Epigenetic and transcriptomic alterations in offspring born to women with type 1 diabetes (the EPICOM study).

BACKGROUND: Offspring born to women with pregestational type 1 diabetes (T1DM) are exposed to an intrauterine hyperglycemic milieu and has an increased risk of metabolic disease later in life. In this present study, we hypothesize that in utero exposure to T1DM alters offspring DNA methylation and gene expression, thereby altering their risk of future disease. METHODS: Follow-up study using data from the Epigenetic, Genetic and Environmental Effects on Growth, Metabolism and Cognitive Functions in Offspring of Women with Type 1 Diabetes (EPICOM) collected between 2012 and 2013. SETTING: Exploratory sub-study using data from the nationwide EPICOM study. PARTICIPANTS: Adolescent offspring born to women with T1DM (n=20) and controls (n=20) matched on age, sex, and postal code. MAIN OUTCOME MEASURES: This study investigates DNA methylation using the 450K-Illumina Infinium assay and RNA expression (RNA sequencing) of leucocytes from peripheral blood samples. RESULTS: We identified 9 hypomethylated and 5 hypermethylated positions (p < 0.005, |ΔM-value| > 1) and 38 up- and 1 downregulated genes (p < 0.005, log2FC ≥ 0.3) in adolescent offspring born to women with T1DM compared to controls. None of these findings remained significant after correction for multiple testing. However, we identified differences in gene co-expression networks, which could be of biological significance, using weighted gene correlation network analysis. Interestingly, one of these modules was significantly associated with offspring born to women with T1DM. Functional enrichment analysis, using the identified changes in methylation and gene expression as input, revealed enrichment in disease ontologies related to diabetes, carbohydrate and glucose metabolism, pathways including MAPK1/MAPK3 and MAPK family signaling, and genes related to T1DM, obesity, atherosclerosis, and vascular pathologies. Lastly, by integrating the DNA methylation and RNA expression data, we identified six genes where relevant methylation changes corresponded with RNA expression (CIITA, TPM1, PXN, ST8SIA1, LIPA, DAXX). CONCLUSIONS: These findings suggest the possibility for intrauterine exposure to maternal T1DM to impact later in life methylation and gene expression in the offspring, a profile that may be linked to the increased risk of vascular and metabolic disease later in life.

Apolipoprotein D and transthyretin are reduced in female adolescent offspring of women with type 1 diabetes: The EPICOM study.

AIMS: Adolescent offspring exposed to maternal diabetes during intrauterine life show a less favourable metabolic profile than the background population. Here, we hypothesize that offspring of women with type 1 diabetes (T1D), possess sex-specific alterations in the serum profile of proteins involved in lipid, metabolic and transport processes and that these alterations are associated with lipid profile and indices of insulin sensitivity and secretion. METHODS: A prospective nationwide follow-up study (EPICOM) in a Danish population. Blood samples were assessed from offspring of women with T1D (index offspring, n = 267, 13-20 years), and matched control offspring (n = 290). Serum proteins were analysed using a 25-plex cardio-metabolic targeted proteomics assay, which includes 12 apolipoproteins and 13 transport and inflammatory proteins. RESULTS: Apolipoprotein D (ApoD) and transthyretin (TTR) were reduced in index females as compared to female controls (-8.1%, p < 0.001 and -6.1%, p = 0.006 respectively), but not in index males (2.2%, p = 0.476 and -2.4%, p = 0.731 respectively). Sex-dependent inverse associations between exposure to maternal T1D in utero and ApoD and TTR were significant after adjusting for age, BMI-SDS and Tanner stage (OR = 0.252 [95% CI 0.085, 0.745], p = 0.013 and OR = 0.149 [95% CI 0.040, 0.553], p = 0.004). ApoD correlated to indices of insulin sensitivity and secretion in a similar sex-specific pattern in crude and adjusted analyses. CONCLUSIONS: Low ApoD may be regarded as an early risk marker of metabolic syndrome. A possible link between ApoD and cardiovascular disease needs further investigation.

