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.

BACKGROUND: The month of diagnosis in childhood type 1 diabetes shows seasonal variation. OBJECTIVE: We describe the pattern and investigate if year-to-year irregularities are associated with meteorological factors using data from 50 000 children diagnosed under the age of 15 yr in 23 population-based European registries during 1989-2008. METHODS: Tests for seasonal variation in monthly counts aggregated over the 20 yr period were performed. Time series regression was used to investigate if sunshine hour and average temperature data were predictive of the 240 monthly diagnosis counts after taking account of seasonality and long term trends. RESULTS: Significant sinusoidal pattern was evident in all but two small centers with peaks in November to February and relative amplitudes ranging from ± 11 to ± 38% (median ± 17%). However, most centers showed significant departures from a sinusoidal pattern. Pooling results over centers, there was significant seasonal variation in each age-group at diagnosis, with least seasonal variation in those under 5 yr. Boys showed greater seasonal variation than girls, particularly those aged 10-14 yr. There were no differences in seasonal pattern between four 5-yr sub-periods. Departures from the sinusoidal trend in monthly diagnoses in the period were significantly associated with deviations from the norm in average temperature (0.8% reduction in diagnoses per 1 °C excess) but not with sunshine hours. CONCLUSIONS: Seasonality was consistently apparent throughout the period in all age-groups and both sexes, but girls and the under 5 s showed less marked variation. Neither sunshine hour nor average temperature data contributed in any substantial way to explaining departures from the sinusoidal pattern.

Trends in childhood type 1 diabetes incidence in Europe during 1989-2008: evidence of non-uniformity over time in rates of increase.

AIMS/HYPOTHESIS: The aim of the study was to describe 20-year incidence trends for childhood type 1 diabetes in 23 EURODIAB centres and compare rates of increase in the first (1989-1998) and second (1999-2008) halves of the period. METHODS: All registers operate in geographically defined regions and are based on a clinical diagnosis. Completeness of registration is assessed by capture-recapture methodology. Twenty-three centres in 19 countries registered 49,969 new cases of type 1 diabetes in individuals diagnosed before their 15th birthday during the period studied. RESULTS: Ascertainment exceeded 90% in most registers. During the 20-year period, all but one register showed statistically significant changes in incidence, with rates universally increasing. When estimated separately for the first and second halves of the period, the median rates of increase were similar: 3.4% per annum and 3.3% per annum, respectively. However, rates of increase differed significantly between the first half and the second half for nine of the 21 registers with adequate coverage of both periods; five registers showed significantly higher rates of increase in the first half, and four significantly higher rates in the second half. CONCLUSIONS/INTERPRETATION: The incidence rate of childhood type 1 diabetes continues to rise across Europe by an average of approximately 3-4% per annum, but the increase is not necessarily uniform, showing periods of less rapid and more rapid increase in incidence in some registers. This pattern of change suggests that important risk exposures differ over time in different European countries. Further time trend analysis and comparison of the patterns in defined regions is warranted.

Birthweight and the risk of childhood-onset type 1 diabetes: a meta-analysis of observational studies using individual patient data.

AIMS/HYPOTHESIS: We investigated whether children who are heavier at birth have an increased risk of type 1 diabetes. METHODS: Relevant studies published before February 2009 were identified from literature searches using MEDLINE, Web of Science and EMBASE. Authors of all studies containing relevant data were contacted and asked to provide individual patient data or conduct pre-specified analyses. Risk estimates of type 1 diabetes by category of birthweight were calculated for each study, before and after adjustment for potential confounders.Meta-analysis techniques were then used to derive combined ORs and investigate heterogeneity between studies. RESULTS: Data were available for 29 predominantly European studies (five cohort, 24 case-control studies), including 12,807 cases of type 1 diabetes. Overall, studies consistently demonstrated that children with birthweight from 3.5 to 4 kg had an increased risk of diabetes of 6% (OR 1.06 [95% CI 1.01-1.11]; p=0.02) and children with birthweight over 4 kg had an increased risk of 10% (OR 1.10 [95% CI 1.04-1.19]; p=0.003), compared with children weighing 3.0 to 3.5 kg at birth. This corresponded to a linear increase in diabetes risk of 3% per 500 g increase in birthweight (OR 1.03 [95% CI 1.00-1.06]; p=0.03). Adjustments for potential confounders such as gestational age, maternal age, birth order, Caesarean section, breastfeeding and maternal diabetes had little effect on these findings. CONCLUSIONS/INTERPRETATION: Children who are heavier at birth have a significant and consistent, but relatively small increase in risk of type 1 diabetes.

