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Pharmacological Treatment Options for Gestational Diabetes
Abstract
The treatment goal for pregnant and non-pregnant diabetic patients is to optimize the glycemic profile. Intensified therapy,
in comparison to the conventional approach, can improve perinatal outcomes. Data from non-diabetic pregnant women suggest
that current targets for glucose management for pregnant women with glucose abnormalities do not approximate glucose fluctuations
in healthy pregnancies. There is a lack of consensus on the medications used to achieve these targets as well. One means of
assessing the viability of a pharmacologic strategy can be the rate of study participants who achieved the targeted level
of glycemia.
... The pathophysiology of type 2 diabetes is characterized by increased hepatic glucose production, abnormal insulin secretion, and increased insulin resistance, all contributors to hyperglycemia. The increase in hepatic glucose production is a secondary phenomenon related mainly to the decrease in insulin action and increased glucagon secretion (Langer, 2010). ...
Summary
Maternal diabetes mellitus represents a serious illness threatening both the mother and fetus by serious complications. These complicated are associated with many morphological and histopathological changes in placenta because of the placenta forms the active interface between the fetus and the mother, providing all functions that are essential for fetal survival, growth and development, including regulation of gas exchange, supply of nutrients, production of essential hormones by the uteroplacental tissues, and establishment of immunological defences. Therefore, the study aimed to investigate the morphological, histopathological changes and histomatrical measurements as well as to assess glycogen deposition and to evaluate the immunohistochemical expression of vascular endothelium growth factor-A in the placental tissues of diabetic compared with non-diabetic women.
A total of 102 cases were included in this study, which includes 34 cases with gestational diabetes, 34 cases with pregestational diabetes and 34 cases with normal pregnancy as a control group. The study was carried out during the period from 2016 to 2018 in the Department of Pathology, College of Medicine/ Al-Nahrain University and Department of Biology, College of Education for Pure Science (Ibn-Haitham)/ University of Baghdad. Fresh placentae were obtained from Department of Obstetrics and Gynaecology in Al-Imamain Al-Kadhimiyain (AS) Medical city, Baghdad Teaching Hospital and Al-Karkh Maternity Hospital for the period 1 December 2016 to 1 May 2017 after obtaining the approval from Iraqi Ministry of Health. In this study, the placenta of three groups were compared according to morphological parameters, histopathological features, histometrical measurement, glycogen deposition with periodic acid-Schiff stain, expression of vascular endothelium growth factor-A by using immunohistochemical technique and ultrastructural features by Transmission Electron Microscope as well as registered of some clinical parameters of mothers and neonates.
The results of this study showed an increased incidence of gestational diabetes significantly (p≤0.05) in age group of 30-39 years, with mean age was 29.82±1.09 years. As for parity and gravida, multiparous and gravida were have been found to be more susceptible for diabetes mellitus women in comparison to the primigravida. As well as the occurrence of preterm higher significantly (p≤0.05) in gestational and pregestational diabetes groups in comparison to control group. Caesarean section was a highly significant occurrence (p≤0.001) in the two diabetic groups. Gestational age at ultrasonography showed non-significant differences (p>0.05) among the three groups, but at the last menstrual period was significant differences (p≤0.05).
Neonate weight and BMI (the weight/ length of the baby) have been significant increases (p≤0. 05), but fetal/placental weight ratio was non-significantly increase (p>0.05) among the three groups. As for maternal parameters, mean glucose levels before labour was also non-significantly increase (p>0.05) among the three studied groups, whereas last maternal glycosylated hemoglobin A1c between two diabetic groups showing highly significant increase (p≤0.001) and the pregestational diabetes group recorded elevation in last maternal glycosylated hemoglobin A1c value.
Placental weight and diameter showed non significant increases (p>0.05) among the three groups, while central thickness has been a significant increase (p≤0.05) so as the number of cotyledons were highly significant increase (p≤0.001) among the three studied groups. Magistral vascular pattern of chorionic blood vessels shown a highly significant (p≤0.001) relationship with the two diabetic groups, whilst dispersal pattern was seen in normal women. The umbilical cord long and diameter have been highly significant increases (p≤0.001) among the three groups as well as umbilical cord insertion onto the chorionic plate, its colour and number of veins in umbilical cord recorded highly significant increases (p≤0.001) among control, gestational and pregestational diabetes groups.
Maternal age of the studied groups recorded a highly significant (p≤0.001) in relationship to the first and second trimester miscarriage or stillbirths in the two diabetic groups together, placental weights and umbilical cord types in the three studied groups together and gestational diabetes group separately. Additionally, same highly significant (p≤0.001) relationship was recorded between each of placental weight with neonatal weight in the three studied groups, umbilical cord length with the gender of neonate in three studied groups together and pregestational diabetes group separately and umbilical cord length with the weight of each neonate and placenta in the three studied groups together, last maternal hemoglobin A1c level with the two diabetes groups and method of its treatment, state of the neonate with the method of treatment in diabetic mother. While no significant (p>0.05) relationship was found between maternal age with neonatal gender and umbilical cord lengths.
Immature villi, syncytial knots, villous fibrosis, basement membrane thickening of villi, cytotrophoblast in terminal villi, extravillous fibrinoid, fibrinoid necrosis, Hofbauer cell population in immature intermediate villi, calcification, chorangiosis, thrombosis and thickening of villi vessels, nucleated fetal red blood cells and villous edema have been more occurrence in placenta of the two diabetic groups in comparison to the normal placenta.
Histometrically, terminal villi and their fetal blood vessels of central and peripheral sections of placentae recorded mostly highly significant increases (p≤0.001) in diameters of males neonates as compared with females neonates of diabetic women. Moreover, the terminal villi diameter in central and peripheral sections of placentae appeared highly significant differences (p≤0.001) between pregestational diabetes type 1 and type 2, but the diameter of fetal blood vessels in this terminal villous did not record any significant difference (p>0.05).
The results of the histochemical study by of periodic acid-Schiff stain showed an increase in glycogen deposition with high significance (p≤0.001) in the placentae of diabetic women within intravillous core, around the fetal vessels and basement membranes. As well as central and peripheral sections of placenta were registered difference in frequency of histochemical features.
