term complication risk in T1DM and that poor adherence to insulin management is common in the paediatric age range, particularly in adolescents, the literature on the impact and the determinants of poor adher-ence in T1DM in children is surprisingly scant. In the few short-term studies available, insulin bolus frequency and SMBG frequency were determinants of HbA1c levels (47). The management of T1DM is intensive and complex. Over the past decades, management of this disease has evolved from a ‘one-size fits all’ MDI approach to a patient-specific multi-disciplinary team approach with many different insulin preparations for MDI, CSII, combined with either SMBG or CGM. With this complex, intensive and multidisciplinary care, the costs of treatment per child have increased significantly (41). Together with the increased T1DM prevalence in children, this will have considerable impact on the national healthcare budget needed to deliver appropriate care for these patients.
From a societal point of view, helping children and their parents to cope with T1DM self-management, will help to lessen the individual and family burden. Depending on the insurance system of a country, the costs involved in proper management and treatment of T1DM will be incurred by the community though health insurance, by the family itself, or a combination of these two. In the Netherlands, T1DM treatment costs are mainly borne by the community through universal health insurance. Efforts to clearly demonstrate the financial impact of T1DM management in a country are quite often hampered by the restricted availability of data on costs and the need to obtain such information from a sometimes overwhelming array of data sources. In the Netherlands, information of health reimbursement data is concentrated in the na- tional healthcare information centre Vektis (48). Vektis was set up by health insurers to sup-port claims reimbursement and enable the main stakeholders in Dutch healthcare to base their decision-making and policy execution on reliable, essential and timely data (48). This allows the assessment of information with regards to the majority of costs in children and adolescents with T1DM in the Netherlands. Information on personal and family expenses in relation to diabetes is more difficult to obtain.
Aims of this thesis
Incidence and prevalence of T1DM in Dutch children
During the last 25 years the prevalence of T1DM increased worldwide. In Europe, the in-crease in incidence rate appears to be 3-4% per annum with a variety in the rate of increase (7). Because recent data on the incidence of T1DM in Dutch children were lacking, the Vektis database was used to examine the prevalence and incidence of T1DM in Dutch children 0-14 years of age over several years (Chapter 2).
Seasonality of diagnosis in children with type 1 diabetes mellitus
The seasonality of many infectious diseases has been described in detail (49). Infectious diseases, which in part also have a seasonal distribution in their occurrence, are one of the most commonly mentioned possible triggers in the development of T1DM. Although seasonality of T1DM in different age groups has been examined (43,19), with most studies reporting a peak incidence in the autumn and winter (50,51), it is unknown whether and to what extent this phenomenon exists in the Netherlands. We therefore studied the seasonal-ity of T1DM diagnosis in Dutch children (Chapter 3).
Thyroid disease and type 1 diabetes mellitus
Although the increased risk of autoimmune thyroid disease in children with T1DM is univer- sally acknowledged, the scientific basis for this association is largely based on the demon-stration of anti-thyroid antibodies in the blood of T1DM patients. Only about half of patients
with such anti-thyroid antibodies will develop overt autoimmune thyroid disease, and the incidence and prevalence of overt autoimmune hypo- and hyperthyroidism in children with T1DM are largely unknown. This was the topic of the study in Chapter 4.
The overall health expenditure of a child with type 1 diabetes mellitus
Studies on costs related to T1DM among children are scarce (52–54). Although the available literature suggests an increase in the T1DM-related costs over the last decades, no data are available on the costs of T1DM management for the Dutch healthcare system. In Chapter 5, both the overall healthcare costs in children with T1DM and the more specific costs related to the management of T1DM were investigated.
Adherence to mealtime insulin bolusing and glycaemic control in adolescents on insulin pump therapy
Poor self-management contributes to insufficient glycaemic control in adolescents with T1DM. However, studies examining the impact of poor adherence to CSII on medium- and long-term glycaemic control are rare in the paediatric age range, specifically in adolescents. In Chapter 6, we investigated the relation between adherence to mealtime boluses and SMBG with glycaemic control in adolescents.
Factors related to optimal insulin pump management in adolescents with T1DM.
