Severity Of Maternal Diabetes Research Articles

Diabetes in Pregnancy for Mothers and Offspring: Reflection on 30 Years of Clinical and Translational Research: The 2022 Norbert Freinkel Award Lecture.

Hyperglycemia during pregnancy is a double-edged sword, affecting both mothers and their offspring and creating a vicious cycle that can affect multiple generations. Research in this field over the past 30 years has greatly improved our understanding of this disease and formed the basis of improved strategies to improve the health of mothers and their babies. Despite this progress, gestational and preexisting diabetes continue to have significant effects on both short- and long-term health of mothers and their offspring. In this article, I provide an overview of the work that my colleagues and I have done to advance the knowledge base around diabetes and pregnancy in four areas: 1) diabetes risk after gestational diabetes mellitus (GDM), including racial and ethnic disparities; 2) the pathophysiology of GDM and subsequent diabetes in Hispanic women; 3) diabetes prevention and β-cell preservation following GDM; and 4) evidence for multiple potential developmental effects in offspring that vary according to the timing of exposure and severity of maternal diabetes during pregnancy. This research continues the legacy of Norbert Freinkel and the concepts that he contributed to the field of diabetes and pregnancy. With the epidemic of obesity, increasing rates of type 1 and type 2 diabetes in youth, and rising prevalence of GDM across all racial and ethnic groups, we have a lot more work to do to combat this disease to break the vicious cycle.

Association of maternal diabetes mellitus with preterm infant outcomes: a systematic review and meta-analysis

ContextThe association between maternal diabetes and outcomes of infants who are born preterm is unclear.ObjectiveTo perform a systematic review and meta-analysis of clinical studies exploring the association between maternal diabetes...

Gestational diabetes –Does it influence the thyroid hormone levels of the foetus in utero?

Introduction: Babies born of mothers with gestational diabetes tend to develop obesity and diabetes in later life. This occurs in spite of good control of gestational diabetes. It was decided to study whether the maternal hyperglycemia produces any alteration in thyroid function of the foetus which could account for the development of insulin resistance and obesity in later years. The present study was done to find the level of thyroid hormones in the cord blood of infants of mothers with gestational diabetes. Materials and Methods: The study included 32 pregnant women who were suffering from gestational diabetes mellitus and their newborn babies. The severity of maternal diabetes was assessed by the fasting and postprandial blood sugar levels and the glycated haemoglobin levels. The glycated haemoglobin was estimated during the third trimester of pregnancy. The thyroid hormone levels and blood sugar was estimated in cord blood. The birth weight of the baby was also noted. Result: In our study, the serum T3 levels in cord blood was very much increased as compared to the normal range The cord blood T3 levels also showed a statistically significant positive correlation with the maternal postprandial glucose levels and the glycated haemoglobin levels. The T3 levels in cord blood of babies were much higher in those mothers who required insulin than the mothers who were controlled with diet alone. Conclusion: The increased T3 levels in cord blood may be an indicator of the hyperglycemia to which the foetus is exposed during intrauterine life. Keywords: Gestational diabetes mellitus, Cord blood thyroid hormone levels, Deiodinase enzyme, Glycated haemoglobin TSH (thyroid stimulating hormone), T4(tetraiodothyronine, T3 (tri iodothyronine), Glucose challenge test, Oral glucose tolerance test.

Severe Uncontrolled Maternal Hyperglycemia Induces Microsomia and Neurodevelopment Delay Accompanied by Apoptosis, Cellular Survival, and Neuroinflammatory Deregulation in Rat Offspring Hippocampus.

