Boyd E. Metzger

International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy

In the accompanying comment letter (1), Weinert summarizes published data from the Brazilian Gestational Diabetes Study (2) and comments on applying International Association of Diabetes and Pregnancy Study Groups (IADPSG) Consensus Panel recommendations (3) for the diagnosis of gestational diabetes mellitus (GDM) to that cohort. The Brazilian study provided evidence that adverse perinatal outcomes are associated with levels of maternal glycemia below those diagnostic of GDM by American Diabetes Association or World Health Organization criteria. However, the results were potentially confounded by the treatment of GDM. It did find that women with GDM were at increased risk for some …

Summary and Recommendations of the Third International Workshop-Conference on Gestational Diabetes Mellitus

The Third International Workshop-Conference on Gestational Diabetes Mellitus (GDM) was convened in Chicago, Illinois, on 8 November 1990 as an invitational meeting sponsored by the American Diabetes Association with the cooperation of the American College of Obstetricians and Gynecologists, the American Academy of Pediatrics, the National Diabetes Advisory Board, the Centers for Disease Control, and the Diabetic Pregnancy Study Group of the European Association for the Study of Diabetes. The meeting provided a forum for the review of new information concerning GDM in the areas of diagnosis and prevalence, perinatal and long-range implications, and management strategies.

Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus

BACKGROUND Multiple laboratory tests are used to diagnose and manage patients with diabetes mellitus. The quality of the scientific evidence supporting the use of these tests varies substantially. APPROACH An expert committee compiled evidence-based recommendations for the use of laboratory testing for patients with diabetes. A new system was developed to grade the overall quality of the evidence and the strength of the recommendations. Draft guidelines were posted on the Internet and presented at the 2007 Arnold O. Beckman Conference. The document was modified in response to oral and written comments, and a revised draft was posted in 2010 and again modified in response to written comments. The National Academy of Clinical Biochemistry and the Evidence Based Laboratory Medicine Committee of the AACC jointly reviewed the guidelines, which were accepted after revisions by the Professional Practice Committee and subsequently approved by the Executive Committee of the American Diabetes Association. CONTENT In addition to long-standing criteria based on measurement of plasma glucose, diabetes can be diagnosed by demonstrating increased blood hemoglobin A(1c) (Hb A(1c)) concentrations. Monitoring of glycemic control is performed by self-monitoring of plasma or blood glucose with meters and by laboratory analysis of Hb A(1c). The potential roles of noninvasive glucose monitoring, genetic testing, and measurement of autoantibodies, urine albumin, insulin, proinsulin, C-peptide, and other analytes are addressed. SUMMARY The guidelines provide specific recommendations that are based on published data or derived from expert consensus. Several analytes have minimal clinical value at present, and their measurement is not recommended.

Impaired Glucose Tolerance in Adolescent Offspring of Diabetic Mothers: Relationship to fetal hyperinsulinism

OBJECTIVE To test the hypothesis that long-term postnatal development may be modified by metabolic experiences in utero. RESEARCH DESIGN AND METHODS We enrolled offspring of women with pregestational diabetes (this included insulin-dependent diabetes mellitus. [1DDM] and non-insulin-dependent diabetes mellitus [NIDDM]) and gestational diabetes in a prospective study from 1977 through 1983. Fetal /3-cell function was assessed by measurement of arrmiotic fluid insulin (AF1) at 32–38 weeks gestation. Postnatally, plasma glucose and insulin were measured yearly from 1.5 years of age after fasting and 2 h after 1.75 g/kg oral glucose. Control subjects had a single oral glucose challenge at 10-16 years. RESULTS In offspring of diabetic mothers, the prevalence of impaired glucose tolerance (IGT) (2-h glucose concentration >7.8 mmol/1) was: 1.2% at <5 years, 5.4% at 5–9 years, and 19.3% at 10–16 years. The 88 offspring of diabetic mothers (12.3 ± 1.7 years), when compared with 80 control subjects of the same age and pubertal stage, had higher 2-h glucose (6.8 ±1.4 vs. 5.7 ± 0.9 mmol/1, P < 0.001) and insulin (660 ± 720 vs. 455 ± 285 pmol/1, P < 0.03) concentrations. The 17 subjects with IGT at > 10 years of age (9 boys and 8 girls) include one girl with NIDDM. IGT was not associated with the etiology of the mothers diabetes (gestational versus pregestational) or macrosomia at birth. IGT was found in only 3.7% (1 of 27) of adolescents whose AFI was normal (≥100 pmol/l) and 33.3% (12 of 36) of those with elevated AFI (P < 0.001). Although most of the children with IGT are obese, AFI and obesity are independently associated with IGT by multiple logistic analysis. CONCLUSIONS In confirmation of our original hypothesis, IGT in the offspring is a long-term complication of maternal diabetes. Excessive insulin secretion in utero, as assessed by AFI concentration, is a strong predictor of IGT in childhood.