In children with a chronic disease such as T1DM, nonadherence is common. Optimal management of T1DM improves both short-term glycaemic control and the prevention of long-term adverse sequelae. Factors underlying optimal adherence to self-management in CSII are largely unknown, however. In Chapter 7, we analysed the association of optimal adherence to CSII self-management in relation to age, gender, diabetes duration and the results of a number of questionnaires assessing the psychological and social consequences of T1DM filled out by patients and parents (including the Fear of self-testing questionnaire, Blood glucose monitoring communication questionnaire, the illness perception question-naire (IPQ), the problem areas in diabetes (PAID–T) questionnaire, and the Diabetes family conflict scale). A general discussion of the finding of these studies are is presented in Chapter 8.
rEfErENCEs 1. Harjutsalo V, Sund R, Knip M, Groop P-H. Incidence of type 1 diabetes in Finland. JAMA. 2013 Jul 24; 310(4): 427–8. 2. Jönsson L, Lundqvist P, Tiberg I, Hallström I. Type 1 diabetes - impact on children and parents at diagnosis and 1 year subsequent to the child’s diagnosis. Scand J Caring Sci. 2015 Mar; 29(1): 126–35. 3. kleiner IS. The action of intravenous injections of páncreas emulsions in experimental diabetes. J Biol 1919 Pp 153-170. 4. https: //www.nobelprize.org/educational/medicine/insulin/discovery-insulin.html. 5. Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA. Pancreatic Extracts in the Treatment of Diabetes Mellitus. Can Med Assoc J. 1922 Mar; 12(3): 141–6. 6. Patterson C, Guariguata L, Dahlquist G, Soltész G, Ogle G, Silink M. Diabetes in the young - a global view and worldwide estimates of numbers of children with type 1 diabetes. Diabetes Res Clin Pract. 2014 Feb; 103(2): 161–75. 7. DIAMOND Project Group. Incidence and trends of childhood Type 1 diabetes worldwide 1990-1999. Diabet Med J Br Diabet Assoc. 2006 Aug; 23(8): 857–66. 8. Mayer-Davis EJ, Lawrence JM, Dabelea D, Divers J, Isom S, Dolan L, et al. Incidence Trends of Type 1 and Type 2 Diabetes among Youths, 2002-2012. N Engl J Med. 2017 13; 376(15): 1419–29. 9. Pettitt DJ, Talton J, Dabelea D, Divers J, Imperatore G, Lawrence JM, et al. Prevalence of diabetes in U.S. youth in 2009: the SEARCH for diabetes in youth study. Diabetes Care. 2014 Feb; 37(2): 402–8. 10. Harjutsalo V, Sjöberg L, Tuomilehto J. Time trends in the incidence of type 1 diabetes in Finnish chil-dren: a cohort study. Lancet Lond Engl. 2008 May 24; 371(9626): 1777–82. 11. Patterson CC, Gyürüs E, Rosenbauer J, Cinek O, Neu A, Schober E, et al. Trends in childhood type 1 diabetes incidence in Europe during 1989-2008: evidence of non-uniformity over time in rates of increase. Diabetologia. 2012 Aug; 55(8): 2142–7. 12. Berhan Y, Waernbaum I, Lind T, Möllsten A, Dahlquist G, Swedish Childhood Diabetes Study Group. Thirty years of prospective nationwide incidence of childhood type 1 diabetes: the accelerating increase by time tends to level off in Sweden. Diabetes. 2011 Feb; 60(2): 577–81. 13. Vaandrager GJ, Bruining GJ, Veenhof FJ, Drayer NM. [The incidence of diabetes mellitus in 0-19-year-olds in the Netherlands (1978-1980)]. Ned Tijdschr Geneeskd. 1983 Dec 24; 127(52): 2355–61. 14. 1996 (HM Reeser, thesis 1998). 15. Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet Lond Engl. 2014 Jan 4; 383(9911): 69–82. 16. Bingley PJ. Clinical applications of diabetes antibody testing. J Clin Endocrinol Metab. 2010 Jan; 95(1): 25–33. 17. Ziegler AG, Rewers M, Simell O, Simell T, Lempainen J, Steck A, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA. 2013 Jun 19; 309(23): 2473–9. 18. Pociot F, Lernmark Å. Genetic risk factors for type 1 diabetes. Lancet Lond Engl. 2016 Jun 4; 387(10035): 2331–9. 19. Cooper JD, Smyth DJ, Walker NM, Stevens H, Burren OS, Wallace C, et al. Inherited variation in vitamin D genes is associated with predisposition to autoimmune disease type 1 diabetes. Diabetes. 2011 May; 60(5): 1624–31. 20. Jongbloet PH, Groenewoud HM, Hirasing RA, Van Buuren S. Seasonality of birth in patients with child-hood diabetes in the Netherlands. Diabetes Care. 1998 Jan; 21(1): 190–1.
