Malformations In Diabetic Pregnancy Research Articles

Decreased alpha-fetoprotein in amniotic fluid and maternal serum in diabetic pregnancy

To determine a reference level for alpha-fetoprotein (AFP) in the amniotic fluid (AF) in pregnant women with insulin-dependent diabetes mellitus in order to suggest an explanation for the observed decrease in maternal serum AFP.Alpha-fetoprotein was measured in AF, maternal serum, or both in the second trimester in 287 pregnant women with insulin-dependent diabetes mellitus. Retrospectively, these AFP values were correlated with glycosylated hemoglobin (HbA1C) levels, early fetal growth delay, and congenital malformations.The median concentration of AFAFP was 0.89 multiples of the normative median (MoM) (n = 280; 95% confidence interval [CI] 0.88-0.93 MoM); the maternal serum AFP (MSAFP) value was 0.78 MoM (n = 155; 95% CI 0.77-0.84 MoM). A statistically significant but weak positive correlation was found between HbA1C and MSAFP (r2 = 0.033, P = .03), but the correlation with AFAFP was not statistically significant. The levels of AFP did not correlate with early fetal growth delay. One neural tube defect, but none of the 11 other major malformations, was detected by AFP screening.A physiologic basis for the decreased AFAFP and MSAFP levels is still obscure. Screening for congenital malformations in diabetic pregnancies should include both a mid-gestation ultrasound scan and MSAFP measurement. However, routine amniocentesis does not seem to be indicated. Concentrations of AFAFP may be corrected for the observed decrease.

Review Article : The Yolk Sac Theory

The purpose of this article is to examine the role of yolk sac failure during organogenesis in the development of diabetes-associated embryopathy. The current literature regarding congenital malformations in diabetic pregnancies was reviewed to elucidate the precise role of the yolk sac in embryonic development and the relation between yolk sac injury and embryopathy. We and others have demonstrated that hyperglycemia produces a teratogenic effect during organogenesis. In addition, we have shown that the yolk sac appears to be the target site of injury induced by hyperglycemia. We have also presented evidence that cell membrane dysfunction leads to failed vitelline vessel formation and that arachidonic acid supplementation prevents many of the morphologic and biochemical alterations observed under hyperglycemic conditions. These data strongly support the teratogenic effect of hyperglycemia, the arachidonic acid deficiency state, the resultant maldevelopment of vitelline vessels, and the ability to prevent these changes by arachidonic acid supplementation. These studies have made significant inroads in explaining why diabetes-associated anomalies occur, and suggest a potential future role for prophylaxis against these organogenetic malformations using dietary polyunsaturated fatty acid supplementation.

Diabetic Embryopathy Studies With Animal and In Vitro Models

Diabetic pregnancy is associated with an increased risk for fetal maldevelopment for a largely unknown reason. A decade ago, Norbert Freinkel suggested that the altered fuel mixture offered to the growing conceptus may be the key to most of the changes in the embryogenesis of diabetic pregnancy. He coined the term fuel-mediated teratogenesis. During early pregnancy, periods of maternal hyper- and hypoglycemia may cause marked changes in the availability of glucose to the conceptus. Also, increased concentrations of lipids, notably ketone bodies, and branched-chain amino acids in the maternal circulation contribute to a changed fuel mixture for the embryo. In a recent experimental study of diabetic rats, it was found that the maternal metabolism of all three major classes of nutrients and maternal somatic growth during gestation covaried with the development of the embryo. Consequently, the maintenance of normal concentrations of metabolites from all nutrient classes may be important for prevention of adverse fetal outcome in diabetic pregnancy. In vitro, a high glucose concentration causes embryonic dysmorphogenesis by generation of free oxygen radicals. An enhanced production of such radicals in embryonic tissues may be directly related to an increased risk of congenital malformations in diabetic pregnancy. Thus, the notion that alterations in the net transfer of cellular fuels from the diabetic mother to her offspring may cause embryonic dysmorphogenesis, which suggests that combustion of the fuel may produce compounds that impair embryonic development, has obtained experimental support. If this is also true for human diabetic pregnancy, it has therapeutic implications.

