A consensus report of the Diabetes in Pregnancy Study Group of North America Conference, Little Rock, Arkansas, May 2002.
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Angiotensin-Converting Enzyme Inhibitors↗
Biomedical subjects
C Homko
Publications and source records attributed to C Homko.
Fetal serum levels of insulin, growth hormone and insulin-like growth factor-I in concordant and discordant twin gestations.
OBJECTIVE: To examine the role of insulin, growth hormone and insulin-like growth factor (IGF)-I in concordant and discordant twin pairs. METHODS: Umbilical cord serum samples were obtained from 20 twin pairs with weight discordancy (intertwin birth weight difference > 20%) and from 20 concordant twins (intertwin birth weight difference < 20%), both groups of similar gestational age, gravidity, and parity. The serum samples were analyzed for the levels of IGF-I, growth hormone and insulin in both maternal and fetal compartments. RESULTS: Among the group of discordant twins, the normally grown twin, in all cases, had significantly higher cord serum IGF-I levels than their growth-restricted co-twin (108 +/- 73 ng/ml vs. 39 +/- 24 ng/ml; p < 0.01). There were no significant intertwin differences in the cord blood IGF-I levels in the concordant twin pairs (87 +/- 44 vs. 88 +/- 48 ng/ml; p = 0.986). Insulin and growth hormone levels did not correlate with intertwin birth weight differences. CONCLUSION: These data demonstrate that IGF-I is important in the regulation of both normal and restricted fetal growth in utero, and its action appears to be, at least in part, through an endocrine action. The precise role of growth hormone and insulin in fetal growth restriction remains uncertain.
Female↗
Insulin secretion during and after pregnancy in patients with gestational diabetes mellitus.
We have determined prehepatic insulin secretion rates (ISRs) in seven patients with gestational diabetes mellitus (GDM) and in eight age- and weight-matched nondiabetic pregnant women during late gestation (third trimester) and again postpartum. Plasma glucose concentrations were raised to approximately 8.9 mM with iv glucose (hyperglycemic clamping), and ISRs were determined by deconvolution of peripheral C-peptide concentrations using C-peptide kinetic parameters that were obtained in every patient during late gestation and again postpartum. Plasma insulin levels were measured by RIA with an antibody with minimal (<0.2%) cross-reactivity with proinsulin. During late gestation, women with GDM were more insulin resistant than nondiabetic controls and had significantly lower ISRs (689 vs. 849 pmol/min, P < 0.05) and glucose uptake rates (30.6 vs. 49.4 micromol/kg.min, P < 0.05) in response to hyperglycemia. Postpartum, ISRs and insulin resistance decreased in women with GDM and controls (ISR by 43% and 43%, respectively, and insulin resistance by 75% and 118%, respectively), and both groups had similar ISRs (352 vs. 408 pmol/min, nonsignificant). Women with GDM, however, continued to be more insulin resistant than controls. In summary, patients with GDM during late pregnancy not only had severe deficiencies in ISR but, in addition, were more insulin resistant than controls. Postpartum, insulin resistance and ISRs (and plasma insulin levels) improved in both groups, and ISRs (and plasma insulin levels) were no longer significantly different in patients with GDM and controls. Insulin resistance, however, remained higher in women with GDM, and their glucose uptake remained lower. We concluded that the women with GDM had a major ss-cell defect that made it impossible for them to compensate for their increased level of insulin resistance, which occurred during late pregnancy.
3-Hydroxybutyric Acid↗
Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects.