21. McKinney PA, EURODIAB Seasonality Of Birth Group. Europe and Diabetes. Seasonality of birth in patients with childhood Type I diabetes in 19 European regions. Diabetologia. 2001 Oct; 44 Suppl 3: B67–74. 22. Patterson CC, Gyürüs E, Rosenbauer J, Cinek O, Neu A, Schober E, et al. Seasonal variation in month of diagnosis in children with type 1 diabetes registered in 23 European centers during 1989-2008: little short-term influence of sunshine hours or average temperature. Pediatr Diabetes. 2015 Dec; 16(8): 573–80. 23. Garmendia Madariaga A, Santos Palacios S, Guillén-Grima F, Galofré JC. The incidence and prevalence of thyroid dysfunction in Europe: a meta-analysis. J Clin Endocrinol Metab. 2014 Mar; 99(3): 923–31. 24. Kakleas K, Soldatou A, Karachaliou F, Karavanaki K. Associated autoimmune diseases in children and adolescents with type 1 diabetes mellitus (T1DM). Autoimmun Rev. 2015 Sep; 14(9): 781–97. 25. Karavanaki K, Kakleas K, Paschali E, Kefalas N, Konstantopoulos I, Petrou V, et al. Screening for as-sociated autoimmunity in children and adolescents with type 1 diabetes mellitus (T1DM). Horm Res. 2009; 71(4): 201–6. 26. Fröhlich-Reiterer EE, Hofer S, Kaspers S, Herbst A, Kordonouri O, Schwarz H-P, et al. Screening fre-quency for celiac disease and autoimmune thyroiditis in children and adolescents with type 1 diabetes mellitus—data from a German/Austrian multicentre survey. Pediatr Diabetes. 2008 Dec; 9(6): 546–53. 27. Thunander M, Petersson C, Jonzon K, Fornander J, Ossiansson B, Torn C, et al. Incidence of type 1 and type 2 diabetes in adults and children in Kronoberg, Sweden. Diabetes Res Clin Pract. 2008 Nov; 82(2): 247–55. 28. Lévy-Marchal C, Patterson CC, Green A, EURODIAB ACE Study Group. Europe and Diabetes. Geographi-cal variation of presentation at diagnosis of type I diabetes in children: the EURODIAB study. European and Dibetes. Diabetologia. 2001 Oct; 44 Suppl 3: B75–80. 29. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2011 Jan; 34 Suppl 1: S62–9.
30. Dayeh T, Ling C. Does epigenetic dysregulation of pancreatic islets contribute to impaired insulin secretion and type 2 diabetes? Biochem Cell Biol Biochim Biol Cell. 2015 Oct; 93(5): 511–21. 31. Temneanu OR, Trandafir LM, Purcarea MR. Type 2 diabetes mellitus in children and adolescents: a relatively new clinical problem within pediatric practice. J Med Life. 2016 Sep; 9(3): 235–9. 32. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2012 Jan; 35 Suppl 1: S64–71. 33. Hattersley A, Bruining J, Shield J, Njolstad P, Donaghue KC. The diagnosis and management of mono-genic diabetes in children and adolescents. Pediatr Diabetes. 2009 Sep; 10 Suppl 12: 33–42. 34. Abraham MB, Nicholas JA, Ly TT, Roby HC, Paramalingam N, Fairchild J, et al. Safety and efficacy of the predictive low glucose management system in the prevention of hypoglycaemia: protocol for randomised controlled home trial to evaluate the Suspend before low function. BMJ Open. 2016 Apr 15; 6(4): e011589. 35. Shah VN, Shoskes A, Tawfik B, Garg SK. Closed-loop system in the management of diabetes: past, present, and future. Diabetes Technol Ther. 2014 Aug; 16(8): 477–90. 36. Shapiro AMJ. Islet Transplantation in Type 1 Diabetes: Ongoing Challenges, Refined Procedures, and Long-Term Outcome. Rev Diabet Stud RDS. 2012; 9(4): 385–406. 37. Farney AC, Sutherland DER, Opara EC. Evolution of Islet Transplantation for the Last 30 Years. Pan-creas. 2016 Jan; 45(1): 8–20. 38. Libby P, Nathan DM, Abraham K, Brunzell JD, Fradkin JE, Haffner SM, et al. Report of the National Heart, Lung, and Blood Institute-National Institute of Diabetes and Digestive and Kidney Diseases
