Children Of Diabetic Mothers Research Articles

Neural Correlates of Emotion Processing in Typically Developing Children and Children of Diabetic Mothers

To examine the neurocognitive sequelae of children born to diabetic mothers (CDMs), event-related potentials (ERPs) in response to three facial expressions (happy, fear, anger) were collected from 42 children (18 CDMs, 24 controls), aged 36 and/or 48 months. A linear mixed models approach was used to model individual variation in amplitude and latency. As infants, CDMs in the present study displayed subtle impairments in attention and memory processing, including face recognition, as indexed by ERPs. Findings indicate that these same children, now ages 3–4 years, continue to display ERP patterns that differ from controls in amplitude, latency, and hemispheric asymmetry.

Mechanisms of Fetal Programming of Adult Hypertension

Epidemiological and experimental studies suggest that the in utero environment plays a critical role in the development of adult disease, including cardiovascular disease and hypertension. Intrauterine growth retardation produced by maternal undernutrition or exposure to maternal glucocorticoids during critical periods of organogenesis impairs fetal growth and produces offspring that develop hypertension early in life.1 This concept of “fetal programming” was first proposed by Barker et al2 to describe the relationship between low birth weight and subsequent risk for the development of cardiovascular disease and hypertension, insulin resistance, and type 2 diabetes mellitus in adult life. Several studies have confirmed and extended the Barker et al2 hypothesis to fetal programming of Parkinson’s disease, dementia, osteoporosis, and polycystic ovary syndrome.3 Although most clinical and experimental studies support the role for fetal programming of adult hypertension, there is still controversy regarding the cause and mechanisms underlying this phenomenon. Studies to date implicate reduced nephron endowment, factors that affect endothelial and arterial compliance, alterations in the function of renin-angiotensin system (RAS), and programming of the major organs and endocrine/neural systems involved in long-term blood pressure regulation.1 Despite intense investigation into the mechanisms underlying fetal programming of adult hypertension, there is still no unifying hypothesis on how these different mechanisms and pathways are programmed in utero and how they ultimately result in dysregulation of blood pressure later in life. It is well documented that premenopausal women exhibit a lower incidence of cardiovascular disease and hypertension compared with age-matched …

Dietary insulin as an immunogen and tolerogen

We have shown that exposure to bovine insulin (BI) in cow's milk (CM) formula induces an insulin-specific immune response in infants. Here we studied the role of human insulin (HI) in breast milk as a modulator of the immune response to insulin. In a group of 128 children participating in the TRIGR pilot study, maternal breast milk samples were collected 3-7 days and/or 3 months after delivery. After exclusive breast-feeding, the children received either CM formula or casein hydrolysate during the first 6-8 months of life. Insulin concentration in breast milk and immunoglobulin G (IgG) antibodies to BI in plasma samples were measured by EIA. The levels of insulin in breast milk samples were higher in mothers affected by type 1 diabetes than in non-diabetic mothers (p = 0.007 and p < 0.001). The concentration of insulin in breast milk correlated inversely with the plasma levels of IgG antibodies to BI at 6 months of age in children who received CM formula (r = -0.39, p = 0.013), and at 12 months of age in all children (r = -0.25, p = 0.029). The levels of breast milk insulin were higher in the mothers of nine children who developed beta-cell autoimmunity when compared with autoantibody-negative children (p = 0.030); this holds true also when only children of diabetic mothers were included (p = 0.045). BI in CM induces higher levels of IgG to insulin in infants than does HI in breast-fed children. Instead, HI in breast milk seems to be tolerogenic and may downregulate the IgG response to dietary BI. However, our results in infants who developed beta-cell autoimmunity suggest that in this subgroup of children breast milk insulin does not promote tolerance.

Impact of breast-feeding on psychomotor and neuropsychological development in children of diabetic mothers: role of the late neonatal period

