Aims/hypothesis We aimed to investigate metabolic risk factors, insulin sensitivity and insulin secretion in adolescent offspring of mothers with type 1 diabetes compared with offspring of non-diabetic mothers. Methods During 1993-1999, pregnancies of women with type 1 diabetes in Denmark were prospectively reported to a central registry in the Danish Diabetes Association. Data included information on maternal demography, diabetes status and pregnancy outcome. We invited 746 eligible children from this cohort (index offspring) to a follow-up examination. Control offspring were identified through The Danish Central Office of Civil Registration and matched with respect to date of birth, sex and postal code. Anthropometric measurements and blood sampling for metabolic characterisation, including an oral glucose tolerance test, were performed.Results We examined 278 index offspring (mean age 16.7 years; range 13.0-19.8 years) and 303 control offspring (mean age 16.8 years; range 13.5-20.4 years). Index offspring had higher BMI SD score (0.44: 95% CI 0.21, 0.66) compared with controls, after adjustments for pubertal development and maternal pre-pregnancy BMI. Furthermore, index offspring had a higher prevalence of components included in metabolic syndrome and prediabetes (impaired fasting glucose and/or impaired glucose tolerance), with reduced insulin sensitivity and relative insulin secretion deficiency, compared with controls. Maternal HbA 1c levels in pregnancy were not directly associated with offspring metabolic outcomes. Conclusions/interpretation Adolescent offspring of mothers with type 1 diabetes had a less favourable metabolic profile and higher frequency of prediabetes than the background population. Significant associations between these outcomes and Electronic supplementary material The online version of this article (doi:10.1007/s00125-015-3589-5) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

OBJECTIVEThis study examined the effect of maternal pregestational type 1 diabetes on offspring primary school performance. RESEARCH DESIGN AND METHODSWe performed a prospective combined clinical and register-based cohort study comparing primary school performance in offspring (n = 707) of women with pregestational type 1 diabetes with matched control offspring (n = 60,341). We also examined the association between HbA 1c levels during pregnancy and later school performance among offspring born to women with pregestational type 1 diabetes. RESULTSOffspring of mothers with pregestational type 1 diabetes obtained similar school grades as control offspring when finishing primary school (regression coefficient [b] = -0.13; 95% CI = -0.30 to 0.03; P = 0.12). Adjusting for parental education also resulted in an insignificant difference between the two groups (b = -0.07; 95% CI = -0.23 to 0.09; P = 0.37). Among offspring of women with type 1 diabetes, increasing maternal HbA 1c pregestationally and throughout the pregnancy was associated with lower average school grades. Offspring born to mothers with good glycemic control in the third trimester obtained higher average school grades compared with control offspring. The opposite applied to offspring born to mothers with inadequate glycemic control, who obtained significantly lower average school grades compared with control offspring. CONCLUSIONSOffspring of mothers with pregestational type 1 diabetes obtained similar average grades when finishing primary school compared with matched control offspring. Among offspring of women with type 1 diabetes, we found a consistent negative association between maternal HbA 1c in pregnancy and primary school grades. However, whether this association reflects a direct causal influence of intrauterine hyperglycemia is uncertain.

OBJECTIVEExposure to maternal diabetes in utero may have a negative impact on the developing brain. The objective was to examine long-term cognitive consequences of intrauterine hyperglycemia in adolescent offspring of women with type 1 diabetes and to ascertain a possible association with maternal HbA 1c . RESEARCH DESIGN AND METHODSOffspring of a prospectively followed cohort of women with type 1 diabetes (n = 277) participated in a follow-up examination at the age of 13-19 years. A control group from the background population was identified (n = 301). Cognitive function was evaluated using Reynolds Intellectual Assessment Scales and classified into indices of composite intelligence, verbal and nonverbal intelligence, and composite memory. Frequencies of reading and writing problems and attendance to classes for children with learning difficulties were assessed. RESULTSOffspring of women with type 1 diabetes scored lower in all normalized and standardized intelligence indices compared with controls: composite intelligence (95.7 vs. 100, P = 0.001), verbal intelligence (96.2 vs. 100, P = 0.004), nonverbal intelligence (96.4 vs. 100, P = 0.008), and composite memory (95.7 vs. 100, P = 0.001). A higher frequency of diabetes-exposed offspring had parent-reported learning difficulties in primary school. Differences between groups remained after adjustment for confounders and potential mediators. We found no direct association between maternal HbA 1c and offspring cognitive function in the exposed group. CONCLUSIONSAdolescent offspring of women with type 1 diabetes had lower cognitive function compared with a control group, also after adjustment for confounders and potential mediators. These differences may reflect direct harmful effects of maternal diabetes on neurodevelopment in the offspring.