The reason for the 3- to 4-h delay between a rise in plasma free fatty acid (FFA) levels and the development of insulin resistance remains unknown. In the current study, we have tested the hypothesis that the delay may be caused by the need for plasma FFAs to first enter muscle cells and to be re-esterified there before causing insulin resistance. To this end, we have determined intramyocellular triglyceride (IMCL-TG) content with proton nuclear magnetic resonance ((1)H-NMR) spectroscopy in healthy volunteers before and 4 h after lowering of plasma FFAs (with euglycemic-hyperinsulinemic clamping) or after increasing plasma FFAs (with lipid plus heparin infusions). Increasing plasma FFAs (from 516 to 1,207 micromol/l or from 464 to 1,857 micromol/l, respectively) was associated with acute increases in IMCL-TG from 100 to 109 +/- 5% (P < 0.05) or to 133 +/- 11% (P < 0.01), respectively, and with a significant increase in insulin resistance (P < 0.05 after 3.5 h). Lowering of plasma FFAs from 560 to 41 micromol/l was associated with a tendency for IMCL-TG to decrease (from 100 to 95 +/- 3%). Changes in plasma FFAs correlated linearly with IMCL-TG (r = 0.74, P < 0.003). The demonstration that acute changes in plasma FFAs were accompanied by corresponding changes in IMCL-TG and with the development of insulin resistance, taken together with previous reports of a close correlation between IMCL-TG and insulin resistance, supported the notion that accumulation of IMCL-TG is a step in the development of FFA-induced insulin resistance.
Adipose Tissue↗
Gestational diabetes mellitus: controversies and current opinions.
The past few years have seen significant controversy over the diagnosis and management of gestational diabetes and its influence on perinatal outcomes. The debate over who to screen and how to screen continues to rage. Even when a diagnosis has been made, there is a lack of consensus regarding appropriate management protocols and glycemic targets. In this review, we will examine many of the controversial areas in gestational diabetes, using contemporary data to discuss these issues.
Diabetes, Gestational↗
Insulin-like growth factors, their binding proteins, and fetal macrosomia in offspring of nondiabetic pregnant women.
The Objective of this paper is to determine the relation between fetal macrosomia in offspring of nondiabetic women, and the levels of insulin-like growth factors (IGF-I, IGF-II), insulin growth factor binding protein-3 (IGFBP-3) and insulin, in maternal and neonatal compartments. Serum samples were obtained from normal pregnant women (n = 60) and their neonates (n = 60) between 37-41 weeks' gestation (mean 39 +/- 9). Neonates were categorized as appropriate for gestational age (AGA; 10th-90th percentile; n = 20), and large for gestational age (LGA; >90th percentile; n = 40). Maternal and neonatal serum samples were analyzed for levels of IGF-I, IGF-II, IGFBP-3 and insulin, by specific radioimmunoassays (RIAs). Serum levels were correlated with birth weight. The mean birth weight of the AGA group was 3296 +/- 500 g versus 4201 +/- 300 g for the LGA group (p <0.0001). Cord blood IGF-I was statistically higher in LGA group than in the AGA infants, (139 +/- 67 ng/mL and 80 +/- 32 ng/mL, respectively; p <0.0001). There was no correlation between maternal IGF-I serum levels and birth weight (363 +/- 131 in the AGA vs. 308 +/- 158 in the LGA group). IGF-II in maternal and cord blood did not correlate with fetal weight. Cord blood IGFBP-3 was significantly higher in the LGA group (1.1 +/- 0.07 microg/mL) than in the AGA group (0.96 +/- 0.05 microg/mL; p < 0.05). Maternal insulin levels were similar between the two groups. Neonatal insulin levels were higher in the LGA group (18 +/- microU/mL) as compared to the AGA group (16 +/- microU/mL), however, this difference did not reach statistical significance. Fetal cord blood levels of IGF-I and IGFBP-3 are directly correlated with the birth weight of large for gestational age fetuses. These data suggest that the somatotropic axis plays a role in fetal growth. Additionally, insulin growth factor-1 appears to be an in utero growth promoter in the development of fetal macrosomia in infants of nondiabetic women.
Adult↗
Pregnancy performance and outcomes associated with diabetic nephropathy.