Vascular endothelium growth factor-A in the trophoblastic cells, villous stroma and fetal vessel endothelial cells in the central section of placentae in the two diabetic women groups have been significantly increased (p≤0.001) compared to the normal women in both manual microscopic analyses and digital quantification.
As well as ultrastructural study of the central section in the placentae of two diabetic women groups revealed a decreased in the thickness of vascular-syncytial membrane and density of syncytiotrophoblast apical microvilli and increased thickness of trophoblastic basement membrane, glycogen deposits and edema.
The study concluded that the morphological, histopathological and histomatrical changed were observed more frequently in the diabetic placentas compared to the controls in both light and electron transmission microscopes. As well as increased glycogen deposition by using Periodic acid-Schiff stain and the expression of vascular endothelium growth factor-A in the placental tissues of diabetic compared with non-diabetic women.
Background Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial. Methods 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or. glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. in the conventional group, the aim was the best achievable FPG with diet atone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye,or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy. Findings Over 10 years, haemoglobin A(1c) (HbA(1c)) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group-an 11% reduction. There was no difference in HbA(1c) among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg). Interpretation Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes. None of the individual drugs had an adverse effect on cardiovascular outcomes. All intensive treatment increased the risk of hypoglycaemia.
To determine whether the use of oral hypoglycemic agents during early pregnancy is associated with a risk of congenital malformations in infants of mothers with non-insulin-dependent diabetes mellitus (NIDDM) independent of maternal metabolic control.
From a prospectively collected data-base of pregnancies complicated by diabetes at a large urban medical center, we identified 332 consecutive infants born to women with NIDDM who did not participate in a preconceptional diabetes care program. Stepwise logistical regression was used to identify maternal characteristics that were independently associated with risks of major and minor congenital malformations in infants.
Overall, 56 (16.9%) of the 332 infants were born with congenital anomalies (11.7% major anomalies and 5.1% minor anomalies). Analysis of data from subgroups of women who were treated with diet therapy, exogenous insulin, or sulfonylurea compounds during the first 8 weeks of gestation did not reveal statistically significant differences in major or minor malformation rates among the three groups. Stepwise logistic regression analysis revealed two maternal characteristics that were independently associated with major malformations in infants: maternal HbA1c at initial presentation for care (direct relationship; P = 0.0007) and the maternal age at onset of diabetes (inverse relationship; P = 0.009). The risk of major malformations was unrelated to the mode of antidiabetic therapy during early pregnancy. No relationship was found between maternal glycemia or treatment modality and rates of minor congenital anomalies.
These data indicate that, in the absence of special preconceptional care, NIDDM is associated with a risk for major congenital anomalies that is in the range reported for pregnancies complicated by insulin-dependent diabetes mellitus. Moreover, the risk in individual patients appears to be related to maternal glycemic control rather than to the mode of antidiabetic therapy during early pregnancy.
Background:
Metformin is a logical treatment for women with gestational diabetes mellitus, but randomized trials to assess the efficacy and safety of its use for this condition are lacking.
Methods:
We randomly assigned 751 women with gestational diabetes mellitus at 20 to 33 weeks of gestation to open treatment with metformin (with supplemental insulin if required) or insulin. The primary outcome was a composite of neonatal hypoglycemia, respiratory distress, need for phototherapy, birth trauma, 5-minute Apgar score less than 7, or prematurity. The trial was designed to rule out a 33% increase (from 30% to 40%) in this composite outcome in infants of women treated with metformin as compared with those treated with insulin. Secondary outcomes included neonatal anthropometric measurements, maternal glycemic control, maternal hypertensive complications, postpartum glucose tolerance, and acceptability of treatment.
Results:
Of the 363 women assigned to metformin, 92.6% continued to receive metformin until delivery and 46.3% received supplemental insulin. The rate of the primary composite outcome was 32.0% in the group assigned to metformin and 32.2% in the insulin group (relative risk, 0.99 [corrected]; 95% confidence interval, 0.80 [corrected] to 1.23 [corrected]). More women in the metformin group than in the insulin group stated that they would choose to receive their assigned treatment again (76.6% vs. 27.2%, P<0.001). The rates of other secondary outcomes did not differ significantly between the groups. There were no serious adverse events associated with the use of metformin.
Conclusions:
In women with gestational diabetes mellitus, metformin (alone or with supplemental insulin) is not associated with increased perinatal complications as compared with insulin. The women preferred metformin to insulin treatment. (Australian New Zealand Clinical Trials Registry number, 12605000311651.).
To compare the immunologic response to insulin lispro with that to regular human insulin, thereby assuring its safety for use in women with gestational diabetes, and to verify that it is effective.
We compared the metabolic and immunologic effects of insulin lispro and regular human insulin in 42 women >18 years of age diagnosed with gestational diabetes by oral glucose tolerance testing at 14-32 weeks of gestation. Patients were randomized to receive regular human insulin or insulin lispro before consuming a test meal. Serum insulin, blood glucose, and C-peptide concentrations were measured. Throughout the remainder of gestation, patients received premeal insulin lispro or regular human insulin combined with basal insulin and performed blood glucose self-monitoring before and after each meal. Insulin antibodies and HbA1c were determined at enrollment and 6 weeks later. In addition, 10 patients received continuous intravenous insulin (4 lispro, 6 regular human insulin) and dextrose infusions intrapartum to assess placental insulin transfer.
Anti-insulin antibody levels were similar in the two groups. Insulin lispro was not detectable in the cord blood. During a meal test, areas under the curve for glucose, insulin, and C-peptide were significantly lower in the lispro group. Mean fasting and postprandial glucose concentrations and end point HbA1c were similar in the two groups. The lispro group demonstrated fewer hypoglycemic episodes (symptoms and blood glucose concentrations <55 mg/dl). No fetal or neonatal abnormalities were noted in either treatment group.
Insulin lispro may be considered a treatment option for women with gestational diabetes.
To assess the relation between glycaemic control in early pregnancy and the risk of congenital malformations in offspring of mothers with Type I (insulin-dependent) diabetes mellitus.
From 1988-1997, we prospectively collected data from 691 pregnancies and 709 offspring of 488 women with Type I diabetes in a specific geographic area in Southern Finland. Glycated haemoglobin A1c at less than 14 weeks of gestation was used as the indicator of glycaemic control. The malformations were diagnosed either by ultrasonography in pregnancy or during the neonatal period. We also studied 729 non-selected control pregnancies in women without diabetes.
