Socio-economic factors influencing the development of end-stage renal disease in people with Type 1 diabetes - a longitudinal population study.

AIMS: The development of end-stage renal disease (ESRD) in Type 1 diabetes is multifactorial. Familial socio-economic factors may influence adherence to and understanding of diabetes treatment, and also general health behaviour. We investigate how parental and personal education level and exposure to low economic status, indicated by the need for income support, influence the development of ERSD caused by Type 1 diabetes. METHODS: Participants were retrieved from the nationwide Swedish Childhood Diabetes Registry, which was linked to the Swedish Renal Registry, to find people with ESRD caused by Type 1 diabetes, and to Statistic Sweden to retrieve longitudinal socio-economic data on participants and their parents. Data were analysed using Cox regression modelling. RESULTS: Of 9287 people with diabetes of duration longer than 14 years, 154 had developed ESRD due to diabetes. Median diabetes duration (range) for all participants was 24.2 years (14.0-36.7 years). Low maternal education (≤ 12 years) more than doubled the risk of developing ESRD, hazard ration (HR) = 2.9 [95% confidence interval (95% CI): 1.7-4.8]. For people with a low personal level of education HR was 5.7 (3.4-9.5). In an adjusted model, the person's own education level had the highest impact on the risk of ESRD. If at least one of the parents had ever received income support the HR was 2.6 (1.9-3.6). CONCLUSIONS: Socio-economic factors, both for the parents and the person with diabetes, have a strong influence on the development of ESRD in Type 1 diabetes. It is important for caregivers to give enough support to more vulnerable people and their families.

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.

Impact of childhood-onset type 1 diabetes on schooling: a population-based register study.

AIMS/HYPOTHESIS: We investigated the impact of type 1 diabetes on educational achievements in compulsory and upper secondary school, as well as potential long-lasting effects. METHODS: Altogether 2,485 individuals with type 1 diabetes, diagnosed at the age of <15 years and born in 1972-1978, were selected from the Swedish Childhood Diabetes Register, which was linked to national population registers including the Swedish Education Register. For each individual, four controls from the general population, matched for year of birth and residence at the time of diagnosis, were selected by Statistics Sweden (n = 9,940). We analysed the impact of diabetes on final school grades at 16 years (compulsory school) and 19 years (upper secondary school) and on participation in the labour market at 29 years using linear, logistic, ordered logistic and quantile regression analyses, controlling for demographics and socioeconomic background. RESULTS: Diabetes had a negative effect on mean final grades (scale of 1-5) in compulsory school (-0.07, p < 0.001) and theoretical programmes in upper secondary school (-0.07, p = 0.001). Children with early-onset diabetes (0-4 years) suffered a greater disadvantage as a result of the disease (-0.15, p = 0.001 in compulsory school). The strongest effect was seen in the lowest deciles of the conditional distribution on mean final grades. At age 29, individuals with diabetes were less likely to be gainfully employed (OR 0.82, 95% CI 0.73, 0.91). CONCLUSIONS/INTERPRETATION: The small but significant negative effect of type 1 diabetes on schooling could affect opportunities for further education and career development. Attention must be paid in school to the special needs of children with diabetes.

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.

Socioeconomic factors, rather than diabetes mellitus per se, contribute to an excessive use of antidepressants among young adults with childhood onset type 1 diabetes mellitus: a register-based study.

AIMS/HYPOTHESIS: Mood disorders, including depression, are suggested to be prevalent in persons with type 1 diabetes and may negatively affect self-management and glycaemic control and increase the risk of diabetic complications. The aim of this study was to analyse the prevalence of antidepressant (AD) use in adults with childhood onset type 1 diabetes and to compare risk determinants for AD prescription among diabetic patients and a group of matched controls. METHODS: Young adults ≥ 18 years on 1 January 2006 with type 1 diabetes (n = 7,411) were retrieved from the population-based Swedish Childhood Diabetes Registry (SCDR) and compared with 30,043 age- and community-matched controls. Individual level data were collected from the Swedish National Drug Register (NDR), the Hospital Discharge Register (HDR) and the Labor Market Research database (LMR). RESULTS: ADs were prescribed to 9.5% and 6.8% of the type 1 diabetes and control subjects, respectively. Female sex, having received economic or other social support, or having a disability pension were the factors with the strongest association with AD prescription in both groups. Type 1 diabetes was associated with a 44% (OR 1.44, 95% CI 1.32, 1.58) higher risk of being prescribed ADs in crude analysis. When adjusting for potential confounders including sex, age and various socioeconomic risk factors, this risk increase was statistically non-significant (OR 1.11, 95% CI 0.99, 1.21). CONCLUSIONS/INTERPRETATION: The risk factor patterns for AD use are similar among type 1 diabetic patients and controls, and socioeconomic risk factors, rather than the diabetes per se, contribute to the increased risk of AD use in young adults with type 1 diabetes.

