Proposed diagnostic thresholds for gestational diabetes mellitus according to a 75-g oral glucose tolerance test. Maternal and perinatal outcomes in 3260 Danish women.

AIMS: To study if established diagnostic threshold values for gestational diabetes based on a 75-g, 2-h oral glucose tolerance test can be supported by maternal and perinatal outcomes. METHODS: Historical cohort study of 3260 pregnant women examined for gestational diabetes on the basis of risk indicators. Information on oral glucose tolerance test results and clinical outcomes were collected from medical records. RESULTS: There was an increased risk of delivering a macrosomic infant in women with 2-h capillary blood glucose of 7.8-8.9 mmol/l compared with women with 2-h glucose < 7.8 mmol/l. Despite treatment, 2-h glucose of 9.0-11.0 mmol/l and > or = 11.1 mmol/l were both associated with increased rates of macrosomia, spontaneous preterm delivery, hypertensive complications, and neonatal hypoglycaemia. Adverse outcomes tended to be more frequent in women with 2-h glucose > or = 11.1 mmol/l than in women with 2-h glucose of 9.0-11.0 mmol/l. CONCLUSIONS: The risk for several maternal and perinatal complications increased with the diagnostic threshold for 2-h glucose. Large-scale blinded studies are needed to clarify the question of a clinically meaningful diagnosis of gestational diabetes mellitus. Until these results are available, a 2-h threshold level of 9.0 mmol/l after a 75-g oral glucose tolerance test seems acceptable.

Perinatal complications in women with gestational diabetes mellitus.

BACKGROUND: The aim of the study was to examine the outcome of the pregnancy and neonatal period in 1) women with gestational diabetes mellitus and non-diabetic pregnant women, and 2) in women with early and late diagnosis of gestational diabetes mellitus. METHODS: Included were 327 women with gestational diabetes mellitus and 295 non-diabetic women, who were screened with a 75 g oral glucose tolerance test because of risk factors for gestational diabetes. Women with gestational diabetes mellitus were treated with low-caloric diet and insulin when appropriate, while women in the control group received routine antenatal care. RESULTS: Gestational age at delivery was significantly lower in the group with gestational diabetes mellitus, both when considering all deliveries (39.1+/-1.7 weeks versus 39.8+/-2.0 weeks, p<0.05) and only those with spontaneous onset of labor (38.8+/-2.0 weeks versus 40.0+/-1.6 weeks, p<0.05). The frequency of macrosomia was increased, although not statistically significant (8% vs. 2%, p=0.07), and the rate of admission to the neonatal ward was significantly increased (18% vs. 9%, p<0.05) in the group with gestational diabetes. Women with early diagnosis of gestational diabetes mellitus had a significantly increased need for insulin treatment during pregnancy (36% vs. 9% p<0.05) and a significantly higher occurrence of diabetes mellitus at follow-up from two months until three years postpartum. CONCLUSIONS: This study of women with gestational diabetes mellitus and non-diabetic pregnant women showed that gestational diabetes mellitus was associated with a significantly lower gestational age at delivery and an increased rate of admission to the neonatal ward. Women diagnosed with GDM before 20 weeks of gestation had an increased need for insulin treatment during pregnancy and a high risk of subsequent overt DM, compared with women diagnosed with GDM later in pregnancy.

Clinical impact of mild carbohydrate intolerance in pregnancy: a study of 2904 nondiabetic Danish women with risk factors for gestational diabetes mellitus.

OBJECTIVE: The objective was to study the clinical impact of mild carbohydrate intolerance in pregnant women with risk factors for gestational diabetes mellitus. STUDY DESIGN: This was a historical cohort study of 2904 pregnant women examined for gestational diabetes on the basis of risk factors. Information on oral glucose tolerance test results and clinical outcomes was collected from laboratory charts and medical records. RESULTS: The following outcomes increased significantly with increasing glucose values during the oral glucose tolerance test: shoulder dystocia, macrosomia, emergency cesarean section, assisted delivery, hypertension, and induction of labor. However, when corrections were made for other risk factors, hypertension and induction of labor were only marginally associated with glucose levels. CONCLUSION: In a group of nondiabetic pregnant women with risk factors for gestational diabetes, there was a graded increase in the frequency of shoulder dystocia and other maternal-fetal complications with increasing glucose levels during an oral glucose tolerance test.

Prevalence of nocturnal hypoglycemia in first trimester of pregnancy in patients with insulin treated diabetes mellitus.