The numbers of major fetal malformations were 30 (4.2%) in patients with Type I diabetes and 10 (1.2%) in the control subjects (relative risk 3.1; 95% confidence interval: 1.6 to 6.2). Even women whose HbA1c was only slightly raised (5.6 to 6.8%, i.e. 2.0 to 5.9 standard deviation units) showed a relative risk of 3.0 (95% confidence interval: 1.2 to 7.5). Haemoglobin A1c retained its statistically significant association with the occurrence of malformations after adjusting for White's class, age at onset of diabetes, duration of diabetes, parity, smoking and participation in pre-pregnancy counselling.
Even a slightly raised HbA1c during early pregnancy in women with Type I diabetes carries an increased risk for fetal malformations. Therefore normoglycaemia should be strived for during early pregnancy.
The purpose of this study was to examine the response of pancreatic beta-cells to changes in insulin sensitivity in women at high risk for type 2 diabetes. Oral glucose tolerance tests (OGTTs) and frequently sampled intravenous glucose tolerance tests (FSIGTs) were conducted on Latino women with impaired glucose tolerance and a history of gestational diabetes before and after 12 weeks of treatment with 400 mg/day troglitazone (n = 13) or placebo (n = 12). Insulin sensitivity was assessed by minimal model analysis, and beta-cell insulin release was assessed as acute insulin responses to glucose (AIRg) and tolbutamide (AIRt) during FSIGTs and as the 30-min incremental insulin response (30-min dINS) during OGTTs. Beta-cell compensation for insulin resistance was assessed as the product (disposition index) of minimal model insulin sensitivity and each of the 3 measures of beta-cell insulin release. In the placebo group, there was no significant change in insulin sensitivity or in any measure of insulin release, beta-cell compensation for insulin resistance, or glucose tolerance. Troglitazone treatment resulted in a significant increase in insulin sensitivity, as reported previously. In response, AIRg did not change significantly, so that the disposition index for AIRg increased significantly from baseline (P = 0.004) and compared with placebo (P = 0.02). AIRt (P = 0.001) and 30-min dINS (P = 0.02) fell with improved insulin sensitivity during troglitazone treatment, so that the disposition index for each of these measures of beta-cell function did not change significantly from baseline (P > 0.20) or compared with placebo (P > 0.3). Minimal model analysis revealed that 89% of the change from baseline in insulin sensitivity during troglitazone treatment was accounted for by lowered plasma insulin concentrations. Neither oral nor intravenous glucose tolerance changed significantly from baseline or compared with placebo during troglitazone treatment. The predominant response of beta-cells to improved insulin sensitivity in women at high risk for type 2 diabetes was a reduction in insulin release to maintain nearly constant glucose tolerance.
To assess the 24-h glucose levels in a group of nondiabetic, nonobese pregnant women and to verify the presence of correlations between maternal glucose levels and sonographic parameters of fetal growth.
A total of 66 Caucasian nonobese pregnant women with normal glucose challenge tests (GCT) enrolled in the study; from this population, we selected 51 women who delivered term (from 37 to 42 weeks completed) live-born infants without evidence of congenital malformations. The women were requested to have three main meals and to perform daily glucose profiles fortnightly from 28-38 weeks without modifying their lifestyle or following any dietary restriction. All subjects were taught how to monitor their blood glucose by using a reflectance meter. Fetal biometry was evaluated by ultrasound scan according to standard methodology at 22, 28, 32, and 36 weeks of pregnancy.
The overall daily mean glucose level during the third trimester was 74.7 +/- 5.2 mg/dl. Daily mean glucose values increased between 28 (71.9 +/- 5.7 mg/dl) and 38 (78.3 +/- 5.4 mg/dl) weeks of pregnancy. We found a significant positive correlation at 28 weeks between 1-h postprandial glucose values and fetal abdominal circumference (AC). At 32 weeks, we documented positive correlations between fetal AC and maternal blood glucose levels 1 h after breakfast, 1 and 2 h after lunch, and 1 and 2 h after dinner. At 36 weeks, there was a positive correlation between fetal AC and 1- and 2-h postprandial blood glucose levels. In addition, there was a negative correlation between head-abdominal circumference ratio and 1-h postprandial blood glucose values.
This longitudinal study first provides a contribution toward the definition of normoglycemia in nondiabetic, nonobese pregnant women; moreover, it reveals significant correlations of postprandial blood glucose levels with the growth of insulin-sensitive fetal tissues and, in particular, between 1-h postprandial blood glucose values and fetal AC.
The purpose of this study was to investigate the relation between life-style habits and glucose abnormalities in Caucasian women with and without conventional risk factors for gestational diabetes.
A total of 126 pregnant women with gestational diabetes, 84 with impaired glucose tolerance and 294 with normal glucose tolerance, identified by sequential screening, were interviewed to determine their usual weekly food pattern, amount of exercise, smoking habits and alcohol intake.
Patients with glucose abnormalities were older and shorter in height and had significantly higher BMI before pregnancy, percentage of diabetic first-degree relatives and higher intake of saturated fat. Patients without known risk factors for gestational diabetes (i. e. younger than 35 years of age, BMI < 25 kg/m2, no first-degree diabetic relatives) included 40 with impaired glucose tolerance or gestational diabetes. In a multiple logistic regression model age, short stature, familial diabetes, BMI and percentages of saturated fat were associated with impaired glucose tolerance or gestational diabetes in all patients, after adjustment for gestational age. In patients without conventional risk factors only percentages of saturated fat (OR = 2.0; 95 %-CI = 1.2-3.2) and polyunsaturated fat (OR = 0.85; 95 %-CI = 0.77-0.92) were associated with gestational hyperglycaemia, after adjustment for age, gestational age and BMI.
Saturated fat has an independent role in the development of gestational glucose abnormalities. This role is more important in the absence of conventional risk factors suggesting that glucose abnormalities could be prevented during pregnancy, at least in some groups of women.
The aim of this study was to characterize the milk-to-plasma ratio and infant dose for metformin in breastfeeding women, and to measure plasma concentrations and assess any effects in their infants. We hypothesized that metformin used by mothers is safe for their breastfed infants.