The purpose of the current study is to report the effect of diabetic nephropathy on pregnancy outcomes based on a review of the world's literature from 1981 to 1996. In addition, the effects of pregnancy on renal function in a select subpopulation of patients is also presented. The Medline Computer System was used to survey the English language literature on diabetic nephropathy complicating pregnancy between 1981 and 1996, which yielded a total patient population of 315. The database was analyzed according to patient population, clinical management, maternal complications and outcomes, and fetal complications and outcomes. The frequency of chronic hypertension was 42% with 60% of women manifesting hypertension by the third trimester. Pre-eclampsia developed in 41% of patients; proliferative retinopathy was observed in 63% of patients prior to pregnancy, and cesarean section delivery was performed in 74% of the patients. Among the fetal outcomes, intrauterine growth restriction (IUGR) was observed in 15%, preterm delivery in 22%, and major congenital malformations in 8% of the patients included in the database. The observed overall perinatal morality rate was 5%. Gestational age at delivery was significantly correlated with first-trimester Cr/Cl (p < 0.01), third-trimester Cr/Cl (p < 0.05), third trimester proteinuria (p < 0.01), and third-trimester blood pressure (p < 0.001). Birth weight was significantly correlated with first-trimester Cr/Cl (p < 0.01), third-trimester Cr/Cl (p < 0.001), third-trimester proteinuria (p < 0.01), and third-trimester blood pressure (p < 0.001). Of the 185 patients available for long-term follow-up (mean 35 months), 17% developed end-stage renal disease, and 5% died as a result of renal insufficiency. Among the renovascular parameters, proteinuria and mean arterial pressure significantly increased from the first to the third trimester (p < 0.05). When these parameters were evaluated at follow-up, blood pressure did not show a significant increase from first trimester values, however, proteinuria did show a weak, but significant, increase postpartum. These data suggest that with contemporary methods of perinatal care, fetal survival rates of 95% are achievable in diabetic women with nephropathy. Furthermore, although many women experienced a temporary decline in renal function during gestation, pregnancy per se, does not appear to worsen the natural progression to end-stage renal disease for most women with renal insufficiency.
Adult↗
Dietary polyunsaturated fatty acid prevents malformations in offspring of diabetic rats.
OBJECTIVE: The purpose of the current study was to determine whether a dietary source of arachidonic acid could serve as a pharmacologic prophylaxis to obviate the teratogenic effects of hyperglycemia. STUDY DESIGN: Eighty-day-old Sprague-Dawley rats were mated, and after conception were randomly allocated to five groups: two groups were nondiabetic normal controls and three groups had diabetes experimentally induced with streptozocin. Of the two control groups, one was fed a normal diet (group 1) and the other group (group 2) received a normal diet and 1.0 ml of safflower oil, a polyunsaturated fatty acid known to increase serum arachidonic acid levels. In the three diabetic groups (groups 3, 4, and 5) glucose levels were allowed to remain > 350 mg/dl by withholding daily insulin therapy. Group 3 received a normal diet without supplementation; group 4 received a normal diet plus normal saline solution sham feedings, whereas group 5 received a normal diet supplemented with 1.0 ml of safflower oil. The oral agents (normal saline solution and polyunsaturated fatty acid) were administered with a tuberculin syringe. RESULTS: Diabetic rats not receiving insulin therapy and receiving normal diets produced offspring with malformation rates of 20% compared with control rates of 4.8%. Supplemental normal saline solution or safflower oil given orally to controls did not alter the growth or malformation rates. These rates were similarly unaffected in the diabetic rats receiving oral supplementation of normal saline solution. However, with safflower oil supplementation to diabetic rats the incidence of neural tube defects was decreased from 20.0% to 7.6% (p < 0.0001). An inverse relationship was observed between the malformation rate and the serum arachidonic acid level: 17.83 (SD 5.84 micrograms/ml) in the nondiabetic controls, with a malformation rate of 4.8%, versus 14.18 (SD 2.58 micrograms/ml) in the diabetic rats, with a malformation rate of 20.0% (p < 0.05). With safflower oil supplementation serum levels of arachidonic increased from 14.18 +/- 2.58 micrograms/ml to 19.99 +/- 7.99 micrograms/ml (p < 0.05); this was associated with a concomitant decline in the malformation rate. CONCLUSION: These data demonstrate that diabetic embryopathy is associated with a deficiency state in essential fatty acid, corroborating our previous in vitro findings. Furthermore, the use of a dietary polyunsaturated fatty acid that specifically increases arachidonic levels significantly reduced the incidence of diabetic embryopathy. These findings may serve as a basis for developing strategies of pharmacologic prophylaxis against diabetes-induced congenital malformations.
