The increased rate of embryonic dysmorphogenesis in diabetic pregnancy is correlated with the severity and duration of the concurrent hyperglycemia during early gestation. Whole embryo culture was used to investigate a possible... more
The increased rate of embryonic dysmorphogenesis in diabetic pregnancy is correlated with the severity and duration of the concurrent hyperglycemia during early gestation. Whole embryo culture was used to investigate a possible association of hyperglycemia-induced disturbances of embryo development with tissue levels of the three alpha-oxoaldehydes: glyoxal, methylglyoxal, and 3-deoxyglucosone (3-DG). Rat embryos exposed to high glucose levels in vitro showed severe dysmorphogenesis and a 17-fold increased concentration of 3-DG compared with control embryos cultured in a low glucose concentration. Exogenous 3-DG (100 micromol/l) added to the medium of control cultures yielded an increased embryonic malformation rate and a 3-DG concentration similar to that of embryos cultured in high glucose. Addition of superoxide dismutase (SOD) to the culture medium decreased the malformation rates of embryos exposed to either high glucose or high 3-DG levels, but it did not decrease the high emb...
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Hydronephrosis causes renal dysfunction and salt-sensitive hypertension, which is associated with nitric oxide deficiency and abnormal tubuloglomerular feedback (TGF) response. We investigated the role of oxidative stress for salt... more
Hydronephrosis causes renal dysfunction and salt-sensitive hypertension, which is associated with nitric oxide deficiency and abnormal tubuloglomerular feedback (TGF) response. We investigated the role of oxidative stress for salt sensitivity and for hypertension in hydronephrosis. Hydronephrosis was induced in superoxide dismutase 1-transgenic (SOD1-tg), SOD1-deficient (SOD1-ko), and wild-type mice and in rats. In mice, telemetric measurements were performed during normal (0.7% NaCl) and high-sodium (4% NaCl) diets and with chronic tempol supplementation. The 8-iso-prostaglandin-F2α (F2-IsoPs) and protein excretion profiles and renal histology were investigated. The acute effects of tempol on blood pressure and TGF were studied in rats. In hydronephrosis, wild-type mice developed salt-sensitive hypertension (114 ± 1 to 120 ± 2 mmHg), which was augmented in SOD1-ko (125 ± 3 to 135 ± 4 mmHg) but abolished in SOD1-tg (109 ± 3 to 108 ± 3 mmHg). SOD1-ko controls displayed salt-sensitive...
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ABSTRACT The aetiology of the dysmorphogenesis (Miller 1946; Naeye 1965; Kucera 1971) and embryo-fetal wastage (Pedersen 1977; Pedersen and Mølsted-Pedersen 1982; Sutherland and Pritchard 1986) found in the offspring of diabetic mothers... more
ABSTRACT The aetiology of the dysmorphogenesis (Miller 1946; Naeye 1965; Kucera 1971) and embryo-fetal wastage (Pedersen 1977; Pedersen and Mølsted-Pedersen 1982; Sutherland and Pritchard 1986) found in the offspring of diabetic mothers is unknown (Freinkel 1980; Mills 1982). To study this problem we have used a rat model in which female rats are made manifestly diabetic with streptozotocin 1–4 weeks prior to mating with non-diabetic males (Eriksson et al. 1980). The animals are an outbred substrain of Sprague-Dawley albino rats, which was originally imported from Zentralinstitut für Versuchtiersucht (Hanover, FRG) to a Swedish commercial breeding institution in 1962 (Anticimex/ALAB, Sollentuna, Sweden). In 1982 the colony was moved to our Department in Uppsala (hence, these animals are denoted U rats) and the Swedish breeder re-imported new outbred Sprague-Dawley rats from the original colony in Hanover (called H rats in the following; see also Fig. 6.1).