Caesarean section is associated with an increased risk of childhood-onset type 1 diabetes mellitus: a meta-analysis of observational studies.

AIMS/HYPOTHESIS: The aim of this study was to investigate the evidence of an increased risk of childhood-onset type 1 diabetes in children born by Caesarean section by systematically reviewing the published literature and performing a meta-analysis with adjustment for recognised confounders. METHODS: After MEDLINE, Web of Science and EMBASE searches, crude ORs and 95% CIs for type 1 diabetes in children born by Caesarean section were calculated from the data reported in each study. Authors were contacted to facilitate adjustments for potential confounders, either by supplying raw data or calculating adjusted estimates. Meta-analysis techniques were then used to derive combined ORs and to investigate heterogeneity between studies. RESULTS: Twenty studies were identified. Overall, there was a significant increase in the risk of type 1 diabetes in children born by Caesarean section (OR 1.23, 95% CI 1.15-1.32, p < 0.001). There was little evidence of heterogeneity between studies (p = 0.54). Seventeen authors provided raw data or adjusted estimates to facilitate adjustments for potential confounders. In these studies, there was evidence of an increase in diabetes risk with greater birthweight, shorter gestation and greater maternal age. The increased risk of type 1 diabetes after Caesarean section was little altered after adjustment for gestational age, birth weight, maternal age, birth order, breast-feeding and maternal diabetes (adjusted OR 1.19, 95% CI 1.04-1.36, p = 0.01). CONCLUSIONS/INTERPRETATION: This analysis demonstrates a 20% increase in the risk of childhood-onset type 1 diabetes after Caesarean section delivery that cannot be explained by known confounders.

Early mortality in EURODIAB population-based cohorts of type 1 diabetes diagnosed in childhood since 1989.

AIMS/HYPOTHESIS: The aims of this study were to provide a contemporary picture of mortality and causes of death in Europe following a diagnosis of type 1 diabetes made before the 15th birthday, and to examine excess mortality by country for possible links to incidence level or national prosperity. METHODS: Thirteen population-based EURODIAB registers in 12 countries followed-up 28,887 children diagnosed since 1989, either by record linkage to population registers or through contact with doctors providing care. RESULTS: There were 141 deaths in the cohort during 219,061 person-years of follow-up compared with 69.1 deaths expected from national mortality rates, a standardised mortality ratio (SMR) of 2.0 (95% CI 1.7-2.4). The SMR varied from 0 to 4.7 between countries, but showed little relationship with the country's incidence rate or gross domestic product (US$ per capita). The SMR did not change significantly with attained age, calendar period or time since diagnosis. The female SMR (2.7; 95% CI 2.0-3.5) was greater than the male SMR (1.8; 95% CI 1.4-2.2), although absolute numbers of excess deaths were similar in the two sexes. One-third of deaths were classified as directly attributable to diabetes (many with mention of ketoacidosis) and half were unrelated to diabetes. There was a non-significant excess of accidental/violent deaths (48 observed vs 40.7 expected; SMR 1.2; 95% CI 0.9-1.6) but little excess in suicides (11 observed, 10.2 expected; SMR 1.1; 95% CI 0.5-1.9). CONCLUSIONS/INTERPRETATION: Before the onset of late complications, significant excess mortality existed following the diagnosis of type 1 diabetes in childhood, even in recent years. Variation between countries in this excess could not be explained.