Differential effects of age and sex on insulin sensitivity and body composition in adolescent offspring of women with type 1 diabetes: results from the EPICOM study.

AIMS/HYPOTHESIS: The aim of this study was to investigate the influence of age and sex on insulin sensitivity and insulin secretion in the adolescent offspring of women with type 1 diabetes, compared with the background population. METHODS: This was a prospective nationwide follow-up study (Epigenetic, Genetic and Environmental Effects on Growth, Cognitive Functions and Metabolism in Offspring of Women with Type 1 Diabetes [EPICOM]) in a Danish population. We examined 278 offspring of women with type 1 diabetes from the Danish Diabetes Association Register born during 1993-1999 (index offspring) and 303 control offspring, identified through the Danish Central Office of Civil Registration and matched to the index offspring with respect to date of birth, sex and postal code. The offspring had an overall mean age of 16.7 years (range 13.0-20.4 years). The main outcomes were age-related changes in fasting OGTT-derived indices for insulin sensitivity (BIGTT-SI0-30-120, Matsuda index, HOMA-IR) and insulin secretion (acute insulin response [BIGTT-AIR0-0-30-120], insulinogenic index, HOMA of insulin secretory function [HOMA-ß], disposition index) and physical activity (International Physical Activity Questionnaire). In addition, we determined total body fat (TBF) percentage using dual-energy x-ray absorptiometry. RESULTS: We observed significantly lower insulin sensitivity in index offspring compared with control offspring, increasing with age. The differences were attenuated after adjustment for TBF percentage, but were still significant at 17 and 18 years of age. We also observed decreased disposition index and insulin secretion-sensitivity index-2 in index offspring at the same age, but we found no significant differences in other indices of insulin secretion compared with control offspring. With age, TBF percentage became increasingly more divergent between index and control offspring, and was consistently higher among female but not male index offspring. CONCLUSIONS/INTERPRETATION: Differences in insulin sensitivity between the offspring of women with type 1 diabetes and control offspring increased with age. This was only partially explained by higher adiposity in the index offspring. TRIAL REGISTRATION: ClinicalTrials.gov NCT01559181.

Impact of type 1 diabetes on maternal long-term risk of hospitalisation and mortality: a nationwide combined clinical and register-based cohort study (The EPICOM study).

