Lars C. Stene

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

Aims/hypothesisThe 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.MethodsAfter 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.ResultsTwenty 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/interpretationThis 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.

Use of cod liver oil during pregnancy associated with lower risk of Type I diabetes in the offspring.

Aims/hypothesis. To test whether cod liver oil or vitamin D supplements either taken by the mother during pregnancy or by the child in the first year of life is associated with lower risk of Type I (insulin-dependent) diabetes mellitus in children. Methods. We carried out a population-based case control study in Vest-Agder county of Norway, evaluating the use of supplements by a mailed questionnaire. We received responses from 85 diabetic subjects and 1071 control subjects. Odds ratios (OR) with 95 % confidence intervals (CI) were estimated using logistic regression analyses. Results. When mothers took cod liver oil during pregnancy their offspring had a lower risk of diabetes. The unadjusted OR was 0.30, 95 % CI: (0.12 to 0.75), p = 0.01. This association changed very little and was still significant after adjusting for age, sex, breastfeeding and maternal education. Mothers taking multivitamin supplements during pregnancy [adjusted OR = 1.11, 95 % CI: (0.69 to 1.77)], infants taking cod liver oil in the first year of life [adjusted OR = 0.82, 95 % CI: (0.47 to 1.42) and the use of other vitamin D supplements in the first year of life [adjusted OR = 1.27, 95 % CI: (0.70 to 2.31)] was significantly associated with the risk of diabetes. Conclusion/interpretation. We found that cod liver oil taken during pregnancy was associated with reduced risk of Type I diabetes in the offspring. This suggests that vitamin D or the n-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid in the cod liver oil, or both, have a protective effect aginst Type I diabetes. [Diabetologia (2000) 43: 1093–1098]

Relation between occurrence of type 1 diabetes and asthma

A negative association has been observed between type 1 diabetes and atopic diseases in individuals, a finding that supports the Th1/Th2 paradigm. By using published data on disease occurrence in different countries, we show a strong positive association between the occurrence of type 1 diabetes and symptoms of asthma at the population level in Europe and elsewhere. Our finding suggests that there may be common factors influencing susceptibility to the two disorders at the country level. Our observation must be accommodated in explanations of the epidemiology of type 1 diabetes or atopic diseases.

Enterovirus Infection and Progression From Islet Autoimmunity to Type 1 Diabetes: The Diabetes and Autoimmunity Study in the Young (DAISY)

OBJECTIVE To investigate whether enterovirus infections predict progression to type 1 diabetes in genetically predisposed children repeatedly positive for islet autoantibodies. RESEARCH DESIGN AND METHODS Since 1993, the Diabetes and Autoimmunity Study in the Young (DAISY) has followed 2,365 genetically predisposed children for islet autoimmunity and type 1 diabetes. Venous blood and rectal swabs were collected every 3–6 months after seroconversion for islet autoantibodies (against GAD, insulin, or insulinoma-associated antigen-2 [IA-2]) until diagnosis of diabetes. Enteroviral RNA in serum or rectal swabs was detected using reverse transcriptase PCR with primers specific for the conserved 5′ noncoding region, detecting essentially all enterovirus serotypes. RESULTS Of 140 children who seroconverted to repeated positivity for islet autoantibodies at a median age of 4.0 years, 50 progressed to type 1 diabetes during a median follow-up of 4.2 years. The risk of progression to clinical type 1 diabetes in the sample interval following detection of enteroviral RNA in serum (three diabetes cases diagnosed among 17 intervals) was significantly increased compared with that in intervals following a negative serum enteroviral RNA test (33 cases diagnosed among 1,064 intervals; hazard ratio 7.02 [95% CI 1.95–25.3] after adjusting for number of autoantibodies). Results remained significant after adjustment for ZnT8-autoantibodies and after restriction to various subgroups. Enteroviral RNA in rectal swabs was not predictive of progression to type 1 diabetes. No evidence for viral persistence was found. CONCLUSIONS This novel observation suggests that progression from islet autoimmunity to type 1 diabetes may increase after an enterovirus infection characterized by the presence of viral RNA in blood.

