Counterpoint: Establishing consensus in the diagnosis of GDM following the HAPO study.

The International Association of Diabetes in Pregnancy Study Groups (IADPSG) recommended a new protocol of 1-step testing with a 75 g oral glucose tolerance test for gestational diabetes in 2010. Since that time, these recommendations have been carefully scrutinized and accepted by a variety of organizations, but challenged or rejected by others. In the current review, we present more details regarding the background to the development of the IADPSG recommendations and seek to place them in context with the available epidemiologic and randomized controlled trial data. In this "counterpoint," we also provide specific rebuttal for errors of fact and disputed contentions provided by Long and Cundy in their 2013 article in Current Diabetes Reports.

Hyperglycemia and adverse pregnancy outcomes.

BACKGROUND: It is controversial whether maternal hyperglycemia less severe than that in diabetes mellitus is associated with increased risks of adverse pregnancy outcomes. METHODS: A total of 25,505 pregnant women at 15 centers in nine countries underwent 75-g oral glucose-tolerance testing at 24 to 32 weeks of gestation. Data remained blinded if the fasting plasma glucose level was 105 mg per deciliter (5.8 mmol per liter) or less and the 2-hour plasma glucose level was 200 mg per deciliter (11.1 mmol per liter) or less. Primary outcomes were birth weight above the 90th percentile for gestational age, primary cesarean delivery, clinically diagnosed neonatal hypoglycemia, and cord-blood serum C-peptide level above the 90th percentile. Secondary outcomes were delivery before 37 weeks of gestation, shoulder dystocia or birth injury, need for intensive neonatal care, hyperbilirubinemia, and preeclampsia. RESULTS: For the 23,316 participants with blinded data, we calculated adjusted odds ratios for adverse pregnancy outcomes associated with an increase in the fasting plasma glucose level of 1 SD (6.9 mg per deciliter [0.4 mmol per liter]), an increase in the 1-hour plasma glucose level of 1 SD (30.9 mg per deciliter [1.7 mmol per liter]), and an increase in the 2-hour plasma glucose level of 1 SD (23.5 mg per deciliter [1.3 mmol per liter]). For birth weight above the 90th percentile, the odds ratios were 1.38 (95% confidence interval [CI], 1.32 to 1.44), 1.46 (1.39 to 1.53), and 1.38 (1.32 to 1.44), respectively; for cord-blood serum C-peptide level above the 90th percentile, 1.55 (95% CI, 1.47 to 1.64), 1.46 (1.38 to 1.54), and 1.37 (1.30 to 1.44); for primary cesarean delivery, 1.11 (95% CI, 1.06 to 1.15), 1.10 (1.06 to 1.15), and 1.08 (1.03 to 1.12); and for neonatal hypoglycemia, 1.08 (95% CI, 0.98 to 1.19), 1.13 (1.03 to 1.26), and 1.10 (1.00 to 1.12). There were no obvious thresholds at which risks increased. Significant associations were also observed for secondary outcomes, although these tended to be weaker. CONCLUSIONS: Our results indicate strong, continuous associations of maternal glucose levels below those diagnostic of diabetes with increased birth weight and increased cord-blood serum C-peptide levels.

Normal and abnormal maternal metabolism during pregnancy.

Metabolic adaptations during pregnancy are essential to meet the physiological demands of pregnancy as well as adequate growth and development of the fetus. There has been considerable interest in carbohydrate metabolism during pregnancy, with diabetes, the main disorder of glucose metabolism, a considerable focus for research. Whereas disorders of protein and lipid metabolism are recognised during pregnancy, their influence has received less attention. Fasting glucose values fall in early pregnancy with a rise in plasma free fatty acids, enhanced ketogenesis and a fall in plasma amino acids. Decreased hepatic insulin sensitivity in later pregnancy plays a key role in bringing about the appropriate changes in carbohydrate, lipid and amino acid metabolism which are essential for normal fetal development and survival.

