OBJECTIVE—The role of intrauterine hyperglycemia and future risk of type 2 diabetes in human offspring is debated. We studied glucose tolerance in adult offspring of women with either gestational diabetes mellitus (GDM) or type 1 diabetes, taking the impact of both intrauterine hyperglycemia and genetic predisposition to type 2 diabetes into account. RESEARCH DESIGN AND METHODS—The glucose tolerance status following a 2-h 75-g oral glucose tolerance test (OGTT) was evaluated in 597 subjects, primarily Caucasians, aged 18–27 years. They were subdivided into four groups according to maternal glucose metabolism during pregnancy and genetic predisposition to type 2 diabetes: 1) offspring of women with diet-treated GDM (O-GDM), 2) offspring of genetically predisposed women with a normal OGTT (O-NoGDM), 3) offspring of women with type 1 diabetes (O-type 1), and 4) offspring of women from the background population (O-BP). RESULTS—The prevalence of type 2 diabetes and pre-diabetes (impaired glucose tolerance or impaired fasting glucose) in the four groups was 21, 12, 11, and 4%, respectively. In multiple logistic regression analysis, the adjusted odds ratios (ORs) for type 2 diabetes/pre-diabetes were 7.76 (95% CI 2.58–23.39) in O-GDM and 4.02 (1.31–12.33) in O-type 1 compared with O-BP. In O-type 1, the risk of type 2 diabetes/pre-diabetes was significantly associated with elevated maternal blood glucose in late pregnancy: OR 1.41 (1.04–1.91) per mmol/l. CONCLUSIONS—A hyperglycemic intrauterine environment appears to be involved in the pathogenesis of type 2 diabetes/pre-diabetes in adult offspring of primarily Caucasian women with either diet-treated GDM or type 1 diabetes during pregnancy.

Gestational diabetes mellitus (GDM) is defined as glucose intolerance of varying severity and is present in about 2–6% of all pregnancies in Europe, making it one of the most common pregnancy disorders. Aside from the short-term maternal, fetal and neonatal consequences associated with GDM, there are long-term consequences for both mother and child. Although maternal glucose tolerance often normalises shortly after pregnancy, women with GDM have a substantially increased risk of developing type 2 diabetes later in life. Studies have reported that women are more than seven times as likely to develop diabetes after GDM, and that approximately 50% of mothers with GDM will develop diabetes within 10 years, making GDM one of the strongest predictors of type 2 diabetes. In women with previous GDM, development of type 2 diabetes can be prevented or delayed by lifestyle intervention and/or medical treatment. Systematic follow-up programmes would be ideal to prevent progression of GDM to diabetes, but such programmes are unfortunately lacking in the routine clinical set-up in most countries. Studies have found that the risks of obesity, the metabolic syndrome, type 2 diabetes and impaired insulin sensitivity and secretion in offspring of mothers with GDM are two- to eightfold those in offspring of mothers without GDM. The underlying pathogenic mechanisms behind the abnormal metabolic risk profile in offspring are unknown, but epigenetic changes induced by exposure to maternal hyperglycaemia during fetal life are implicated. Animal studies indicate that treatment can prevent long-term metabolic complications in offspring, but this remains to be confirmed in humans. Thus, diabetes begets diabetes and it is likely that GDM plays a significant role in the global diabetes epidemic. This review summarises a presentation given at the ‘Gestational diabetes: what’s up?’ symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Marja Vääräsmäki, DOI: 10.​1007/​s00125-016-3976-6 , and by Cuilin Zhang and colleagues, DOI: 10.​1007/​s00125-016-3979-3 ) and an overview by the Session Chair, Kerstin Berntorp (DOI: 10.​1007/​s00125-016-3975-7 ).

Context: In animal studies, exposure to intrauterine hyperglycemia increases the risk of cardiovascular disease through only partly understood epigenetic mechanisms. Human long-term follow-up studies on the same topic are few. Objective: The aim was to study the risk of overweight and the metabolic syndrome in adult offspring of women with diet-treated gestational diabetes mellitus (GDM) or type 1 diabetes, and additionally to study associations between estimates of maternal hyperglycemia and outcome in the offspring. Design and Setting: We conducted a follow-up study of 1066 primarily Caucasian women aged 18–27 yr in the Center for Pregnant Women with Diabetes, Rigshospitalet, Copenhagen, Denmark. Participants: Offspring of women with diet-treated GDM (n = 168) and an unexposed reference group (n = 141) participated, as well as offspring of women with type 1 diabetes (n = 160) and offspring from the background population representing an unexposed reference group (n = 128). The follow-up rate was 56% (597 of 1066). Main Outcome Measures: Women with body mass index of at least 25 kg/m² were considered overweight. The metabolic syndrome was determined by the International Diabetes Federation 2006 criteria. Results: The risk of overweight was doubled in offspring of women with diet-treated GDM or type 1 diabetes compared with offspring from the background population, whereas the risk of the metabolic syndrome was 4- and 2.5-fold increased, respectively. Offspring risk of the metabolic syndrome increased significantly with increasing maternal fasting blood glucose as well as 2-h blood glucose (during oral glucose tolerance test). Conclusions: Adult offspring of women with diet-treated GDM or type 1 diabetes are risk groups for overweight and the metabolic syndrome. Intrauterine hyperglycemia may in addition to genetics and other factors contribute to the pathogenesis of overweight and the metabolic syndrome.

OBJECTIVE—The aim of this study was to compare pregnancy outcomes in type 1 diabetic pregnancies with the background population. RESEARCH DESIGN AND METHODS—This nationwide prospective multicenter study took place in eight Danish centers treating pregnant women with type 1 diabetes during 1993–1999. A total of 990 women with 1,218 pregnancies and delivery after 24 weeks (n = 1,215) or early termination due to severe congenital malformations (n = 3) were included. Data were collected prospectively by one to three caregivers in each center and reported to a central registry. RESULTS—The perinatal mortality rate was 3.1% in type 1 diabetic pregnancies compared with 0.75% in the background population (RR 4.1 [95% CI 2.9–5.6]), and the stillbirth rate was 2.1% compared with 0.45 (4.7 [3.2–7.0]). The congenital malformation rate was 5.0% in the study population and 2.8% (1.7 [1.3–2.2]) in the background population. Six of the perinatal deaths (16%) were related to congenital malformations. Only 34% of women performed daily home monitoring of blood glucose at conception, and 58% received preconceptional guidance. Pregnancies with serious adverse outcomes (perinatal death and/or congenital malformations) were characterized by higher HbA_1c values before and during pregnancy and a lesser degree of maternal self-care and preconceptional guidance. Women who performed daily self-monitoring of blood glucose at any time during pregnancy had lower HbA_1c values than women who did not measure their daily profile. Likewise, daily self-monitoring was associated with a reduction in serious adverse outcomes. The caesarean section rate was 55.9 and 12.6%, respectively, and the risk of preterm delivery was 41.7 and 6.0%, respectively. CONCLUSIONS—Type 1 diabetic pregnancies are still complicated by considerably higher rates of severe perinatal complications compared with the background population, and women with poor self-care are at the highest risk. Adequate glycemic control using daily glucose monitoring before and during pregnancy is a crucial step toward reaching the goals of the St. Vincent declaration.