Working Group on Cardiovascular Complications of Type 1 Diabetes Mellitus. Circulation. 2005 Jun 28; 111(25): 3489–93. 39. Livingstone SJ, Looker HC, Hothersall EJ, Wild SH, Lindsay RS, Chalmers J, et al. Risk of cardiovascular disease and total mortality in adults with type 1 diabetes: Scottish registry linkage study. PLoS Med. 2012; 9(10): e1001321. 40. Kordonouri O, Klingensmith G, Knip M, Holl RW, Aanstoot H-J, Menon PSN, et al. ISPAD Clinical Practice Consensus Guidelines 2014. Other complications and diabetes-associated conditions in children and adolescents. Pediatr Diabetes. 2014 Sep; 15 Suppl 20: 270–8. 41. Bruno G, Pagano E, Rossi E, Cataudella S, De Rosa M, Marchesini G, et al. Incidence, prevalence, costs and quality of care of type 1 diabetes in Italy, age 0-29 years: The population-based CINECA-SID ARNO Observatory, 2002-2012. Nutr Metab Cardiovasc Dis NMCD. 2016; 26(12): 1104–11. 42. Grey M, Lipman T, Cameron ME, Thurber FW. Coping behaviors at diagnosis and in adjustment one year later in children with diabetes. Nurs Res. 1997 Dec; 46(6): 312–7. 43. Santer M, Ring N, Yardley L, Geraghty AWA, Wyke S. Treatment non-adherence in pediatric long-term medical conditions: systematic review and synthesis of qualitative studies of caregivers’ views. BMC Pediatr. 2014 Mar 4; 14: 63. 44. Mortensen HB. Practical aspects of managing diabetes in adolescents. Acta Paediatr Oslo Nor 1992 Suppl. 1998 Oct; 425: 72–6. 45. Brorsson AL, Viklund G, Örtqvist E, Lindholm Olinder A. Does treatment with an insulin pump improve glycaemic control in children and adolescents with type 1 diabetes? A retrospective case-control study. Pediatr Diabetes. 2015 Nov; 16(7): 546–53.
46. American Diabetes Association. (11) Children and adolescents. Diabetes Care. 2015 Jan; 38 Suppl: S70–6. 47. Rohan JM, Delamater A, Pendley JS, Dolan L, Reeves G, Drotar D. Identification of self-management patterns in pediatric type 1 diabetes using cluster analysis. Pediatr Diabetes. 2011 Nov; 12(7): 611–8. 48. https: //www.vektis.nl/. 49. Fisman D. Seasonality of viral infections: mechanisms and unknowns. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2012 Oct; 18(10): 946–54. 50. Moltchanova EV, Schreier N, Lammi N, Karvonen M. Seasonal variation of diagnosis of Type 1 diabetes mellitus in children worldwide. Diabet Med J Br Diabet Assoc. 2009 Jul; 26(7): 673–8.
51. Svensson J, Lyngaae-Jørgensen A, Carstensen B, Simonsen LB, Mortensen HB, Danish Childhood Diabetes Registry. Long-term trends in the incidence of type 1 diabetes in Denmark: the seasonal variation changes over time. Pediatr Diabetes. 2009 Jun; 10(4): 248–54. 52. Wiréhn A-B, Andersson A, Ostgren CJ, Carstensen J. Age-specific direct healthcare costs attributable to diabetes in a Swedish population: a register-based analysis. Diabet Med J Br Diabet Assoc. 2008 Jun; 25(6): 732–7. 53. Bächle CC, Holl RW, Straßburger K, Molz E, Chernyak N, Beyer P, et al. Costs of paediatric diabetes care in Germany: current situation and comparison with the year 2000. Diabet Med J Br Diabet Assoc. 2012 Oct; 29(10): 1327–34. 54. Ying AK, Lairson DR, Giardino AP, Bondy ML, Zaheer I, Haymond MW, et al. Predictors of direct costs of diabetes care in pediatric patients with type 1 diabetes. Pediatr Diabetes. 2011 May; 12(3 Pt 1): 177–82.