Untreated Mild Hyperglycemia During Pregnancy and Anthropometric Measures of Obesity in Offspring at Age 5-7 Years.

OBJECTIVE: Obesity in the offspring of women with hyperglycemia during pregnancy has been reported, but the results are conflicting. This study examined the association of hyperglycemia during pregnancy and anthropometry in 5- to 7-year-old offspring whose mothers participated in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study at the Belfast Centre. RESEARCH DESIGN AND METHODS: Women in the HAPO study underwent a 75-g oral glucose tolerance test (OGTT) at approximately 28 weeks of gestation. Mothers and caregivers remained blinded to the results unless the fasting plasma glucose (FPG) concentration was >5.8 mmol/L or the 2-h plasma glucose (2hPG) concentration was >11.1 mmol/L. Offspring weight, height, and skinfold thicknesses (triceps, subscapular, and suprailiac) were measured at age 5-7 years. Overweight, obesity, and extreme obesity were defined as a BMI z score ≥85th, ≥95th, and ≥99th percentile, respectively, based on the 1990 British Growth Standard. RESULTS: Belfast HAPO offspring (n = 1,320, 82%) aged 5-7 years attended for follow-up. With use of multiple regression, maternal FPG, 1h PG, and 2hPG did not show any relation to offspring BMI z score or offspring skinfold sum independent of maternal BMI at OGTT and offspring birth weight z score. This lack of association with maternal glycemia persisted with the offspring BMI z score expressed as ≥85th, ≥95th, or 99th percentile and the sum of skinfolds expressed as ≥90th percentile specific for sex. The initially significant relation between FPG and all offspring adiposity measures was explained by maternal BMI at the OGTT. CONCLUSIONS: After adjustment for maternal BMI at the OGTT, higher maternal FPG concentration during pregnancy (short of diabetes) is no longer a risk factor for obesity, as reflected by BMI and the sum of skinfolds in offspring aged 5-7 years.

Diabetes and pregnancy: an endocrine society clinical practice guideline.

OBJECTIVE: Our objective was to formulate a clinical practice guideline for the management of the pregnant woman with diabetes. PARTICIPANTS: The Task Force was composed of a chair, selected by the Clinical Guidelines Subcommittee of The Endocrine Society, 5 additional experts, a methodologist, and a medical writer. EVIDENCE: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. CONSENSUS PROCESS: One group meeting, several conference calls, and innumerable e-mail communications enabled consensus for all recommendations save one with a majority decision being employed for this single exception. CONCLUSIONS: Using an evidence-based approach, this Diabetes and Pregnancy Clinical Practice Guideline addresses important clinical issues in the contemporary management of women with type 1 or type 2 diabetes preconceptionally, during pregnancy, and in the postpartum setting and in the diagnosis and management of women with gestational diabetes during and after pregnancy.

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/m(2)), 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.

Frequency of gestational diabetes mellitus at collaborating centers based on IADPSG consensus panel-recommended criteria: the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study.

OBJECTIVE: To report frequencies of gestational diabetes mellitus (GDM) among the 15 centers that participated in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study using the new International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria. RESEARCH DESIGN AND METHODS: All participants underwent a 75-g oral glucose tolerance test between 24 and 32 weeks' gestation. GDM was retrospectively classified using the IADPSG criteria (one or more fasting, 1-h, or 2-h plasma glucose concentrations equal to or greater than threshold values of 5.1, 10.0, or 8.5 mmol/L, respectively). RESULTS: Overall frequency of GDM was 17.8% (range 9.3-25.5%). There was substantial center-to-center variation in which glucose measures met diagnostic thresholds. CONCLUSIONS: Although the new diagnostic criteria for GDM apply globally, center-to-center differences occur in GDM frequency and relative diagnostic importance of fasting, 1-h, and 2-h glucose levels. This may impact strategies used for the diagnosis of GDM.

Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study: associations of maternal A1C and glucose with pregnancy outcomes.

OBJECTIVE: To compare associations of maternal glucose and A1C with adverse outcomes in the multinational Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and determine, based on those comparisons, if A1C measurement can provide an alternative to an oral glucose tolerance test (OGTT) in pregnant women. RESEARCH DESIGN AND METHODS: Eligible pregnant women underwent a 75-g OGTT at 24-32 weeks' gestation. A sample for A1C was also collected. Neonatal anthropometrics and cord serum C-peptide were measured. Associations with outcomes were assessed using multiple logistic regression with adjustment for potential confounders. RESULTS: Among 23,316 HAPO Study participants with glucose levels blinded to caregivers, 21,064 had a nonvariant A1C result. The mean ± SD A1C was 4.79 ± 0.40%. Associations were significantly stronger with glucose measures than with A1C for birth weight, sum of skinfolds, and percent body fat >90th percentile and for fasting and 1-h glucose for cord C-peptide (all P < 0.01). For example, in fully adjusted models, odds ratios (ORs) for birth weight >90th percentile for each measure higher by 1 SD were 1.39, 1.45, and 1.38, respectively, for fasting, 1-, and 2-h plasma glucose and 1.15 for A1C. ORs for cord C-peptide >90th percentile were 1.56, 1.45, and 1.35 for glucose, respectively, and 1.32 for A1C. ORs were similar for glucose and A1C for primary cesarean section, preeclampsia, and preterm delivery. CONCLUSIONS: On the basis of associations with adverse outcomes, these findings suggest that A1C measurement is not a useful alternative to an OGTT in pregnant women.

Maternal glucose at 28 weeks of gestation is not associated with obesity in 2-year-old offspring: the Belfast Hyperglycemia and Adverse Pregnancy Outcome (HAPO) family study.

OBJECTIVE: Diabetes during pregnancy is a strong risk factor for obesity in the offspring, but the age at which this association becomes apparent is unknown. The purpose of this study was to examine the relation of glycemia during pregnancy with anthropometry in offspring of nondiabetic pregnant women from the Belfast U.K. center of the multinational Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. RESEARCH DESIGN AND METHODS: Women from the HAPO Study were invited to participate in follow-up of their offspring aged 2 years. Measurements included height, weight, and thickness of triceps, subscapular, and suprailiac skinfolds. RESULTS: A total of 1,165 offspring (73% of eligible children; 598 boys and 567 girls) were seen from ages 22-30 completed months. The only association that reached statistical significance was between categories of maternal 1-h glucose and BMI Z score >or=85th percentile at 2 years (P = 0.017). Overall the correlations between maternal glucose during pregnancy and BMI Z score at age 2 years were weak (fasting glucose r = 0.05, P = 0.08; 1-h glucose r = 0.04, P = 0.22; 2-h glucose r = 0.03, P = 0.36; and area under the curve for glucose r = 0.04, P = 0.18). CONCLUSIONS: This study found little association between maternal glucose during pregnancy and obesity in the offspring at this young age. These findings are not unexpected given that study results for young offspring whose mothers had diabetes during pregnancy were indistinguishable from those for normal offspring at this age. It will be interesting to see whether, as these children age, maternal glucose during pregnancy in the ranges included in the HAPO Study will be associated with obesity in their children.

Hyperglycemia and adverse pregnancy outcome study: neonatal glycemia.