BACKGROUND: Excellent metabolic control before conception and during diabetic pregnancies is the aim in order to avoid malformations and perinatal morbidity. Since an inverse correlation between median blood glucose concentration (BG) and hypoglycemia as well as a high prevalence of nocturnal hypoglycemia have been described, we investigated the frequency of nocturnal hypoglycemia and the predictive value of bedtime blood glucose concentration for development of this condition in insulin treated diabetic patients. METHODS: During hospitalization, with no other changes in the patients' normal schedules, hourly blood samples were drawn from an iv-cannula from 22.00 h to 07.00 h for one night. BG (venous whole blood) and hemoglobin A1c were determined the following day. RESULTS: Fifty-three patients participated; subsequently ten were excluded due to discontinuation of blood sampling during the night, caused by either discomfort or cannula problems. Of the remaining 43 patients, 16 (37%) had at least one blood glucose <3.0 mmol/l. The duration of hypoglycemia was 2.4 (1-7) h with the highest prevalence at 05 h. Only one patient felt hypoglycemic during the night. Hemoglobin A1c was similar in patients with (7.1+/-1.2%, mean+/-s.d.) and without (6.8+/-0.8%) nocturnal hypoglycemia. Women with nocturnal hypoglycemia had significantly lower BG before bedtime compared to patients without hypoglycemia, 6.4+/-3.6 mmol/l vs. 7.9+/-2.4 mmol/l, p<0.05. The best predictive value for nocturnal hypoglycemia was a BG below 6.0 mmol/l at 23.00, which resulted in a risk of nocturnal hypoglycemia of 71%. Conversely, if the BG was > or =6.0 mmol/l, the chance of avoiding nocturnal hypoglycemia was 83%. CONCLUSION: Nocturnal hypoglycemia was seen with a prevalence of 37% during a night in the first trimester of pregnancy in insulin treated patients. Only one patient registered the hypoglycemia. Nocturnal hypoglycemia could be predicted in the majority of patients by measurements of BG before bedtime.

Oral hypoglycaemic agents in 118 diabetic pregnancies.

AIMS: To assess maternal and neonatal complications in pregnancies of diabetic women treated with oral hypoglycaemic agents during pregnancy. METHODS: 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. RESULTS: 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). CONCLUSION: Treatment with metformin during pregnancy was associated with increased prevalence of pre-eclampsia and a high perinatal mortality.

Urinary albumin excretion and 24-hour blood pressure as predictors of pre-eclampsia in Type I diabetes.

AIMS/HYPOTHESIS: To evaluate the value of 24-h blood pressure monitoring compared to office blood pressure and urinary albumin excretion in predicting pre-eclampsia in Type I (insulin-dependent) diabetes mellitus. METHODS: The study included 136 consecutive pregnancies in Caucasian women with Type I diabetes before gestation without diabetic nephropathy, anamnestic hypertension or early abortion. Values of urinary albumin excretion and office blood pressure before pregnancy and the HbA1C value at the time of conception were obtained. Microalbuminuria was defined as urinary albumin excretion of 30-300 mg/24 h in two out of three consecutive urine samples. Single measurements of 24-h urinary albumin excretion, office blood pressure and HbA1C were done five 5 times during pregnancy. In a subgroup of 74 women 24-h blood pressure measurements were done at 10 and 28 weeks of gestation. Pre-eclampsia was defined as office blood pressure higher than 140/90 mmHg accompanied by proteinuria above 0.3 g/24 h later than 20 weeks of gestation. RESULTS: Urinary albumin excretion and systolic blood pressure were higher before and throughout pregnancy in 14 women developing pre-eclampsia compared with women remaining normotensive (p <0.001; p < 0.05, respectively). By logistic regression analysis the best predictor for pre-eclampsia was microalbuminuria before pregnancy (p < 0.05) with no additive predictive effect of 24-h blood pressure or office blood pressure measurement. The night:day ratio of blood pressure was similar in the two groups. CONCLUSION/INTERPRETATION: Microalbuminuria before pregnancy is the strongest predictor of pre-eclampsia in Type I diabetes. Measuring 24-h blood pressure early in pregnancy did not improve the ability to identify women at risk.

Serum levels of human placental lactogen, pregnancy-associated plasma protein A and endometrial secretory protein PP14 in first trimester of diabetic pregnancy.

OBJECTIVE: To study maternal serum levels of human placental lactogen (hPL), pregnancy-associated plasma protein A (PAPP-A) and endometrial secretory protein PP14 (PP14) in first trimester of diabetic pregnancy. METHODS: Seventy-nine insulin-dependent diabetic women and 93 normal pregnant women had a venous blood sample drawn in weeks 8-14, ultrasound age. Serum levels were measured by radioimmunoassays and expressed in multiples of the median serum value in normal pregnancy at that ultrasound age. RESULTS: Levels of hPL were significantly lower in diabetic mothers than in controls, z'= -5.502, p<0.00001. Levels of PAPP-A were also significantly lower, z' =2.263, p=0.024, but were significantly less depressed than those of hPL, z'=2.41, p=0.015. The PP14 levels did not deviate from normal. CONCLUSION: In first trimester of diabetic pregnancy there appears to be both a more general depression of trophoblast function, and also a specific depression of the hPL release.