Seven women taking metformin (median dose 1500 mg orally daily) and their infants were studied. Metformin concentrations in plasma and milk were measured by high performance liquid chromatography. Infant exposure was estimated as the product of estimated milk production rate and the average concentration of the drug in milk and also expressed as a percentage of the weight-normalized maternal dose.
The mean milk-to-plasma ratio for metformin was 0.35 (95%CI 0.2-0.5). The mean of its average concentrations in milk over the dose interval was 0.27 mg/l (0.15-0.39 mg/l). The absolute infant dose averaged 0.04 mg x kg(-1) x day(-1) (0.02-0.06 mg x kg(-1) x day(-1)) and the mean relative infant dose was 0.28% (0.16-0.4%). Metformin was present in very low or undetectable concentrations in the plasma of four of the infants who were studied. No health problems were found in the six infants who were evaluated.
The concentrations of metformin in breast milk were generally low and the mean infant exposure to the drug was only 0.28% of the weight-normalized maternal dose. As this is well below the 10% level of concern for breastfeeding, and because the infants were healthy, we conclude that metformin use by breastfeeding mothers is safe. Nevertheless, each decision to breastfeed should be made after conducting a risk:benefit analysis for each mother and her infant.
The homeostasis of the conceptus is affected by the function of the placenta as early as 1 week of human gestation, and the trophoblast undergoes many changes during gestation. Therefore, when assessments of placental function and its influence on the conceptus are made by using the term placenta, the developmental differences in the placenta need to be taken into consideration.
Obesity in children and adolescents is associated with significant health problems in the pediatric age group, and it is important early risk factor for a great deal of adult morbidity and mortality. Metabolic syndrome (visceral adiposity, impaired glucose tolerance, diabetes mellitus type 2, insulin resistance, dyslipidemia, high blood pressure), was a huge problem in obese adults, until now. In the recent reports metabolic syndrome was found in 24 to 51% of overweight youths. Therefore, it is very important to recognize children at-risk for developing metabolic syndrome, and to begin with therapy at time, in purpose to prevent late complications.
At least four different classes of oral agents are now available to manage type 2 diabetes. A new trial seems to open the door to the use of one of these in the third trimester by women with gestational diabetes.
In many circumstances, the glycemic profile may be pertinent for several different thresholds for fetal and maternal complications. For each complication, a different zone of normality might be required for each of the associations of glucose abnormality. A spectrum of different glucose zones can be established and used appropriately to prevent each complication. The classic complications include spontaneous abortion, anomalies, stillbirths, and fetal macrosomia and its accompanying complications (metabolic, trauma, and respiratory). This review outlines tile concept of normality and what definitions of normality should he used to evaluate tile relationship between level of glycemia and perinatal outcome. The level of glycemia in nondiabetic women during pregnancy, under the naturally occurring personal and environmental conditions of everyday life, will be used as a yardstick for normality in comparing the associations between levels of glycemia found in the presence of diabetic complications and their relationship to normality. It is suggested that different levels of glycemia are required to prevent different diabetic complications, Thus, although it is not always possible to achieve optimum glycemic control in all patients, any improvement will be beneficial because it will reduce the zones of complications.
BACKGROUND
Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications.
METHODS
A total of 1441 patients with IDDM -- 726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly.
RESULTS
In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of ≥ 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of ≥ 300 mg per 24 hours) by 54 percent (95 percent confidence interval, 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia.
CONCLUSIONS
Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.
Context:
The increasing prevalence of obesity is a major public health concern, since obesity is associated with several chronic diseases.
Objective:
To monitor trends in state-specific data and to examine changes in the prevalence of obesity among adults.
Design:
Cross-sectional random-digit telephone survey (Behavioral Risk Factor Surveillance System) of noninstitutionalized adults aged 18 years or older conducted by the Centers for Disease Control and Prevention and state health departments from 1991 to 1998.
Setting:
States that participated in the Behavioral Risk Factor Surveillance System.
Main outcome measures:
Body mass index calculated from self-reported weight and height.
Results:
The prevalence of obesity (defined as a body mass index > or =30 kg/m2) increased from 12.0% in 1991 to 17.9% in 1998. A steady increase was observed in all states; in both sexes; across age groups, races, educational levels; and occurred regardless of smoking status. The greatest magnitude of increase was found in the following groups: 18- to 29-year-olds (7.1% to 12.1%), those with some college education (10.6% to 17.8%), and those of Hispanic ethnicity (11.6% to 20.8%). The magnitude of the increased prevalence varied by region (ranging from 31.9% for mid Atlantic to 67.2% for South Atlantic, the area with the greatest increases) and by state (ranging from 11.3% for Delaware to 101.8% for Georgia, the state with the greatest increases).
Conclusions:
Obesity continues to increase rapidly in the United States. To alter this trend, strategies and programs for weight maintenance as well as weight reduction must become a higher public health priority.
The prevalence and magnitude of childhood obesity are increasing dramatically. We examined the effect of varying degrees of obesity on the prevalence of the metabolic syndrome and its relation to insulin resistance and to C-reactive protein and adiponectin levels in a large, multiethnic, multiracial cohort of children and adolescents.
We administered a standard glucose-tolerance test to 439 obese, 31 overweight, and 20 nonobese children and adolescents. Baseline measurements included blood pressure and plasma lipid, C-reactive protein, and adiponectin levels. Levels of triglycerides, high-density lipoprotein cholesterol, and blood pressure were adjusted for age and sex. Because the body-mass index varies according to age, we standardized the value for age and sex with the use of conversion to a z score.
The prevalence of the metabolic syndrome increased with the severity of obesity and reached 50 percent in severely obese youngsters. Each half-unit increase in the body-mass index, converted to a z score, was associated with an increase in the risk of the metabolic syndrome among overweight and obese subjects (odds ratio, 1.55; 95 percent confidence interval, 1.16 to 2.08), as was each unit of increase in insulin resistance as assessed with the homeostatic model (odds ratio, 1.12; 95 percent confidence interval, 1.07 to 1.18 for each additional unit of insulin resistance). The prevalence of the metabolic syndrome increased significantly with increasing insulin resistance (P for trend, <0.001) after adjustment for race or ethnic group and the degree of obesity. C-reactive protein levels increased and adiponectin levels decreased with increasing obesity.
