Could the E/A ratio be included in the cardiological evaluation of the offspring of diabetic mothers? A case-control study in South Sardinia

Pre-gestational maternal diabetes mellitus (DM) is a well-established risk factor for congenital malformations in the offspring [1]. Recent epidemiological studies have shown a significant increase of anomalies also in the offspring of gestational diabetic mothers [3, 5]. Certain malformations have been recognised to be overrepresented, namely cardiovascular, CNS, and musculoskeletal defects, caudal regression in particular [1, 3, 4]. An association between maternal DM and renal and urinary tract malformations has been postulated as well, but reported cases have been mostly anecdotal and rather nonspecific [1, 3, 4]. Multicystic dysplastic kidney (MDK) is generally considered to represent a sporadic form of congenital cystic renal disease. It is thought to arise early (at about 5 to 6 weeks of gestation) due to obstruction of the ureteric bud. Thus MDK is an ideal malformation for studying the possible effects of the imbalance of maternal glucose metabolism on embryonic development of the kidneys and the urinary tract. In the present study the relationship between both pregestational and gestational DM, and MDK in the offspring was investigated in a well-defined population. The study population comprised all infants born with MDK between 1990 and 2001 in the Greater Helsinki area, Finland. During the study period, altogether 209,125 live infants were born in the same area (population data, Greater Helsinki area, Finland). An ultrasound examination was performed routinely in all mothers. Of the mothers studied, 0.38% had pre-gestational DM and 0.50% had gestational DM [2]. Gestational DM was diagnosed using a 75 g 2 h oral glucose tolerance test (OGTT) at 28–32 gestational weeks. For pathological thresholds, mean glucose values +2SD were chosen and at least two out of three had to be abnormal (fasting 4.4 mmol/l, 1 h 9.1 mmol/ l, 2 h 7.4 mmol/l, venous whole blood). An OGTT was performed in all women with any known risk factor for gestational DM. Maternity clinic and obstetric records of all women with MDK in the offspring were carefully reviewed, including not only maternal DM but also other common teratogenic factors (e.g. teratogenic medications, reproductive hormones, alcohol, narcotics, teratogenic infections). None of the infants with MDK had been exposed to any of these other common teratogenic factors during gestation. MDK was defined as a renal tissue conglomerate consisting ultrasonographically of cysts of variable size, with scanty or no identifiable renal parenchyma in between, and with no uptake in the renal isotope scan. For statistical evaluation, the relative risk (RR) was calculated and the Chi squared test used to estimate the statistical significance. In the study population, 51 infants were born with MDK. The prevalence of MDK was thus 1 in 4100 live births. Eight babies with MDK were born to diabetic mothers, comprising 16% of the total. Three mothers had insulin-dependent pre-gestational DM and five had gestational DM. The overall RR for MDK among infants of mothers with pre-gestational (n=795) or gestational (n=1046) DM was as high as 20.95 (P<0.0001) (Table 1). Improved preconceptional, gestational and postnatal care has significantly decreased the incidence of spontaneous abortions and stillbirths in offspring of diabetic mothers. The frequency of congenital malformations has, interestingly, remained constant. Careful examination for congenital anomalies, including the urinary tract and the kidneys in particular, of infants born to diabetic mothers, is recommended. Eur J Pediatr (2002) 161: 634–635 DOI 10.1007/s00431-002-1043-4

Offspring of mothers with diabetes are at increased risk of metabolic disorders in later life. Increased offspring BMI is a plausible mediator. We performed a systematic review and meta-analysis of studies examining offspring BMI z score in childhood in relation to maternal diabetes. Papers reporting BMI z scores for offspring of diabetic (all types, and pre- and during-pregnancy onset) and non-diabetic mothers were included. Citations were identified in PubMed; bibliographies of relevant articles were hand-searched and authors contacted for additional data where necessary. We compared offspring BMI z score with and without adjustment for maternal pre-pregnancy BMI. We performed fixed effect meta-analysis except where significant heterogeneity called for use of a random effects analysis. Data were available from nine studies. In the diabetic group unadjusted mean offspring BMI z score was 0.28 higher (all diabetic mothers vs controls (95% CI 0.09, 0.47; p = 0.004; nine studies; offspring of diabetic mothers n = 927, controls n = 26,384) and with adjustment for maternal pre-pregnancy BMI, 0.07 higher (95% CI -0.15, 0.28; p = 0.54; three studies; offspring of diabetic mothers n = 244, controls n = 11,206). There was no evidence of a difference in offspring BMI z score in relation to type of diabetes (gestational vs type 1, p = 0.95). Maternal diabetes is associated with increased offspring BMI z score, although this is no longer apparent after adjustment for maternal pre-pregnancy BMI in the limited number of studies in which this is reported. Causal mediators of the effect of maternal diabetes on offspring outcomes remain to be established; we recommend that future research includes adjustment for maternal pre-pregnancy BMI.