CHAPTEr 2
The incidence of type 1 diabetes mellitus is sti ll
increasing in the Netherlands, but has stabilised
in children under fi ve (young dudEs-1)
Engelina A.J.M. Spaans, Lisett e M.A. Gusdorf, Klaas H. Groenier, Paul L.P. Brand, Henk J. Veeze, Hans M. Reeser, Henk J.G. Bilo, Nanne Kleefstra
AbStrAct
Aim: This study described the incidence and prevalence of type 1 diabetes mellitus in chil-dren in the Netherlands in 2010-2011 and to compare these results with earlier studies. Methods: This was a retrospective nationwide cohort study of Dutch children aged 14 years or younger. Patients were identified using health insurance reimbursement registries for hospital care and invoices for insulin. In the Netherlands, all children with diabetes are treated by hospital-based paediatricians and healthcare for all Dutch citizens is covered by law. results: The incidence of type 1 diabetes mellitus almost doubled between 1978-1980 and 2010-2011, from 11.1 to 21.4 per 100,000. In the youngest age group, who were under 5 years, the incidence rate doubled between 1996 and 1999 and remained stable after that. There were no relevant incidence differences between the sexes. The overall prevalence of type 1 diabetes mellitus in the Netherlands during 2009-2011 was 143.6 (95% confidence interval 141.1-146.2) per 100,000 children and was similar for boys and girls. Conclusion: The incidence of type 1 diabetes mellitus in children in the Netherlands almost doubled between 1978-1980 and 2010-2011, but the incidence in children under five years appeared to stabilise between 1996 and 1999. There were no statistical differences between the sexes.
iNTroduCTioN
Type 1 diabetes mellitus is one of the most common chronic disorders in childhood. This autoimmune-mediated disease is not only associated with diabetes-related complications, but also with a relevant decrease in quality of life (1,2). Despite many developments in management and insulin treatment, the risks of acute complications like hypoglycaemia and ketoacidosis as well as developing microvascular and macrovascular complications in the future still remain (3-5).
The Worldwide incidence of type 1 diabetes mellitus increased steadily by 2.8% per year during the period 1990-1999, with up to about 79 000 new cases per year in children younger than 15 years of age (6,7). In Europe, the increase in incidence rate appears to be even larger, approximately 3-4% per year (8,9). The prevalence of type 1 in the United States increases annually with almost 3% (2001-2009) (10). The estimated worldwide prevalence of type 1 diabetes mellitus in children younger than 15 years of age was almost 500 000 in 2013 (11,12). The incidence and prevalence rates of type 1 diabetes mellitus vary, showing large differences in different time periods as well as within and between different, even neighbouring, countries (9-14). The estimated prevalence is highest in Europe and South-East Asia and lowest in the West pacific region including China (12). In the World Health Organization Diamond Project 1990-1999, the incidence rate of type 1 diabetes mellitus in children younger than 15 years of age ranged from 0.1 per 100 000 in China and Venezuela to 60 per 100 000 per year in Finland (6,15). These global differences are related by a multitude of factors, for example differences in genetic predisposition, differences in environmental exposure to potential triggers of the immune system and differences in the ability to ascertain the diagnosis, the organisation of healthcare, the accessibility of facilities and quality of registration (16-18). The purpose of this study was to assess the incidence and prevalence of type 1 diabetes mellitus in children in the Netherlands during the period 2009 to 2011 and to compare these with earlier reports on the rising incidence of type 1 diabetes mellitus between 1978 and 1999 (19-23).
MATEriAl ANd METHods study design This was a retrospective cohort study covering a 3-year period from 2009 to 2011. This study forms part of the Young DUDEs initiative, with DUDEs standing for DUtch Diabetes Estimates. In the Netherlands, all children with type 1 diabetes mellitus are treated by hospital-based paediatricians. During the time period 2009-2011, reimbursement of hospital care was ex-clusively claimed using the Diagnose-Behandel Combinatie (DBC) code - Dutch for diagnosis treatment combination - that physicians are required to record for reimbursement purposes.
Each DBC code contains information about the specialism of the treating physician, the pa-tient’s diagnosis and the type of treatment provided. All DBC codes are stored in a national database, managed by Vektis (Vektis, Zeist, the Netherlands). Vektis also manages other databases, such as the Basic Health Insurance Information System, containing demographic information, such as date of birth and sex, for all children registered as inhabitants in the Netherlands. The coverage of this system is 98%, as previously described in a study in type 2 diabetes mellitus (24).