AIMS/HYPOTHESIS: The aims of this study were to examine long-term mortality and morbidity rates in mothers with type 1 diabetes, both overall and according to the level of albuminuria prior to pregnancy, the presence of hypertension, pre-eclampsia and periconceptional HbA1c. METHODS: This study was a part of the EPICOM (Environmental Versus Genetic and Epigenetic Influences on Growth, Metabolism and Cognitive Function in Offspring of Mothers with Type 1 Diabetes) study, which is a prospective follow-up study focusing on pregnancies complicated by maternal type 1 diabetes. We carried out a nationwide combined clinical and register-based cohort study of mortality rates and hospital admissions in mothers with diabetes (n = 986) who gave birth between 1992 and 2000. Control mothers (n = 91,441) were women from the background population, matched according to age and year of childbirth. Age at follow-up was 32-66 years. RESULTS: Mortality rate was increased threefold in mothers with diabetes compared with control mothers (HR 3.41 [95% CI 2.42, 4.81]; p < 0.0001), and was also increased with pre-gestational kidney dysfunction (normoalbuminuria, HR 2.17 [95% CI 1.28, 3.68]; microalbuminuria, HR 3.36 [95% CI 0.82, 13.8]; macroalbuminuria, HR 12.9 [95% CI 5.45, 30.7]). Moreover, the presence of hypertension prior to or at any time during pregnancy and of pre-eclampsia also increased mortality rate (hypertension, HR 4.34 [95% CI 2.13, 8.84]; pre-eclampsia, HR 5.55 [95% CI 2.71, 11.4]). Mortality rate also increased with higher levels of HbA1c in early pregnancy (HbA1c ≤75 mmol/mol [≤9%], HR 2.15 [95% CI 1.31, 3.53]; HbA1c >75 mmol/mol [>9%], HR 6.10 [95% CI 2.67, 14.0]). However, in mothers with diabetes and HbA1c <64 mmol/mol (<8%) in the first trimester and normal pre-gestational urinary albumin excretion rate (n = 517), mortality rate was comparable with that of control mothers. Among mothers with diabetes, mortality rate was associated with HbA1c level: per 11 mmol/mol (1 percentage point) increase in HbA1c, HR was 1.52 (95% CI 1.19, 1.94; p = 0.001). In mothers with diabetes, the overall incidence of hospital admissions was more than double (incidence rate ratio [IRR] 2.69 [95% CI 2.59, 2.80]; p < 0.0001) that of control mothers, as were admissions with various diagnoses from 14 out of 19 ICD-10 chapters. Among mothers with diabetes, the IRR for hospital admissions increased with the level of HbA1c: per 11 mmol/mol (1 percentage point) increase in HbA1c, HR was 1.07 (95% CI 1.04, 1.10; p < 0.0001). CONCLUSIONS/INTERPRETATION: Overall, mothers with type 1 diabetes have a two- to threefold increase in mortality and morbidity rates. HbA1c levels, level of albuminuria around the time of conception, and the presence of hypertension and pre-eclampsia are important risk factors for mortality/morbidity in this cohort. However, it is reassuring that mothers with type 1 diabetes without kidney complications and with HbA1c <64 mmol/mol (<8%) in early pregnancy have a similar survival potential during the period where they are raising their children to that of control mothers from the background population.

Increased metabolic risk in adolescent offspring of mothers with type 1 diabetes: the EPICOM study.

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 HbA1c 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 maternal HbA1c levels in pregnancy could not be demonstrated. TRIAL REGISTRATION: ClinicalTrials.gov NCT01559181.

Fetal sonographic characteristics associated with shoulder dystocia in pregnancies of women with type 1 diabetes.

INTRODUCTION: Shoulder dystocia is a rare but severe complication of vaginal delivery and diabetic women are at high risk. The aim of this study was to identify fetal sonographic and maternal glycemic characteristics associated with shoulder dystocia in pregnant women with type 1 diabetes. MATERIAL AND METHODS: Twelve cases (5%) of shoulder dystocia among 241 consecutive vaginal deliveries in women with type 1 diabetes followed at Rigshospitalet University Hospital in 2009-2013 were retrospectively identified in a local database. Fetal sonographic and clinical data were compared with 69 women with type 1 diabetes and uncomplicated vaginal deliveries. RESULTS: Women experiencing shoulder dystocia compared with women with uncomplicated deliveries had a higher glycated hemoglobin (HbA1c) in early pregnancy [median 7.0% (range 5.9-8.1) vs. 6.6% (range 5.4-10.0, P = 0.04)], whereas in late pregnancy, HbA1c in the two groups of women was comparable [6.1% (range 5.5-6.9) vs. 6.0% (range 4.7-8.4, P = 0.30)]. Fetal biometry at 36 weeks showed a higher estimated fetal weight of 3597 g (range 3051-4069) vs. 2989 g (range 2165-4025), P < 0.001, corresponding to 20% (4-41%) vs. 5% (-20 to 44%) above the mean estimated fetal weight for gestational age (P = 0.002) and a greater abdominal circumference SD score of 2.51 (range 1.56-4.20) vs. 1.33 (range -1.08 to 4.25), P = 0.001). Head circumference was comparable. Vacuum extraction was more frequent during deliveries with shoulder dystocia (58 vs. 17%, P = 0.005). Seven (58%) newborns with shoulder dystocia had brachial plexus injuries, fractures, intra-abdominal bleeding or needed resuscitation. CONCLUSIONS: Excessive estimated fetal weight and abdominal circumference at 36 weeks' sonographic examination may help in identifying diabetic women at high risk of later shoulder dystocia.