The receptor for Advanced Glycation End products (RAGE) is implicated in the pathogenesis of diabetic complications, but its importance in diabetic embryopathy is unclear. We therefore investigated the role of RAGE in diabetic embryopathy... more
The receptor for Advanced Glycation End products (RAGE) is implicated in the pathogenesis of diabetic complications, but its importance in diabetic embryopathy is unclear. We therefore investigated the role of RAGE in diabetic embryopathy using streptozotocin induced diabetes in female wild type (WT) C57Bl/6N and RAGE knockout C57Bl/6N (RAGE(-/-)) mice, mated with control males of the same genotype. Maternal diabetes induced more fetal resorption and malformation (facial skeleton, neural tube) in the WT than in the RAGE(-/-) fetuses. Maternal plasma glucose and methylgyoxal concentrations, as well as embryonic N(ε)-carboxymethyl-lysine (CML) levels were increased to the same extent in diabetic WT and RAGE(-/-) pregnancy. However, maternal diabetes induced increased fetal hepatic isoprostane 8-iso-PGF2α levels (oxidative stress marker) and embryonic activation of NFκB in WT only (not in RAGE(-/-) embryos). The association between RAGE knockout and diminished embryonic dysmorphogenesi...
Research Interests: Kinetics, Plant Biology, In Vitro, Tissue culture, Glucagon, and 7 moreMice, Animals, Blood, Male, Culture Media, islets of Langerhans, and Aprotinin
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The effects of maternal diabetes on somatic development and activity of the polyol pathway were investigated during early and late gestation in a rat model for diabetic pregnancy. We studied embryo-fetal growth, mortality, and... more
The effects of maternal diabetes on somatic development and activity of the polyol pathway were investigated during early and late gestation in a rat model for diabetic pregnancy. We studied embryo-fetal growth, mortality, and malformation rate in the offspring of nondiabetic rats and in the offspring of diabetic rats either treated with an aldose reductase inhibitor during gestation or left untreated. The numbers of embryo-fetal resorptions and malformations were significantly increased in the diabetic groups compared with the controls despite maternal treatment with the aldose reductase inhibitor. The sorbitol content of embryos and membranes from the diabetic rats in early gestation was increased 3-5 times over the control values. Similarly, elevated sorbitol levels were observed in the fetal livers and placentas of the diabetic rats in late gestation. Administration of the aldose reductase inhibitor to the pregnant diabetic rats normalized the sorbitol levels in the embryos and their membranes, whereas the sorbitol contents of the fetal livers and placentas were significantly lowered but not completely corrected. Furthermore, in the diabetic groups, no differences in sorbitol levels could be demonstrated between malformed and nonmalformed offspring. The results of this study suggest that enhanced polyol metabolism leading to increased sorbitol accumulation is present in the embryos of diabetic mothers as early as organogenesis. This accumulation is apparently not a major factor in the early developmental disturbances (e.g., growth perturbations and congenital malformations) of diabetic pregnancy.
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We aimed to investigate the extent to which maternal diabetes with or without folic acid (FA) supplementation affects mRNA levels and protein distribution of ROS scavenging enzymes, vascular endothelial growth factor-A (Vegf-A), folate... more
We aimed to investigate the extent to which maternal diabetes with or without folic acid (FA) supplementation affects mRNA levels and protein distribution of ROS scavenging enzymes, vascular endothelial growth factor-A (Vegf-A), folate binding protein-1 (Folbp-1), and apoptosis-associated proteins in the yolk sacs of rat embryos on gestational days 10 and 11. Commencing at conception and throughout pregnancy, half of the streptozotocin-diabetic and half of the control rats received daily FA injections. Maternal diabetes impaired vascular morphology and decreased CuZnSOD and GPX-1 gene expression in yolk sacs. Maternal diabetes also increased the levels of CuZnSOD protein, increased the Bax/Bcl-2 protein ratio and decreased Vegf-A protein distribution. FA treatment normalized vascular morphology, decreased mRNA levels of all three SOD isoforms and increased Vegf-A mRNA levels, rectified CuZnSOD protein distribution and Bax/Bcl-2 ratio. A teratogenic diabetic environment produces a state of vasculopathy, oxidative stress, and mild apoptosis in the yolk sac. FA administration normalizes vascular morphology, diminishes apoptotic rate, and increases Vegf-A gene expression and protein distribution in the yolk sac of diabetic rats.