Onset of breast and pubic hair development in 1231 preadolescent Lithuanian schoolgirls.

BACKGROUND: Correct staging of puberty is essential in order to differentiate different pathologies, as various components of the endocrine system influence breast, pubic, and axillary hair development. AIMS: To determine the current timing of adrenarche and breast development in Lithuanian preadolescent schoolgirls. METHODS: Cross-sectional study of 1231 schoolgirls aged 7.0-11.6 years. Puberty was staged according to the method of Tanner. Mean age at entry into each pubertal stage was calculated by probit analysis. RESULTS: Of the 255 girls aged 7 years, two had premature adrenarche (0.8%) and one premature thelarche (0.4%). Mean age of onset of pubic/axillary hair development was 11.0 years, and for breast development (Stage 2) 10.2 years. Breast Stage 3 development was attained at 11.3 years and Stage 4 at 13.9 years. Mean BMI, height, weight, and systolic blood pressure SD scores were higher in pubertal than in prepubertal girls. Skinfold thickness was also significantly higher in girls with isolated adrenarche than in prepubertal girls. The increase in BMI and weight resulted from an increase in body fat as evidenced by measures of subscapular and triceps skinfold thickness. Girls with only signs of adrenarche or thelarche did not differ from each other from the anthropometric standpoint. CONCLUSIONS: Premature thelarche and premature adrenarche were relatively uncommon in this population. Pubertal onset was slightly earlier than the UK Tanner standards and tended to occur in girls with a higher BMI.

Time trend of childhood type 1 diabetes incidence in Lithuania and Sweden, 1983-2000.

AIM: To compare the time trend of childhood type 1 diabetes over an 18-y period in Lithuania and Sweden--countries with different incidence levels and different socio-economic conditions. METHODS: Percent average incidence change per year between 1983 and 2000, based on 8031 Swedish and 1100 Lithuanian cases in the age group 0-14 y, was calculated using Poisson regression. RESULTS: Average age- and sex-standardized incidence/100 000/y was 28.9 (95% CI: 28.2-29.5) in Sweden and 7.5 (95% CI: 7.1-8.0) in Lithuania. Between 1983 and 2000, the average increase per year was 2.2% in Sweden (95% CI: 1.7-2.6) and 2.3% in Lithuania (95% CI: 1.1-3.5), but the latter trend depended on an increase during the last few years of the period, and only for girls. In Sweden, incidence increased significantly in all age groups, but more so in the younger groups (3.0%, 2.2% and 1.7% per year in 0-4, 5-9 and 10-14-y age groups, respectively), while in Lithuania a significant increase was found only in the 10-14-y age group (3.0%). In Sweden, a trend towards a younger age at diagnosis was indicated for both boys and girls when comparing 1983-1991 and 1992-2000, whereas in Lithuania, the changes in age distribution over time were small, with an opposite tendency for boys. CONCLUSION: Incidence variability over time differed considerably in the two countries in the region of the Baltic Sea, suggesting a complex effect of environmental risk factors, some of which may be associated with wealth and socio-economic conditions.

Severity at onset of childhood type 1 diabetes in countries with high and low incidence of the condition.

Severity of Type 1 diabetes mellitus (DM) at presentation was compared between south-east Sweden and Lithuania where incidence of childhood Type 1 diabetes is three times lower than in Sweden. New cases of diabetes at age 0-15 years from August 1995 to March 1999 in south-east Sweden and from August 1996 to August 2000 in Lithuania were included. Symptoms and clinical characteristics at diagnosis were recorded. Data about the close environment were collected using questionnaires. Lithuanian children were diagnosed in a more severe condition, mean pH 7.30 and HbA(1c) 11.5% compared with mean pH 7.36 and HbA(1c) 9.7% in Swedish children (P<0.0001). More Lithuanian than Swedish children were diagnosed in ketoacidosis (pH < or = 7.2, hyperglycaemia and ketonuria), 21.3 versus 7.3% (P<0.0001). Only 4.6% of Swedish children and 1.0% of Lithuanian children had no symptoms (P=0.007). Children in families with at least one first degree relative with diabetes (12.2% in Sweden and 8.4% in Lithuania, NS) had laboratory values at diagnosis closer to normal than sporadic cases in either country. Factors predicting ketoacidosis in Sweden were an unemployed mother and absence of infections in the 6 months before diagnosis. In Lithuania it was younger age and mother with less education. Additional educational activities for doctors are needed in countries with low incidence to reduce prevalence of ketoacidosis at onset.

