The type 1 diabetes protective HLA DQB1*0602 allele is less frequent in gestational diabetes mellitus.

AIMS/HYPOTHESIS: We tested whether gestational diabetes mellitus (GDM) is associated with HLA-DQ genotypes. METHODS: A total of 764 mothers with non-autoimmune (GAD65, insulinoma-associated protein 2 [IA-2] and insulin autoantibody-negative) GDM were ascertained between September 2000 and August 2004 in the population-based Diabetes Prediction in Skåne (DiPiS) study. HLA-DQB1 genotypes were determined in these mothers and in 1191 randomly selected non-diabetic control mothers also negative for islet autoantibodies. The data were analysed in relation to maternal age, country of birth, number of pregnancies/siblings and pregnancy weight gain. RESULTS: The frequency of type 1 diabetes high-risk HLA-DQ alleles (DQB1*0201, DQB1*0302) did not differ between GDM mothers and controls. In contrast, the low-risk DQB1*0602 allele was less prevalent (OR 0.64, 95% CI = 0.51-0.80, p = 0.0006) in GDM than in control mothers. The difference in DQB1*0602 frequency between GDM mothers and controls remained after multiple logistic regression analysis correcting for maternal age, country of birth, number of pregnancies/siblings and weight gain during pregnancy (OR 0.67, 95% CI 0.51-0.88, p = 0.009). CONCLUSIONS/INTERPRETATION: The negative association between mothers who have non-autoimmune GDM and HLA-DQ*0602 suggest that this allele may protect not only from type 1 diabetes but also from GDM.

Cord blood islet autoantibodies and seasonal association with the type 1 diabetes high-risk genotype.

OBJECTIVE: Human leukocyte antigen DQ (HLA-DQ) genetic factors and islet autoantibodies are strongly associated with type 1 diabetes (T1D) and are currently used to predict T1D. This study examined whether islet autoantibodies in the cord blood of newborns to nondiabetic mothers were associated with the (T1D) high-risk genotype HLA-DQ2/8, gestational infections or both. STUDY DESIGN: Cord blood samples were taken from 33 683 newborns and used for HLA typing and analyses of islet autoantibodies. Parents completed questionnaires when the child was 2 months of age. RESULT: The prevalence of newborn islet autoantibodies consistently varied with season over 4 years (P<0.0001); lowest in first quarter (1.2%) and highest in third (2.4%). Cord blood islet autoantibodies were associated with HLA-DQ2/8 in the second (OR, 2.30; P=0.02), third (OR, 2.12; P=0.008) and fourth quarters (OR, 2.49; P=0.007), but not in the first (OR, 1.13). Reported gastroenteritis was additionally associated with islet autoantibodies in the third quarter (OR, 1.80, P=0.04). CONCLUSION: An association between HLA and islet autoimmunity may depend on environmental exposure during pregnancy. Follow-up of mothers and children will determine risk of T1D.

Islet cell autoantibody levels after the diagnosis of young adult diabetic patients.

AIMS: The aim was to determine the course of islet cell antibodies [glutamate decarboxylase (GADA), tyrosine phosphatase-like islet antigen 2 (IA-2A) and islet cell (ICA)] after the diagnosis of the diabetic patient. METHODS: The Diabetes Incidence Study in Sweden (DISS) attempted to prospectively enrol all newly diagnosed diabetic patients aged 15-34 years during 1992 and 1993. C-peptide and autoantibody levels were determined from venous blood samples at diagnosis and again at yearly intervals for 6 years. RESULTS: After the first year, the odds of remaining GADA positive decreased by 9% per year [odds ratio (OR) = 0.91, 95% confidence interval (CI) = 0.85-0.96] while the mean GADA index remained unchanged ( = 0.8, P = 0.37). There was no change in the percentage of subjects testing IA-2A positive after the first year ( = 0.1, P = 0.75). However, the mean index decreased 0.04 per year (95% CI: 0.03-0.05)-a 7.9% decline (95% CI: 5.4-10.4%). The odds of a subject testing positive for ICA decreased by 24% per year (OR = 0.76, 95% CI = 0.70-0.82). The mean ICA levels decreased 0.75 per year (95% CI: 0.66-0.84)-a 16.4% decline (95% CI: 14.1-18.6%). The rate of change in titres for all three autoantibodies was independent of gender, human leucocyte antigen genotype and C-peptide status. CONCLUSIONS: GADA levels remained high while ICA levels declined. In contrast to a previous study, we found that the proportion of IA-2A subjects remaining positive did not decrease after the first year, while the average index decreased slightly.