Research Interests: Folic acid, Apoptosis, Gene expression, Embryo, Biological Sciences, and 15 moreAntioxidants, Female, Animals, CAT, Catalase, Glutathione Peroxidase, Bcl, Enzyme, Caspase, Apoptose, Gestational Age, Embryos, Diabetic Rat, N, and Dfa(Antioxidants, Female, Animals, CAT, Catalase, Glutathione Peroxidase, Bcl, Enzyme, Caspase, Apoptose, Gestational Age, Embryos, Diabetic Rat, N, and Dfa)
(Antioxidants, Female, Animals, CAT, Catalase, Glutathione Peroxidase, Bcl, Enzyme, Caspase, Apoptose, Gestational Age, Embryos, Diabetic Rat, N, and Dfa)
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. In order to elucidate cellular mechanisms causing skeletal malformations in offspring of diabetic rats we studied the incorporation of thymidine and sulphate into embryonic (pre)chondrocytes exposed to increased levels of D-glucose and... more
. In order to elucidate cellular mechanisms causing skeletal malformations in offspring of diabetic rats we studied the incorporation of thymidine and sulphate into embryonic (pre)chondrocytes exposed to increased levels of D-glucose and β-hydroxybutyric acid for six days in vitro. The (pre)chondrocytes were prepared from embryos of normal or diabetic rats of a malformation-prone strain or from embryos of normal rats of a non-malformation-prone strain. Diabetic female rats of the former strain are known to produce a high proportion of offspring with mandibular and lumbosacral malformations. Increased β-hydroxybutyric acid caused decreased thymidine incorporation in all types of chondrocytes, and decreased sulphate incorporation in limb bud cells from embryos of normal rats from both strains. Elevated D-glucose levels yielded a slight decrease in thymidine incorporation in mandibular arch cells from embryos of normal rats of the malformation-prone strain, and a marked decrease of both sulphate and thymidine incorporation in mandibular arch cells from embryos of diabetic rats of this strain. The observations suggest that elevated levels of D-glucose or β-hydroxybutyric acid are able to inhibit the differentiation and growth of (pre)chondrocytes and illustrate a selective sensitivity of mandibular arch (pre)chondrocytes to a diabetic environment. The data are compatible with the view that both D-glucose and β-hydroxybutyric acid may cause aberrations in the development of rat mandibular arch chondrocytes, suggesting a role for these compounds in diabetic teratogenesis.
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The aim of the present study was to evaluate a rat model of placental dysfunction/preeclampsia in pregnancies complicated by maternal diabetes. A second objective was to evaluate the effects of vitamin E treatment in this model. Normal... more
The aim of the present study was to evaluate a rat model of placental dysfunction/preeclampsia in pregnancies complicated by maternal diabetes. A second objective was to evaluate the effects of vitamin E treatment in this model. Normal and streptozotocin-induced diabetic rats of two different strains (U and H) were given intraperitoneal (IP) injections of the angiogenesis inhibitor Suramin (Sigma Chemical Co, St Louis, MO) or saline in early pregnancy, and fed standard or vitamin E-enriched food. The outcome of pregnancy was evaluated on gestational day 20. In both rat strains Suramin caused fetal growth retardation, decreased placental blood flow, and increased placental concentration of the isoprostane 8-iso-PGF(2alpha). In the U rats Suramin also caused increased fetal resorption rate, increased maternal blood pressure, decreased renal blood flow, and diminished maternal growth. Diabetes caused severe maternal and fetal growth retardation, increased resorption rate, and increased placental 8-iso-PGF(2alpha) concentration independent of Suramin administration. The maternal and fetal effects of Suramin and diabetes were more pronounced in the U strain than in the H strain. Vitamin E treatment improved the status of Suramin-injected diabetic rats: in U rats the blood pressure increase was normalized; and in both U and H rats the decreased placental blood flow was marginally enhanced, and the increase in placental 8-iso-PGF(2alpha) was partly normalized by vitamin E. Suramin injections to pregnant rats cause a state of placental insufficiency, which in U rats resembles human preeclampsia. The induction of this condition is at least partly mediated by oxidative stress, and antagonized by antioxidative treatment. Maternal diabetes involves increased oxidative stress, and causes both maternal and fetal morbidity, which are only marginally affected by additional Suramin treatment.
