Elisabeth R. Trimble

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.

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.

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.

Measurement of malondialdehyde in plasma by high performance liquid chromatography with fluorimetric detection

The thiobarbituric acid test for malondialdehyde is widely used as an indicator of lipid peroxidation and free radical activity. We describe a simple and sensitive high performance liquid chromatographic (HPLC) method for measuring the malondialdehyde-thiobarbituric acid adduct using fluorimetric detection. Extraction into organic solvent or other complex sample preparation is not required and the assay is sensitive to <0 · 05 μmol/L. This method could easily be applied to any setting where a measure of lipid peroxidation is required.

The effect of ascorbate supplementation on oxidative stress in the streptozotocin diabetic rat

An increase in oxidative stress may contribute to the development of diabetic complications. The key aqueous-phase chain-breaking antioxidant ascorbate is known to be deficient in diabetes, and we have therefore investigated the effects of ascorbate supplementation on oxidative stress in the streptozotocin diabetic rat. Markers of lipid peroxidation (malondialdehyde [MDA] and diene conjugates) were increased in plasma and erythrocytes of untreated diabetic animals, and levels of the antioxidants ascorbate and retinol were reduced. Plasma tocopherol was unchanged. Insulin treatment normalized MDA and ascorbate levels, although ascorbate metabolism remained disturbed, as indicated by increased levels of dehydroascorbate. High-dose ascorbate supplementation in the absence of insulin treatment restored plasma ascorbate to normal and increased plasma retinol and tocopherol levels. However, MDA and diene conjugate levels remained unchanged, possibly as a result of increased iron availability. High-dose ascorbate supplementation should be approached with caution in diabetes, as ascorbate may exert both antioxidant and prooxidant effects in vivo.

The effects of desferrioxamine and ascorbate on oxidative stress in the streptozotocin diabetic rat

Oxidative stress and protein glycation are closely related processes that may contribute to the development of complications in diabetes mellitus. Treatment with antioxidants could protect against these processes at a biochemical level, and we have therefore investigated the effects of ascorbate and desferrioxamine treatment in the streptozotocin diabetic rat. Diabetic animals were given ascorbate 1 g/l in drinking water or desferrioxamine 6 mg/kg/day by subcutaneous injection and were killed after 6 weeks. In diabetic animals, oxidative stress was increased as shown by increased levels of conjugated dienes (CD) in plasma and malondialdehyde (MDA) in plasma, erythrocyte membranes, and urine. In addition, there was depletion of the nutritional antioxidants ascorbate, alpha-tocopherol, and retinol. Insulin treatment returned all of these parameters to normal. Ascorbate supplementation or desferrioxamine treatment alone failed to reduce oxidative stress, but a combination of both interventions restored MDA, CD, and antioxidant vitamins to control values. Both ascorbate and desferrioxamine also reduced HbA1c and glycated albumin levels. Treatment with antioxidants can reduce both oxidative stress and protein glycation and may help to reduce the risk of developing diabetic complications. However, ascorbate can have both prooxidant and antioxidant effects in vivo, and its use in pharmacological doses should be approached with caution.

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.

ANTIOXIDANT STATUS AND LIPID PEROXIDATION IN HEREDITARY HAEMOCHROMATOSIS

Hereditary haemochromatosis is characterised by iron overload that may lead to tissue damage. Free iron is a potent promoter of hydroxyl radical formation that can cause increased lipid peroxidation and depletion of chain-breaking antioxidants. We have therefore assessed lipid peroxidation and antioxidant status in 15 subjects with hereditary haemochromatosis and age/sex matched controls. Subjects with haemochromatosis had increased serum iron (24.8 (19.1-30.5) vs. 17.8 (16.1-19.5) mumol/l, p = 0.021) and % saturation (51.8 (42.0-61.6) vs. 38.1 (32.8-44.0), p = 0.025). Thiobarbituric acid reactive substances (TBARS), a marker of lipid peroxidation, were increased in haemochromatosis (0.59 (0.48-0.70) vs. 0.46 (0.21-0.71) mumol/l, p = 0.045), and there were decreased levels of the chain-breaking antioxidants alpha-tocopherol (5.91 (5.17-6.60) vs. 7.24 (6.49-7.80) mumol/mmol cholesterol, p = 0.001), ascorbate (51.3 (33.7-69.0) vs. 89.1 (65.3-112.9), p = 0.013), and retinol (1.78 (1.46-2.10) vs. 2.46 (2.22-2.70) mumol/l, p = 0.001). Patients with hereditary haemochromatosis have reduced levels of antioxidant vitamins, and nutritional antioxidant supplementation may represent a novel approach to preventing tissue damage. However, the use of vitamin C may be deleterious in this setting as ascorbate can have prooxidant effects in the presence of iron overload.

A rapid method for measurement of the susceptibility to oxidation of low-density lipoprotein.

Oxidation of low-density lipoprotein (LDL) may be important in the pathogenesis of atherosclerosis. We describe a method which measures the oxidation resistance of LDL isolated by a rapid procedure without added antioxidants. LDL was isolated from heparinized plasma by density gradient ultracentrifugation and desalted by gel filtration. The protein concentration was standardized to 50 mg/L and oxidation was promoted by copper (2 μmol/L) at 37°C. The total sample preparation time was 2·5 h. Conjugated diene production was monitored at λ = 234 nm with computation of the lag time. LDL oxidation was inhibited by EDTA but not heparin. Albumin inhibited LDL oxidation but only in concentrations greater than 50 mg/L. LDL was stable in frozen plasma (–70°C) for 10 weeks, but unstable in the isolated and desalted state. The lag time for LDL from patients treated with the antioxidant probucol was markedly prolonged compared to normal subjects.