OBJECTIVE: The goal was to describe the temporal pattern of neonatal plasma glucose levels and associations with maternal glucose levels, cord serum C-peptide levels, and neonatal size and adiposity. METHODS: A total of 17,094 mothers and infants were included in the Hyperglycemia and Adverse Pregnancy Outcome Study (15 centers in 9 countries). Mothers underwent a 75-g, 2-hour, oral glucose tolerance test (OGTT) at 24 to 32 weeks of gestation. Cord blood and neonatal blood samples were collected. Biochemical neonatal hypoglycemia was defined as glucose levels of <10th percentile (2.2 mmol/L). Clinically identified hypoglycemia was ascertained through medical record review and associations were assessed. RESULTS: Plasma glucose concentrations were stable during the first 5 hours after birth. Maternal glucose levels were weakly positively associated with biochemical neonatal hypoglycemia (odds ratios: 1.07-1.14 for 1-SD higher OGTT glucose levels). Frequency of neonatal hypoglycemia was higher with higher cord C-peptide levels (odds ratio: 11.6 for highest versus lowest C-peptide category). Larger and/or fatter infants were more likely to have hypoglycemia (P < .001), and infants with hypoglycemia tended to have a higher frequency of cord C-peptide levels of >90th percentile. CONCLUSIONS: Mean neonatal plasma glucose concentrations varied little in the first 5 hours after birth, which suggests normal postnatal adjustment. Biochemical and clinical hypoglycemia were weakly related to maternal OGTT glucose measurements but were strongly associated with elevated cord serum C-peptide levels. Larger and/or fatter infants were more likely to develop hypoglycemia and hyperinsulinemia. These relationships suggest physiologic relationships between maternal glycemia and fetal insulin production.

Leptin concentrations in maternal serum and cord blood in diabetic and nondiabetic pregnancy.

OBJECTIVE: The purpose of this study was to examine the relationships between maternal and cord leptin concentrations, maternal and neonatal outcomes, and measures of glycemic control in diabetic and nondiabetic pregnancy. STUDY DESIGN: This was a prospective study of 60 type 1 diabetic and 50 nondiabetic pregnancies in a university teaching hospital. Serum leptin and hemoglobin A(1c) were measured serially throughout pregnancy; leptin, insulin, insulin-like growth factor-1, and C-peptide in venous cord blood were measured at delivery. Leptin was measured with the use of enzyme-linked immunosorbent assay. Data were analyzed with specific computer software. RESULTS: Maternal leptin levels correlated with cord leptin levels in the nondiabetic group only. Cord leptin levels correlated with cord C-peptide, cord insulin-like growth factor-1, birth weight, birth weight corrected for gestational age, and neonatal anthropometry in both groups and with hemoglobin A(1c) in the diabetic group only. Cord leptin levels increased significantly with increasing birth weight corrected for gestational age but remained significantly higher at all birth weights in the diabetic group. CONCLUSION: There are strong associations between cord leptin levels and other measures of fetal growth in both groups and with glycemic control in the diabetic group.

Preprandial versus postprandial blood glucose monitoring in type 1 diabetic pregnancy: a randomized controlled clinical trial.

OBJECTIVE: This study was undertaken to compare preprandial and postprandial capillary glucose monitoring in pregnant women with type 1 diabetes. STUDY DESIGN: Sixty-one women with type 1 diabetes were randomly assigned at 16 weeks' gestation to preprandial or postprandial blood glucose monitoring using memory-based glucose reflectance meters throughout pregnancy. Serial measurements of hemoglobin A1c and fructosamine were obtained throughout pregnancy. Insulin, glucose, and insulin-like growth factor-I (IGF-I) were measured in cord blood at delivery. Neonatal anthropometric measures were performed within 72 hours of delivery RESULTS: Maternal age, parity, age of onset of diabetes, number of prior miscarriages, smoking status, social class, weight gain in pregnancy, and compliance with therapy were similar in the two groups. The postprandial monitoring group had a significantly reduced incidence of preeclampsia (3% vs 21%, P<.048), a greater success in achieving glycemic control targets (55% vs 30%, P<.001) and a smaller neonatal triceps skinfold thickness (4.5+/-0.9 vs 5.1+/-1.3, P=.05). CONCLUSION: Postprandial capillary blood glucose monitoring in type 1 diabetic pregnancy may significantly reduce the incidence of preeclampsia and neonatal triceps skinfold thickness compared with preprandial monitoring.