Research Interests: Obstetrics, Antioxidants, Lipids, Pregnancy, Humans, and 15 morePlacenta, Blood Pressure, Female, Animals, Perfusion, Clinical Sciences, Gynecology, Electrolytes, Blood Flow, Body Weight, Genetic Susceptibility, Nitrites, Pre Eclampsia, Angiogenesis inhibitors, and Paediatrics and reproductive medicine
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Superoxide (O 2 –), main reactive oxygen species in the vasculature, plays a major role in both renal hemodynamic and blood pressure control. O 2 – levels are limited by superoxide dismutase (SOD) isoforms. Their functional significance... more
Superoxide (O 2 –), main reactive oxygen species in the vasculature, plays a major role in both renal hemodynamic and blood pressure control. O 2 – levels are limited by superoxide dismutase (SOD) isoforms. Their functional significance in renal and systemic hemodynamics is not clear. The role of SOD1 in afferent arteriolar responsiveness and in angiotensin II (Ang II)-induced hypertension was investigated in SOD1-deficient (SOD1-ko), SOD1-transgenic (SOD1-tg) mice and in littermate controls (wild-type). Arteriolar constrictions to Ang II (10 –14 –10 –6 mol/l) were weaker in SOD1-tg (–14%) and stronger in SOD1-ko (–89%) compared with wild-types (–41%). Unspecific nitric oxide synthase (NOS) inhibition with N-Nitro-L-arginine methyl ester hydrochloride (L-NAME; 10 –4 mol/l) reduced basal diameters in wild-types by –8%, in SOD1-ko by –2%, and in SOD1-tg by –38%. Simultaneous application of L-NAME and Ang II caused a similar response in all groups. SOD-mimetic (Tempol; 10 –4 mol/l) had...
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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... more
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 o...
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N-Deacetylation is the initial polymer modification step in heparan sulfate biosynthesis and a prerequisite to subsequent N- and O-sulfation. It has previously been shown that the sulfation of liver heparan sulfate is lowered in diabetes... more
N-Deacetylation is the initial polymer modification step in heparan sulfate biosynthesis and a prerequisite to subsequent N- and O-sulfation. It has previously been shown that the sulfation of liver heparan sulfate is lowered in diabetes (Kjellén, L., Bielefeld, D., and Höök, M. (1983) Diabetes 32, 337-342). To investigate whether the reduced sulfation is the result of a lowered N-deacetylase activity, we have assayed this enzyme in hepatocytes from streptozotocin-diabetic rats. In addition, the activity of the glucuronosyl C5-epimerase, which catalyzes a modification reaction subsequent to N-sulfation, was measured. The deacetylase activity, expressed per microgram of cell protein, was about 40% lower in diabetic hepatocytes as compared with control cells, whereas the epimerase activity was unaffected. Recently, a approximately 110-kDa glycoprotein that carries N-sulfotransferase activity was identified as one of at least two protein components required for N-deacetylation in mouse...