Increasing incidence of childhood-onset type I diabetes in 3 Baltic countries and Finland 1983-1998.

AIMS/HYPOTHESIS: We aimed to study the incidence of Type I diabetes in 4 countries, Estonia, Latvia, Lithuania and Finland, during 1983-1998, focusing on the two separate periods of 1983-1990 and 1991-1998. METHODS: Population-based incidence data from nationwide diabetes registries were used. Crude and age-standardized incidence rates using the proportions of 39%, 32% and 29% for 5-year age groups (0-4, 5-9 and 10-14 years) were calculated. Yearly incidence was evaluated and the means between the two periods compared. RESULTS: Between 1983-1990 and 1991-1998 there was a statistically significant incidence increase in all 4 countries of Estonia, Lativia, Lithuania and Finland (relative risk 1.15, 95%-Confidence interval 1.10-1.19) and as well as in the 3 Baltic states of Estonia, Latvia, Lithuania (relative risk 1.13, 95%. Confidence interval 1.04-1.22). The crude incidence increased in Estonia from 10.1 (95%-Confidence interval 8.9-11.4) to 12.3 (11.0-13.8), in Latvia from 6.6 (5.8-7.3) to 7.4 (6.6-8.2) and in Lithuania from 6.8 (6.2-7.5) to 7.8 (7.1-8.5). In Finland the incidence rose from 34.6 (33.3-36.0) in 1983-1990 to 40.8 (39.4-42.2) in 1991-1998. In children under 5 years of a age a statistically important increase was seen in Estonia and Finland. The highest incidence for a single year was recorded for all participating countries in the late 1990 s. The highest annual incidence rate of childhood onset Type I diabetes in the world ever known was recorded in Finland in 1998 with 48.5 cases per 100 000 person-years. CONCLUSION/HYPOTHESIS: The incidence of Type I diabetes has increased since 1983 in the three Baltic states as well as in Finland. Long-term monitoring is needed for a better detection in changes in incidence.

A comparison of the prevalence of islet autoantibodies in children from two countries with differing incidence of diabetes.

AIMS/HYPOTHESIS: To examine the prevalence of sub-: clinical islet autoimmunity in children from two countries with a twofold to threefold difference in incidence of childhood Type I (insulin-dependent) diabetes mellitus. METHODS: Sera were collected from 2,860 English and 3,053 Lithuanian non-diabetic schoolchildren according to the same protocol. Occult diabetes was excluded by blood glucose measurement. Antibodies to GAD and the protein tyrosine phosphatase IA-2 were measured with standardised radiobinding assays in a single laboratory. Islet cell antibodies and insulin autoantibodies were additionally measured in all samples with GAD and/or IA-2 antibody levels above the 97.5th centile of the English schoolchildren. RESULTS: Of Lithuanian schoolchildren 2.7 % had GAD antibodies above the 97.5th centile of the English schoolchildren but only 0.2 % had antibodies to IA-2 above this threshold (p < 0.001). Islet cell and/ or insulin autoantibodies above the 97.5th centile were found in 22 Lithuanian and 16 English schoolchildren and the overall prevalence of two or more antibodies on or above the 97.5th centile was similar [0.7 % (0.5-1.1) vs 0.6 % (0.4-1.0)] in the two cohorts. CONCLUSION/INTERPRETATION: The prevalence of multiple antibody markers was similar in the cohorts from the two populations, despite the two to three-fold difference in incidence of diabetes. The unexpectedly high prevalence of subclinical islet autoimmunity suggests that the incidence of diabetes in Lithuania is likely to increase in the near future.