Maternal diabetes constitutes an unfavorable intrauterine environment for offspring development. Although it is known that diabetes can cause brain alterations and increased risk for neurologic disorders, the relationship between neuroimmune activation, brain changes, and neurodevelopment deficits in the offspring remains unclear. In order to elucidate the short- and long-term biological basis of the developmental outcomes caused by the severe uncontrolled maternal hyperglycemia, we studied apoptosis, neurogenesis, and neuroinflammation pathways in the hippocampus of neonates and young rats born to diabetic dams. Diabetes was induced on gestational day 5 by an injection of streptozotocin. Evaluations of milestones, body growth, and inhibitory avoidance were performed to monitor the offspring development and behavior. Hippocampal modifications were studied through cellular survival by BrdU in the dentate gyrus, expression of apoptosis-regulatory proteins (procaspase 3, caspase 3, and Bcl-2), BDNF, and neuroinflammatory modulation by interleukins, MHC-I, MHC-II, Iba-1, and GFAP proteins. Severe maternal diabetes caused microsomia and neurodevelopmental delay in pups and decrease of Bcl-2, procaspase 3, and caspase 3 in the hippocampus. Moreover, in a later stage of development, it was found an increase of TNF-α and a decrease of procaspase 3, caspase 3, MHC-I, IL-1β, and BDNF in the hippocampus, as well as impairment in cellular survival in the dentate gyrus. This study showed significant short- and long-term commitments on the development, apoptosis, cell survival, and neuroinflammation in the offspring hippocampus induced by severe uncontrolled maternal hyperglycemia. The data reinforce the need for treatment of maternal hyperglycemic states during pregnancy and breast-feeding.

Maternal Gestational Diabetes Mellitus, Type 1 Diabetes, and Type 2 Diabetes During Pregnancy and Risk of ADHD in Offspring.

To examine the relative importance of maternal preexisting type 1 diabetes (T1D), preexisting type 2 diabetes (T2D), and gestational diabetes mellitus (GDM) on risk of attention deficit/hyperactivity disorder (ADHD) in offspring. This retrospective birth cohort study included 333,182 singletons born in 1995-2012 within Kaiser Permanente Southern California hospitals. Children were prospectively followed through electronic medical records from age 4 years. Relative risks of ADHD associated with diabetes exposures in utero were estimated by hazard ratios (HRs) using Cox regression with adjustment for potential confounders. For GDM, timing of exposure was evaluated by gestational age at diagnosis and severity was assessed by the need for antidiabetes medication treatment during pregnancy. A total of 37,878 (11.4%) children were exposed to diabetes (522 exposed to T1D, 7,822 T2D, and 29,534 GDM). During a median of 4.9 years (interquartile range 2.2, 9.6) of follow-up after age 4 years, 17,415 (5.2%) children were diagnosed with ADHD. ADHD risk was not associated with GDM taken as a whole (P = 0.50) or with gestational age at GDM diagnosis (P = 0.16). However, the risk was significantly greater for the GDM requiring versus not requiring antidiabetes medications (P < 0.001). Compared with children unexposed to diabetes, the adjusted HRs for ADHD in children were 1.57 (95% CI 1.09-2.25) for exposure to T1D, 1.43 (1.29-1.60) for T2D, 1.26 (1.14-1.41) for GDM requiring antidiabetes medications, and 0.93 (0.86-1.01) for GDM not requiring medications. The hierarchy of risks suggests that severity of maternal diabetes (T1D vs. T2D vs. GDM requiring antidiabetes medications) influences the risk of ADHD in offspring of mothers with diabetes.

Post-weaning high-fat diet accelerates kidney injury, but not hypertension programmed by maternal diabetes.

The aim of this study was to establish the underlying mechanisms by which a post-weaning high-fat diet (HFD) accelerates the perinatal programming of kidney injury occurring in the offspring of diabetic mothers. Male mice, offspring of nondiabetic and diabetic dams were fed with normal diet (ND) or HFD from 4 to 20 wk of age. Rat renal proximal tubular cells were used in vitro. On ND, the offspring of dams with severe maternal diabetes had an intrauterine growth restriction (IUGR) phenotype and developed mild hypertension and evidence of kidney injury in adulthood. Exposing the IUGR offspring to HFD resulted in rapid weight gain, catch-up growth, and later to profound kidney injury with activation of renal TGFβ1 and collagen type IV expression, increased oxidative stress, and enhanced renal lipid deposition, but not systemic hypertension. Given our data, we speculate that HFD or free fatty acids may accelerate the process of perinatal programming of kidney injury, via increased CD36 and fatty acid-binding protein 4 expression, which may target reactive oxygen species, nuclear factor-kappa B, and TGFβ1 signaling in vivo and in vitro. Early postnatal exposure to overnutrition with a HFD increases the risk of development of kidney injury, but not hypertension, in IUGR offspring of dams with maternal diabetes.