Previous data from our Kaulsdorf Cohort Study (KCS) suggest that early neonatal ingestion (1st week) of breast milk from diabetic mothers (diabetic breast milk, DBM) may increase the risk of being overweight and delay speech development in offspring of diabetic mothers (ODM). Late neonatal DBM ingestion (2nd-4th week), however, not independently influenced the risk of overweight. We investigated whether late neonatal DBM ingestion might independently influence neuro-development. Achievement of developmental milestones according to late neonatal DBM intake was analyzed in 242 ODM. No impact of DBM ingestion on psychomotor parameters was observed. In contrast, it negatively influenced onset of speaking (no DBM: median 44.0 weeks, range 31.0-72.0; some DBM: 48.0, 24.0-100.0; DBM only: 52.0, 28.0-84.0; P=0.037) and halved the probability of reaching this milestone at any time point (hazard ratio: 0.53, 95% confidence interval: 0.31-0.91). However, adjustment for DBM volume ingested during the early neonatal period weakened the hazard ratio towards non-significance. In the fully adjusted model, the hazard ratio was halved, but insignificant. Our results underscore that neonatal DBM ingestion, particularly during the first week of life, may delay speech development, an important indicator of cognitive development. Further studies are urgently recommended on consequences of breast-feeding for neurodevelopment in ODM.

424 Long-Term Effect of Pregestational and Gestational Diabetes Mellitus on Offspring

Background: It has been suggested that maternal diabetes during pregnancy increases childhood risk of developing obesity and impaired glucose tolerance. The aim of the study was to compare the impact of pregestational (PGDM) and gestational (GDM) diabetes on selected metabolic and developmental parameters in children of diabetic mothers. Material and methods: A total of 26 offspring of mothers with PGDM and 28 offspring of mothers with GDM were examined at 4–8 years of age. All children had an oral glucose tolerance test (OGTT) performed, with glucose and insulin measured at 0, 30, 60 and 120 min after loading. Glycated hemoglobin and lipids levels were measured in fasting plasma. Basic body measurements were taken and BMI and symmetry index were calculated. Results: Offspring of mothers with GDM had higher BMI (17.1 ± 2.28 vs. 15.8 ± 2.52; p<0.05), symmetry index (1.12 ± 0.18 vs. 1.02 ± 0.18; p<0.01) and percentage of age-adjusted normal body weight (114.72 ± 21.93 vs. 101.32 ± 19.58; p<0.05) than offspring of mothers with PGDM. Similarly, the percentage of children with body weight, BMI and symmetry index above 75th percentile was also significantly higher in offspring of mothers with GDM compared to offspring of mothers with PGDM (respectively: 31.5% vs. 11.1%, 29.6% vs. 11.1% and 29.6% vs. 11.1%; p<0.05). Fasting glucose, cholesterol, triglyceride, LDL and glycated hemoglobin levels as well as glucose tolerance were not significantly different between groups. Conclusions: GDM seems to predispose to higher body weight, BMI and symmetry index in offspring compared to PGDM. However, there is no difference in glucose tolerance, glycated hemoglobin and lipids levels between both groups. The tendency to overweight and obesity observed in offspring of mothers with GDM is type 2 diabetes risk factor and might be related to the fetal metabolic experience, genetic predisposition or family life style.

Long-Term Impact of Breast-Feeding on Body Weight and Glucose Tolerance in Children of Diabetic Mothers

Offspring of diabetic mothers (ODM) are at increased risk of developing overweight and impaired glucose tolerance (IGT). Recently, we observed that early neonatal ingestion of breast milk from diabetic mothers (DBM) may dose-dependently increase the risk of overweight in childhood. Here, we investigate whether DBM intake during the late neonatal period and early infancy also influences later adipogenic and diabetogenic risk in ODM. A total of 112 ODM were evaluated for influence of DBM ingestion during the late neonatal period (2nd-4th neonatal week) and early infancy on relative body weight (RBW) and glucose tolerance in early childhood. Exclusive breast-feeding was associated with increased childhood RBW (P = 0.011). Breast-fed ODM had an increased risk of overweight (odds ratio 1.98 [95% CI 1.12-3.50]). Breast-feeding duration was also positively related to childhood RBW (P = 0.004) and 120-min blood glucose during an oral glucose tolerance test (P = 0.022). However, adjustment for the DBM volume ingested during the early neonatal period, i.e., 1st week of life, eliminated all these relations with late neonatal breast-feeding and its duration. Interestingly, no relationship was observed between maternal blood glucose in the middle of the third trimester and the outcome. Neither late neonatal DBM intake nor the duration of breast-feeding has an independent influence on childhood risk of overweight or IGT in ODM. Therefore, the 1st week of life appears to be the critical window for nutritional programming in ODM by ingestion of maternal "diabetic" breast milk.