Hospitalization for vascular complications in childhood onset type 1 diabetes--effects of gender and age at onset.

AIMS: To study the cumulative incidence of hospitalization for severe diabetic vascular complications in childhood onset type 1 diabetes patients with special regards to age at onset and gender. METHODS: The Swedish Childhood Diabetes Register (SCDR) was linked to the Swedish Hospital Discharge Register up to 31 December 2004. The following diagnoses were traced: diabetic kidney disease, myocardial infarction, stroke, lower limb arterial disease and diabetes with multiple complications. Cox proportional hazards survival method was applied with the following covariates: maternal age, birthweight deviation from gestational week standard, age at onset and gender. RESULTS: Until 31 December 9974 children had been followed for at least 10 years corresponding to 141 839 person years at risk and 103 (7.3 per 1000 person years) had been hospitalized at least once at the maximum duration of follow-up of 26 years. Diabetic kidney disease was the most common cause of hospitalization and 63 patients had more than one diabetic complication. Female gender (RR=2.02, 95% CI=1.05-3.89) and age at onset of diabetes (RR=1.37, 95% CI=1.20-1.56) were significant risk factors for severe complication. CONCLUSIONS: Hospitalization for severe diabetic complications at a maximum follow-up of 26 years is rather low in Sweden. There is a higher hospitalization rate among females than among males, and also among patients diagnosed with diabetes after 10 years of age than among patients diagnosed before the age of 10 years.

Worldwide childhood type 1 diabetes incidence--what can we learn from epidemiology?

Type 1 diabetes is the most common form of diabetes in most part of the world, although reliable data are still unavailable in several countries. Wide variations exist between the incidence rates of different populations, incidence is lowest in China and Venezuela (0.1 per 100,000 per year) and highest in Finland and Sardinia (37 per 100,000 per year). In most populations girls and boys are equally affected. In general, the incidence increases with age, the incidence peak is at puberty. After the pubertal years, the incidence rate significantly drops in young women, but remains relatively high in young adult males up to the age 29-35 years. Prospective national and large international registries (DIAMOND and EURODIAB) demonstrated an increasing trend in incidence in most regions of the world over the last few decades and increases seem to be the highest in the youngest age group. Analytical epidemiological studies have identified environmental risk factors operating early in life which might have contributed to the increasing trend in incidence. These include enteroviral infections in pregnant women, older maternal age (39-42 years), preeclampsia, cesarean section delivery, increased birthweight, early introduction of cow's milk proteins and an increased rate of postnatal growth (weight and height). Optimal vitamin D supplementation during early life has been shown to be protective. Some of these environmental risk factors such as viruses may initiate autoimmunity toward the beta cell, other exposures may put on overload on the already affected beta cell and thus accelerate the disease process.

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.

School marks for Swedish children whose mothers had diabetes during pregnancy: a population-based study.

AIMS/HYPOTHESIS: To study, at a population level, school performance when leaving compulsory school of Swedish children whose mothers had diabetes during pregnancy compared with a reference population. METHODS: We linked the Swedish Medical Birth Register with the Swedish School Mark Register, which contains school marks for all children in Sweden when leaving compulsory school. A total of 6,397 children were identified whose mothers had a diagnosis of diabetes during pregnancy in the years 1973 to 1986. Data on these children were compared with 1,300,683 children whose mothers had no diagnosis of diabetes during pregnancy. Risks were estimated as odd ratios (ORs) after adjustment for year of birth, maternal age, parity and educational level of the mother. RESULTS: The children's average numerical school marks (for children leaving school between 1988 and 1997) were statistically significantly lower among children born to mothers with diabetes in pregnancy compared with reference children (3.13 +/- 0.01 vs 3.23, p < 0.001). The effect was similar among boys and girls. There was also an effect of maternal diabetes during pregnancy on the risk of the child not completing compulsory school (OR 1.25; 95% CI 1.10-1.43, and after exclusion of infants with certain perinatal characteristics an OR of 1.25; 95% CI 1.02-1.53). When sports and the core subjects mathematics, English and Swedish were studied, there were increased risks of having scores below pass level and decreased probabilities of having scores above pass level for children of mothers with diabetes during pregnancy. CONCLUSIONS/INTERPRETATION: Children of mothers with diabetes during pregnancy performed slightly but significantly less well than reference children when leaving compulsory school at about 16 years old; this was also seen after adjustment for some putative perinatal and social confounders.