Catalase Prevents Maternal Diabetes–Induced Perinatal Programming via the Nrf2–HO-1 Defense System

We investigated whether overexpression of catalase (CAT) in renal proximal tubular cells (RPTCs) could prevent the programming of hypertension and kidney disease in the offspring of dams with maternal diabetes. Male offspring of nondiabetic and diabetic dams from two transgenic (Tg) lines (Hoxb7-green fluorescent protein [GFP]-Tg [controls] and Hoxb7/CAT-GFP-Tg, which overexpress CAT in RPTCs) were studied from the prenatal period into adulthood. Nephrogenesis, systolic blood pressure, renal hyperfiltration, kidney injury, and reactive oxygen species (ROS) generation were assessed. Gene expression of transforming growth factor-β1 (TGF-β1), nuclear factor erythroid 2p45–related factor-2 (Nrf2), and heme oxygenase-1 (HO-1) was tested in both in vitro and in vivo studies. Renal dysmorphogenesis was observed in offspring of Hoxb7-GFP-Tg dams with severe maternal diabetes; the affected male offspring displayed higher renal ROS generation and developed hypertension and renal hyperfiltration as well as renal injury with heightened TGF-β1 expression in adulthood. These changes were ameliorated in male offspring of diabetic Hoxb7/CAT-GFP-Tg dams via the Nrf2–HO-1 defense system. CAT promoted Nrf2 nuclear translocation and HO-1 gene expression, seen in both in vitro and in vivo studies. In conclusion, CAT overexpression in the RPTCs ameliorated maternal diabetes–induced perinatal programming, mediated, at least in part, by triggering the Nrf2–HO-1 defense system.

Very low alpha-fetoprotein in Down syndrome maternal serum screening.

To establish the frequency of very low maternal serum AFP and to differentiate congenital AFP deficiency from those diseases known to be associated with low AFP. AFP values below 2 microg/L and borderline values up to 3 microg/L were retrospectively analysed in 839 773 singleton pregnancies included in a programme for routine screening of trisomy 21 maternal serum markers. Serum AFP was undetectable (< or =2 microg/L) in 8 cases, giving a frequency of 1/105 000. The calculated risk of Down syndrome was > or =1/250 in 5 cases. Fetal karyotype was normal. Seven of these pregnancies went to term (39-41 weeks) uneventfully, and birth weight was normal (3050-4110 g). In the 8th case, fetal death occurred at 35 weeks due to severe maternal diabetes. AFP levels between 2.1 and 3.0 microg/L were noted in 7 other cases. The calculated risk of Down syndrome was > or =1/250 in 5 cases, and fetal karyotype was normal. Pregnancies went to term in 4 cases (33-41 weeks), and birth weight was normal (3000-3380 g). In 3 cases, low hCG (<0.6 MoM) was associated with low AFP, and fetal death occurred at 15 to 16 weeks. Once technical errors have been excluded (repeat assay in a second run, calcium assayed to exclude the interference of EDTA for fluorimetric methods, dilution to exclude interfering antibodies, running on an alternative analyser, checking a second sample), very low second-trimester maternal serum AFP should prompt ultrasound examination in order to check fetal viability. Congenital AFP deficiency, an extremely rare disorder (1/100 000), should be suspected. It has no consequences for fetal and infant development, and parents should be reassured.

Long-term consequences for offspring of diabetes during pregnancy.