The prevalence of the metabolic syndrome is high among obese children and adolescents, and it increases with worsening obesity. Biomarkers of an increased risk of adverse cardiovascular outcomes are already present in these youngsters.
Resistance to insulin-stimulated glucose uptake is present in the majority of patients with impaired glucose tolerance (IGT) or non-insulin-dependent diabetes mellitus (NIDDM) and in ∼25% of nonobese individuals with normal oral glucose tolerance. In these conditions, deterioration of glucose tolerance can only be prevented if the β-cell is able to increase its insulin secretory response and maintain a state of chronic hyperinsulinemia. When this goal cannot be achieved, gross decompensation of glucose homeostasis occurs. The relationship between insulin resistance, plasma insulin level, and glucose intolerance is mediated to a significant degree by changes in ambient plasma free-fatty acid (FFA) concentration. Patients with NIDDM are also resistant to insulin suppression of plasma FFA concentration, but plasma FFA concentrations can be reduced by relatively small increments in insulin concentration.Consequently, elevations of circulating plasma FFA concentration can be prevented if large amounts of insulin can be secreted. If hyperinsulinemia cannot be maintained, plasma FFA concentration will not be suppressed normally, and the resulting increase in plasma FFA concentration will lead to increased hepatic glucose production. Because these events take place in individuals who are quite resistant to insulinstimulated glucose uptake, it is apparent that even small increases in hepatic glucose production are likely to lead to significant fasting hyperglycemia under these conditions. Although hyperinsulinemia may prevent frank decompensation of glucose homeostasis in insulin-resistant individuals, this compensatory response of the endocrine pancreas is not without its price. Patients with hypertension, treated or untreated, are insulin resistant, hyperglycemic, and hyperinsulinemic. In addition, a direct relationship between plasma insulin concentration and blood pressure has been noted. Hypertension can also be produced in normal rats when they are fed a fructose-enriched diet, an intervention that also leads to the development of insulin resistance and hyperinsulinemia. The development of hypertension in normal rats by an experimental manipulation known to induce insulin resistance and hyperinsulinemia provides further support for the view that the relationship between the three variables may be a causal one. However, even if insulin resistance and hyperinsulinemia are not involved in the etiology of hypertension, it is likely that the increased risk of coronary artery disease (CAD) in patients with hypertension and the fact that this risk if not reduced with antihypertensive treatment are due to the clustering of risk factors for CAD, in addition to high blood pressure, associated with insulin resistance. These include hyperinsulinemia, IGT, increased plasma triglyceride concentration, and decreased high-density lipoprotein cholesterol concentration, all of which are associated with increased risk for CAD. It is likely that the same risk factors play a significant role in the genesis of CAD in the population as a whole. Based on these considerations the possibility is raised that resistance to insulin-stimulated glucose uptake and hyperinsulinemia are involved in the etiology and clinical course of three major related diseases— NIDDM, hypertension, and CAD.
The observation that several Mexican-American women were taking oral hypoglycaemic agents while pregnant led to a study to confirm reports of associations between these agents and congenital abnormalities. 20 non-insulin-dependent (NIDDM) pregnant diabetic women with exposure to oral hypoglycaemic drugs during embryogenesis and 40 pregnant NIDDM women matched for age, race, parity, weight, and glycaemic control but not exposed to oral hypoglycaemic drugs were followed up. 10 infants (50%) in the exposed group had congenital malformations, compared with only 6 (15%) in the control group (p less than 0.002). 5 (25%) infants in the exposed group had ear malformations, anomalies not commonly described in diabetic embryopathy. Hyperbilirubinemia (p less than 0.04), polycythaemia, and hyperviscosity requiring partial exchange transfusions (p less than 0.03) were commoner among babies in the exposed than in the control group. 3 babies in the exposed group but none in the comparison group had severe prolonged neonatal hypoglycaemia lasting 2, 4, and 7 days; 2 of the 3 had been exposed for 22 and 28 weeks during gestation, whereas the third had been exposed throughout the first trimester. Although exposure to oral hypoglycaemic drugs during fetal life seems to be associated with congenital malformations and neonatal hypoglycaemia, a large, prospective study is needed to exclude the confounding effect of maternal metabolic derangement secondary to diabetes.
No data exist concerning human placental transfer of oral hypoglycemic agents during pregnancy. This study characterizes the transport of glyburide in 10 term human placentas with the single-cotyledon placental model. Serial samples were taken from both the maternal and fetal reservoirs during each 3-hour perfusion, and the percent transport and metabolism of tritiated glyburide was calculated with liquid scintillation spectrometry and high-performance liquid chromatography. Antipyrine labeled with carbon 14 was added to the perfusate solution during these experiments as a control. Virtually no transfer of glyburide occurred, and no appreciable metabolism of the drug was detected. Neither variation in the albumin concentration nor increase in the maternal glyburide levels to 100 times therapeutic concentration materially altered the rate of transport. These data show that insignificant transport of glyburide occurs across the human placenta in vitro and suggest that fetal exposure to maternally administered glyburide likewise may be insignificant.
A prospective study of 57 women with gestational diabetes mellitus was undertaken to determine actual insulin requirements throughout pregnancy. Women were placed on a multiple injection, mixed insulin regimen and monitored their blood glucose level 6.5 +/- 1 times per day using a memory-based reflectance meter to obtain verified data. A significant (p less than 0.01) increase in total insulin dose was found during the initial treatment period (7 +/- 2 days) until the target glucose range was achieved. Insulin requirements continued to significantly (p less than 0.01) rise until 30 +/- 1 gestational weeks, despite a stabilization of glucose level. Thereafter, there was no significant change (3%) in insulin requirement. A correlation of r = 0.58 (p less than 0.001) for the relationship between insulin dose at the 24 and 32 weeks' gestation, and an r = 0.99 (p less than 0.0001) for the relationship between insulin dose at 32 and 39 weeks' gestation was found. We concluded that an emphasis on ambulatory blood glucose control and insulin adjustments should occur in the early treatment phase of gestational diabetes.