Impact of Early Neonatal Breast-Feeding on Psychomotor and Neuropsychological Development in Children of Diabetic Mothers

In general, breast-feeding positively influences development of psychomotor function and cognition in children. Offspring of diabetic mothers (ODM) have delayed psychomotor and cognitive development. Recently, we observed a dose-dependent negative effect of early neonatal ingestion of breast milk from diabetic mothers (diabetic breast milk [DBM]) on the risk of overweight during early childhood. Here, we investigated the influence of early neonatal intake of DBM on neurodevelopment in ODM. A total of 242 ODM were evaluated for age of achieving major developmental milestones (Denver Developmental Scale) according to the volume of DBM ingested during the first week of life, using Kruskal-Wallis and Kaplan-Meier analysis. Children in the upper tertile of early neonatal ingestion of DBM achieved early psychomotor developmental milestones ("lifting head while prone," "following with eyes") earlier than those in lower tertiles (P = 0.002). In contrast, a delay in the onset of speaking was observed in children who had ingested larger volumes of DBM compared with those with lower DBM intake (P = 0.002). This negative impact of DBM ingestion was not confounded by birth characteristics, total milk intake, or socioeconomic/educational status. Our data indicate differential effects of early neonatal DBM ingestion on psychomotor and cognitive development. Ingesting larger compared with smaller volumes of DBM may normalize early psychomotor development in ODM but delays onset of speaking as a parameter indicative of cognitive development. This effect may result from qualitative alterations in the composition of DBM. Further studies are urgently recommended on the benefits and harms of breast-feeding in ODM.

Neonatal Care of the Infant of the Diabetic Mother

After completing this article, readers should be able to: 1. Describe the most significant factor influencing neonatal morbidity in the diabetic pregnancy. 2. Characterize the impact of maintaining as normal a metabolic state as possible on the potential for perinatal and neonatal complications. 3. Describe the optimal location and services for delivery of a diabetic parturient. 4. Characterize the evaluation of an infant of a diabetic mother who requires resuscitation after birth. 5. Delineate the factor that most increases the chance of successful management of an infant of a diabetic mother in a regular nursery setting. Although many infants of diabetic mothers (IDMs) have an uneventful perinatal course, there is still an increased risk of complications, even in the infant born to the woman who has gestational diabetes. This discussion highlights specific factors that are critical in the immediate care of the IDM in the delivery room, in the nursery, and after discharge from the hospital. The care of this neonate builds on the pathophysiologic concepts presented in “The Infant of the Diabetic Mother” also appearing in this issue and other recent reviews of the subject. (1)(2) The physician responsible for the care and delivery of the parturient must inform the neonatologist, pediatrician, or their designee responsible for the care of the neonate of the mother’s condition well in advance of delivery to ensure optimal care of the newborn. Among the specific factors that are of utmost importance are the type of diabetes and degree of maternal control, prior pregnancy history, and complications occurring during the pregnancy, including data about fetal monitoring for determination of fetal size and maturation. This information allows the physician caring for the neonate to anticipate many, if not most, of the potential fetal and neonatal complications and assist in determining if a neonatologist needs to be present …

Long-term impact of neonatal breast-feeding on body weight and glucose tolerance in children of diabetic mothers.

Offspring born to women with pregnancies complicated by diabetes are at increased childhood risk of developing obesity and impaired glucose tolerance (IGT). In population-based studies, breast-feeding has been shown to be protective against obesity and diabetes later in life. To date, the role of breast-feeding on offspring of diabetic mothers (ODM) has not been investigated in this context. A total of 112 ODM (type 1 diabetes, n = 83; gestational diabetes, n = 29) were evaluated prospectively for impact of ingestion of either diabetic breast milk (DBM) or nondiabetic banked donor breast milk (BBM) during the early neonatal period (day 1-7 of life) on relative body weight and glucose tolerance at a mean age of 2 years. There was a positive correlation between the volume of DBM ingested and risk of overweight at 2 years of age (odds ratio [OR] 2.47, 95% CI 1.25-4.87). In contrast, the volume of BBM ingested was inversely correlated to body weight at follow-up (P = 0.001). Risk of childhood IGT decreased by increasing amounts of BBM ingested neonatally (OR 0.19, 95% CI 0.05-0.70). Stepwise regression analysis showed volume of DBM to be the only significant predictor of relative body weight at 2 years of age (P = 0.001). Early neonatal ingestion of breast milk from diabetic mothers may increase risk of becoming overweight and, consequently, developing IGT during childhood. Additional studies are needed to assess long-term consequences that might result from the type of neonatal nutrition in ODM.