GAD65 autoantibodies and glucose tolerance in offspring born to women with and without type 1 diabetes (The EPICOM study).

The aims of this study were to examine presence of GAD65 autoantibodies (GAD65aab) in offspring born to women with type 1 diabetes (T1D) and controls and if more were GAD65aab-positive if diagnosed with diabetes or pre-diabetes. This EPICOM study is a prospective follow-up study focussing on pregnancies complicated by maternal T1D. The EPICOM study includes offspring (n = 278) born to mothers with pre-gestational T1D between 1993 and 1999 and matched un-exposed controls (n = 303). Age at the time of follow-up was 16.7 years (13.0-20.4 years). GAD65aab was measured using the Glutamic Acid Decarboxylase Autoantibody RIA kit from RSR© . An Oral Glucose Tolerance Test (OGTT) was performed, and abnormal glucose tolerance was defined as having either diabetes, impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). GAD65aab could be measured in 561 participants. Of these, 17 (3%) were positive for GAD65aab (≥25 U/ml) with 11 (4%) offspring being born to women with T1D and 6 (2%) controls. The difference in GAD65aab status was not statistically significant (p = .2). One was diagnosed with GAD65aab-negative diabetes during the study, 18 were diagnosed with IFG, and 44 with IGT. Overall, more were GAD65aab-positive if diagnosed with abnormal glucose tolerance (p = .03). We found no association between GAD65aab status and HOMA-IR, HOMA-IS, birthweight, mode of delivery or maternal BMI prior to pregnancy. Our study found no overall difference in GAD65 status between offspring born to women with T1D and their matched controls. However, among the participants diagnosed with pre-diabetes more were GAD65-positive.

Impact of Lean Body Mass and Insulin Sensitivity on the IGF-1-Bone Mass Axis in Adolescence: the EPICOM Study.

CONTEXT: Insulin-like growth factor-1 (IGF-1) is involved in the growth of muscle and bone mass and contributes to glucose homeostasis. The offspring of mothers with diabetes during pregnancy have an increased risk of insulin resistance (IR). OBJECTIVE: We hypothesized that bone mass was decreased in the offspring of mothers with type 1 diabetes (T1D), and that the IGF-1-bone mass relationship would be negatively influenced by IR. DESIGN: Data from the Epigenetic, Genetic and Environmental Effects on Growth, Metabolism and Cognitive Functions in Offspring of Women with Type 1 Diabetes (EPICOM) study performed from 2012 to 2013 were included. SETTING: This work is a follow-up study of a nationwide register study. PATIENTS: A total of 278 adolescent index offspring whose mothers had T1D and 303 matched controls were studied. MAIN OUTCOME MEASURE: Bone mineral content (BMC) determined by a dual-energy x-ray absorptiometry scan and the interaction with IGF-1 and insulin sensitivity were measured. RESULTS: There was no difference in BMC, bone mineral density, height (SD score [SDS]), or BMC/height between index and control offspring. IGF-1 (SDS) did not differ between the groups but insulin-like growth factor-binding protein 3 (SDS) was higher in index boys compared to controls (B = .31 [95% CI, 0.06-0.57], P = .02). The statistical path analysis showed that IGF-1 predicted BMC/height (B = .24 [95% CI, 0.02-0.45], P = .03), but lean mass was a mediator of this. IGF-1 and the homeostatic model assessment of IR were positively associated (B = .75 [95% CI, 0.37-1.12], P < .001). There was no moderating effect of the interaction between IR and IGF-1 on lean mass in the entire cohort (B = .005 [95% CI, -0.03 to 0.04], P = .81) or when analyzing index cases and controls separately. CONCLUSION: We found that lean mass was an intermediary factor in the IGF-1-bone mass relationship in a large cohort of adolescents, and this relationship was not moderated by IR.