Claims records for pharmaceutical care were derived from the Pharmacy Information System, which had 99% coverage in 2010 (24). It contains information on the date the drug was supplied, who prescribed the drug, the specific drug that was supplied, includ-ing the Anatomical Therapeutic Chemical (ATC) code and the quantity supplied. Because all healthcare 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 healthcare and over time (25).
Before being made available for research, all claims and personal data were stripped of their identifying characteristics to ensure anonymity: the Citizen Service Number was encrypted, the date of birth was converted into the person’s age and the postcode was recoded to limit its identifying properties to an estate/neighbourhood level. Under Dutch law, retrospective studies using anonymised database are exempt from ethical review. Patients Children aged 14 years or younger on the first of July were selected for every single year in the period 2009 to 2011. In this group, individuals with at least one DBC claim for diabetes with a paediatrics code (0316) and diabetes diagnosis code (7104) or an internal medicine code (0313) and a diabetes diagnosis code (221, 222 or 223) were selected. Patients were also classified as having type 1 diabetes mellitus if pharmaceutical claims showed they were issued with prescriptions and picked up insulin in at least 2 years, including 2008. Patients with a diagnosis code of diabetes were excluded from further analysis if there was no re-cords of diabetes medication. To avoid including children treated with insulin for temporary hyperglycaemia, especially neonates, we only included children that had at least 2 years of pharmaceutical claims for insulin. Children were classified into three age categories under - 5 years, 5-9 years and 10-14 years – and into boys and girls. They were then compared to population statistics obtained from the Central Bureau of Statistics covering the Netherlands. statistical analysis Incidences and prevalences were calculated as percentages or as the number of cases per 100 000 and 95% confidence intervals (CI) were computed using the Byar method (26).
rEsulTs
The changes in the prevalence of children with type 1 diabetes mellitus in the Netherlands from 2009 to 2011 are presented in Table 1.
Table 1. The prevalence from 2009 to 2011 in the Netherlands
Number of children with
T1dM (0-14 years) Boys girls Total number of children (0-14 years) in the Netherlands Prevalence per 100,000
2009 4232 2166 2066 2,923,058 144.8 (95%CI;140.5-149.2) 2010 4101 2116 1985 2,912,911 140.8 (95%CI;136.5-145.2) 2011 4226 2143 2083 2,907,075 145.4 (95%CI;141.0-149.8) There was no consistent trend in overall type 1 diabetes mellitus prevalence during this time period. There were no significant differences in prevalence between boys (143.6, 95% C140.1-147.2) and girls (143.7, 95% CI 140.1-147.3). The estimated prevalence in earlier studies were 70 per 100 000 in 1978-1980 (19) and 80 per 100 000 (95%CI 0.77-0.83) in 1996 (HM Reeser, thesis 1998). The annual incidence of type 1 diabetes mellitus in children of 14 years of age or younger in the Netherlands was calculated for 2010 and 2011 (Table 2). Table 2. Incidence (95%CI) of T1DM in the Netherlands 1978-1980 1988-1990 1996-1999 2010-2011
Boys and girls Boys girls
0-4 years 6.8 (6.6-7.1) (6.2-6.7)6.4 (12.0-13.9)12.9 (10.9-14.1)12.4 (10.4-15.0)12.5 (10.1-14.8)12.3 5-9 years 10.9 (10.3-11.6) (12.0-12.7)12.4 (18.0-20.7)19.3 (21.5-25.8)23.6 (19.3-25.2)22.1 (22.0-28.4)25.0 10-14 years 14.3 (13.4-15.3) (17.6-18.6)18.1 (21.9-26.6)24.2 (25.3-30.0)27.6 (24.0-30.5)27.1 (24.8-31.6)28.0 Total (0-14 years) 11.1 (10.5-11.7) (12.0-12.8)12.4 (20.2-22.6)21.4 (19.2-22.5)20.8 (20.4-23.8)22.0 We identified 1243 newly diagnosed children from birth to 14 years of age with type 1 diabe- tes mellitus in the Netherlands in 2010 and 2011, comprising 618 boys and 627 girls. In 2010-2011, the incidence of type 1 diabetes mellitus in the youngest age group, under 5 years of age, was comparable to the rate during the period 1996-1999, which was double the rate in 1978-1990. In the other age groups, however, the rising trend of incidence of type 1 diabetes mellitus observed in earlier studies continued through 2010-2011 to a similar degree in 5 to 9 year olds and 10 to 14 year olds. There were no significant incidence differences between the sexes, although the boy girl ratio increased slightly from 1.00 in 1988-1990, to 1.07 in 1996-1999 and 1.09 in 2009-2011.