Malformations in offspring of diabetic rats: morphometric analysis of neural crest-derived organs and effects of maternal vitamin E treatment.

We have previously reported on a malformation-prone Sprague-Dawley rat substrain (U), which presents a high frequency of micrognathia in the offspring of diabetic mothers. This malformation is related to impaired development of the cranial neural crest cells (NCC); the defect may be prevented by antioxidative treatment of the mother. We have therefore investigated whether fetuses of diabetic rats display other malformations associated with altered cranial NCC development and whether maternal vitamin E supplementation may affect such malformations. Fetuses of diabetic rats showed low-set external ears, severely malformed Meckel's cartilage, small thyroid and thymus, and absence of parathyroid glands. Cardiac anomalies were frequently observed, including rightward displacement of the aorta, double outlet right ventricle (DORV), persistent truncus arteriosus (PTA) combined with ventricular septal defects due to a malaligned outlet septum. The malformations in the outflow tract included abnormalities of the great arteries; right-sided aortic arch/descending aorta, and double aortic arches. These defects tended to occur together within individual fetuses. Maternal dietary treatment with 2% vitamin E markedly reduced the severity of the malformations. The phenotypic appearance of these defects is strikingly similar to the DiGeorge anomaly in humans, which has been found in children of diabetic mothers together with an overrepresentation of PTA and DORV. The malformations associated with defective NCC development in the offspring of diabetic U rats show several morphological similarities to those in humans; hence the teratogenic mechanisms may be similar and accessible for study.

Oculoauriculovertebral abnormalities in children of diabetic mothers

Maternal diabetes is known to have teratogenic effects. Malformations including neural tube defects, caudal dysgenesis, vertebral defects, congenital heart defects, femoral hypoplasia, and renal anomalies are described in infants of diabetic mothers. However, craniofacial anomalies have rarely been reported in such infants. Here we document craniofacial anomalies of patients born to diabetic mothers. We describe two patient populations: individuals evaluated through our genetics services for multiple malformations and individuals identified through a database search in our craniofacial clinic. The first group consists of 14 individuals evaluated in our genetics clinics who were born to diabetic mothers and had craniofacial anomalies. The second group consists of seven individuals who were identified from a craniofacial database search of patients with hemifacial microsomia and who were born to diabetic mothers. Thus, both groups were born to diabetic mothers and had hemifacial microsomia (67%), microtia (52%), hearing loss (43%), epibulbar dermoids (24%), and fused cervical vertebrae (24%). Therefore, the teratogenic effects of maternal diabetes probably include such craniofacial malformations as the oculoauriculovertebral/Goldenhar complex. Infants of diabetic mothers should be evaluated for craniofacial anomalies. Conversely, mothers of infants with craniofacial anomalies should be evaluated for diabetes to aid in counseling concerning cause and recurrence risks.

Oculoauriculovertebral abnormalities in children of diabetic mothers

Maternal diabetes is known to have teratogenic effects. Malformations including neural tube defects, caudal dysgenesis, vertebral defects, congenital heart defects, femoral hypoplasia, and renal anomalies are described in infants of diabetic mothers. However, craniofacial anomalies have rarely been reported in such infants. Here we document craniofacial anomalies of patients born to diabetic mothers. We describe two patient populations: individuals evaluated through our genetics services for multiple malformations and individuals identified through a database search in our craniofacial clinic. The first group consists of 14 individuals evaluated in our genetics clinics who were born to diabetic mothers and had craniofacial anomalies. The second group consists of seven individuals who were identified from a craniofacial database search of patients with hemifacial microsomia and who were born to diabetic mothers. Thus, both groups were born to diabetic mothers and had hemifacial microsomia (67%), microtia (52%), hearing loss (43%), epibulbar dermoids (24%), and fused cervical vertebrae (24%). Therefore, the teratogenic effects of maternal diabetes probably include such craniofacial malformations as the oculoauriculovertebral/Goldenhar complex. Infants of diabetic mothers should be evaluated for craniofacial anomalies. Conversely, mothers of infants with craniofacial anomalies should be evaluated for diabetes to aid in counseling concerning cause and recurrence risks. Am. J. Med. Genet. 90:303–309, 2000. © 2000 Wiley-Liss, Inc.