School performance in children with type 1 diabetes--a population-based register study.

AIMS/HYPOTHESIS: We examined the school marks of diabetic children in Sweden at the time of leaving compulsory education. Marks were examined in comparison with non-diabetic children and with special regard to age at onset of diabetes. SUBJECTS AND METHODS: The study involved 5,159 children who developed diabetes between 1 July 1977 and 1 July 2000, and 1,330,968 non-diabetic children. We linked the nationwide Swedish Childhood Diabetes Register to the Swedish School-Mark Register, which contains school marks for all children in Sweden at the time of leaving compulsory education (usually at 16 years old). Adjustment was made for potential confounders such as year of birth, maternal age, parity and educational level. RESULTS: The mean of all numerical school marks for diabetic children was slightly but statistically significantly lower than those of the referent children (3.15 +/- 0.01 [mean + SD] vs 3.23, p < 0.001). The lowest mean score was among children with diabetes diagnosis before the age of 2 years (2.97 +/- 0.09 vs 3.08-3.17 in the older age groups, p = 0.10). When individual subjects were studied (sports, mathematics, English and Swedish), a more complex picture emerged. In four subjects (mathematics, English, Swedish and sports) the risk of a diabetic child not getting a school mark or not passing was increased; in sports and English the diabetic children had significantly reduced odds of getting a high mark. CONCLUSIONS/INTERPRETATION: Despite a well-developed diabetes care system, we have not succeeded in preventing the disease from affecting school achievements. Among children with a young age at onset and therefore longer duration, the negative effects tend to be greater.

Genetic influences of the intercellular adhesion molecule 1 (ICAM-1) gene polymorphisms in development of Type 1 diabetes and diabetic nephropathy.

AIM: The intercellular adhesion molecule-1 (ICAM-1) gene is located on chromosome 19p13, which is linked to Type 1 diabetes (T1D). ICAM-1 expression is related to development of T1D and diabetic nephropathy. The present study aims to evaluate the genetic influence of ICAM-1 gene polymorphisms on the development of T1D and diabetic nephropathy. METHODS: Five valid single nucleotide polymorphisms (SNPs) were genotyped in 432 T1D patients (196 patients had diabetic nephropathy) and 187 non-diabetic control subjects by using dynamic allele-specific hybridization (DASH) and pyrosequencing. RESULTS: SNPs rs281432(C/G) and rs5498 E469K(A/G) had high heterozygous indexes. They were significantly associated with T1D [P = 0.026, OR = 1.644 (95% CI 1.138-2.376) and P < 0.001, OR = 2.456 (1.588-3.8)]. Frequencies of the C allele in SNP rs281432(C/G) and the A allele in SNP rs5498 E469K(A/G) increased stepwise from non-diabetic control subjects to T1D patients without diabetic nephropathy and T1D patients with diabetic nephropathy. Further analysis for these two SNPs indicated that T1D patients had increased frequency of the common haplotype C-A, in comparison with non-diabetic control subjects (38.1 vs. 32.1%, P = 0.035). CONCLUSION: The present study provided evidence that SNPs rs281432(C/G) and rs5498 E469K(A/G) in the ICAM-1 gene confer susceptibility to the development of T1D and might also be associated with diabetic nephropathy in Swedish Caucasians.

Can we slow the rising incidence of childhood-onset autoimmune diabetes? The overload hypothesis.