International Association of Diabetes and Pregnancy Study Groups Recommendations on the Diagnosis and Classification of Hyperglycemia in Pregnancy: Response to Weinert

In the accompanying comment letter (1), Weinert summarizes published data from the Brazilian Gestational Diabetes Study (2) and comments on applying International Association of Diabetes and Pregnancy Study Groups (IADPSG) Consensus Panel recommendations (3) for the diagnosis of gestational diabetes mellitus (GDM) to that cohort. The Brazilian study provided evidence that adverse perinatal outcomes are associated with levels of maternal glycemia below those diagnostic of GDM by American Diabetes Association or World Health Organization criteria. However, the results were potentially confounded by the treatment of GDM. It did find that women with GDM were at increased risk for some …

Prevention of Diabetes in Women with a History of Gestational Diabetes: Effects of Metformin and Lifestyle Interventions

CONTEXT A past history of gestational diabetes mellitus (GDM) confers a very high risk of postpartum development of diabetes, particularly type 2 diabetes. OBJECTIVE The Diabetes Prevention Program (DPP) sought to identify individuals with impaired glucose tolerance (IGT) and intervene in an effort to prevent or delay their progression to diabetes. This analysis examined the differences between women enrolled in DPP with and without a reported history of GDM. DESIGN The DPP was a randomized, controlled clinical trial. SETTING The study was a multicenter, National Institutes of Health-sponsored trial carried out at 27 centers including academic and Indian Health Services sites. PATIENTS A total of 2190 women were randomized into the DPP and provided information for past history of GDM. This analysis addressed the differences between those 350 women providing a past history of GDM and those 1416 women with a previous live birth but no history of GDM. INTERVENTIONS Subjects were randomized to either standard lifestyle and placebo or metformin therapy or to an intensive lifestyle intervention. MAIN OUTCOMES The primary outcome was the time to development of diabetes ascertained by semiannual fasting plasma glucose and annual oral glucose tolerance testing. Assessments of insulin secretion and insulin sensitivity were also performed. RESULTS Whereas entering the study with similar glucose levels, women with a history of GDM randomized to placebo had a crude incidence rate of diabetes 71% higher than that of women without such a history. Among women reporting a history of GDM, both intensive lifestyle and metformin therapy reduced the incidence of diabetes by approximately 50% compared with the placebo group, whereas this reduction was 49 and 14%, respectively in parous women without GDM. These data suggest that metformin may be more effective in women with a GDM history as compared with those without. CONCLUSIONS Progression to diabetes is more common in women with a history of GDM compared with those without GDM history despite equivalent degrees of IGT at baseline. Both intensive lifestyle and metformin are highly effective in delaying or preventing diabetes in women with IGT and a history of GDM.

Long-term prospective evaluation of offspring of diabetic mothers.

We have suggested that altered maternal metabolism may affect the subsequent anthropometrie and neuropsychological development of children who were in utero during disturbances in maternal fuel economy. This study reports the physical growth through 8 yr of age and the neuropsychological development through 4 yr of age in offspring of diabetic mothers (ODM). At birth, 50% of infants had weights >90th percentile for gestational age. By 12 mo, length and weight were similar to the general population. Height remained normal until 7 yr of age, when it became slightly greater than average. After 5 yr of age, relative weight increased dramatically, and by 8 yr of age, half of the ODM had weights >90th percentile. This childhood obesity in ODM is correlated with maternal prepregnant weight and independently with amniotic fluid insulin at 32–38 wk gestation. The Brazelton Neonatal Behavioral Assessment Scale (BNBAS) was administered to 185 newborn ODM. Significant correlations were found between poorer second- and third-trimester glycemie regulation and lower scores in three of four newborn BNBAS dimensions. The Stanford-Binet Intelligence Scale was measured in 102 ODM at 4 yr of age. We found an inverse correlation between childhood IQ and second- and third-trimester maternal lipid metabolism (serum free fatty acids and β-hydroxybutyrate). This correlation is not explained by adverse perinatal events, socioeconomic status, maternal IQ, ethnicity, or diabetes type. These long-range associations between altered maternal metabolism and childhood growth and development continue to support Freinkels hypothesis of fuel-mediated teratogenesis.