PERINATAL COMPLICATIONS AND THREE-YEAR FOLLOW UP OF INFANTS OF DIABETIC MOTHERS WITH DIABETIC NEPHROPATHY STAGE IV

The objective of the study was to evaluate differences in the perinatal complications and in the 3-year follow up of infants of diabetic mothers with and without diabetic nephropathy stage IV. We compared the fetal and maternal complications and the early postpartal development until 3 years after delivery in 10 children of nephropathic diabetic mothers and 30 children of diabetic mothers without nephropathy. The mean (± SD) birthweight of the infants of nephropathic women was 2250 ± 496 g versus 3544 ± 435 g in the women without nephoropathy (p < 0.01). Births were premature in six pregnancies (60%) of the nephrotic women but in none of the women without nephropathy (p < 0.01). Three infants (30%) of the women with nephropathy showed respiratory distress syndrome in contrast to two babies (6%) of the women without nephropathy. Pre-eclampsia or eclampsia occurred in 6 (60%) pregnant women with and in two women (6%) without diabetic nephropathy (p < 0.01). Nephrotic syndrome was observed in 7 nephrotic women (70%) in contrast to none women without nephropathy. Three years postpartum, six of the children (60%) of nephropathic women had a body weight < the 50th percentile but none of the children of the women without nephropathy did so (p < 0.01). In addition, the children of nephropathic mothers started to speak significantly later (15 ± 3 versus 12 ± 3 months postpartum, p < 0.05) and had infectious diseases more commonly (60% versus 6%, p < 0.01) than the children of women without nephropathy. It can be concluded that in pregnancies of diabetic women the birth weights of the infants are significantly smaller and the fetal as well as maternal complication-rates significantly higher than in those of women without nephropathy. Also 3 years after delivery, the body weight of the children of nephropathic diabetic women is significantly lower than that of children of diabetic women without nephropathy. Additionally, children of nephropathic women are retarded in terms of linguistic development and their resistance to infections is reduced.

Hyperglycemia-Induced Vasculopathy in the Murine Vitelline Vasculature: Correlation with PECAM-1/CD31 Tyrosine Phosphorylation State

Maternal diabetes mellitus is associated with an increased incidence of congenital abnormalities as well as embryonic and perinatal lethality. In particular, a wide range of cardiovascular abnormalities have been noted in children of diabetic mothers and in the offspring of diabetic animals. The vascular system is the first organ system to develop in the embryo and is critical for normal organogenesis. The organization of mesodermal cells into endothelial and hematopoietic cells and into a complex vascular system is, in part, mediated by a series of specific cell-cell, cell-extracellular matrix, and cell-factor interactions. PECAM-1 expression has been observed during the earliest stages of vasculogenesis, and changes in PECAM-1 tyrosine phosphorylation have been associated with endothelial cell migration, vasculogenesis, and angiogenesis both in vitro and in vivo. In this report we demonstrate that exposure to hyperglycemia during gastrulation causes yolk sac and embryonic vasculopathy in cultured murine conceptuses and in the conceptuses of streptozotocin-induced diabetic pregnant mice. In addition, we correlate the presence of yolk sac and embryonic vasculopathy with the failure of PECAM-1 tyrosine dephosphorylation during the formation of blood islands/vessels from clusters of extra-embryonic and embryonic angioblasts in the murine conceptus using both in vitro and in vivo models. The importance of these findings in the development of vasculopathy in the offspring of diabetic mothers and the potential effects and benefits of glucose regulation during the periods of vasculogenesis/angiogenesis in embryonic development are discussed.

Natural history of myocardial hypertrophy and its association with hyperinsulinism in infants of diabetic mothers

To test the hypothesis that myocardial hypertrophy is associated with increased serum insulin levels in children of diabetic mothers and to determine the frequency and timing of this spontaneous regression. Seventy-two patients were studied (54 children of diabetic mothers and 18 controls). Diagnosis of myocardial hypertrophy was made by fetal echocardiography. Amniotic fluid insulin levels were obtained from a previous prenatal study on hypertrophic cardiomyopathy, since the participation of the mothers was common to both projects. There were 10 cases of myocardial hypertrophy among children of diabetic mothers (18.52%). Septal thickness was significantly different between the 2 groups (children of diabetic mothers and controls) in the evaluation performed at the age of 1 month (p = 0.04). Insulin levels were still increased in children of diabetic mothers until the age of 3 months. During this period insulin levels were significantly higher than those of controls (p = 0.003 and p = 0.001, at 1 and 3 months, respectively). The association between regression of ventricular septum thickness and the decrease of insulin levels occurred up to the age of 1 month. There was spontaneous regression of ventricular septum thickness in children of diabetic mothers during the first 6 months of life. The association between hyperinsulinism and hypertrophic cardiomyopathy was present up to the first month of life.