Animals↗
Is there a correlation between aortic Doppler velocimetric findings in diabetic pregnant women and fetal outcome?
At present, the role of Doppler velocimetry in monitoring fetal well-being in diabetic pregnancies is controversial. The present study was conducted to determine if fetal aortic velocity waveforms were correlated with fetal outcome in pregnancies complicated by diabetes mellitus. Fetal aortic blood flow was prospectively assessed in 30 pregnant women with insulin-dependent diabetes mellitus. Systolic-diastolic ratios were obtained at 2 week intervals between 18 and 38 weeks of gestation. They were analyzed according to several fetal outcome variables. Infants with presumed fetal distress during labor and neonates with respiratory abnormalities (respiratory distress syndrome, persistent fetal circulation, or transient tachypnea of the newborn) showed statistically significant elevations of aortic Doppler indices (P < 0.031 and < 0.011, respectively). However, these correlations lacked clinical relevance. The infants demonstrated no evidence of fetal distress at birth since Apgar scores were > 7 at 5 min in all but one neonate. No relationship was found between the mean third trimester fetal aortic systolic-diastolic ratios and perinatal death, preterm deliveries, birth weight, Apgar scores at 1 and 5 min, and neonatal metabolic abnormalities. These data demonstrate a poor correlation between fetal aortic Doppler waveform analysis and fetal outcome. Therefore, fetal aortic Doppler velocimetry cannot be used as a means of assessing impending fetal compromise in offspring of diabetic mothers.
Adolescent↗
Toward fetal therapy using needle embryofetoscopy.
Our objective was to explore the feasibility of using both transvaginal endoscopy and transabdominal needle embryofetoscopy for early prenatal diagnosis. Our experience with both terminating and continuing pregnancies is presented in this report. Following the granting of informed consent, patients undergoing first-trimester terminations were invited to participate in this program. Initially, a transvaginal endoscope was used in these studies: a rigid fiberoptic endoscope 30 cm in length with a diameter of 1.5 mm. Subsequently, a specially designed 16-gauge, double-barrel needle sheath, equipped with a 0.8-mm fiberoptic endoscope and a customized 27-gauge heparinized needle were used. In either case, the endoscope was passed under ultrasound guidance into the exocelomic space, from which the anatomy of the embryo/fetus was scrutinized. For continuing pregnancies, patients were selected when at high risk for various dysmorphology syndromes. To date, we have successfully performed more than 300 transvaginal procedures, successfully visualized the fetus in 95% of cases, and verified sonographically suspected anomalies in all of the five cases studied. We have also performed 20 transabdominal procedures, 15 in terminating pregnancies and five in continuing pregnancies, without adverse effects. Our experience establishes the feasibility of first-trimester diagnostic endoscopy. This new development is expected to serve as a prelude for further studies that attempt to diagnose and treat congenital diseases in early pregnancy. Potential applications include gene and stem-cell therapy at a time when the embryo is immunologically naive.
Abortion, Induced↗
Metabolic changes in diabetic and nondiabetic subjects during pregnancy.