Overload of the beta cell, mediated by a variety of mechanisms, may sensitise it to immune damage and apoptosis, and thus accelerate ongoing autoimmune processes leading to its destruction. Environmental risk determinants that may exert such overload effects include insulin resistance due to excess fat cell accumulation, and increased insulin requirement due to a high growth rate, physical stress (infection, inflammation) or psychological stress. The increasing incidence of childhood diabetes, and the shift to younger age at onset, is unlikely to be driven by environmental risk factors that have been associated with initiation of autoimmunity, e.g. virus infections or early infant feeding. Risk factors that may accelerate beta cell destruction have shown a steady increase in the population, and are more plausible causes of such a pattern of change. Child growth, weight and birthweight are well-established estimates of community wealth and increase in most countries of Europe. Overfeeding of children early in life leads to both accelerated growth and weight, and even a moderate excess of child growth, not necessarily associated with obesity, is associated with risk of type 1 diabetes. New, safe and effective immune-modulating drugs for possible arrest of the autoimmune process may become available in time, but in the interim these accelerating factors may be targeted. Public health programmes for pregnant mothers and young families, aiming at changing overfeeding and the sedentary lifestyle of the children would be preferable to other alternatives. Interventions such as these would be safe and could potentially influence future risks of type 1 and type 2 diabetes and other major threats to adult health.

Birthweight and risk of type 1 diabetes in children and young adults: a population-based register study.

AIMS/HYPOTHESIS: We investigated the association between type 1 diabetes and birthweight by age at disease onset. METHODS: This population-based case-referent study used data from two nationwide case registers that are linked to the Swedish Medical Birth Registry and cover incident cases of type 1 diabetes in the 0- to 14-year (since 1 July 1977) and 15- to 34-year age groups (since 1 January 1983). Of the cases linked to the Medical Birth Registry, a total of 9,283 cases with onset before 15 years of age was recorded before 1 January 2003, and 1,610 cases were recorded with onset before 30 years of age and born after 1973 (together 95% of eligible cases). Multiple births and babies of diabetic mothers were excluded. Sex-specific birthweight by gestational week is expressed as multiples of the standard deviation (SDS) and adjusted for year of birth, maternal age and parity. RESULTS: Cases with onset before 10 years of age (n = 5,792) showed a significant linear trend in odds ratio (OR) by SDS of adjusted birthweight (OR by SDS: 0.062; 95% CI: 0.037-0.086; p < 0.0001), while cases with onset at the age of 10-29 years showed no significant trend (OR by SDS: 0.004; 95% CI: -0.007 to 0.0014; p = 0.22). CONCLUSIONS/INTERPRETATION: The association between type 1 diabetes risk and birthweight seems to be limited to cases with disease onset in younger years.

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.

Acute intermittent porphyria in childhood: a population-based study.

AIM: To establish age-adjusted reference intervals of urinary delta-aminolaevulinic acid (U-ALA) and porphobilinogen (U-PBG) in children, and to analyse the frequency and type of clinical manifestations of acute intermittent porphyria (AIP) in childhood. METHODS: Concentrations of U-ALA and U-PBG in healthy children aged 3-16y were analysed. In a population-based study in northern Sweden of 61 children aged < 18 y with DNA-verified AIP, the clinical manifestations of AIP in childhood were analysed prospectively (up to 2.5 y). Initially the children underwent a standardized investigation (anamnesis, physical examination, laboratory tests). Instructions were issued to keep a structured diary and to provide urine samples for ALA and PBG analyses in all situations of suspected AIP attacks (prospectively). RESULTS: Reference intervals for U-ALA and U-PBG showed age-group variations in children. Baseline levels of U-ALA and U-PBG are increased in gene carriers, one-quarter of them exceeding the 90th percentile of age- and gender-matched controls. Baseline levels did not distinguish symptomatic from non-symptomatic children in a short-term perspective. Clinical evidence of AIP attacks was found in 10% of child AIP gene carriers; in all cases the first attack occurred before the age of 15 y. CONCLUSION: AIP symptoms in children may be vague and of short duration and U-ALA and U-PBG levels are often elevated only slightly or not at all; thus, symptoms and signs may differ from those in adults. Children of AIP gene carriers should be DNA tested, followed up and carefully instructed on preventive measures to avoid developing manifest AIP.

The incidence of Type I diabetes has not increased but shifted to a younger age at diagnosis in the 0-34 years group in Sweden 1983-1998.