Pregnancy outcomes in mothers with pregestational diabetes: a population-based study in North Rhine (Germany) from 1988 to 1993.

The purpose of this study was to estimate the proportion of pregnancies with pregestational diabetes in Germany, to compare the outcome of these pregnancies to pregnancies in nondiabetic mothers and to identify risk factors for poor pregnancy outcomes in mothers with pregestational diabetes. Data of the "Perinatalerhebung Nordrhine" from 1988-1993 were analysed. The Perinatalerhebung is an ongoing quality assurance programme of prenatal and perinatal care in the region of North Rhine (South Western part of North Rhine-Westphalia). During the observation period a proportion of 93%-100% of the annual births in the region (n = approximately 100000) were included in the study. Their data had been documented by the obstetricians in a standard multiple choice questionnaire. The outcome parameters perinatal mortality, macrosomia, prematurity, and malformations were analysed in relation to several defined explanatory variables. There were 2,402 births in mothers with pregestational diabetes (0.4% of all births). The proportions of poor pregnancy outcomes in women with pregestational diabetes were 2.8% for perinatal mortality, 27.6% for macrosomia, 21.1% for prematurity and 2.1% for malformations . The respective relative risks compared to the non diabetic mothers were 4.3 (95% CI 3.4-5.5) for perinatal mortality, 3.1 (95% CI 2.9-3.3) for macrosomia, 2.7 (95% CI 2.5-2.9) for prematurity and 1.7 (95% CI 1.3-2.3) for malformations . The main risk factor for perinatal mortality in children of diabetic mothers after adjustment for maternal smoking, ethnicity, parents' professional achievement, type of obstetric hospital, and maternal age was substandard use of prenatal care. The prevalence of births from mothers with pregestational diabetes and their pregnancy outcomes were similar to those in other Western countries. The standard for non-diabetic mothers has not been reached yet. Further improvements may be achieved if all diabetic women are convinced to use the standard prenatal care facilities throughout pregnancy.

Behavioral adjustment in children of diabetic mothers.

The aim of this study was to evaluate whether maternal diabetes in pregnancy may adversely affect the children's behavioral adjustment, in a sample of 201 mothers (68 with pre-gestational diabetes, 50 with gestational diabetes, and 83 with non-diabetic pregnancies) and their singleton offspring. After accounting for socioeconomic status, ethnicity and maternal attitudes, none of the Child Behavior Checklist ratings correlated significantly with maternal patient group or several indices of antepartum maternal metabolism. Child obesity, a common sequela of diabetic pregnancies, correlated positively with Internalizing Behavior problems and three narrow-band sub-scales: Somatic Complaints, Anxious/Depressed, and Social Problems. Results suggest that children of diabetic mothers are at increased risk for a variety of developmental disturbances. Screening for learning and behavioral difficulties should be made at regular pediatric visits, with follow-up evaluations warranted by positive indications, excessive weight gain, or other evolving medical concerns.

Perinatal autoimmunity in offspring of diabetic parents. The German Multicenter BABY-DIAB study: detection of humoral immune responses to islet antigens in early childhood.

IDDM results from immune-mediated destruction of insulin-producing pancreatic beta-cells in individuals genetically susceptible for the disease. There is evidence that the 65-kDa isoform of GAD plays a critical role in the induction of autoimmune diabetes in NOD mice. In humans, it is still unclear when and to what beta-cell antigens autoreactive lymphocytes become activated during early disease. We conducted a prospective study from birth, BABY-DIAB, among children of mothers with IDDM or gestational diabetes or fathers with IDDM, and we investigated the temporal sequence of antibody responses to islet cells (ICA), insulin (IAA), GAD (GADA), and the protein tyrosine phosphatase IA-2/ICA512 (IA-2A). Of 1,019 children included at birth, we have currently followed 513 to the age of 9 months, 214 to the age of 2 years, and 37 to the age of 5 years. At birth, all antibody specificities were frequent in newborns of diabetic mothers but not fathers and are suggested to be transplacentally acquired because they are strongly correlated with antibody levels in their diabetic mothers. In early childhood, antibody levels were <99th percentile of control subjects in the majority of children. However, 37 children exhibited elevated antibody levels; these were most frequently detected at the age of 2 years. The antibody prevalence at age 2 years was 2.3% for ICA, 7% for IAA, 4.2% for GADA, and 2.8% for IA-2A (8.9% positive for at least one antibody). Children of diabetic fathers were positive for at least one antibody more frequently than were children of diabetic mothers (9 months of age: 8.5 vs. 3.6%; 2 years of age: 16.7 vs. 7.9%). There was no specific sequence in the appearance of positive autoantibodies, but 13 (35%) antibody-positive cases already had more than one ICA before the age of 2 years and 7 (19%) showed reactivity to three islet cell antigens before age 5 years. The presence of multiple antibodies confers high risk for the future development of diabetes; three of six children who exhibited positive antibody responses to all four antibodies tested and another child with two positive antibodies developed clinical diabetes at the ages of 13, 21, and 27 months and 5 years. We conclude that loss of tolerance to beta-cell autoantigens and appearance of autoimmune phenomena occur very early in life in individuals with genetic susceptibility for IDDM. Screening programs to identify candidates for disease-prevention therapies can therefore be focused on this young age-group, in whom the disease process may be less advanced and who may therefore be best suited to such therapies.