Infections and risk of Type I (insulin-dependent) diabetes mellitus in Lithuanian children.

AIMS/HYPOTHESIS: The role of infections in the aetiology of Type I diabetes is controversial. Certain enteroviral infections might be involved in triggering the beta-cell destruction but insufficient exposure to early infections might increase the risk. We studied how the number of infections experienced during several periods from birth to onset influence diabetes risk. METHODS: The study group came from the five largest Lithuanian cities: 124 patients, selected from the 0-14 years-of-age childhood diabetes register and 372 population-based control subjects matched with them for age group and sex. Information about infections and duration of breastfeeding was collected from health care booklets, other data from a mailed questionnaire, returned by 94.4% of patients and 72.6 % of control subjects. RESULTS: One or more infections experienced during the first half year of life tended to reduce diabetes risk. Crude odds ratios (95% confidence intervals) in the 0-14, 0-4 and 5-14 years-of-age groups were 0.66 (0.42-1.04), 1.06 (0.48-2.36) and 0.52 (0.30-0.90) respectively. Adjustment for the duration of breastfeeding, number of people in the household, duration of mother's education and birth order of the index child made little difference. Odds ratios (95 % confidence intervals) in the 0-14, 0-4 and 5-14 years-of-age groups were 0.60 (0.37-0.98), 0.94 (0.40-2.20) and 0.47 (0.26-0.87), respectively. The number of infections recorded during the last pre-onset year or from birth to onset did not influence diabetes risk. CONCLUSION/INTERPRETATION: Exposure to infections early in life could decrease diabetes risk, particularly for children diagnosed after the age of 4 years.

Mortality in patients with childhood-onset type 1 diabetes in Finland, Estonia, and Lithuania: follow-up of nationwide cohorts.

OBJECTIVE: To assess mortality of population-based cohorts of childhood-onset type 1 diabetic patients from the Eastern European countries of Estonia and Lithuania and compare this information with recent data from Finland. RESEARCH DESIGN AND METHODS: Estonian (n = 518) and Finnish (n = 5,156) type 1 diabetic cohorts were diagnosed between 1980 and 1994, and the Lithuanian (n = 698) cohort was diagnosed between 1983 and 1994. The mortality of these cohorts was determined in 1995. Life-table analysis, Cox survival analysis with covariates, and standardized mortality ratios (SMRs) were used. Causes of death were analyzed. RESULTS: Survival after 10 years duration of type 1 diabetes was similar in Estonia (94.3%) and Lithuania (94.0%), but much higher in Finland (99.1%). In the Cox survival analysis with covariates, the country of origin and age at diagnosis were found to be significant predictors of mortality. The SMR for the Estonian cohort was 4.35 (95% CI 2.25-7.61), the highest for the Lithuanian cohort was 7.55 (4.89-11.15), and the lowest for the Finnish cohort was 1.62 (1.10-2.28). The most common cause of death in Estonia and Lithuania was diabetic ketoacidosis (DKA), and in Finland, it was violent causes. No deaths from late complications of diabetes have been documented so far in any of the three countries. CONCLUSIONS: Our results demonstrate a high rate of short-term deaths due to DKA and inferior survival of childhood-onset type 1 diabetic patients in Estonia and Lithuania compared with Finland. In Finland, the survival of childhood-onset type 1 diabetic patients has improved and is only slightly inferior to that of the background population.

Seasonal variation in the incidence of Type 1 diabetes mellitus during 1983 to 1992 in the countries around the Baltic Sea.