Three infants whose diabetic mothers were given chlorpropamide and one infant whose diabetic mother was given acetohexamide up to the time of delivery were studied in the neonatal period because each became severely hypoglycaemic. The sulphonylurea drugs given to the mother crossed the placenta, and fetal plasma concentrations were in the therapeutic range for adults with diabetes mellitus. Each baby had severe hyperinsulinaemia resulting in profound hypoglycaemia. These acutely ill infants needed vigorous and prolonged treatment to correct the hypoglycaemia. In two infants exchange transfusion was performed to remove the drug. These sulphonylurea drugs should not be used to control diabetes mellitus in pregnancy.
Ordinarily, the hypoglycemia of infants of diabetic mothers is brief and asymptomatic.1 It is considered to result from fetal hyperinsulinism secondary to prenatal hyperglycemia. The infant described below had prolonged symptomatic hypoglycemia associated with maternal chlorpropamide (Diabinese) therapy.
Case Report
The patient, a 3,715 gm white male, was the product of a 37-week gestation of a gravida 3, para 2, A positive, 36-year-old mother by repeat cesarean section. The mother, a mild diabetic since age 31, had been receiving 250 mg chlorpropamide twice daily, including the morning of her delivery.
The infant's blood sugar was 20 mg/100 ml at 4 hours of age, and he was then transferred to Babies Hospital for further care.
The routine use of self-monitoring of capillary blood glucose by pregnant diabetic patients currently provides the basis for both clinical management and ongoing investigation. Strategies must therefore be developed to ensure that these data are reliable and accurately reported by patients and are not influenced by diverse socioeconomic levels or varied geographic locations. To explore this issue, we used glucose reflectance meters with a memory microchip capable of storing up to 440 consecutive blood glucose determinations. Two diverse groups of women from Texas and New York who had gestational diabetes performed self-monitoring of blood glucose from diagnosis until delivery. Both groups recorded their blood glucose results daily in a logbook. The reporting performance of all the participating subjects resulted in an actual compliance rate of 60% to 70% of testings required of the patients. Comparison of African-American, Mexican-American, and white populations revealed no significant differences in patient performance or compliance. Moreover, no differences were found between the groups at different geographic locations (New York, Texas) in patients' willingness and ability to comply with the regimen of self-monitoring blood glucose. These findings suggest that the use of memory reflectance meters, in conjunction with patient education and positive interaction between patient and care provider, will result in high patient compliance regardless of socioeconomic level or ethnic diversity.
To determine, in women having newly diagnosed gestational diabetes mellitus, the effect of intensified treatment on the patients' emotional status and the relation between metabolic control and emotional well-being.
English-speaking women with newly diagnosed gestational diabetes mellitus (N = 206) and nondiabetic controls (N = 95) were compared for maternal characteristics and test results on the Profile of Mood States-Bipolar test, a standardized Likert scale measuring mood dimensions in terms of six bipolar affective states. Women with gestational diabetes mellitus were stratified according to treatment modality (diet or insulin therapy) and level of glycemic control (good control, mean blood glucose less than 105 mg/dL; poor control, mean blood glucose 105 mg/dL or greater). Because emotional profile can be influenced by actual glucose values depicted on the memory reflectance meter, glucose determinations were categorized as hypoglycemia, normoglycemia, mild hyperglycemia, and hyperglycemia. An Average Mood Disturbance score was used to determine the relation between total mood status and categories of glucose determinations.
There was no significant difference between women with gestational diabetes mellitus in either the diet- or insulin-managed group and nondiabetic controls on each of the subscales of the Profile of Mood States-Bipolar test. Patients with stringent glycemic control were less distressed than those having poor control. Intensified therapy (self-monitoring of blood glucose levels and liberal use of insulin) for gestational diabetes mellitus does not negatively affect patients' emotional status. Insulin therapy by multiple injection does not adversely affect mood state. Stepwise regression analysis found a significant association between Average Mood Disturbance score and the number of determinations within the normoglycemic and hyperglycemic categories, marital status, and maternal age.
Intensified management of newly diagnosed gestational diabetes mellitus does not increase patient anxiety and depression. Moreover, achievement of glycemic control contributes to patient reassurance. Psychological adjustment to the temporary disease state is then equal to that of a nondiabetic individual.
This study compares the human placental transport of glyburide, glipizide, chlorpropamide, and tolbutamide.
The recirculating single cotyledon human placenta model tested maternal-to-fetal transport in term placentas perfused immediately after delivery. Drug levels were measured by high-performance liquid chromatography and liquid scintillation spectrometry, and transport rates were calculated by comparing maternal and fetal concentrations.
The transport of these substances differed significantly over a tenfold range (analysis of variance, p < 0.0008). A significant association exists by multiple linear regression between drug transfer and molecular weight, dissociation constant, and the octanol-water partition coefficient (R2 = 0.91, p < 0.0001).
There is significant variability in human placental transfer rates of the oral hypoglycemics, which strongly correlates with molecular properties. These data suggest that less fetal exposure may occur with second-generation sulfonylureas and anticipate that regression models may be useful in selecting agents that minimize placental transport to the fetus.
We tested the hypothesis that intensified management of gestational diabetes mellitus on the basis of stringent glycemic control, verified glucose data, and adherence to an established criterion for insulin initiation results in near normoglycemia control and reduction of adverse outcomes.
A prospective, population-based study compared the effect on perinatal outcome of conventional (n = 1316) and intensified (n = 1145) management. Group assignment was based on availability of memory-based reflectance meters at entry to the program. A contemporaneous randomized control group (nondiabetic, n = 4922) was selected.
The diabetic groups were comparable in demographic characteristics and in factors associated with higher risk for adverse pregnancy outcome, such as previous macrosomia, previous gestational diabetes mellitus, and family history of diabetes. The control group was younger, less obese, and had a lower rate of previous macrosomia. The intensified management group had rates of macrosomia, cesarean section, metabolic complications, shoulder dystocia, stillbirth, neonatal intensive care unit days, and respiratory complications lower than those in the conventional management group and comparable to those of the nondiabetic controls. Other maternal complication rates, such as for preeclampsia, chronic hypertension, and infection, were similar for the three groups. Mean blood glucose levels were a good predictor of perinatal outcome. Gestational age at delivery, previous history of macrosomia, and overall mean blood glucose levels were the only significant predictors of birth weight percentile in both diabetic groups (logistic regression).
The intensified management approach is significantly associated with enhanced perinatal outcome. This management strategy clarifies the relationship between glycemic control and neonatal outcome.