The Hyperglycemia and Adverse Pregnancy Outcome Study: Associations of GDM and obesity with pregnancy outcomes

OBJECTIVE To determine associations of gestational diabetes mellitus (GDM) and obesity with adverse pregnancy outcomes in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. RESEARCH DESIGN AND METHODS Participants underwent a 75-g oral glucose tolerance test (OGTT) between 24 and 32 weeks. GDM was diagnosed post hoc using International Association of Diabetes and Pregnancy Study Groups criteria. Neonatal anthropometrics and cord serum C-peptide were measured. Adverse pregnancy outcomes included birth weight, newborn percent body fat, and cord C-peptide >90th percentiles, primary cesarean delivery, preeclampsia, and shoulder dystocia/birth injury. BMI was determined at the OGTT. Multiple logistic regression was used to examine associations of GDM and obesity with outcomes. RESULTS Mean maternal BMI was 27.7, 13.7% were obese (BMI ≥33.0 kg/m2), and GDM was diagnosed in 16.1%. Relative to non-GDM and nonobese women, odds ratio for birth weight >90th percentile for GDM alone was 2.19 (1.93–2.47), for obesity alone 1.73 (1.50–2.00), and for both GDM and obesity 3.62 (3.04–4.32). Results for primary cesarean delivery and preeclampsia and for cord C-peptide and newborn percent body fat >90th percentiles were similar. Odds for birth weight >90th percentile were progressively greater with both higher OGTT glucose and higher maternal BMI. There was a 339-g difference in birth weight for babies of obese GDM women, compared with babies of normal/underweight women (64.2% of all women) with normal glucose based on a composite OGTT measure of fasting plasma glucose and 1- and 2-h plasma glucose values (61.8% of all women). CONCLUSIONS Both maternal GDM and obesity are independently associated with adverse pregnancy outcomes. Their combination has a greater impact than either one alone.

Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study: Associations with Neonatal Anthropometrics

OBJECTIVE—To examine associations of neonatal adiposity with maternal glucose levels and cord serum C-peptide in a multicenter multinational study, the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study, thereby assessing the Pederson hypothesis linking maternal glycemia and fetal hyperinsulinemia to neonatal adiposity. RESEARCH DESIGN AND METHODS—Eligible pregnant women underwent a standard 75-g oral glucose tolerance test between 24 and 32 weeks gestation (as close to 28 weeks as possible). Neonatal anthropometrics and cord serum C-peptide were measured. Associations of maternal glucose and cord serum C-peptide with neonatal adiposity (sum of skin folds >90th percentile or percent body fat >90th percentile) were assessed using multiple logistic regression analyses, with adjustment for potential confounders, including maternal age, parity, BMI, mean arterial pressure, height, gestational age at delivery, and the babys sex. RESULTS—Among 23,316 HAPO Study participants with glucose levels blinded to caregivers, cord serum C-peptide results were available for 19,885 babies and skin fold measurements for 19,389. For measures of neonatal adiposity, there were strong statistically significant gradients across increasing levels of maternal glucose and cord serum C-peptide, which persisted after adjustment for potential confounders. In fully adjusted continuous variable models, odds ratios ranged from 1.35 to 1.44 for the two measures of adiposity for fasting, 1-h, and 2-h plasma glucose higher by 1 SD. CONCLUSIONS—These findings confirm the link between maternal glucose and neonatal adiposity and suggest that the relationship is mediated by fetal insulin production and that the Pedersen hypothesis describes a basic biological relationship influencing fetal growth.

Incidence of Spontaneous Abortion among Normal Women and Insulin-Dependent Diabetic Women Whose Pregnancies Were Identified within 21 Days of Conception

Whether pregnant women with insulin-dependent diabetes mellitus have an increased risk of spontaneous abortion is controversial. To address this question, we enrolled 386 women with insulin-dependent diabetes and 432 women without diabetes before or within 21 days after conception and followed both groups prospectively. Sixty-two diabetic women (16.1 percent) and 70 control women (16.2 percent) had pregnancy losses (odds ratio, 0.99; 95 percent confidence interval, 0.67 to 1.46). After adjustment for known risk factors for spontaneous abortion, the rate was still not significantly higher in the diabetic group (odds ratio, 0.91; 95 percent confidence interval, 0.59 to 1.40). Nonetheless, among the diabetic women, most of whom had good metabolic control, those who had spontaneous abortions had higher fasting and postprandial glucose levels in the first trimester than those whose pregnancies continued to delivery (P = 0.01 for fasting glucose levels and P = 0.005 for postprandial levels). In the small subgroup of diabetic women with poor control, who had elevated values for glycosylated hemoglobin in the first trimester, each increase of 1 SD above the normal range was associated with an increase of 3.1 percent in the rate of pregnancy loss (95 percent confidence interval, 0.6 to 5.6). We conclude that diabetic women with good metabolic control are no more likely than nondiabetic women to lose a pregnancy, but that diabetic women with elevated blood glucose and glycosylated hemoglobin levels in the first trimester have a significantly increased risk of having a spontaneous abortion.