Birth weight and childhood onset type 1 diabetes: population based cohort study

Abstract Objective: To assess the associations between birth weight or gestational age and risk of type 1 diabetes. Design: Population based cohort study by record linkage of the medical birth registry and the National Childhood Diabetes Registry. Setting: Two national registries in Norway. Participants: All live births in Norway between 1974 and 1998 (1 382 602 individuals) contributed a maximum of 15 years of observation, a total of 8 184 994 person years of observation in the period 1989 to 1998. 1824 children with type 1 diabetes were diagnosed between 1989 and 1998. Main outcome measures: Estimates of rate ratios with 95% confidence intervals for type 1 diabetes from Poisson regression analyses. Results: The incidence rate of type 1 diabetes increased almost linearly with birth weight. The rate ratio for children with birth weights 4500 g or more compared with those with birth weights less than 2000 g was 2.21 (95% confidence interval 1.24 to 3.94), test for trend P=0.0001. There was no significant association between gestational age and type 1 diabetes. The results persisted after adjustment for maternal diabetes and other potential confounders. Conclusion: There is a relatively weak but significant association between birth weight and increased risk of type 1 diabetes consistent over a wide range of birth weights. What is already known on this topic Results of case-control studies of birth weight and risk of type 1 diabetes have been inconsistent It is possible that a relatively weak association exists, and large studies are needed to find out if this is the case What this study adds This is the largest study of birth weight and type 1 diabetes published to date, and the first one to use a cohort design The incidence of type 1 diabetes increased almost linearly with increasing birth weight over a wide range of birth weights, independent of gestational age, maternal diabetes, and other potential confounders The trend was highly significant, but the increment in risk with increasing birth weight was still relatively low

Maternal Serum Levels of 25-Hydroxy-Vitamin D During Pregnancy and Risk of Type 1 Diabetes in the Offspring

Previous studies indicate reduced risk of type 1 diabetes after intake of vitamin D supplements during pregnancy or early childhood. We aimed to test whether lower maternal serum concentrations of 25-hydroxy-vitamin D (25-OH D) during pregnancy were associated with an increased risk of childhood-onset type 1 diabetes. In this case-control study nested within a cohort of 29,072 women in Norway, 25-OH D levels were measured using a radioimmunoassay on samples from late pregnancy in 109 women delivering a child who developed type 1 diabetes before 15 years of age (case subjects) and from 219 control women. Dividing the levels of maternal 25-OH D into quartiles, there was a trend toward a higher risk of type 1 diabetes with lower levels of vitamin D during pregnancy. The odds of type 1 diabetes was more than twofold higher for the offspring of women with the lowest levels of 25-OH D compared with the offspring of those with levels above the upper quartile. Given future replication in independent cohorts, our findings provide support for the initiation of a randomized intervention trial to prevent type 1 diabetes in children by enhancing maternal 25-OH D status during pregnancy.

High Prevalence of Human Enterovirus A Infections in Natural Circulation of Human Enteroviruses

ABSTRACT Human enterovirus (HEV) infections can be asymptomatic or cause only mild illness; recent evidence may implicate HEV infection in type 1 diabetes mellitus and myocarditis. Here, we report the molecular characterization of HEV obtained in serial monthly collections from healthy Norwegian infants. A total of 1,255 fecal samples were collected from 113 healthy infants beginning at age 3 months and continuing to 28 months. The samples were analyzed for HEV nucleic acid by real-time PCR. Fifty-eight children (51.3%) had HEV infections. One hundred forty-five positive samples were typed directly by nucleotide sequencing of the VP1 region. HEV-A was detected most frequently, with an overall prevalence of 6.8%. HEV-B was present in 4.8% of the samples and HEV-C in only 0.2% of the samples. No poliovirus or HEV-D group viruses were detected. Twenty-two different serotypes were detected in the study period: the most common were EV71 (14.5%), CAV6 (10.5%), CAV4 (8.9%), E18 (8.9%), and CBV3 (7.3%). These findings suggest that the prevalence of HEV infections in general, and HEV-A infections in particular, has been underestimated in epidemiological studies based on virus culture.