ObjectiveThe aim of this study was to examine the potential association between intrauterine exposure to maternal diabetes and attention deficits in the offspring.Research design and methodsAdolescent offspring of a prospectively followed cohort of women with type 1 diabetes (n = 269) and a control group from the background population (n = 293) participated in a follow-up assessment in 2012–2013. We used scores from Conners Continuous Performance Test II to assess attention and based on a principal component analysis we evaluated scores on five different attention factors: focused attention, vigilance, hyperactivity/impulsivity, sustained attention and response style.ResultsA higher frequency of the exposed offspring had a parent/self-reported use of Attention Deficit Hyperactivity Disorder (ADHD) medication compared to the control group (2.2% vs. 0.0%, p = 0.01). Clinical significant differences between adolescents exposed to maternal diabetes and unexposed controls were not found in either single scores on Conners Continuous Performance Test or on any of the five attention factors identified.ConclusionsExposure to maternal type 1 diabetes did not seem to increase the risk of attention deficits in the adolescent offspring. However, a higher self-reported use of ADHD medication in the exposed group could suggest a difference in attention not revealed by the applied test.

Intrauterine exposure to maternal type 1 diabetes is associated with a less favorable metabolic profile later in life. Nonalcoholic fatty liver disease is the hepatic manifestation of a cluster of metabolic abnormalities linked to insulin resistance. This study aimed to evaluate the effect of maternal pregestational type 1 diabetes on the presence of fatty liver in offspring and the association between maternal BMI, glycemic control during pregnancy, offspring metabolic risk factors, and offspring level of soluble CD163 (sCD163) (a marker of macrophage activation) and risk of fatty liver. RESEARCH DESIGN AND METHODS This study was a prospective nationwide follow-up study of offspring (n = 278) of mothers with pregestational type 1 diabetes between 1993 and 1999 and matched control subjects (n = 303). Mean age at the time of follow-up was 16.7 years (range 13.0-20.4 years). We used the fatty liver index (FLI) and waist-to-height ratio (WHtR) to evaluate the presence of fatty liver among the offspring. An FLI ‡60 or WHtR >0.469 were used as cutoff points for fatty liver. RESULTS More type 1 diabetes-exposed offspring had high FLI and WHtR indices compared with unexposed control subjects. We found significant associations between increasing maternal prepregnancy BMI, being born large for gestational age, offspring level of sCD163, as well as offspring metabolic risk factors (decreasing adiponectin and HDL cholesterol and increasing leptin, HOMA of insulin resistance, and HOMA of insulin secretion) and degree of fatty liver. CONCLUSIONS Intrauterine exposure to maternal type 1 diabetes and higher maternal prepregnancy BMI may predispose to fatty liver in the offspring. Offspring metabolic risk factors, including sCD163 levels, are associated with indices of fatty liver. Along with the worldwide increase in obesity, the prevalence of nonalcoholic fatty liver disease (NAFLD) is rising, and in the pediatric population, NAFLD is now considered one of the leading causes of hepatic disease (1). Offspring of women with diabetes have an increased risk of developing type 2 diabetes, prediabetes, and obesity (2). This applies to both offspring of mothers with pregestational diabetes as well as gestational diabetes mellitus, and our research group has previously published data from the EPICOM (Epigenetic, Genetic, and Environmental Effects on Growth, Cognitive Functions, and Metabolism in Offspring of Women

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OBJECTIVEThis study examined the long-term consequences for offspring born to mothers with pregestational type 1 diabetes regarding mortality, hospital admissions, and medication. We also examined the association between HbA 1c levels during pregnancy and mortality and incidence of hospital admissions. RESEARCH DESIGN AND METHODSWe performed a prospective combined clinical and register-based cohort study comparing mortality, hospital admissions, and use of medication in offspring (n = 1,326) of women with pregestational type 1 diabetes (index children) with matched control subjects (n = 131,884). We also examined the association between HbA 1c levels during pregnancy and mortality and the incidence of hospital admissions. Participants were monitored from birth to the age of 13-21 years. RESULTSOverall mortality was significantly increased for index children (hazard ratio 2.10, 95% CI 1.33-3.30, P = 0.001). The incidence of hospital admissions for index children was significantly increased (incidence rate ratio [IRR] 1.45, 95% CI 1.38-1.53, P < 0.001), and this was the case for all age groups until the age of 15 years. The incidence of hospital admissions among index children was positively associated with maternal HbA 1c before pregnancy and in the first trimester. In addition, the overall use of medication was increased in index children (IRR 1.13, 95% CI 1.07-1.19, P < 0.001). CONCLUSIONSType 1 diabetes during pregnancy has long-term implications on the health of offspring, with increased mortality, incidence of hospital admissions, and use of medication. Among mothers with type 1 diabetes, glycemic regulation is positively associated with incidence of hospital admissions in offspring.Women with type 1 diabetes have an increased risk of adverse pregnancy outcome, including stillbirth, perinatal mortality, and congenital malformations (1-4). However, studies concerning long-term offspring outcome are sparse and results conflicting. Some studies have demonstrated an increased risk of type 2 diabetes and obesity, whereas others have found no association with BMI, glucose, insulin, or