AIM: To examine seasonal patterns of incidence of Type 1 diabetes mellitus incidence in children aged 0-14 years in Finland, Sweden, Estonia, Latvia and Lithuania during 1983-1992 (1987-1992 for Finland). METHODS: The study used a method that models incidence data using combinations of sine waves to model seasonal variation around a possible linear trend. RESULTS: In Finland, a significant pattern was found for combined sexes and age groups 0-9 and 10-14 years. A significant pattern was also confirmed for 10-14 year-old boys. In Sweden, the best model with significant pattern was found separately for boys and girls and age groups 0-9 and 10-14 years, however, a significant pattern was confirmed for older girls only. A seasonal pattern in older boys in Finland and girls in Sweden was characterized by two cycles with decreased incidence in June and November-December. The pattern among younger children (0-9 or 5-9 years) had one cycle with a decreased incidence in May-June. In Estonia, a significant pattern was found for the age group 0-14 years and combined sexes. No significant seasonal patterns were found in Latvia and Lithuania. CONCLUSIONS: The seasonal pattern with two cycles among older children and one cycle only among younger children may indicate different triggers of Type 1 diabetes mellitus for different age groups.

Incidence trends in childhood onset IDDM in four countries around the Baltic sea during 1983-1992.

We present secular trends of childhood onset insulin-dependent diabetes mellitus (IDDM) in Finland, Estonia, Latvia and Lithuania during the period of 1983-1992. Incidence data were obtained from the national IDDM registries. The average age-standardized incidence per 100,000/year was 35.0 in Finland, followed by 10.2 in Estonia, 7.1 in Lithuania and 6.5 in Latvia. A male excess in incidence was recorded in Finland (1.15) and Latvia (1.01). In all countries, the highest age-specific risk of IDDM was observed in the 11-13 year age range. The large difference in incidence between Finland and other Baltic countries was see even in 1-2 year-old children. During the 10-year study period overall changes in incidence of IDDM were relatively small in these four countries. The incidence increased in Finland and Lithuania on average by 1% and 1.4% per year, respectively. A statistically significant increase was recorded only in 0-4 year old children in Finland, at 5.6% per year. In Estonia, an 8.3% increase in this age group, however, was not statistically significant. The different trends in the age-group specific incidence rates were confirmed in Finland. In conclusion, from 1983 to 1992 the incidence of childhood onset IDDM was increasingly in Finland and Lithuania, while in Latvia and Estonia it was stable. There are still great differences in IDDM incidence between the countries around the Baltic Sea.

Comparison of the incidence of insulin-dependent diabetes mellitus in childhood among five Baltic populations during 1983-1988.

We have carried out a comparison of the incidence of childhood onset insulin-dependent diabetes mellitus (IDDM) between five populations around the Baltic Sea. These were Finland, Estonia, Latvia, Lithuania and Poland. The risk of IDDM is highest in the world in Finland and also very high in Sweden, on the western and northern side of the Baltic Sea. The risk of IDDM in children on the eastern side of the Baltic Sea has not been known before. The data collection period covered the years 1983-1988. A marked variation in incidence was seen within this relatively small geographical area. Among these five populations, the incidence increased with the latitude. Our present results confirmed the very high incidence of IDDM in Finland. The average age-standardized yearly incidence of IDDM/100,000 was in males under 15 years of age 36.9 in Finland, 10.7 in Estonia, 6.4 in Latvia, 6.5 in Lithuania and 6.0 in Poland. In females the incidence was 31.6, 10.0, 6.9, 7.0 and 6.4 in these five populations, respectively. The differential in incidence in Estonia as compared with Latvia, Lithuania and Poland was statistically significant (P = 0.0002). A slight male excess in incidence was found in countries with higher incidence--Finland and Estonia, but in lower incidence countries the sex ratio was opposite (P = 0.019 for the interaction sex-population). During 1983-1988 the incidence increased significantly in Finland but not in other populations although a large year-to-year variation in incidence was observed in each country, particularly in males. We recorded a peak in IDDM incidence in most of these populations around 1986.