There is evidence that the diabetic intra-uterine environment has consequences for later life. Maternal diabetes mainly results in asymmetric macrosomia. This macrosomia is associated with an increased insulin secretion and overstimulation of the insulin producing B-cells during fetal life. In later life, a reduced insulin secretion is found. Intra-uterine growth restriction is present in severe maternal diabetes associated with vasculopathy. Intra-uterine growth restriction is associated with low insulin secretion and reduced development of the insulin receptors. In later life, these alterations can induce insulin resistance. The long-term consequences of an abnormal intra-uterine environment are of primary importance world-wide. Concentrated efforts are needed to explore how these long-term effects can be prevented.

Estudo Longitudinal, Bioquímico e Histoquímico, de Placentas de Ratas Diabéticas: Relação com a Macrossomia e o Retardo de Crescimento Intra-uterino

Objetivo: o estudo longitudinal, entre o 18o e o 21o dias de prenhez, das alteracoes bioquimicas e histoquimicas das placentas de ratas diabeticas, cujos fetos tiveram macrossomia e retardo de crescimento intra-uterino (CIUR). Material e Metodo: usando modelo experimental em ratas, foram estudados 3 grupos: controle, diabete moderado e grave. A prenhez foi resolvida por cesarea no 18o ou no 21o dia. Compararam-se as glicemias materna e fetal; a incidencia de recem-nascidos (RN) de peso pequeno (PIP), adequado (AIP) e grande (GIP) para tempo de prenhez; peso, indice e conteudo de DNA, RNA e proteinas placentarios e quantidade de glicogenio na superficie de trocas materno-fetais. Resultados: no diabete moderado houve maior proporcao de RN-GIP com placentas ricas em DNA e diminuicao progressiva de glicogenio em suas membranas no final da prenhez. No diabete grave houve predominio de RN-GIP e as placentas exibiram menor conteudo de DNA, sintese aumentada de RNA e tendencia a maior producao proteica, com manutencao dos depositos de glicogenio. Conclusoes: concluiu-se que, entre o 18o e o 21o dias, os desvios do crescimento fetal no diabete materno, moderado e grave relacionam-se a alteracoes placentarias distintas. No moderado ha apenas hiperplasia celular, com desaparecimento do glicogenio no final da prenhez. No grave, a superficie de trocas materno-fetais e mais espessada e, alem de hiperplasia, ha hipertrofia das celulas, com manutencao dos estoques placentarios de glicogenio.

Expression of genes involved in placental glucose uptake and transport in the nonobese diabetic mouse pregnancy

Maternal diabetes alters placental glucose metabolism and maternofetal glucose transport. The purpose of this study was to determine whether genes involved in placental glucose uptake and transport were concomitantly altered, resulting in the observed changes in the state of maternal diabetes. By means of the nonobese diabetic pregnant mouse we examined the expression of placental glucose transporters, hexokinase I, glycogen content, glycogen-regulating enzyme activities in control animals (blood glucose 8.5 +/- 0.2 mmol/L, n = 25), moderate maternal diabetes (blood glucose 10 to 13.9 mmol/L, n = 16), and severe maternal diabetes (blood glucose > 16.7 mmol/L, n = 12). Comparisons by the analysis of variance and the Newman-Keuls test were performed. Although changes in placental glucose transporters and hexokinase I messenger ribonucleic acid levels occurred, neither state of diabetes altered the corresponding protein levels. Changes in placental deoxyribonucleic acid (p < 0.05) and glycogen content (p < 0.01), fetal insulin levels (p < 0.02), and fetal size (p < 0.05) occurred in the moderately diabetic group, and changes in placental weight (p < 0.05) and fetal glucose levels (p < 0.02) were observed in the severely diabetic group. Placental glucose transporting and phosphorylating protein levels by themselves do not regulate diabetes-induced fetoplacental alterations. The lack of a protective decline in these proteins may account for the observed fetoplacental adaptations to excess glucose.