Offspring of diabetic mothers have increased risk of the metabolic syndrome in adulthood. Studies examining BP in offspring of diabetic mothers have conflicting conclusions. We performed a systematic review and meta-analysis of studies reporting offspring BP in children born to diabetic mothers. Citations were identified in PubMed. Authors were contacted for additional data. Systolic and diastolic BP in offspring of diabetic mothers and controls were compared. Subgroup analysis of type of maternal diabetes and offspring sex were performed. Fixed-effects models were used, and random-effects models where significant heterogeneity was present. Meta-regression was used to test the relationship between offspring systolic BP and prepregnancy BMI. Fifteen studies were included in the review and 13 in the meta-analysis. Systolic BP was higher in offspring of diabetic mothers (mean difference 1.88 mmHg [95% CI 0.47, 3.28]; p = 0.009). Offspring of mothers with gestational diabetes had similar diastolic BP to controls, but higher systolic BP (1.39 mmHg [95% CI 0.00, 2.77]; p = 0.05); results for type 1 diabetes were inconclusive and there were no separate data available on offspring of type 2 diabetic mothers. Male offspring of diabetic mothers had higher systolic BP (2.01 mmHg [95% CI 0.93, 3.10]; p = 0.0003) and diastolic BP (1.12 mmHg [95% CI 0.36, 1.88]; p = 0.004) than controls; in female offspring there was no difference (systolic: 0.54 mmHg [95% CI -1.83, 2.90], p = 0.66; diastolic: 0.51 mmHg [95% CI -1.07, 2.09], p = 0.52). The correlation between offspring systolic BP and maternal prepregnancy BMI was not significant (p = 0.37). Offspring of diabetic mothers have higher systolic BP than controls. Differences related to sex and type of maternal diabetes require further investigation.

Background: Previous studies suggest a 3- to-10-fold increased risk of multiple sclerosis (MS) in offspring of mothers with diabetes mellitus (DM). Objectives: To examine MS risk in offspring of diabetic mothers, overall and according to type of maternal DM, that is, pregestational DM or gestational DM, as well as to examine MS risk among offspring of diabetic fathers. Methods: The study cohort included all 1,633,436 singletons born in Denmark between 1978 and 2008. MS diagnoses were identified in the Danish Multiple Sclerosis Registry, and parental DM diagnoses in the National Patient Register. We used Cox proportional hazards regression analyses to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for the association of parental DM with MS risk in the offspring. Results: MS risk among individuals whose mothers had pregestational DM was 2.3-fold increased compared with that among individuals with nondiabetic mothers (HR = 2.25; 95% CI: 1.35–3.75, n = 15). MS risk was statistically non-significant among offspring of mothers with gestational DM (HR = 1.03 (95% CI: 0.49–2.16), n = 7) and among offspring of diabetic fathers (HR = 1.40 (95% CI: 0.78–2.54), n = 11). Conclusion: Our nationwide cohort study utilizing high-quality register data in Denmark over several decades corroborates the view that offspring of diabetic mothers may be at an elevated risk of developing MS.

Diabetes during pregnancy is thought to contribute to metabolic changes in the fetus, which predispose the offspring of diabetic mothers to obesity, insulin resistance, diabetes and cardiovascular disease. Altered maternal fuels, including but not limited to glucose, may affect the development of the endocrine pancreas in the fetus, resulting in increased adiposity and decreased beta cell mass and/or function. Prospective studies in the Pima Indians and at Northwestern University in Chicago have demonstrated increased adiposity among children exposed to diabetes in utero, although not all studies have replicated this relationship. Impaired glucose tolerance (IGT), which can result from either reduced insulin secretion or increased insulin resistance, has also been associated with exposure to diabetes in utero. Type 2 diabetes is more common in offspring of mothers with diabetes than in offspring of nondiabetic and prediabetic women among the Pima Indians. Further, a diabetic intrauterine environment has been shown to induce biochemical alterations in the cardiovascular system, and children born to diabetic mothers have increased cardiovascular risk factors compared with children not exposed to diabetes in utero. Type 2 diabetes has a known genetic component and tends to cluster in families. As a result, obesity, IGT and type 2 diabetes may be more common in offspring of diabetic mothers due to maternal genes rather than metabolic imprinting during fetal development. In order to disentangle genetic vs. environmental causes of type 2 diabetes, several methods were employed. The offspring of mothers with early onset type 2 diabetes have been compared by exposure to intrauterine diabetes, with a higher prevalence of type 2 diabetes demonstrated in exposed Pima Indian children compared with unexposed children. Adjustment for maternal obesity, which is a marker for genetic predisposition to type 2 diabetes, does not explain the increased risk of obesity in the offspring of diabetic mothers, further supporting an environmental contribution of excess maternal fuel. A comparison of offspring with maternal vs. paternal type 2 diabetes also allows for the disentangling of genetic and environmental causes, since fathers would transmit the same genetic risk of type 2 diabetes as mothers. However, the strongest evidence for the role of intrauterine diabetes in the development of type 2 diabetes in the offspring of diabetic mothers has come from the comparison of siblings born before and after the development of maternal diabetes. Animal studies have allowed for the investigation of experimentally manipulated intrauterine environment on metabolism and glucose homeostasis in the offspring. Hyperglycemia can be induced either to a mild degree late in pregnancy to mimic gestational diabetes or to a severe degree early in pregnancy to mimic type 1 diabetes. An additional genetic model of diabetes has been examined using rats selectively bred for IGT. These animal models have allowed for insight into the effects of maternal hyperglycemia on beta cell mass and pancreatic development. Diabetes prevalence is increasing worldwide, and it is one of the most pressing public health issues due to the increased costs, comorbidity and mortality associated with diabetes. The exposure to diabetes in utero may create a vicious cycle where the offspring of diabetic mothers are more likely to develop obesity and glucose intolerance, leading to an increased risk of developing gestational diabetes or type 2 diabetes during pregnancy themselves, and therefore perpetuate a destructive cycle of metabolic dysfunction. Reducing obesity and type 2 diabetes must be a primary goal of public health organizations and clinicians.