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The overall aim of the studies reviewed in this communication was to investigate the factors influencing the induction of malformations in diabetic pregnancy. Some of the main conclusions from a large body of clinical and theoretical... more
The overall aim of the studies reviewed in this communication was to investigate the factors influencing the induction of malformations in diabetic pregnancy. Some of the main conclusions from a large body of clinical and theoretical studies were summarized by Norbert Freinkel into the concept of "fuel-mediated teratogenesis"--that alterations in the fuel mixture offered to the conceptus due to the metabolic derangement of the mother are instrumental in the induction of dysmorphogenesis in the offspring. This concept also involves the assumption that an alteration in the fuel mixture given to the conceptus would have different effects at different time periods of the pregnancy, i.e., it would be teratogenic in early pregnancy, leading to CNS disturbances in middle gestation (potentially altering behavior) and causing subtle and complex disturbances of an anthropometric-metabolic nature in the offspring when the changed fuel mixture is present in the later stages of gestati...
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Congenital malformations are more common in infants of diabetic women than in children of non-diabetic women. The etiology, pathogenesis and prevention of the diabetes-induced malformations have spurred considerable clinical and basic... more
Congenital malformations are more common in infants of diabetic women than in children of non-diabetic women. The etiology, pathogenesis and prevention of the diabetes-induced malformations have spurred considerable clinical and basic research efforts. The ultimate aim of these studies has been to obtain an understanding of the teratogenic process, which may enable precise preventive therapeutic measures in diabetic pregnancies. The results of the clinical and basic studies support the view of an early gestational induction of the malformations in diabetic pregnancy by a teratogenic process of multifactorial etiology. There may be possible targets for new therapeutic efforts revealed by the research work. Thus, future additions to the therapeutic efforts may include supplementation with antioxidants and/or folic acid, although more research is needed to delineate the dosages and compounds to be used. As the research into genetic predisposition for the teratogenic induction of malfor...
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The increased rate of fetal malformation in diabetic pregnancy represents both a clinical problem and a research challenge. In recent years, experimental and clinical studies have given insight into the teratological mechanisms and... more
The increased rate of fetal malformation in diabetic pregnancy represents both a clinical problem and a research challenge. In recent years, experimental and clinical studies have given insight into the teratological mechanisms and generated suggestions for improved future treatment regimens. The teratological role of disturbances in the metabolism of inositol, prostaglandins, and reactive oxygen species has been particularly highlighted, and the beneficial effect of dietary addition of inositol, arachidonic acid and antioxidants has been elucidated in experimental work. Changes in gene expression and induction of apoptosis in embryos exposed to a diabetic environment have been investigated and assigned roles in the teratogenic processes. The diabetic environment appears to simultaneously induce alterations in several interrelated teratological pathways. The complex pathogenesis of diabetic embryopathy has started to unravel, and future research efforts will utilize both clinical in...
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Previous studies have suggested that production of reactive oxygen species by embryonic mitochondria may have a role in the induction of both high-amplitude mitochondrial swelling and embryonic dysmorphogenesis in diabetic pregnancy. The... more
Previous studies have suggested that production of reactive oxygen species by embryonic mitochondria may have a role in the induction of both high-amplitude mitochondrial swelling and embryonic dysmorphogenesis in diabetic pregnancy. The present study analyzed the relationships between a putative metabolite-induced production of free oxygen radicals, mitochondrial lipid peroxidation, and high-amplitude mitochondrial swelling in embryos during organogenesis. For studies in vitro, day 9 embryos of normal rats were cultured for 48 h with a high concentration of glucose in the absence or presence of alpha-cyano-4-hydroxycinnamic acid (CHC), a mitochondrial pyruvate transport inhibitor. The morphology of mitochondria in the neuroepithelium of the embryos was studied with the aid of transmission electron microscopy. For studies in vivo, normal and diabetic pregnant rats were fed a diet supplemented with the antioxidants alpha-tocopherol (vitamin E) or 2,6-di-tert-butyl-4-methylphenol (BHT...