The effects of severe maternal diabetes on glucose transport in the fetal rat

We mimicked the condition of severe maternal diabetes by administering high doses of streptozotocin (STZ) to the pregnant rat to determine the effects of increased glucose availability on fetal glucose transport and to assess whether a relationship might exist between glucose transport and altered fetal growth. Fetuses of STZ-treated pregnant rats were growth retarded (3.86 +/- 0.13 vs. 5.29 +/- 0.06 g), hyperglycemic (30.0 +/- 1.0 vs. 5.5 +/- 0.5 mM/liter), and hyperinsulinemic (1263.8 +/- 138.3 vs. 817.9 +/- 116.7 pM/liter). Glucose uptake, Glut 1 messenger RNA (mRNA), and Glut 1 protein were greater in STZ-treated fetal brain than in controls (50%, 83%, and 50%, respectively; P < 0.05). Glut 3 mRNA levels in STZ-treated and control fetal brain were equivalent and significantly less than levels of Glut 1. Glucose uptake in muscle of STZ fetuses was 70% greater than control values (P < 0.05). Glut 1 mRNA levels were increased by 93% in STZ fetal muscle (P < 0.05). Neither Glut 3 nor Glut 4 mRNA could be detected in STZ-treated and control fetal muscle. Glut 1 protein levels were increased by 70% in STZ-treated fetal muscle compared to control muscle (P < 0.05). These observations indicate that altered glucose transport per se does not directly contribute to fetal growth retardation with maternal STZ diabetes. Perturbations in other physiological and metabolic factors may contribute to the pathogenesis of fetal growth retardation in STZ-induced diabetes during pregnancy.

The effects of severe maternal diabetes on glucose transport in the fetal rat.

We mimicked the condition of severe maternal diabetes by administering high doses of streptozotocin (STZ) to the pregnant rat to determine the effects of increased glucose availability on fetal glucose transport and to assess whether a relationship might exist between glucose transport and altered fetal growth. Fetuses of STZ-treated pregnant rats were growth retarded (3.86 +/- 0.13 vs. 5.29 +/- 0.06 g), hyperglycemic (30.0 +/- 1.0 vs. 5.5 +/- 0.5 mM/liter), and hyperinsulinemic (1263.8 +/- 138.3 vs. 817.9 +/- 116.7 pM/liter). Glucose uptake, Glut 1 messenger RNA (mRNA), and Glut 1 protein were greater in STZ-treated fetal brain than in controls (50%, 83%, and 50%, respectively; P < 0.05). Glut 3 mRNA levels in STZ-treated and control fetal brain were equivalent and significantly less than levels of Glut 1. Glucose uptake in muscle of STZ fetuses was 70% greater than control values (P < 0.05). Glut 1 mRNA levels were increased by 93% in STZ fetal muscle (P < 0.05). Neither Glut 3 nor Glut 4 mRNA could be detected in STZ-treated and control fetal muscle. Glut 1 protein levels were increased by 70% in STZ-treated fetal muscle compared to control muscle (P < 0.05). These observations indicate that altered glucose transport per se does not directly contribute to fetal growth retardation with maternal STZ diabetes. Perturbations in other physiological and metabolic factors may contribute to the pathogenesis of fetal growth retardation in STZ-induced diabetes during pregnancy.

Hypoxia-Induced Sympathetic Inhibition of the Fetal Plasma Insulin Response to Hyperglycemia

Large-for-delivery date babies, considered characteristic of diabetic pregnancy, are believed to result from fetal hyperinsulinemia. Paradoxically, infant birth weights tend to be low-for-delivery date in mothers with more severe diabetes. We tested the hypothesis that hypoxemia in such fetuses leads to sympathoadrenal stimulation and inhibition of insulin secretion; and, thus, produces a net reduction in the growth-promoting effects. Fetal sheep were prepared with chronic peripheral and adrenal cannulas. Fetal blood gases, lactate, norepinephrine, and epinephrine secretion rates; and plasma norepinephrine, glucose, and immunoreactive insulin concentrations were determined at 30-min intervals during a 2-h baseline period and a 4-h period of hyperglycemia divided into 2-h segments of hypoxemia (with and without alpha-blockade) and hyperoxia. Hypoxemia-hyperoxia sequences were varied randomly. Well-oxygenated fetuses responded to a threefold increase in glucose with a sixfold increase in plasma immunoreactive insulin. With hypoxemia, norepinephrine and epinephrine secretion were elevated and the insulin response was blocked. With hypoxemia and phentolamine blockade, the insulin response was enhanced with a 10-fold increase above baseline. In severe maternal diabetes with vascular disease or with poor control and very high glucose levels, the fetus is likely to be relatively hypoxemic. Our experiments suggest that in this situation, the fetal insulin response to hyperglycemia will be attenuated; this effect is mediated, at least partly, through sympathoadrenal stimulation.