Protection by free oxygen radical scavenging enzymes against glucose-induced embryonic malformations in vitro

This study addresses the possibility that the teratogenic effects of a diabetic pregnancy are associated with increased embryonic activities of free oxygen radicals. Rat embryos were cultured in 50 mmol/l glucose for 48 h and subsequently showed pronounced growth retardation and severe malformations. The enzyme inducer citiolone and the free oxygen radical scavenging enzymes superoxide dismutase, catalase and glutathione peroxidase protected against the disturbed growth and development of the embryos at 50 mmol/l glucose when added to the culture media. Enzymatic measurements indicated that citiolone induced an increased activity of superoxide dismutase in the embryonic tissues and that the added enzymes were taken up by both the yolk sac and the embryo proper. The protection against embryonic maldevelopment was thus conferred by agents that increased the free oxygen radical scavenging capacity of the embryonic tissues. The results suggest that a high glucose concentration in vitro causes embryonic dysmorphogenesis by generation of free oxygen radicals. An enhanced production of such radicals in embryonic tissues may be directly related to the increased risk of congenital malformations in diabetic pregnancy.

Diet Composition Modifies Embryotoxic Effects Induced by Experimental Diabetes in Rats

Despite improvements in prenatal care, the incidence of congenital malformations in diabetic pregnancies is still 3-4 times higher than in normal pregnancies. These defects could be attributed to alterations of intrauterine environment due to disorder of the maternal metabolism. If this were true, the quality of food could play a role in diabetes-induced embryotoxicity. To check this hypothesis, female CD rats were made diabetic by injecting intravenously 50 mg/kg of streptozotocin 2 weeks before mating. From the first day of pregnancy they were divided into three groups and maintained on the following diets: (1) standard diet (Italiana Mangimi); (2) purified high protein diet (protein 55%, carbohydrates 25.5%, fat 7.5%, fiber 4.5%, ash 7.5%); (3) purified normoprotein diet (protein 19%, carbohydrates 62.5%, fat 7.5%, fiber 4%, ash 7%). Nondiabetic pregnant females fed with standard diet served as negative control. No significant differences were observed in blood glucose levels among the groups (range 410-500 mg/dl). The group fed on normoprotein diet showed at term of pregnancy: (1) higher rate of resorptions; (2) lower fetal weight; (3) higher frequency of major malformations than the groups fed standard and hyperproteic diets. Although we are not able at this time to discriminate between a protective effect of a diet with a high protein content and a disruptive effect of a diet containing high quantity of carbohydrates, the results of this trial support the hypothesis of a fuel-mediated teratogenesis in diabetic pregnancy.

Metabolism inVitroof Cartilage Proteoglycans in Rat (Pre)chondrocytes from Different Embryonic Regions

Diabetes in the mother may cause disturbances in the chondrocyte development in the embryo. A rat model was used to investigate whether this was reflected in the production of proteoglycans by cells from two embryonic regions. One of these regions is resistant (limb bud) and the other susceptible (mandibular arch) to malformation in diabetic pregnancy. Chondroitin sulphate proteoglycans from cultures of day-12 rat embryo limb bud and mandibular arch chondrocytes were extracted with guanidine-HCl and analyzed by gel chromatography after in vitro 35S-sulphate-labeling. Two sizes of proteoglycans (Kav 0.26 and 0.66 on CL-2B Sepharose) were found in both types of chondrocytes and in all media. The polysaccharide chain length was the same (Kav 0.36 on CL-6B Sepharose) for both proteoglycans. Elevated levels of D-glucose or beta-hydroxybutyric acid had no effect on either proteoglycan size or proportion, nor on polysaccharide chain length. However, there were differences (in all culture conditions) between limb bud and mandibular arch cultures in that the larger proteoglycan accounted for 80% of total radioactivity in the limb bud cultures, 53% in the mandibular arch cultures, and only 25-29% in the media from both types of cultures. Furthermore, different ratios between radioactive proteoglycans in medium and matrix suggested markedly different efficiencies for matrix formation in the two cell types. These findings indicate differences in the metabolism of the proteoglycans in these two cell types which may be related to the induction of mandibular malformation in diabetic pregnancy.