Ultrastructural evaluation of B-cell recruitment in virgin and pregnant offspring of diabetic mothers

The aim was to investigate the relationship between body mass index (BMI), plasma leptin, glucose, insulin and C-peptide levels in the offspring of diabetic mothers (DM) and non-diabetic healthy mothers (HM). Seventy-two offspring (37 girls and 35 boys, age 4-20 years) of DM were investigated in a prospective study. Those 14-16 years old (Tanner stage II-IV) were compared with age-matched offspring of HM (33 girls and 33 boys). BMI strongly correlated with plasma leptin concentration in the offspring of both DM and HM children. There were higher BMI and plasma leptin and glucose levels in DM than in HM children. There was no difference in plasma insulin or C-peptide levels between HM and age-matched DM children. There was a highly significant positive correlation between plasma leptin and C-peptide in boys of DM. The higher plasma leptin found in the offspring of DM reflects their higher BMI. A moderately high but still normal glycemia might be a preclinical sign of insulin resistance or other disturbance of glucoregulation.

Congenital anomalies are two to four times more frequent in the offspring of diabetic mothers than in those of non-diabetic mothers, and represent an increasingly important cause of perinatal mortality. These anomalies involve multiple organ systems more often than those found in the children of non-diabetic mothers. The excess of anomalies associated with maternal diabetes occurs in many organ systems. Anomalies are no more frequent in the offspring of diabetic fathers and pre-diabetic mothers than among those of non-diabetics, suggesting that non-genetic factors are the important determinants. Anomalies are most frequent in the offspring of mothers who have developed diabetes at an early age, many of whom have diabetes of long duration, are insulin-treated, and may have vascular complications. The relative importance of each of these factors in the pathogenesis of anomalies is unknown, but present evidence is consistent with a hypothesis that anomalies are the result of metabolic disturbances in the intrauterine environment during the first trimester of pregnancy. Whether or not their incidence can be reduced by optimum metabolic control of maternal diabetes during this period is unknown.