Significant decrease in congenital malformations in newborn infants of an unselected population of diabetic women

In an unselected and consecutive series of 1858 newborn infants of diabetic mothers, born in the Rigshospital, Copenhagen, in the period 1967 to 1986, congenital malformations were studied. The malformation rate in White Classes B to F was remarkably constant from 1967 to 1981, but a significant decrease in major congenital malformations was found in the period 1982 to 1986 versus 1977 to 1981 (2.7% vs. 7.4%, p less than 0.05). This decrease was mainly due to a fourfold decline in major congenital malformations in White Classes D and F (p less than 0.01), and consequently a correlation between the severity of maternal diabetes and the frequency of congenital malformations was no longer present. In the offspring of a control group of 1715 nondiabetic women, major congenital malformations were found in 1.7% (p greater than 0.05). Seventy-five percent of the diabetic pregnancies were planned, and in these pregnancies only 1% of the infants had major congenital malformations. The frequency of fatal malformations in White Classes B to F was still significantly higher than in the control group (p less than 0.001).

The development of the fetal rat intestine and its reaction to maternal diabetes: II. Effect of mild and severe maternal diabetes

Diabetes during pregnancy induces specifically structural and functional changes in the fetal endocrine pancreas. Other organs are affected as well. In this study, the fetal intestinal tract which is in close connection with the endocrine pancreas was analysed during diabetic gestation. The disease was induced by two different doses of streptozotocin which led to a mild or severe diabetic state in the mother. In fetuses from mildly diabetic as well as from severely diabetic rats, the time sequence in the appearance of the differentiated cells was identical and similar to that of controls. However, morphometric analysis of the intestine of fetuses from severely diabetic rats revealed a decrease in each of the parameters measured which led to a general hypotrophy of the intestine. In the fetuses from mildly diabetic rats, the values of the morphometric parameters of the duodenal mucosa remained unchanged and comparable to those of the control group. The vascularisation of the duodenum is modified in these fetuses because the volume density of the blood vessels is significantly increased. In conclusion, both diabetic states of the mother induce various alterations in the fetal intestine, including the blood vessels. The nature of the structural changes observed in the intestine could lead to modifications in the function of the entero-pancreatic system in these fetuses.

Maternal and Fetal Endocrine Pancreas in the Spontaneously Diabetic BB Rat

The maternal and fetal endocrine pancreas were investigated in the diabetic BB rat on day 21 of pregnancy. The maternal pancreas of the diabetic rat contained practically no insulin-positive B cells. The A and D cell mass were also decreased, while plasma glucagon and somatostatin levels were normal or increased, confirming previous data. Six of 11 diabetic rats had B-cell-specific surface antibodies (ICSA), whereas only 1 of 10 nondiabetic rats was ICSA-positive. The volume density of insulin-positive cells was decreased in the fetal pancreas of diabetic BB rats compared to fetuses of nondiabetic rats, but the volume density of glucagon- and somatostatin-positive cells remained normal. The B cells of these fetuses were ultrastructurally less granulated and showed signs of increased cellular activity. Plasma insulin levels were decreased while plasma glucagon and somatostatin concentrations were normal. ICSA were not detected in fetuses of nondiabetic and diabetic rats. There were no differences in the histology of the spleen and thymus between both groups of fetuses. Metabolic characterization of the growth-retarded fetuses of diabetic rats revealed, besides lower plasma insulin concentrations, increased branched chain amino acid levels, and normal plasma Sm/IGF-I levels. The main conclusions from this study are: (1) Severe maternal diabetes decreases the pancreatic insulin-positive cell mass and plasma insulin levels in the fetus, but not the A and D cell mass and function; (2) ICSA are not detectable in fetal plasma; (3) the influence of maternal BB rat diabetes on fetal endocrine pancreas and metabolic environment resembles that of severe streptozotocin-induced diabetes.