Our purpose was to determine whether the biguanide oral antihyperglycemic agent metformin increases human placental uptake and transport of glucose to the fetal circulation.
The human single-cotyledon model was used to compare transport of tritiated glucose in the maternal to fetal direction in eight human placentas between control placentas and those exposed to metformin in vitro. Transport was calculated from the serial perfusate glucose levels obtained in each 3-hour experiment, and placental uptake was determined from homogenates of the perfused cotyledon. Liquid scintillation spectrometry measured levels of both glucose and the reference substance antipyrine. Transport was compared by the Mann-Whitney U test.
Mean maternal and fetal glucose levels were 77.5 +/- 4.9 mg/dl and 61.3 +/- 5.9 mg/dl, respectively, in the metformin group and 83.8 +/- 4.3 mg/dl and 60.4 +/- 12.4 mg/dl, respectively, in controls at 2 hours. Placental glucose uptake was 91.1 +/- 42.2 microg/gm placenta in the metformin experiments and 104.9 +/- 76.9 microg/gm placenta in controls. No difference in placental glucose uptake or transport could be demonstrated.
Metformin does not affect human placental glucose uptake or transport.
This multicenter, randomized, placebo-controlled study of glimepiride, a new oral sulfonylurea, was conducted in patients with type 2 diabetes for whom dietary treatment was unsuccessful (fasting plasma glucose [FPG] = 151-300 mg/dL) during a 1-week screening period. Patients were randomized to receive glimepiride (n = 123) or placebo (n = 126) once daily for a 10-week dose-titration period, then maintained on an individually determined optimal dose (1-8 mg of glimepiride or placebo) for 12 weeks. Glimepiride lowered FPG by 46 mg/dL, hemoglobin A1C (HbA1C) by 1.4%, and 2-hour postprandial glucose by 72 mg/dL more than placebo. Glimepiride improved postprandial insulin and C-peptide responses without producing clinically meaningful increases in fasting insulin or C-peptide levels. Good glycemic control (HbA1C < or = 7.2%) was achieved by 69% of the patients taking glimepiride versus 32% of those taking placebo. The overall incidence of adverse events was similar in both groups. No clinically noteworthy abnormal laboratory values or hypoglycemia (blood glucose < 60 mg/dL) occurred. Glimepiride is safe and effective for treatment of patients with type 2 diabetes for whom diet therapy is unsuccessful.
We sought to test the hypothesis that long-term postnatal development may be modified by metabolic experiences in utero. We enrolled offspring of women with pregestational diabetes (this included type 1 and type 2 diabetes) and gestational diabetes in a prospective study from 1977 to 1983. Fetal β- cell function was assessed by measurement of amniotic fluid insulin (AFI) concentration at 32-38 weeks' gestation. Postnatally, offspring were seen yearly for neuropsychological testing, measurement of anthropometrics, and modified glucose tolerance testing. Neuropsychological control subjects were followed longitudinally. Additional control subjects had anthropometrics measured once, and a random subset of these had a single oral glucose challenge at 10-16 years. The rates of major neuropsychological disturbances in our cohort did not differ significantly from national estimates. However, aberrant maternal metabolism was associated with poorer intellectual performance and psychomotor development. The macrosomia observed at birth in offspring of diabetic mothers (ODM) resolves by 1 year of age. Obesity recurs in childhood; and by 14-17 years, the mean BMI is 24.6 ± 5.8 kg/m2 in ODM versus 20.9 ± 3.4 kg/m2 in control subjects. Obesity in adolescence is associated with sex, mother's weight, and AFI concentration. Impaired glucose tolerance (IGT) is found in 36% of ODM and is also associated with elevated amniotic fluid insulin in utero. In confirmation of our original hypothesis, aberrant maternal metabolism is associated with poorer intellectual and psychomotor development, obesity, and IGT in offspring. Excessive insulin secretion in utero, as assessed by AFI concentration, is a predictor of both obesity and IGT in adolescence.
In the last decade, it has become clear that gestational diabetes is a clinical entity associated with perinatal mortality and morbidity. Thus, the attention to and management of gestational diabetes during pregnancy are mandatory. In this review, results of 58 original studies (spanning the past 20 years) addressing criteria for insulin management in gestational diabetes were assessed. The level of glycemic control and its evaluation through self-monitoring of blood glucose are the foundation for ascertaining optimal pregnancy outcome. This review addresses the criteria for insulin initiation: insulin requirements, identification of the right patient, the timing for insulin initiation, and the behavioral adjustment and compliance during insulin therapy. It is recommended that patients with fasting plasma glucose on the oral glucose tolerance test (OGTT) of < 96 mg/dl (and ideally nonobese) be assigned to diet therapy. Obese women or those with fasting plasma glucose > 95 mg/dl on the OGTT should be referred to insulin therapy in order to minimize exposure of the fetus to a hyperglycemic environment.
This article provides the reader with relevant information regarding the association between level of glycemia and perinatal outcome in preexisting diabetes. Although the glycemic profile is a continuum in nature, different thresholds of glucose are associated with fetal complications such as stillbirth, spontaneous abortion, congenital anomalies, fetal macrosomia, and metabolic and respiratory complications. For each complication, a different targeted threshold of normality is required. Thus, although it is not always possible to achieve optimal glycemic control in all patients, any improvement will be beneficial because it will reduce the rate of complications for a given glucose threshold.
To assess maternal and neonatal complications in pregnancies of diabetic women treated with oral hypoglycaemic agents during pregnancy.
A cohort study including all consecutively registered, orally treated pregnant diabetic patients set in a diabetic obstetrical service at a university hospital: 50 women treated with metformin, 68 women treated with sulphonylurea during pregnancy and a reference group of 42 diabetic women treated with insulin during pregnancy.
The prevalence of pre-eclampsia was significantly increased in the group of women treated with metformin compared to women treated with sulphonylurea or insulin (32 vs. 7 vs. 10%, P < 0.001). No difference in neonatal morbidity was observed between the orally treated and insulin-treated group; no cases of severe hypoglycaemia or jaundice were seen in the orally treated groups. However, in the group of women treated with metformin in the third trimester, the perinatal mortality was significantly increased compared to women not treated with metformin (11.6 vs. 1.3%, P < 0.02).