Maternal and paternal age at delivery, birth order, and risk of childhood onset type 1 diabetes: population based cohort study

Abstract Objective: To estimate the associations of maternal and paternal age at delivery and of birth order with the risk of childhood onset type 1 diabetes. Design: Cohort study by record linkage of the medical birth registry and the national childhood diabetes registry in Norway. Setting: Norway. Subjects: All live births in Norway between 1974 and 1998 (1.4 million people) were followed for a maximum of 15 years, contributing 8.2 million person years of observation during 1989-98. 1824 cases of type 1 diabetes diagnosed between 1989 and 1998 were identified. Main outcome measures: Incidence of type 1 diabetes. Results: There was no association between maternal age at delivery and type 1 diabetes among firstborn children, but among fourthborn children there was a 43.2% increase in incidence of diabetes for each five year increase in maternal age (95% confidence interval 6.4% to 92.6%). Each increase in birth order was associated with a 17.9% reduction in incidence (3.2% to 30.4%) when maternal age was 20-24 years, but the association was weaker when maternal age was 30 years or more. Paternal age was not associated with type 1 diabetes after maternal age was adjusted for. Conclusions: Intrauterine factors and early life environment may influence the risk of type 1 diabetes. The relation of maternal age and birth order to risk of type 1 diabetes is complex. What is already known on this topic Maternal age at birth is positively associated with risk of childhood onset type 1 diabetes Studies of the effect of birth order on risk of type 1 diabetes have given inconsistent results What does this study add? In a national cohort, risk of diabetes in firstborn children was not associated with maternal age Increasing maternal age was a risk factor in children born second or later The strength of the association increased with increasing birth order

Vitamin D status among immigrant mothers from Pakistan, Turkey and Somalia and their infants attending child health clinics in Norway.

High prevalences of vitamin D deficiency have been reported in non-Western immigrants moving to Western countries, including Norway, but there is limited information on vitamin D status in infants born to immigrant mothers. We aimed to describe the vitamin D status and potentially correlated factors among infants aged 6 weeks and their mothers with Pakistani, Turkish or Somali background attending child health clinics in Norway. Eighty-six healthy infants and their mothers with immigrant background were recruited at the routine 6-week check-up at nine centres between 2004 and 2006. Venous or capillary blood was collected at the clinics from the mother and infant, and serum separated for analysis of 25-hydroxyvitamin D (s-25(OH)D) and intact parathyroid hormone (s-iPTH). The mean maternal s-25(OH)D was 25.8 nmol/l, with 57 % below 25 nmol/l and 15 % below 12.5 nmol/l. Of the mothers, 26 % had s-iPTH>5.7 pmol/l. For infants, mean s-25(OH)D was 41.7 nmol/l, with 47 % below 25 nmol/l and 34 % below 12.5 nmol/l. s-25(OH)D was considerably lower in the thirty-one exclusively breast-fed infants (mean 11.1 nmol/l; P < 0.0001). Use of vitamin D supplements and education showed a positive association with maternal s-25(OH)D. There was no significant association between mothers and childs s-25(OH)D, and no significant ethnic or seasonal variation in s-25(OH)D for mothers or infants. In conclusion, there is widespread vitamin D deficiency in immigrant mothers and their infants living in Norway. Exclusively breast-fed infants who did not receive vitamin D supplements had particularly severe vitamin D deficiency.

Atopic disorders and risk of childhood-onset type 1 diabetes in individuals

Background Data on the relationship between Th2‐biased atopic disorders and Th1‐biased autoimmune diseases such as type 1 diabetes are conflicting. Many studies have not defined the time sequence of disease appearance, and few have investigated the role of candidate risk factors.