Relationship between increased relative birthweight and infections during pregnancy in children with a high-risk diabetes HLA genotype.

AIMS/HYPOTHESIS: Children with high-risk type 1 diabetes HLA genotype have increased risk of high relative birthweight (HrBW), while cord blood islet autoantibodies decrease the risk. As gestational infections may affect offspring type 1 diabetes risk, the aims were to test whether: (1) children of mothers reporting gestational infections have increased HrBW; (2) gestational infections explain islet autoantibody reduction of HrBW; and (3) gestational infections affect the association between HLA and HrBW. SUBJECTS AND METHODS: HLA genotypes and autoantibodies to glutamic acid decarboxylase, insulinoma-associated protein 2 and insulin were determined in cord blood of children born to non-diabetic mothers in the Diabetes Prediction in Skåne (DiPiS) study. Mothers reported gestational infections when the child was 2 months old. RESULTS: Fever or gastroenteritis during pregnancy was reported by 2,848/19,756 mothers (14%); 339 in more than one trimester. Children whose mothers reported infections had increased risk of HrBW (p = 0.0003), particularly in the absence of cord blood islet autoantibodies (interaction between HrBW, islet autoantibodies and infections, p = 0.0005). The effect on HrBW by high-risk HLA-DQ2/8 was aggravated by infections in more than one trimester (odds ratio [OR] = 5.24; p = 0.003) (interaction; p = 0.022). When infections were reported, cord blood islet autoantibodies decreased HrBW (OR = 0.34; p = 0.0002). CONCLUSIONS/INTERPRETATION: This study revealed that: (1) gestational fever, gastroenteritis, or both, increased the risk of HrBW; (2) cord blood islet autoantibodies decreased the risk of HrBW only in combination with infections; and (3) infections aggravated the association between HLA-DQ2/8 and HrBW. These data suggest an interaction between HLA, gestational infections, islet autoantibodies and fetal growth.

Diabetes-associated HLA genotypes affect birthweight in the general population.

AIMS/HYPOTHESIS: The aim of our study was to test the hypothesis that HLA genotypes conferring risk of diabetes, cord blood autoantibodies, or both are associated with increased birthweight. METHODS: HLA genotypes were determined in dried blood spots of cord blood from a total of 16,709 children born to healthy mothers in the Diabetes Prediction in Skåne (DiPiS) study, a population-based observational clinical investigation of newborn children. Children born to mothers with diabetes or gestational diabetes were excluded. Autoantibodies to glutamic acid decarboxylase (GAD65Ab) and insulinoma-associated protein 2 were determined in standard radioligand binding assays. Birthweight was adjusted for gestational age and divided into quartiles. The upper quartile was defined as high relative birthweight (HrBW) and the lower quartile as low relative birthweight (LrBW). RESULTS: Genotypes conferring risk of type 1 diabetes were strongly associated with relative birthweight (rBW) (p=0.01). The high-risk HLA-DQ2/8, DQ8/0604 and DQ8/X genotypes were associated with HrBW (odds ratio [OR] [95% CI]=1.20 [1.08-1.33], p=0.0006). The HLA-DQB1*0603 allele, which is negatively associated with type 1 diabetes, was also associated with HrBW (p=0.025), confirming a previous report on DQB1*0603-linked HLA-DR13. GAD65Ab were negatively associated with HrBW (OR [95% CI]=0.72 [0.56-0.93], p=0.01). Regression analysis showed that the HLA-associated increase in rBW was independent of confounding factors. CONCLUSIONS/INTERPRETATION: HLA genotypes may be associated with intrauterine growth independent of type 1 diabetes risk. The epidemiological observation that high birthweight is a risk factor for type 1 diabetes could possibly result from a moderating effect on intrauterine growth of HLA genotypes conferring a high risk of diabetes.

Symptoms of depression are important to psychological adaptation and metabolic control in children with diabetes mellitus.