Treatment with metformin during pregnancy was associated with increased prevalence of pre-eclampsia and a high perinatal mortality.
Gestational diabetes mellitus has been a contentious subject since it was first described. From a global perspective, authors have questioned its very existence, the burden of morbidity that it causes, and whether making the diagnosis simply increases the expense and complexity of perinatal care. Arguments have raged over who should be tested for gestational diabetes, when during pregnancy the testing should be done, what results define the disorder, and how affected women should be treated. For those willing to acknowledge that moderate abnormalities in carbohydrate metabolism during pregnancy require attention, there has been one point of agreement: if diet and . . .
Women with gestational diabetes mellitus are rarely treated with a sulfonylurea drug, because of concern about teratogenicity and neonatal hypoglycemia. There is little information about the efficacy of these drugs in this group of women.
We studied 404 women with singleton pregnancies and gestational diabetes that required treatment. The women were randomly assigned between 11 and 33 weeks of gestation to receive glyburide or insulin according to an intensified treatment protocol. The primary end point was achievement of the desired level of glycemic control. Secondary end points included maternal and neonatal complications.
The mean (+/-SD) pretreatment blood glucose concentration as measured at home for one week was 114+/-19 mg per deciliter (6.4+/-1.1 mmol per liter) in the glyburide group and 116+/-22 mg per deciliter (6.5+/-1.2 mmol per liter) in the insulin group (P=0.33). The mean concentrations during treatment were 105+/-16 mg per deciliter (5.9+/-0.9 mmol per liter) in the glyburide group and 105+/-18 mg per deciliter (5.9+/-1.0 mmol per liter) in the insulin group (P=0.99). Eight women in the glyburide group (4 percent) required insulin therapy. There were no significant differences between the glyburide and insulin groups in the percentage of infants who were large for gestational age (12 percent and 13 percent, respectively); who had macrosomia, defined as a birth weight of 4000 g or more (7 percent and 4 percent); who had lung complications (8 percent and 6 percent); who had hypoglycemia (9 percent and 6 percent); who were admitted to a neonatal intensive care unit (6 percent and 7 percent); or who had fetal anomalies (2 percent and 2 percent). The cord-serum insulin concentrations were similar in the two groups, and glyburide was not detected in the cord serum of any infant in the glyburide group.
In women with gestational diabetes, glyburide is a clinically effective alternative to insulin therapy.
Pediatric Research publishes original papers, invited reviews, and commentaries on the etiologies of diseases of children and disorders of development, extending from molecular biology to epidemiology. Use of model organisms and in vitro techniques relevant to developmental biology and medicine are acceptable, as are translational human studies.
To assess whether metformin safely reduced development of gestational diabetes in women with the polycystic ovary syndrome (PCOS).
Prospective and retrospective study.
Outpatient clinical research center.
The prospective study included 33 nondiabetic women with PCOS who conceived while taking metformin and had live births; of these, 28 were taking metformin through delivery. The retrospective study included 39 nondiabetic women with PCOS who had live birth pregnancies without metformin therapy.
Metformin, 2.55 g/d, throughout pregnancy in women with PCOS.
Development of gestational diabetes in women with PCOS.
Before metformin therapy, after covariance adjustment for age, the two cohorts did not differ in height, weight, basal metabolic index, insulin, insulin resistance, or insulin secretion. Both cohorts had high fasting insulin, were insulin resistant, and had high insulin secretion. Among the 33 women who received metformin, gestational diabetes developed in 1 of 33 (3%) pregnancies versus 8 of 12 (67%) of their previous pregnancies without metformin. Among the 39 women who did not take metformin, gestational diabetes developed in 14 of 60 (23%) pregnancies. When all live births were combined, gestational diabetes occurred in 22 of 72 pregnancies (31%) in women who did not take metformin versus 1 of 33 pregnancies (3%) in those who took metformin. With gestational diabetes as the response variable and age at delivery and treatment group (metformin or no metformin) as explanatory variables, the odds ratio for gestational diabetes in women with metformin versus without metformin was 0.093 (95% CI: 0.011 to 0.795). With gestational diabetes in 93 pregnancies as the response variable and age at delivery and treatment group (metformin no metformin) as explanatory variables, the odds ratio of gestational diabetes in pregnancies in women taking metformin versus without metformin was 0.115 (95% CI: 0.014 to 0.938).
In PCOS, use of metformin is associated with a 10-fold reduction in gestational diabetes (31% to 3%). It also reduces insulin resistance and insulin secretion, thus decreasing the secretory demands imposed on pancreatic beta-cells by insulin resistance and pregnancy.
To compare the costs associated with glyburide compared to insulin for the treatment of gestational diabetes unresponsive to dietary therapy.
A cost model was designed. The model excluded costs that were identical for both treatment arms, such as the cost of monitoring glucose control. Insulin treatment costs included average wholesale drug costs, wholesale delivery costs (syringes, alcohol pads), and costs of office staff educating patients. Glyburide costs were based on average wholesale drug costs. Downstream costs of potential inpatient evaluation for hypoglycemia were included in the model.
In our baseline model, glyburide was significantly less costly than insulin for the treatment of gestational diabetes. The average cost saving per patient based on wholesale drug costs and hospital costs was US$165.84. Actual retail drug savings and hospital charge savings are potentially considerably greater. The strongest determinant of cost savings was medication cost. The model was less sensitive to the one-time costs of inpatient treatment and patient education.
Glyburide is less costly than insulin for the treatment of gestational diabetes. Cost models can be useful to physicians deciding between two equally efficacious medications, allowing them to incorporate information about their individual practice styles with a complex balance of cost implications.
This article outlines the probable positive relationship between levels of maternal glycemia and perinatal morbidity and mortality. A spectrum of different glucose thresholds can be established and used appropriately to prevent each complication. This article also outlines the concept of normality and what definitions of normality should be used to evaluate the relationship between the level of glycemia and perinatal outcome. Definitive conclusions are hampered by a lack of uniformity in definitions and interventions, and by a failure in some analyses to control for confounding variables. However, it is suggested that different levels of glycemia are required to prevent different diabetic complications. Thus, although it is not always possible to achieve targeted levels of glycemic control in all patients, any improvement will be beneficial because it will affect fetal complications associated with that glucose threshold.