Diabetes mellitus with its resulting derangement of various metabolic fuels, carbohydrates, amino acids, lipids, and ketones has the potential to adversely affect the developing fetus. Therefore, strict glycemic control in pregnancy has become the standard of care in modern obstetrics. A considerable amount of research has been undertaken into the metabolic changes that occur during pregnancy in both women with insulin-dependent diabetes and gestational diabetes. This paper will review current research in normal and diabetic pregnancies both in the fasting and fed states as well as during episodes of hypoglycemia. In normal pregnancy insulin secretion increases throughout gestation whereas peripheral insulin sensitivity is decreased. Fasting levels of plasma glucose are reduced by approximately 10 per cent during the first trimester. Maternal amino acid levels are also reduced in normal pregnancy, although cholesterol and triglyceride levels are increased, most dramatically in the second trimester. As gestation advances, progressively increasing amounts of insulin antagonistic hormones are secreted by the placenta. This leads to gestational diabetes in 2 to 3 per cent of women who exhibit hyperglycemia despite an increased insulin response to oral glucose as well as an increased insulin/glucagon ratio. In insulin dependent diabetes mellitus, the insulin-deficient state results in fasting and postprandial hyperaminoacidemia, hyperlipidemia, and hyperglycemia. These metabolic changes and the resulting hyperglycemic milieu can lead to fetal macrosomia that will result in maternal and fetal morbidity. Therefore, normalization of these fuels with the use of intensive insulin regimens is the goal of therapy during pregnancy.
Amino Acids↗
Diabetes mellitus in pregnancy and the assessment of umbilical artery waveforms using pulsed Doppler ultrasonography.
The utility of Doppler ultrasonography as a means of assessing potential alterations of vascular resistance prior to fetal or maternal compromise is very attractive. We investigated this relationship by prospectively performing Doppler studies of the fetal umbilical artery in 56 diabetic patients, 14 of whom had varying degrees of vascular complications. When regression curves were established for the S/D ratio, the Pourcelot index, and the resistance index of the fetal umbilical artery, the mean Doppler values were higher in diabetic patients with vasculopathy than in nondiabetic control patients or in diabetic patients without vasculopathy. The third trimester S/D ratio was greater than 3.0 in almost 50% of patients with vasculopathy. A tendency toward adverse outcomes was observed at S/D ratios approaching 4.0. Statistically significant correlations were found between elevated Doppler indices and maternal vasculopathy associated with hypertension and worsening renal insufficiency. Intrauterine growth retardation and neonatal metabolic complications were also significantly correlated with elevated Doppler indices. There was, however, no correlation between Doppler indices and glucose values, although most were within a euglycemic range. The aforementioned data indicate an increased resistance circuit among diabetics with vasculopathy, which may reflect a relative reduction in basal uteroplacental blood flow and the need for cautious interpretation of Doppler indices in these patients.
Adult↗
Retinal and pregnancy outcomes in the presence of diabetic proliferative retinopathy.
The objective of this study was to examine the retinal and pregnancy outcomes of pregnancies complicated by advanced diabetic retinopathy. Twenty pregnancies complicated by advanced diabetic retinopathy were included in this retrospective study. The data were analyzed to determine trends in perinatal outcome and to document the ophthalmologic performance. Ophthalmologic management included frequent funduscopic examinations by ophthalmologists of the Yale Retina Center. Among the 20 pregnancies, spontaneous abortion occurred in 2 (10%) and stillbirth in 1 (5%); the remaining 17 (85%) pregnancies culminated in live births at a mean gestational age of 36 weeks (+/- 2.3 SD), with a mean birth weight of 2,620 g (+/- 834 SD). The perinatal survival rate was 94%. Photocoagulation therapy was necessary prior to pregnancy in 45%, during pregnancy in 60% and postpartum in 65%. No pregnancies were terminated because of progressive visual changes that did not respond to photocoagulation therapy. Retinal status should not preclude pregnancy since contemporary methods of management can result in satisfactory retinal and pregnancy outcomes even in the presence of advanced diabetic microvascular disease.
Adult↗
Transabdominal needle embryofetoscopy: a new technique paving the way for early fetal therapy.