disCussioN
This study shows that the incidence of type 1 diabetes mellitus in children in the Nether-lands has increased steadily by an average of 2.1% per year since 1978-1980, particularly in children aged from 5 to 14 years of age. This accumulates to an overall current type 1 diabetes mellitus prevalence of 0.144% or one child with type 1 diabetes mellitus in every 699 children. The increase in incidence in children under the age of 5 years, which was observed in previous national surveys in our country, appears to have halted, although the number of cases might be too small in this age group to allow definitive conclusions. This could also be due to the fact that, as in other European countries, increases of the incidence of type 1 diabetes mellitus is not uniform, showing periods of less rapid and more rapid increases in incidence in some registers (15). This pattern of change suggests that important risk exposures differ over time in different European countries. Although there is an overall worldwide increase in the incidence of type 1 diabetes mellitus in children, the size of this increase differs considerably between countries and between age groups. In Finland, the country with the highest incidence worldwide, the largest increase in incidence has been found in the youngest age group, of birth to 4 years, with 4.7% more affected children every year (13). Similarly, the increase in incidence was also largest in the youngest children in the EURODIAB and DIAMOND studies (6,8,15). The EURODIAB study found an overall estimated annual incidence increase of 3.9%, with the highest incidence rise in children under 5 years of age (5.4%) (15). In contrast, in New Zealand, the greatest increase of incidence was observed in children aged 10-14 years and the increase was lowest in the children aged under 5 years (27). This is in agreement with the changes in incidence observed in the Netherlands (23). In the Netherlands, children with type 1 diabetes mellitus are solely treated by paediatri-cians and in rare cases by internists. Reimbursement to medical specialists for diabetes care in the Netherlands is exclusively linked to the DBC system. As a result, the number of patients with type 1 diabetes mellitus missed in this nationwide study is expected to be very small and the number of children with type 2 diabetes mellitus in this cohort will probably be very small. However, a limitation of our study remains that some cases of type 2 diabetes mellitus may have been incorrectly classified as type 1 diabetes mellitus, if these patients were only treated with insulin for at least 1 year. We used both a medication database and a diagnosis registration database, and a previous study has shown almost 100% coverage for both systems (24). The number of patients included in this study solely on the basis of insulin use, and not on the diagnosis registration, database comprised 109 children (2.3%), which confirms good registration by paediatricians and that very few children with type 1 diabetes mellitus in the Netherlands were missed. If a child was not included because of a DBC and received insulin for the first time in 2011, they were not included in 2011, which means that a small number of patients could have been missed.
CoNClusioN
We conclude that the incidence of type 1 diabetes mellitus in children in the Netherlands continues to increase, particularly in 5 to 14 year old children, but the incidence in children under the age of 5 years appears to have stabilised.
rEfErENCEs
1. Cameron FJ. The impact of diabetes on health-related quality of life in children and adolescents.
Pediatr Diabetes 2003; 4:132–136.
2. Frøisland DH, Graue M, Markestad T, Skrivarhaug T, Wentzel-Larsen T, Dahl-Jørgensen K. Health-related quality of life among Norwegian children and adolescents with type 1 diabetes on intensive insulin treatment: a population-based study. Acta Paediatr 2013; 102: 889-95. 3. Laing SP, Swerdlow AJ, Slater SD, Burden AC, Morris A, Waugh NR et al. Mortality from heart disease in a cohort of 23,000 patients with insulin-treated diabetes. Diabetologia 2003; 46: 760–765. 4. Livingstone SJ, Looker HC, Hothersall EJ, Wild SH, Lindsay RS, Chalmers J et al. Risk of cardiovascular disease and total mortality in adults with Type 1 Diabetes: Scottish Registry Linkage Study. PloS Med 2012; 9: e1001321. 5. Johnson SR, Cooper MN, Davis EA, Jones TW. Hypoglycaemia, fear of hypoglycaemia and quality of life in children with Type 1 diabetes and their parents. Diabet Med 2013; 30: 1126-31. 6. DIAMOND Project Group. Incidence and trends of childhood type 1 diabetes worldwide 1990-1999. Diabet Med 2006; 23: 857-66. 7. Stanescu DE, Lord K, Lipman TH. The Epidemiology of type 1 diabetes in children. Endocrinol Metab Clin N Am 2012; 41: 679-694. 8. Patterson CC, Gyürüs E, Rosenbauer J, Cinek O, Neu A, Schober E et al. Trends in childhood type 1 diabetes incidence in Europe during 1989-2008: evidence of non-uniformity over time in rates of increase. Diabetologia 2012; 55: 2142-7.