AIMS/HYPOTHESIS: To analyse the incidence of Type I (insulin-dependent) diabetes mellitus in the 0-34 years age group in Sweden 1983-1998. METHODS: Incidence and cumulative incidence per 100 000 and Poisson regression analysis of age-period effects was carried out using 11 751 cases from two nation-wide prospective registers. RESULTS: Incidence (95%-CI) was 21.4 (20.8-21.9) in men and 17.1 (16.6-17.5) in women between 0 and 34 years of age. In boys aged 0-14 and girls aged 0-12 years the incidence increased over time, but it tended to decrease at older age groups, especially in men. Average cumulative incidence at 35 years was 748 in men and 598 in women. Cumulative incidence in men was rather stable during four 4-year periods (736, 732, 762, 756), while in women it varied more (592, 542, 617, 631). In males aged 0-34 years, the incidence did not vary between the 4-year periods ( p=0.63), but time changes among the 3-year age groups differed ( p<0.001). In females the incidence between the periods varied ( p<0.001), being lower in 1987-1990 compared to 1983-1986, but time changes in the age groups did not differ ( p=0.08). For both sexes median age at diagnosis was higher in 1983-1986 than in 1995-1998 ( p<0.001) (15.0 and 12.5 years in males; 11.9 and 10.4 in females, respectively). CONCLUSION/INTERPRETATION: During a 16-year period the incidence of Type I diabetes did not increase in the 0-34 years age group in Sweden, while median age at diagnosis decreased. A shift to younger age at diagnosis seems to explain the increasing incidence of childhood Type I diabetes.

The combination of several polymorphic amino acid residues in the DQalpha and DQbeta chains forms a domain structure pattern and is associated with insulin-dependent diabetes mellitus.

IDDM is positively associated with HLA-DQA1*0301-DQB1*0302 (DQ8) and DQA1*0501-DQB1*0201 (DQ2) and negatively associated with DQA1*0102-DQB1*0602 (DQ6). The aim of the present study was to analyze the importance of several polymorphic residues and domains of DQalpha and DQbeta, in addition to residue 52 DQalpha and residue 57 DQbeta, with regard to susceptibility or resistance in new-onset 0- to 15-year-old Swedish children with IDDM (n = 425) and matched controls (n = 367). HLA genotyping identified several polymorphic residues of the DQalpha and DQbeta to be either positively or negatively associated with IDDM, including Arg 52 DQalpha and Asp 57 DQbeta. Leu 69 DQalpha was positively (OR 7.02, P < 0.0001), Ala 69 DQalpha was negatively (OR 0.22, P < 0.0001), Gln 47 DQalpha was positively (OR 5.8, P < 0.0001), Cys 47 DQalpha was positively (OR 2.2, P < 0.0001), Lys 47 DQalpha was negatively (OR 0.47, P < 0.005), and Arg 47 DQalpha was negatively (OR 0.22, P < 0.005) associated with IDDM. Similarly, residues at 11, 18, 45, 48, 50, 53, 55, 61, 64, 66, 76, and 80 were either positively or negatively associated with IDDM. Likewise, for DQbeta, Leu 53 DQbeta was positively (OR 11.01, P < 0.0001), Gln 53 DQbeta was negatively (OR 0.22, P < 0.0005), Arg 70 DQbeta was positively (OR 11.01, P < 0.0001), and Gly 70 DQbeta was negatively (OR 0.19, P < 0.0001) associated like other residues at 71, 74, 84, 85, 86, 89, and 90 DQbeta with IDDM. Certain domains in the DQalpha, RFTIL (at DQalpha positions 52, 61, 64, 66, and 69), were present in 95% of patients compared to 69% of controls (OR 9.01, P(c) < 0.0001), and DQbeta domain GR (at DQbeta positions 45 and 70) was present in 95% of patients and 68% of controls (OR 8.68, P < 0.0001), which correlated better than the individual amino acid residues with IDDM. A combination of the DQalpha and DQbeta chain domains was present in 94% of patients compared to 60% of controls (OR 10.6, P < 0.001). In conclusion, domains in the DQalpha, DQbeta, or both in the DQ molecule explain susceptibility or resistance to IDDM better than individual amino acid residues of DQA1 and DQB1.

Coeliac disease is associated with intrauterine growth and neonatal infections.