AIMS: Sixty-two children (37 girls, 25 boys) between 9 and 18 years of age were enrolled to investigate: (1) the relationship between adaptation to diabetes mellitus (DM) and psychological functioning; (2) if adaptation or psychological functioning was related to metabolic control; and (3) if the patients' ability to cope with diabetes as assessed by physicians, was correlated to adaptation or psychological functioning. METHODS: Psychological functioning was measured by three general psychological instruments for depressive symptoms, self-esteem and fear. Diabetes adaptation was evaluated by questionnaires and coping with diabetes by an assessment of the physicians. Metabolic control was expressed by the individual HbA1c measured during the last year. RESULTS: Adaptation to diabetes correlated to psychological functioning (depression, P<0.001; self-esteem, P<0.01; and fear, P<0.01). Multiple regression analyses showed that metabolic control was predicted by adaptation (P=0.0013) with monitoring of diabetes as the only significant aspect of the adaptation (P < or = 0.0001). In turn, adaptation was predicted by symptoms of depression and metabolic control (P<0.0001). In support of this observation, a depressed (n = 9) and a non depressed (n= 53) group showed significant differences in metabolic control (P < or = 0.01), adaptation (P < or = 0.001) and self-esteem (P < or = 0.001). The only significant variable for the physicians assessment was metabolic control, which explained 35 % of the variance (P < 0.001). CONCLUSIONS: The major conclusion is that symptoms of depression affect both adaptation and metabolic control. It should be of concern to identify patients with depressive symptoms, offer treatment for their emotional difficulties and increase the support for taking care of their diabetes.

Ten-year clinical, developmental, and intellectual follow-up of children with congenital cytomegalovirus infection without neurologic symptoms at one year of age.

OBJECTIVE: This study was undertaken to ascertain whether children with congenital cytomegalovirus (CMV) infection at birth, but without neurologic symptoms at 1 year of age, differed in somatic, neurologic, developmental, or intellectual status from matched control children at long-term follow-up. MATERIAL AND METHODS: Congenital CMV infection, as demonstrated by isolation of the virus within the first week of life, was diagnosed in 44 (0.5%) of 9806 infants. From this basic CMV-infected population, children who developed neurologic disturbances including sensorineural deafness before 1 year of age were excluded (n = 7), as were those unwilling to participate (n = 2). Congenitally infected infants (n = 35) and matched control infants (n = 53) were followed up clinically and neurologically. At 21 months, development was assessed with the Griffiths' Developmental Scale and at 7 years of age neurologic status was assessed with the Stott test and intellectual development with the Wechsler Intelligence Scale for Children. RESULTS: As reported previously, 18% (8/44) of the CMV-infected infants manifested symptoms at birth, as compared to 8% (4/53) in the control group. In the congenital CMV group 7% (2/30) children tested had abnormal Stott test results, as compared to 2% (1/43) in the control group. Thirty-two CMV-infected and 51 control group children were assessed with the Griffiths' scale at 21 months of age. The two groups did not differ significantly, either in mean scores (6.3 +/- 2.3 vs 6.1 +/- 1.9) or in the proportion of children with scores below normal (19% [6/32] vs 16% [8/51]). Twenty-five CMV-infected and 41 control group children were assessed with the Wechsler Intelligence Scale for Children at 7 years of age (median 86 months; range, 82 to 90 and 82 to 91, respectively). The two groups did not differ significantly, either in mean scores (5.8 +/- 2.0 vs 6.4 +/- 1.6) or in the proportion of children with scores below normal (12% [3/25] vs 5% [2/41]). CONCLUSION: Children with congenital CMV infection are unlikely to be at an increased risk of subsequent neurodevelopmental or intellectual impairment if they show normal development at 12 months of age.

Psychological reactions at the onset of insulin-dependent diabetes mellitus in children and later adjustment and metabolic control.

The initial psychological reactions at the onset of insulin-dependent diabetes mellitus (IDDM) in a population-based sample of 76 children were studied with staff observations and a self-report questionnaire for children 12 years of age and more. Younger children reacted with more anger and less distress than the older children. High initial self-reported distress was associated with poorer subjective psychological IDDM adjustment at a follow-up 10 months later for the older children. The children's initial reactions as well as later adjustment were intimately associated with maternal initial reactions in the total group. The metabolic control, estimated as the mean level of the major fraction of glycosylated haemoglobin (Hb AIc) during the first 2 years, was poorer in the adolescent group. Initial anxiety over injections and protest but low general distress in mothers and children were associated with better metabolic control.