OBJECTIVE: To explore the feasibility of using a newly devised needle endoscope to conduct transabdominal first-trimester endoscopy for both embryonic visualization and blood sampling. METHODS: Following informed consent, 12 patients at 8-12 weeks' gestation undergoing first-trimester termination were invited to participate in this study. Transabdominal needle embryofetoscopy was also performed in one continuing pregnancy. A specially designed 16-gauge, double-barrel instrument sheath equipped with 0.8-mm fiberoptic endoscope and a customized 27-gauge heparinized needle were passed transabdominally under ultrasound guidance through the uterine wall and into the exocoelomic space. RESULTS: Using first-trimester transabdominal needle embryofetoscopy, we were able to identify the normal anatomical landmarks of the embryo and were also able to gain access to the embryonic circulation by advancing the 27-gauge needle into the umbilical vessels. In addition, we were able to infuse indigo carmine dye into the fetal circulation of three subjects. Needle embryofetoscopy was also used in a continuing pregnancy for prenatal diagnosis. CONCLUSION: Our experience establishes the feasibility of first-trimester transabdominal needle embryofetoscopy for embryonic visualization and access to the circulation. This new development is expected to serve as a basis for further studies attempting to diagnose and treat congenital diseases in early pregnancy.
Abdomen↗
Office care of newly diagnosed IDDM.
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Diabetes Mellitus↗
Stringent controls in diabetic nephropathy associated with optimization of pregnancy outcomes.
To evaluate maternal-fetal outcomes in pregnancies complicated by diabetic nephropathy were evaluated. Nephropathy was defined as proteinuria of >300 mg/24, or albuminuria >300 mg/24 hr in the absence of infection. Twenty-seven pregnant women with variable degrees of diabetic nephropathy were included in the study. Prenatal care included stringent metabolic control and management of hypertension. Fetal and maternal outcomes were obtained by medical record review. There were no fetal deaths. One neonatal death occurred in a fetus delivered at 29 weeks gestation. IUGR and major congenital malformations were observed in 9% of the neonates; 26% of the infants were delivered preterm. Chronic hypertension (77%) and preeclampsia (53%) were common maternal complications; 63% of women required delivery by cesarean section. Successful pregnancy outcomes were achieved in >95% of the women in our population. Modern management of the pregnancy complicated by diabetes has substantially improved the outcome of class F/FR diabetic mothers and their infants.
Abnormalities, Multiple↗
Factors associated with fetal macrosomia in offspring of gestational diabetic women.
OBJECTIVE: To determine whether there is a relationship between birthweight and interval between 1-h and 3-h glucose tolerance test (GTT) as well as other factors. METHODS: We performed a retrospective analysis of our computerized diabetes database for the years 1992-1997. Ninety-four women with gestational diabetes fulfilled the inclusion criteria (i.e., singleton gestation, term delivery, absence of medical conditions, and known interval between 1-h and 3-h GTT). They were evaluated based on prepregnancy body mass index (BMI), mean glucose values, interval between diagnostic testing, and gestational age of 3-h GTT. RESULTS: Subjects with GDM had a mean glucose value of 96.8 mg/dl and average prepregnancy BMI of 29.3 kg/m2. When GDM subjects with and without macrosomic infants were compared, mean glucose values (97.4 vs. 96.6 mg/dl) and mean interval (18.1 vs. 17.0 days) between diagnostic testing did not significantly differ. However, maternal prepregnancy BMI was higher in the group of women who gave birth to macrosomic infants (32.2 vs. 28.22 kg/m2, P = 0.008). Using stepwise multiple regression, maternal prepregnancy BMI was the only variable found to be predictive of macrosomia. CONCLUSION: We were unable to show a statistical relationship between interval of diagnostic testing and rate of macrosomia. However, we demonstrated a clear relationship between maternal BMI and infant birthweight.
Adult↗
The yolk sac theory: closing the circle on why diabetes-associated malformations occur.
OBJECTIVE: The purpose of this article is to examine the role of yolk sac failure during organogenesis in the development of diabetes-associated embryopathy. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Animals↗