Long-term prognosis of infants of diabetic mothers. Relationship between metabolic disorders in newborns and adult offspring.

The aim of our study was to find out whether the metabolic disorders in the newborns of insulin-dependent diabetic mothers (NDM) in the neonatal adaptation period could be associated with their condition in adulthood. We examined 148 children of diabetic mothers (CDM) aged 20.75 +/- 0.31 years (mean +/- SE); 11 were diabetic patients, while in the remaining 137 CDM, the oral glucose tolerance test (OGTT) was performed. CDM were compared with 31 matched control offspring of healthy mothers. Of the characteristic abnormalities occurring in NDM, the following were present in our study: macrosomia, hypoglycaemia, hyperlactacidaemia, hyperbilirubinaemia. In adulthood, the sum of the blood glucose and plasma insulin values during OGTT, body mass index (BMI) and blood pressure were determined. The observed abnormalities and the degree of their relevance in the neonatal period were not related to the sum of blood glucose and plasma insulin levels, BMI and blood pressure in adulthood, but the values of all these parameters in adulthood were significantly higher in CDM than in controls (P < 0.05-0.001).

Alterations of lymphocyte subsets in children of diabetic mothers.

To investigate the impact of diabetic mothers on the maturation of the immune system in their offspring, immunophenotypic markers of major lymphocyte subpopulations were evaluated by two-colour flow cytometric analysis in 160 healthy children of diabetic mothers (100 with insulin-dependent diabetes mellitus (IDDM): 48 with gestational diabetes), including 22 neonates, 45 infants aged 8-12 months, 46 children aged 1-2 years, 29 children aged 3-6 years and 18 children aged 7-17 years. Results were compared with 21 neonates of healthy mothers from our hospital and with 110 paediatric subjects of a reference population. In neonates of diabetic mothers, percentages of total lymphocytes (p = 0.044), T and B lymphocytes (p = 0.004, respectively) were significantly decreased compared to our neonates of healthy mothers. By subdividing the group of neonates in offspring of mothers with IDDM (n = 15) or gestational diabetes (n = 7), differences compared to normal neonates were mainly observed in neonates of mothers with IDDM (T lymphocytes: p = 0.006; B lymphocytes: p = 0.008). In cord blood, 45.5% of neonates had antibodies to islet cells, insulin or glutamic acid decarboxylase, most likely transmitted through the placenta of the diabetic mother. No association was found between alterations of lymphocyte subsets and antibody-positivity in cord blood, nor was there any correlation of lymphocyte counts and mean HbA1 during pregnancy, maternal age at delivery, diabetes duration, or neonatal birth weight, respectively. Comparisons among age groups from newborn infants through adolescents revealed higher percentages of total lymphocytes and lower percentages of activated T cells in children of diabetic mothers compared to children of the reference population between the age of 1 to 6 years (67-73% of the cases above and 62-77% below the interquartiles of the reference range, respectively). No significant differences in lymphocyte subpopulations between children of mothers with IDDM diabetes and gestational diabetes have been detected. In addition, there were no abnormalities of lymphocyte subsets in children who are at high risk for the development of IDDM. In summary, we suggest that the observed changes in children of diabetic mothers may reflect a cellular immune reaction to the particular maternal environment, characterized by both an abnormal metabolic state and persisting autoimmunity in the affected mother.