Relations between age, metabolic control, disease adjustment and psychological aspects in insulin-dependent diabetes mellitus.

The relations between age, metabolic control, disease adjustment, and psychological factors in boys and girls with recently diagnosed insulin-dependent diabetes mellitus (IDDM) were studied. Older girls had significant higher postremission glycosylated haemoglobin A (Hb AIc) levels (p = 0.008). Girls with more hospitalizations had a lower developmental level (p = 0.05), and had significantly more problems in the behavioural rating (p = 0.05). Boys with more hospitalizations had a more external locus of control (p = 0.01), more difficulties with disease adjustment, more emotional problems, and were also clinically assessed as having more behavioural problems. Boys showing more difficulties in psychological adjustment to the disease also had higher postremission Hb AIc levels (p = 0.02). Although Swedish children with IDDM of short disease duration do not differ from healthy children in important psychological aspects, older girls and a small group of problematic younger boys are at risk of developing metabolic imbalance after a short disease duration.

Psychosocial aspects of type 1 diabetes mellitus in children 0-14 years of age.

A total clinic sample of 67 diabetic and their parents were followed prospectively together with a referent group in this longitudinal study of psychosocial factors in childhood diabetes. Measurements of psychosocial stress showed statistically more negative life events and coping problems in the diabetic group during the first two years of life. The crisis/coping pattern at onset of the disease varied but most parents/and children scored low distress already after 4 weeks. High distress at onset correlated to high distress at a twelve month follow-up interview. Among the parents planful problem solving and distancing were the most prevalent coping mechanisms. The diabetic children had a rather good adaptation to the disease after 12 months of disease duration. Psychiatric problems were not more common in the diabetic children compared to a normal group. Metabolic imbalance correlated to external locus of control, low development quotient and many life events.

Congenital cytomegalovirus infection and sensorineural hearing loss.

In a prospective study still in progress, infants with congenital cytomegalovirus (CMV) infection were followed with audiological, ophthalmological, neurological, and psychological tests; 10,328 infants were investigated within a 5-year period (1977-1982) by virus isolation in urine within the first week of life. Fifty (0.5%) had a congenital CMV infection. In this group four children turned out to have total deafness and a fifth possibly a mild hearing disorder. In one case the deafness was associated with severe mental retardation and spastic tetraplegia. The mother of the child had a primary CMV infection in the first trimester. In one of the other cases of severe deafness it could be proven that the mother had had a secondary CMV infection and in further two cases, presumed secondary infections. Prospective serological tests of the mothers would not have revealed more than one of the high risk pregnancies. The value of vaccination against congenital CMV infection is questioned. Screening of newborn infants for congenital CMV infection is recommended in order to reveal infants at high risk for deafness and make an early habilitation possible.

Congenital cytomegalovirus infection and disease in Sweden and the relative importance of primary and secondary maternal infections. Preliminary findings from a prospective study.

In a prospective Swedish study started in 1977 and still in progress 10 328 newborn infants in an urban district were investigated for cytomegalovirus (CMV) excretion in the urine by the virus isolation test. Congenital infection was found in 50 cases (0.5%). Of 47 infected infants with known clinical status at birth 9 (19%) had hepatomegaly, splenomegaly, jaundice and/or petechiae. The symptoms were moderate or mild. Of the infants followed up, 2 (25%) of 8 neonatally symptomatic ones and 3 (9%) of 35 asymptomatic ones developed neurologic sequelae. Altogether 5 (12%) of 43 had permanent neurologic symptoms corresponding to 0.06% in the general population. The children ranged in age from 6 months to 4 yr at the last examination. 21 mothers of the 47 infants with known status at birth had a confirmed or presumed primary infection, 15 a confirmed or presumed secondary infection and 11 an undetermined type of infection. Of the 5 infants with neurologic sequelae, 1 with a grave psychomotor retardation and deafness was born to a mother with a primary infection in the 1st trimester; 1 infant with a moderate retardation and 3 deaf infants were all exposed to confirmed or presumed secondary maternal infections. Prospective serological studies of maternal sera in early pregnancy would have suspected only the gravely retarded infant to be at risk.