Congenital Malformations in Offspring of Diabetic Rats: Experimental Study on the Influence of the Diet Composition and Magnesium Intake

In spite of improvements in the treatment of diabetes, the risk of congenital malformations in diabetic pregnancy is three to four times higher than in normal pregnancy. This might be due to the metabolic abnormalities of diabetic pregnancy that also affect mineral metabolism. Since diabetes can lower both maternal and fetal blood Mg levels, and Mg deficiency has been shown to be teratogenic in laboratory animals, we decided to investigate which effects Mg deficiency would have in inducing embryopathy in diabetic animals. Female CD rats were divided into six groups. Groups 1 and 2 were fed a standard diet (Mg content 4,200 ppm), groups 3-6 a purified diet (Mg contents 4,200, 500, 250, or 125 ppm). Groups 2-6 had been made diabetic by an intravenous injection of 50 mg/kg streptozocin 1 week before mating. The rats were killed on day 21 of pregnancy, and the live fetuses were examined for external, skeletal, and visceral malformations. The maternal and fetal blood glucose levels were the same in all diabetic groups. The maternal Mg levels in groups 2 and 3 were the same as in controls, but definitely lower in groups 4-6. Embryotoxicity (embryonic deaths, delayed development, congenital malformations) was higher in the groups fed the purified diet than in group 2, but without a clear relation to the dietary Mg levels. We cannot draw any conclusions about the effects of Mg deficiency in diabetic pregnancy from our results, but they show that the quality of the diet is of major importance in the manifestation of embryotoxicity in diabetes.

Mechanisms of congenital malformations in diabetic pregnancy.

The reasons for the increased rate of congenital malformations in diabetic pregnancy are unclear. Several different teratological agents may be considered. In clinical investigations and animal experimentation hyperglycemia and hypoglycemia, hyperketonemia, altered trace metal metabolism, and a genetic predisposition have been suggested to be of significance in the teratogenic process of diabetic pregnancy. Studies of these possible etiological factors have so far failed to reveal a single agent or mechanism as the most important. The diabetic pregnancy, therefore, appears to be of multifactorial origin.

The effect of maternal diabetes on trace element status and fetal development in the rat.

Despite improvements in prenatal care, there is a high incidence of congenital malformations in diabetic pregnancies. Not only is the diabetic patient characterized by a disorder of total fuel metabolism, but abnormal trace element metabolism occurs as well. In the present study, maternal and fetal zinc (Zn), copper (Cu), manganese (Mn), iron (Fe), magnesium (Mg), and calcium (Ca) status has been studied in Sprague-Dawley (SD) and Wistar rats. In addition, the effect of maternal diabetes on fetal development was also investigated. Rats were injected 27 days before mating with streptozocin (STZ, 45 mg/kg) in citrate buffer. On day 20 of gestation, litters were taken by cesarean section. Fetuses from diabetic dams weighed less, and had shorter crown-rump lengths and larger placentas than fetuses from controls. Evaluation of fetal skeletal development revealed fewer calcified sternal sites, anterior phalanges and caudal vertebrae, and an increased frequency of malformations in fetuses of diabetic dams. In dams, diabetics had larger adrenals, kidneys, and liver, and smaller thymus. Abnormal trace element metabolism was evident in diabetic dams and their fetuses. Mn was elevated in maternal liver, kidney and placenta of diabetic animals as well as in fetal liver of pups from diabetic dams. Maternal Cu and Zn levels were also higher in the liver and kidney of diabetic rats. In contrast, fetal liver Zn from fetuses of diabetic mothers was significantly decreased when compared with controls. These results suggest that diabetes may have induced fetal Zn deficiency. If this deficiency is present during embryogenesis/organogenesis, this could be one of the mechanisms of the teratogenicity of the diabetic state.

Congenital malformations in diabetic pregnancy: the clinical relevance of experimental animal studies.