Outcome of Pregnancy in Insulin-dependent (Type 1) Diabetic Women between 1971 and 1984

We have looked at the outcome of pregnancy in women with type 1 (insulin-dependent) diabetes mellitus who were confined at Glasgow Royal Maternity Hospital between 1971 and 1984. Of 134 pregnancies, 123 proceeded beyond 28 weeks' gestation and yielded 125 live infants. The perinatal mortality rate was 16/1000, due solely to congenital foetal malformation. Malformations were not related either to the severity of maternal diabetes (as graded by the White classification) or the glycaemic control in the first trimester (as judged by maternal glycosylated haemoglobin concentration). Over the period of study, there has been a marked reduction in the frequency of ketoacidosis during pregnancy and in the delivery of small-for-dates babies; more mature lecithin:sphingomyelin ratios have been obtained by amniocentesis; and better Apgar scores have been demonstrated in the infants at delivery. The Caesarean section rate has fallen from 83 to 30 per cent, and babies now spend less time separated from their mothers in paediatric units. These improvements largely reflect better diabetic treatment (improved insulin regimens and glycaemic control) and closer obstetric assessment. Foetal malformation occurred overall in 11.4 per cent of pregnancies and did not become less frequent over the period of study. Further major improvement in the outcome of diabetic pregnancy will only come from a reduction in the congenital malformation rate, which implies better diabetic control at and around the time of conception.

Congenital malformations in diabetic pregnancies. Clinical viewpoints.

A consecutive series of 2,587 newborn infants of diabetic mothers treated during pregnancy and delivery in the period 1926 to 1983 has been analysed. The malformation rate was 6.6%. The series has been divided into five consecutive periods each comprising around 500 infants. During the first four periods the frequency of congenital malformations (CM) was remarkably constant also when related to the severity of the maternal diabetes. During the latest period from 1979 to 1983 a significant decrease in the frequency and severity of CM in infants of diabetic mothers was seen, most marked in the group with more severe maternal diabetes (White's classes D + F). One hundred and thirty-five insulin-dependent diabetic women with regular menstrual histories were examined by ultrasonic scanning in the 7th to 14th week of pregnancy. As judged by the crown-rump length 53 fetuses were smaller than normal. The term early growth delay is used for this phenomenon. Nine of the 135 fetuses had major CM and seven of them were smaller than normal in early pregnancy. These observations show that fetuses that are significantly smaller than normal in early pregnancy carry a higher risk of being malformed and suggest a common mechanism behind early growth delay and induction of abnormal embryogenesis.

Increased fetal insulin receptors and changes in membrane fluidity and lipid composition.

Fetal tissues exposed to hyperinsulinemia in utero have significantly greater numbers of insulin receptors than do those of controls. We have studied this upregulation phenomenon using crude microsomal membranes from fetal rabbit litters exposed to varying degrees of hyperinsulinemia in diabetic pregnant rabbits. We have observed that insulin binding capacity of membranes increased directly with the severity of maternal diabetes, ranging from 8.5 ng in controls to 44.6 ng insulin/mg membrane protein in offspring of severely diabetic animals and related directly with increasing fetal insulin levels (r = 0.77, P less than 0.005). Lipid analyses of fetal lung membranes showed that reduction of phospholipid to protein ratios occurred in the presence of maternal diabetes. Membrane cholesterol-to-phospholipid ratios were also altered in the presence of maternal diabetes. Significantly, increases in plasma membrane microviscosity were noted in the membranes from diabetic offspring. The data suggest that reduction of membrane fluidity is associated with increases in fetal membrane insulin receptors in severely diabetic pregnancies.