Donald R. Coustan

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.

Managing preexisting diabetes for pregnancy: Summary of evidence and consensus recommendations for care

This document presents consensus panel recommendations for the medical care of pregnant women with preexisting diabetes, including type 1 and type 2 diabetes. The intent is to help clinicians deal with the broad spectrum of problems that arise in management of diabetes before and during pregnancy, and to prepare diabetic women for treatment that may reduce complications in the years after pregnancy. A thorough discussion of the evidence supporting the recommendations is presented in the book, Management of Preexisting Diabetes and Pregnancy , authored by the consensus panel and published by the American Diabetes Association (ADA) in 2008 (1). A consensus statement on obstetrical and postpartum management will appear separately. The recommendations are diagnostic and therapeutic actions that are known or believed to favorably affect maternal and perinatal outcomes in pregnancies complicated by diabetes. The grading system adapted by the ADA was used to clarify and codify the evidence that forms the basis for the recommendations (2). Unfortunately there is a paucity of randomized controlled trials (RCTs) of the different aspects of management of diabetes and pregnancy. Therefore our recommendations are often based on trials conducted in nonpregnant diabetic women or nondiabetic pregnant women, as well as on peer-reviewed experience before and during pregnancy in women with preexisting diabetes (3–4). We also reviewed and adapted existing diabetes and pregnancy guidelines (5–10) and guidelines on diabetes complications and comorbidities (2,3,11–14). ### A. Organization of preconception and pregnancy care #### Recommendations

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.

Pregnancy as state of physiologic absorptive hypercalciuria

An increase in circulating, 1,25-dihydroxyvitamin D level and net intestinal calcium absorption have been previously demonstrated in pregnant women and have been widely regarded as compensatory mechanisms whereby fetal mineral demands are satisfied. The alternate possibility, that these adjustments might anticipate such demands, has not previously been considered. To examine the effects of pregnancy on the intestinal absorption and renal excretion of calcium, oral calcium tolerance tests were performed and urinary calcium excretion was measured in 16 healthy women receiving a moderate calcium intake during and after pregnancy. Circulating 1,25-dihydroxyvitamin D levels and indexes of parathyroid function were also measured. As expected, 1,25-dihydroxyvitamin D levels were significantly (p less than 0.05) elevated throughout pregnancy (94 +/- 11, 118 +/- 9, and 117 +/- 11 pg/ml in the first, second, and third trimesters, respectively, versus 51 +/- 5 pg/ml after delivery). Twenty-four-hour calcium excretion also increased sharply (247 +/- 54, 316 +/- 42, 300 +/- 61 mg versus 91 +/- 18 mg), often to the point of hypercalciuria. Calcium tolerance test results included significant increases in the calciuric and calcemic responses during each trimester, whereas fasting calcium excretion and parathyroid function remained normal. These findings portray normal pregnancy as a state of physiologic absorptive hypercalciuria and call into question the widespread practice of supplementing calcium intake in otherwise well-nourished women during pregnancy.

Prophylactic insulin treatment of gestational diabetes reduces the incidence of macrosomia, operative delivery, and birth trauma

Four hundred and forty-five gestational diabetic women who were delivered over a 5-year period were evaluated. One hundred and fifteen were treated with insulin and diet, 184 with diet alone, and 146 with neither insulin nor dietary manipulation. The incidence of babies weighing more than 4000 gm was 7% in the insulin-treated group, 18.5% in the diet-treated group, and 17.8% in the untreated group (p less than 0.05). The incidence of operative delivery (midforceps, midcavity vacuum extraction, or primary cesarean section) was 16.3% in the insulin-treated group, 30.4% in the diet-treated group, and 28.5% in the untreated group (p less than 0.05). The incidence of birth trauma (shoulder dystocia, Erbs palsy, cephalhematoma, soft tissue injury) was 4.8% in the insulin-treated group, 13.4% in the diet-treated group, and 20.4% in the untreated group (p less than 0.05). These data suggest that prophylactic insulin treatment prevents not only macrosomia but also its sequel of traumatic delivery.

The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study: paving the way for new diagnostic criteria for gestational diabetes mellitus

The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study was performed in response to the need for internationally agreed upon diagnostic criteria for gestational diabetes, based upon their predictive value for adverse pregnancy outcome. Increases in each of the 3 values on the 75-g, 2-hour oral glucose tolerance test are associated with graded increases in the likelihood of pregnancy outcomes such as large for gestational age, cesarean section, fetal insulin levels, and neonatal fat content. Based upon an iterative process of decision making, a task force of the International Association of Diabetes and Pregnancy Study Groups recommends that the diagnosis of gestational diabetes be made when any of the following 3 75-g, 2-hour oral glucose tolerance test thresholds are met or exceeded: fasting 92 mg/dL, 1-hour 180 mg/dL, or 2 hours 153 mg/dL. Various authoritative bodies around the world are expected to deliberate the adoption of these criteria.

Gestational diabetes: Predictors of subsequent disordered glucose metabolism

OBJECTIVE We tested the hypothesis that the development of abnormal glucose metabolism after gestational diabetes can be predicted readily by means of available clinical variables. STUDY DESIGN Three hundred fifty nonpregnant former gestational diabetic women delivered during the previous 10 years underwent glucose tolerance tests. Variables including body mass index before the index pregnancy, pregnancy glucose tolerance test values, gestational diabetes treatment, complications, gestational age at diagnosis of gestational diabetes, and time elapsed since pregnancy were analyzed with logistic regression. RESULTS Variables that distinguished subjects who later developed diabetes or impaired glucose tolerance included prepregnancy body mass index (28.5 +/- 7 versus 25 +/- 5 kg/m2, p < 0.001) and fasting glucose on the pregnant oral glucose tolerance test (109 +/- 20 vs 92 +/- 15 mg/dl, p < 0.001). Logistic results with these two variables plus time since the index pregnancy predict subsequent glucose tolerance test abnormality by the following equation: estimated risk = 1/[1 + e-(-10.37 + 0.04 (fasting plasma glucose) + 0.08 (body mass index) + 0.03 (months since delivery))]. CONCLUSION The risk for subsequent glucose abnormality among individuals with previous gestational diabetes is quantifiable based on prepregnant body mass index and fasting plasma glucose during pregnancy.

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.

Insulin therapy for gestational diabetes.

Seventy-two patient with gestational diabetes were randomly treated with insulin (20 units NPH and 10 units regular) and diabetic diet, diet alone, or neither. Of the 27 patients treated with insulin and diet, 2 (7%) had babies weighing more than 8 1/2 pounds. Of the 11 patients treated with diet alone, 4 (36.4%) had babies weighing more than 8 1/2 pounds. Of the 34 patients treated with neither diet nor insulin, 17 (50%) had babies weighing more than 8 1/2 pounds. These data support the hypothesis that treatment of the gestational diabetic with insulin will reduce the incidence of fetal macrosomia.