Fatty Liver Among Adolescent Offspring of Women With Type 1 Diabetes (the EPICOM Study).

OBJECTIVE: 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.

Abnormal levels of adipokines in adolescent offspring of women with type 1 diabetes - Results from the EPICOM study.

AIMS/HYPOTHESIS: To investigate long-term consequences of diabetes during pregnancy, we determined adiponectin and leptin levels in adolescents born by women with type 1 diabetic (T1D) or non-diabetic mothers, and determined associations between adiponectin and leptin levels in adolescence and the magnitude of intrauterine hyperglycemia. RESEARCH DESIGN AND METHODS: We measured serum adiponectin and leptin and calculated leptin to adiponectin ratio (LAR) in 271 offspring of T1D women (index offspring) (13-20years), and 297 matched control offspring. Anthropometry included total body fat (TBF) by dual-energy X-ray absorptiometry and an oral glucose tolerance test. RESULTS: Adiponectin levels were lower in index females (-8.0% (95% CI; -13.9, -1.6)), but not in index males (0.4% (95% CI; -7.3, 8.6)). Leptin levels were approximately 30% higher in index than control offspring, irrespective of gender. In males, this was seen despite similar TBF in index and control offspring. LAR was increased in index offspring (both males and females) compared with control offspring. There were no association between offspring adiponectin and maternal HbA1c levels in pregnancy. Leptin and LAR seemed to be associated with third trimester HbA1c levels in females in unadjusted, but not adjusted analyses. CONCLUSION: Male and female offspring of women with T1D demonstrated increased serum leptin and LAR, whereas serum adiponectin was reduced in females only. These results suggest that abnormal regulation of adipokines is a consequence of being born to mothers with T1D. No direct association between maternal glycemic control and adiponectin and leptin levels or LAR in the adolescence was found. CLINICAL TRIAL REGISTRATION NUMBER: NCT01559181.

Assessment of Attention Deficits in Adolescent Offspring Exposed to Maternal Type 1 Diabetes.

OBJECTIVE: The 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 METHODS: Adolescent 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. RESULTS: A 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. CONCLUSIONS: Exposure 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.

Long-term Cognitive Implications of Intrauterine Hyperglycemia in Adolescent Offspring of Women With Type 1 Diabetes (the EPICOM Study).

OBJECTIVE: Exposure 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 HbA1c. RESEARCH DESIGN AND METHODS: Offspring 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. RESULTS: Offspring 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 HbA1c and offspring cognitive function in the exposed group. CONCLUSIONS: Adolescent 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.

Academic Achievement in Primary School in Offspring Born to Mothers With Type 1 Diabetes (the EPICOM Study): A Register-Based Prospective Cohort Study.

OBJECTIVE: This study examined the effect of maternal pregestational type 1 diabetes on offspring primary school performance. RESEARCH DESIGN AND METHODS: We 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 HbA1c levels during pregnancy and later school performance among offspring born to women with pregestational type 1 diabetes. RESULTS: Offspring of mothers with pregestational type 1 diabetes obtained similar school grades as control offspring when finishing primary school (regression coefficient [ß] = -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 (ß = -0.07; 95% CI = -0.23 to 0.09; P = 0.37). Among offspring of women with type 1 diabetes, increasing maternal HbA1c 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. CONCLUSIONS: Offspring 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 HbA1c in pregnancy and primary school grades. However, whether this association reflects a direct causal influence of intrauterine hyperglycemia is uncertain.

Multisystem Morbidity and Mortality in Offspring of Women With Type 1 Diabetes (the EPICOM Study): A Register-Based Prospective Cohort Study.

OBJECTIVE: This 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 HbA1c levels during pregnancy and mortality and incidence of hospital admissions. RESEARCH DESIGN AND METHODS: We 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 HbA1c levels during pregnancy and mortality and the incidence of hospital admissions. Participants were monitored from birth to the age of 13-21 years. RESULTS: Overall 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 HbA1c 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). CONCLUSIONS: Type 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.