UNLABELLED: To investigate whether factors in the fetal or neonatal period influence the risk of later development of coeliac disease we conducted a population-based register study. The Swedish Medical Birth Register was linked with the Hospital Discharge Register and identified 3392 singleton infants born in the period 1987-97 who developed coeliac disease. Perinatal data for these children were compared with all children born in these years. Exposure variables: Maternal age, parity and smoking habits in early pregnancy, preeclampsia, pregnancy duration and birthweight, birthweight by gestational week, Apgar score, neonatal icterus, neonatal infections, maternal-fetal blood group incompatibility, exchange transfusion, phototherapy. Odds ratios and test-based confidence intervals were calculated. Analyses were made with stratification for year of birth and other risk factors. The risk of developing coeliac disease decreased with maternal age and was lower in first-born than in second-born children. Maternal smoking in early pregnancy was a weak risk factor, as was low birthweight. The most evident risk factors were being exposed to neonatal infections (OR = 1.52, confidence limits 1.19: 1.95) and being small for gestational age (OR = 1.45, confidence limits 1.20; 1.75). These risk factors were independent of each other. CONCLUSIONS: We have demonstrated that the intrauterine environment, mainly as mirrored by a low birthweight for gestational age and, independently, neonatal infection diagnosis, is associated with the risk of developing coeliac disease, supporting the idea of a multifactorial aetiology of the disease.

Neurological sequelae in children born after in-vitro fertilisation: a population-based study.

BACKGROUND: There is an absence of population-based long-term studies on the risk of neurological sequelae in children born after in-vitro fertilisation (IVF). Our aim was to compare the frequency of such problems between IVF-born children and controls. METHODS: We did a population-based retrospective cohort study in which we compared development of neurological problems in 5680 children born after IVF, with 11360 matched controls. For 2060 twins born after IVF, a second set of controls (n=4120), all twins, were selected. We obtained data on neurological problems from the records of the Swedish habilitation centres. FINDINGS: Children born after IVF are more likely to need habilitation services than controls (odds ratio 1.7, 95% CI 1.3-2.2). For singletons, the risk was 1.4 (1.0-2.1). The most common neurological diagnosis was cerebral palsy, for which children born after IVF had an increased risk of 3.7(2.0-6.6), and IVF singletons of 2.8 (1.3-5.8). Suspected developmental delay was increased four-fold (1.9-8.3) in children born after IVF. Twins born after IVF did not differ from control twins with respect to risk of neurological sequelae. Low-birthweight and premature infants were more likely to need habilitation than fullterm babies. Maternal age did not affect risk. INTERPRETATION: Our study suggests that children born after IVF have an increased risk of developing neurological problems, especially cerebral palsy. These risks are largely due to the high frequency of twin pregnancies, low birthweight, and prematurity among babies born after IVF. To limit these risks, we recommend that only one embryo should be transferred during IVF.

Is childhood-onset type I diabetes a wealth-related disease? An ecological analysis of European incidence rates.

AIMS/HYPOTHESIS: To describe the epidemiology of childhood-onset Type I (insulin-dependent) diabetes mellitus in Europe, the EURODIAB collaborative group established prospective, geographically-defined registers of children diagnosed under 15 years of age. A total of 16,362 cases were registered by 44 centres during the period 1989-1994. The registers cover a population of approximately 28 million children with most European countries represented. METHODS: In most centres a primary and a secondary source of ascertainment were used so that the completeness of registration could be assessed by the capture-recapture method. Ecological correlation and regression analyses were used to study the relationship between incidence and various environmental, health and economic indicators. RESULTS: The standardised average annual incidence rate during the period 1989-94 ranged from 3.2 cases per 100,000 person-years in the Former Yugoslavian Republic of Macedonia to 40.2 cases per 100,000 person-years in Finland. Indicators of national prosperity such as infant mortality (r = -0.64) and gross domestic product (r = 0.58) were most strongly and significantly correlated with incidence rate and previously-reported associations with milk consumption (r = 0.58), coffee consumption (r = 0.51) and latitude (r = 0.40) were also observed. CONCLUSION/INTERPRETATION: The wide variation in childhood Type I diabetes incidence rates within Europe could be partially explained by indicators of national prosperity. These indicators could reflect differences in environmental risk factors such as nutrition or lifestyle that are important in determining a country's incidence rate.