Research Interests: Free Radicals, Mitochondria, Biological Sciences, Antioxidants, Brain, and 14 morePregnancy, Female, Animals, Male, Vitamin E, Lipid peroxidation, Rats, Experimental Diabetes Mellitus Type 1 and 2, Embryos, Superoxides, Butylated hydroxytoluene, Mitochondrial swelling, Medical and Health Sciences, and In Vitro Techniques
Previous studies in vivo and in vitro have suggested that the oxidative metabolism of the embryo may have a role in the teratogenicity of diabetic pregnancy. In particular, the production of reactive oxygen species by the embryonic... more
Previous studies in vivo and in vitro have suggested that the oxidative metabolism of the embryo may have a role in the teratogenicity of diabetic pregnancy. In particular, the production of reactive oxygen species by the embryonic mitochondria has been implicated in the teratological process. The induction of congenital malformations by the diabetic milieu occurs during the early embryonic development. The present study aimed to estimate the role of the embryonic mitochondria in the teratological process of diabetic pregnancy by studying mitochondrial morphology in the embryos exposed to a diabetic environment in vivo or in vitro during early organogenesis and late fetal development. For studies in vivo embryos of control or streptozotocin-diabetic rats were taken at gestational days 9-11 and subjected to light and electron microscopical analysis. The brain, heart, and liver of day-15 fetuses were also observed. For studies in vitro day-9 embryos of normal rats were cultured in a w...
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Lung slices from human mid-trimester fetuses were incubated for 3 days. Hydrocortisone tended to decrease the biosynthesis of pulmonary phospholipids. It is suggested that cell proliferation is inhibited without inducing functional... more
Lung slices from human mid-trimester fetuses were incubated for 3 days. Hydrocortisone tended to decrease the biosynthesis of pulmonary phospholipids. It is suggested that cell proliferation is inhibited without inducing functional maturity.
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The fetal pulmonary glycogen content and the pulmonary biosynthesis of neutral lipids and phospholipids were estimated at gestational days 18, 20, and 22 in the offspring of normal, manifest diabetic, and insulin-treated diabetic rats. In... more
The fetal pulmonary glycogen content and the pulmonary biosynthesis of neutral lipids and phospholipids were estimated at gestational days 18, 20, and 22 in the offspring of normal, manifest diabetic, and insulin-treated diabetic rats. In all groups the fetal pulmonary glycogen concentration was highest on gestational day 20 and decreased during the subsequent 2 days. At the same time the biosynthesis of neutral lipids and phospholipids increased in the fetal lungs. The fetuses of the manifest diabetic rats showed an increased glycogen concentration and decreased total lipid biosynthesis compared with the other two groups. Insulin treatment of the rat mothers largely normalized the pulmonary lipid biosynthesis and glycogen accumulation in their fetuses. These data suggest that the diabetic maternal environment induces a transient block in the fetal utilization of pulmonary glycogen for the biosynthesis of lipids, in particular for the production of surfactant phospholipids.
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In 56 strictly controlled diabetic pregnancies, altogether 60 amniotic fluid samples were analysed for their content of lipid-carrying cells and the presence of phosphatidylglycerol. The outcome of the amniotic fluid tests was examined... more
In 56 strictly controlled diabetic pregnancies, altogether 60 amniotic fluid samples were analysed for their content of lipid-carrying cells and the presence of phosphatidylglycerol. The outcome of the amniotic fluid tests was examined for its association to macrosomia and to minor neonatal complications such as hypoglycaemia, hypocalcaemia, respiratory disturbances and hyperbilirubinaemia. The predictive value of these tests was nil, since all cases of neonatal complications occurred in the group showing maturity in tests at week 37. At term, phosphatidylglycerol was detected in 80% of the pregnancies, a finding corresponding to our observations in non-diabetic pregnancies. Lipid-carrying cells were present in quantities indicating maturity (greater than or equal to 10%) in 65% of the pregnancies at term, compared with 87% in non-diabetic pregnancies, suggesting a somewhat disturbed skin maturation secondary to the maternal diabetic state. The failure of these tests to predict neon...
Research Interests: Pregnancy, Humans, Female, Amniotic Fluid, Newborn Infant, and 2 moreAdult and Gestational Age(Adult and Gestational Age)
(Adult and Gestational Age)