9. EURODIAB ACE Study Group. Variation and trends in incidence of childhood diabetes in Europe.
Lancet 2000; 355: 873-6.
10. Dabelea D, Mayer-Davis EJ, Saydah S, Imperatore G, Linder B, Divers j et al. SEARCH for Diabetes in Youth Study. Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009. JAMA 2014; 311: 1778-86.
11. Patterson C, Guariguata L, Dahlquist G, Soltész G, Ogle G, Silink M. Diabetes in the young - a global view and worldwide estimates of numbers of children with type 1 diabetes. Diabetes Res Clin Pract 2013; pii: S0168-8227(13)00388-4. 12. Diabetes in the young in International Diabetes Federation. IDF Diabetes Atlas 5th edition. Brussels, Belgium: International Diabetes federation; 2011. http: //www.idf.org/diabetesatlas. 13. Harjutsalo V, Sjöberg L, Tuomilehto J. Time trends in the incidence of type 1 diabetes in Finnish chil-dren: a cohort study. Lancet 2008; 371(9626): 1777-82. 14. Rytkönen M, Ranta J, Tuomilehto J, Karvonen M, The SPAT Study Group, The Finnish Childhood Diabe-tes Registry Group. Bayesian analysis of geographical variation in the incidence of Type I diabetes in Finland. Diabetologia 2001; 44: 37–44. 15. Patterson CC, Dahlquist GG, Gyurus E, Green A, Soltesz G; EURODIAB Study Group. Incidence trends for childhood type 1 diabetes in Europe during 1989–2003 and predicted new cases 2005–20: a multicentre prospective registration study. Lancet 2009; 373: 2027–33. 16. Hermann R, Knip M, Veijola R, Simell O, Laine A-P, Åkerblom HK et al., the Finn Diane Study Group. Temporal changes in the frequencies of HLA genotypes in patients with type 1 diabetes indication of an increased environmental pressure? Diabetologia 2003; 46: 420–425. 17. Stankov K, Benc D, Draskovic D. Genetic and epigenetic factors in etiology of diabetes mellitus type 1. Pediatrics 2013; 132: 1112-22. 18. Muirhead CR, Cheetham TD, Court S, Begon M, McNally RJ. How do childhood diagnoses of type 1 diabetes cluster in time? PLoS One 2013; 8: e60489.
19. Vaandrager GJ, Bruining GJ, Veenhof FJ, Drayer NM. The incidence of diabetes mellitus in 0-19-year-olds in the Netherlands (1978-1980). Ned Tijdschr Geneeskd 1983; 127: 2355-61.
20. Vaandrager GJ, Bruining GJ, Veenhof FJ, Drayer NM. Incidence of childhood diabetes in the Nether-lands: a decrease from north to south over north-western Europe? Diabetologia 1984; 27: 203-6. 21. Hirasing RA. The incidence of diabetes 0-19 in the Netherlands (1988-1990) Ned Tijdschr Geneesk
1995; 139: 1088-92.
22. Ruwaard D, Hirasing RA, Reeser HM et al. Increasing incidence of type I diabetes in the Netherlands. The second nationwide study among children under 20 years of age. Diabetes Care 1994; 17: 599-601. 23. van Wouwe JP, Mattiazzo GF, el Mokadem N, Reeser HM, Hirasing RA. The incidence and initial
symptoms of diabetes mellitus type 1 in 0-14-year-olds in the Netherlands, 1996-1999. Ned Tijdschr Geneeskd 2004; 148: 1824-9. 24. http: //www.rivm.nl/bibliotheek/rapporten/260013001.pdf 25. http: //www.government.nl/issues/identification-documents/the-citizen-service-number 26. Rothman KJ, Boice JD, Jr. 1982. Epidemiologic Analysis with a Programmable Calculator, New Edition. Boston, MA: Epidemiology Resources, Inc. 27. Derraik JGB, Reed PW, Jefferies C, Cutfield SW, Hofman PL, Cutfield WS. Increasing incidence and age at diagnosis among children with type 1 diabetes mellitus over a 20-year period in Auckland (New Zealand). PLoS One 2012; 7: e32640.
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