The aim of this work was to present recent observations on the occurrence of malformations in the offspring of diabetic rats and to discuss these findings in the light of present clinical experience. Comparison of malformation rates between different substrains of Sprague-Dawley rats showed marked differences in the occurrence of diabetes-induced malformations. These findings suggest that congenital malformations in diabetic pregnancy may result from a teratological insult in genetically predisposed individuals. Recent clinical reports seem to link facial malformations to an increased incidence of sacral-caudal malformations in human diabetic pregnancy. The present rat model, which expresses both these aberrations--micrognathia and sacral dysgenesis--may therefore be a useful tool in studies of the aetiological relationships between disturbed maternal metabolism and skeletal malformations in the offspring. Malformations in fetuses of diabetic animals seem to arise from teratogenic insult(s) early in pregnancy. Hyperglycemia and hyperketonemia may both singly, and in combination, be of teratological significance. Insulin itself does not appear to be directly teratogenic. Furthermore, there is evidence to suggest that disturbed levels of trace metals, primarily zinc, may be a significant factor in the production of congenital malformations. The increased rate of malformations in diabetic pregnancy, therefore, appears to be multifactorial in origin.

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.

Diabetes in Pregnancy: Retarded Fetal Growth, Congenital Malformations and Feto-Maternal Concentrations of Zinc, Copper and Manganese in the Rat

The possible relationship between trace metal alterations, disturbed somatic growth and congenital malformations in diabetic pregnancy was studied in an animal model in which skeletal malformations are known to occur in the offspring of experimentally diabetic rats. The diabetic state was induced with streptozotocin more than 2 weeks before mating. In some of the diabetic animals, a zinc supplement in the drinking water (1 ppm or 15 ppm) was given during pregnancy. The contents of zinc, copper and manganese in the maternal livers and whole fetuses were examined on gestational days 18, 20 and 22. The resorption and malformation rates were significantly increased in the diabetic groups. In addition, the fetuses of the diabetic rats exhibited marked growth retardation at all times compared to the normal offspring whether or not the mothers were zinc-treated. There was an excessive accumulation of zinc, copper and manganese in the maternal livers of the diabetic rats. In the offspring of the diabetic rats, however, the total-body concentration of zinc was strikingly decreased. The fetal zinc deficiency in the diabetic group persisted despite maternal zinc supplement during pregnancy. The copper concentrations in the fetuses of normal and diabetic mothers were largely similar, whereas the fetal manganese concentrations were increased in the fetuses of diabetic rats. The findings are compatible with the view that trace metal aberrations may be related to the disturbed fetal growth, and furthermore, that these changes in trace metal levels may also be of teratogenic importance in diabetic pregnancy.

Early fetal growth delay detected by ultrasound marks increased risk of congenital malformation in diabetic pregnancy

Early fetal growth delay detected by ultrasound marks increased risk of congenital malformation in diabetic pregnancy

Early Fetal Growth Delay Detected by Ultrasound Marks Increased Risk of Congenital Malformation in Diabetic Pregnancy

Early Fetal Growth Delay Detected by Ultrasound Marks Increased Risk of Congenital Malformation in Diabetic Pregnancy

Early fetal growth delay detected by ultrasound marks increased risk of congenital malformation in diabetic pregnancy.

Ninety-nine insulin-dependent diabetic women with regular menstrual histories were examined by ultrasonic scanning in the seventh to 14th weeks of pregnancy. As judged by the crown-rump length 38 fetuses were smaller than normal. The term early growth delay is suggested for this phenomenon. Nine fetuses had major congenital malformations, and seven of them were smaller than normal in early pregnancy (p less than 0.02). The risk of fetal malformation in diabetic pregnancy increases with the severity of the diabetes. Early fetal growth delay is apparently another risk marker, in this series indicating a risk of 18% (7/38). The combination of severe maternal diabetes (White's classes D and F) and early growth delay yielded a risk of major congenital malformation of 27% (6/22). These observations suggest a common mechanism behind early growth delay and induction of abnormal embryogenesis (and maybe even fetal death). The mechanism is unknown but probably influenced by the quality of regulation of diabetes.