Childhood obesity has contributed to an increased incidence of type 2 diabetes mellitus and metabolic syndrome (MS) among children. Intrauterine exposure to diabetes and size at birth are risk factors for type 2 diabetes mellitus, but their association with MS in childhood has not been demonstrated. We examined the development of MS among large-for-gestational-age (LGA) and appropriate-for-gestational age (AGA) children. The major components of MS (obesity, hypertension, dyslipidemia, and glucose intolerance) were evaluated in a longitudinal cohort study of children at age 6, 7, 9, and 11 years who were LGA (n = 84) or AGA (n = 95) offspring of mothers with or without gestational diabetes mellitus (GDM). The cohort consisted of 4 groups, ie, LGA offspring of control mothers, LGA offspring of mothers with GDM, AGA offspring of control mothers, and AGA offspring of mothers with GDM. Biometric and anthropometric measurements were obtained at 6, 7, 9, and 11 years. Biochemical testing included measurements of postprandial glucose and insulin levels and high-density lipoprotein (HDL) cholesterol levels at 6 and 7 years and of fasting glucose, insulin, triglyceride, and HDL cholesterol levels at 9 and 11 years. We defined the components of MS as (1) obesity (BMI >85th percentile for age), (2) diastolic or systolic blood pressure >95th percentile for age, (3) postprandial glucose level >140 mg/dL or fasting glucose level >110 mg/dL, (4) triglyceride level >95th percentile for age, and (5) HDL level <5th percentile for age. There were no differences in baseline characteristics (gender, race, socioeconomic status, and maternal weight gain during pregnancy) for the 4 groups except for birth weight, but there was a trend toward a higher prevalence of maternal obesity before pregnancy in the LGA/GDM group. Obesity (BMI >85th percentile) at 11 years was present in 25% to 35% of the children, but rates were not different between LGA and AGA offspring. There was a trend toward a higher incidence of insulin resistance, defined as a fasting glucose/insulin ratio of <7, in the LGA/GDM group at 11 years. Analysis of insulin resistance at 11 years in a multivariate logistic regression revealed that childhood obesity and the combination of LGA status and maternal GDM were associated with insulin resistance, with odds ratios of 4.3 (95% confidence interval [CI]: 1.5-11.9) and 10.4 (95% CI: 1.5-74.4), respectively. The prevalence at any time of > or =2 components of MS was 50% for the LGA/GDM group, which was significantly higher than values for the LGA/control group (29%), AGA/GDM group (21%), and AGA/control group (18%). The prevalence of > or =3 components of MS at age 11 was 15% for the LGA/GDM group, compared with 3.0% to 5.3% for the other groups. Cox regression analysis was performed to determine the independent hazard (risk) of developing MS attributable to birth weight, gender, maternal prepregnancy obesity, and GDM. For Cox analyses, we defined MS as > or =2 of the following 4 components: obesity, hypertension (systolic or diastolic), glucose intolerance, and dyslipidemia (elevated triglyceride levels or low HDL levels). LGA status and maternal obesity increased the risk of MS approximately twofold, with hazard ratios of 2.19 (95% CI: 1.25-3.82) and 1.81 (95% CI: 1.03-3.19), respectively. GDM and gender were not independently significant. To determine the cumulative hazard of developing MS with time, we plotted the risk according to LGA or AGA category for the control and GDM groups from 6 years to 11 years, with Cox regression analyses. The risk of developing MS with time was not significantly different between LGA and AGA offspring in the control group but was significantly different between LGA and AGA offspring in the GDM group, with a 3.6-fold greater risk among LGA children by 11 years. We showed that LGA offspring of diabetic mothers were at significant risk of developing MS in childhood. The prevalence of MS in the other groups was similar to the prevalence (4.8%) among white adolescents in the 1988-1994 National Health and Nutrition Examination Survey. This effect of LGA with maternal GDM on childhood MS was previously demonstrated for Pima Indian children but not the general population. We also found that children exposed to maternal obesity were at increased risk of developing MS, which suggests that obese mothers who do not fulfill the clinical criteria for GDM may still have metabolic factors that affect fetal growth and postnatal outcomes. Children who are LGA at birth and exposed to an intrauterine environment of either diabetes or maternal obesity are at increased risk of developing MS. Given the increased obesity prevalence, these findings have implications for perpetuating the cycle of obesity, insulin resistance, and their consequences in subsequent generations.

The outcome of pregnancy in diabetic women: I. Fetal wastage, mortality, and morbidity in the offspring of diabetic and normal control mothers

Diabetic pregnancy in rats leads to impaired glucose metabolism in offspring involving tissue-specific dysregulation of 11β-hydroxysteroid dehydrogenase type 1 expression

Decreased risk of type I diabetes in offspring of mothers who acquire diabetes during adrenarchy.

Prenatal and perinatal influences on long-term psychomotor development in offspring of diabetic mothers

We investigated whether maternal diabetes programs the offspring to develop hypertension and kidney injury in adulthood and examined potential underlying mechanisms. In a murine model we studied the offspring of three groups of dams (non-diabetic, diabetic, and diabetic treated with insulin). Mean systolic blood pressure in the offspring was monitored from 8 to 20 weeks. Body and kidney weights in the offspring of diabetic mothers were significantly lower than in offspring of non-diabetic mothers. Offspring of diabetic mothers developed hypertension, microalbuminuria, and glucose intolerance. Increased accumulation of extracellular matrix proteins in the glomeruli and marked upregulation of angiotensinogen, angiotensin II type 1 receptor, angiotensin-converting enzyme, transforming growth factor beta-1 (TGF-beta1), and plasminogen activator inhibitor-1 (PAI-1) gene expression were evident in the renal cortex of hypertensive offspring of diabetic mothers. By contrast, angiotensin-converting enzyme-2 (ACE2) gene expression was lower in the hypertensive offspring of diabetic mothers than in that of non-diabetic mothers. These changes were prevented in the offspring of insulin-treated diabetic mothers. These data indicate that maternal diabetes induces perinatal programming of hypertension, renal injury, and glucose intolerance in the offspring and suggest a central role for the activation of the intrarenal renin-angiotensin system and TGF-beta1 gene expression in this process.

Short- and long-range complications in offspring of diabetic mothers