[Management of pregnant diabetics]. / Behandling av gravide diabetikere.

The impressive decrease in perinatal mortality rates among the offspring of diabetic mothers, reported from many centres during the past 50 years (Fig. 1), is attributed to a multiplicity of factors, in particular improvements in the diabetic control of prospective mothers, both before conception and during pregnancy. Centres for preconceptional counselling and pregnancy planning and for diabetic gravidae management, are to be strongly recommended. In cases where diabetic is diagnosed during pregnancy, the diabetic gravidae centre should assume responsibility for the regular follow-up of these women. Although the combined efforts of diabetologists, obstetricians and neonatologists have resulted in substantial reduction of perinatal mortality and the frequency of severe congenital malformations among the offspring of diabetic mothers, there has been less reduction in the frequency of pregnancy complications and less improvement in long-term prognosis for the offspring of diabetic mothers.

Effect of 1,25-dihydroxycholecalciferol on glucose metabolism in gestational diabetes mellitus.

The effect of 1,25-dihydroxyvitamin D supplement on glucose metabolism was evaluated in 12 women with gestational diabetes mellitus (GDM). All women had an oral glucose tolerance test (OGTT) performed at inclusion in the study. Thereafter, each patient was instructed to continue their normal diet during the following 2 days, after which they received 2 micrograms/m2 Etalpha i.v. 2 h prior to the second OGTT. During the next 14 days each patient received 0.25 microgram Etalpha orally, after which a third OGTT was performed. On average the level of 1,25-dihydroxyvitamin D3 at inclusion at baseline significantly increased after i.v. 1,25-dihydroxyvitamin D3 (from 92 to 138 ng/l [p < 0.001]), but returned to the baseline level after 2 weeks of oral Etalpha (85 ng/l). Simultaneously, the glucose level decreased from 5.6 to 4.8 mmol/l (p < 0.01) after i.v. treatment with 1,25-dihydroxyvitamin D3, but did not differ significantly from inclusion following 2 weeks of oral Etalpha. There was no difference between the glucose concentrations during OGTT prior to and after i.v. or oral 1,25-dihydroxyvitamin D3, in contrast to the insulin levels which tended to be lower after both i.v. and oral supplementation. In a multiple regression model including 1,25-dihydroxyvitamin D3, insulin, weight and height against glucose, only 1,25-dihydroxyvitamin D3 and insulin were selected for the final model (r2 = 0.73, p < 0.0001). Our results suggest that supplements of 1,25-dihydroxyvitamin D3 influence glucose metabolism in patients with GDM probably by increasing the insulin sensitivity.

GAD65 autoantibodies in women with gestational or insulin dependent diabetes mellitus diagnosed during pregnancy.

We have studied the presence of GAD65 autoantibodies in women with insulin-dependent diabetes mellitus (IDDM) (n = 28) or gestational diabetes (GDM) (n = 139) diagnosed during pregnancy and investigated the temporal relationship between these autoantibodies and the subsequent recurrence or development of IDDM. Among the GDM patients, 4.3% (6 of 139) developed true IDDM during a median follow-up period of 6.3 years (range 4.0-11.0). Of these, 2.2% (3 of 139) were positive for GAD65 autoantibodies at diagnosis of GDM compared to 0% (0 of 27) of healthy pregnant women. All 3 GAD65 autoantibody positive GDM patients subsequently developed IDDM after a median of 14 months (range 4-34). GAD65 autoantibodies were present in 50% (14 of 28) of sera from women with IDDM diagnosed during pregnancy. The non-insulin-requiring remission period was significantly shorter in GAD65 autoantibody positive patients (median 0.5 years [range 0-6.0 years]) than in GAD65 antibody negative patients (median 2.6 years; range 0-9.7 years; p < 0.05). The results suggest that screening for GAD65 autoantibodies in women with GDM or IDDM diagnosed during pregnancy may be useful for predicting the clinical course of the disease.

A longitudinal study of plasma insulin and glucagon in women with previous gestational diabetes.

OBJECTIVE: To investigate whether plasma insulin or glucagon predicts later development of diabetes in women with gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: The subjects studied were 91 women with diet-treated GDM and 33 healthy women. Plasma insulin and glucagon during a 50-g oral glucose tolerance test (OGTT) were measured during pregnancy, postpartum, and at follow-up 5-11 years later. At follow-up, the women were also examined with a 75-g OGTT or an intravenous glucagon test. RESULTS: Twenty-seven (30%) of the women with previous GDM had abnormal glucose tolerance at follow-up (2 had insulin-dependent diabetes mellitus, 13 had non-insulin-dependent diabetes mellitus, and 12 had impaired glucose tolerance). Compared with the control subjects, women with previous GDM had relatively impaired insulin secretion (decreased insulinogenic index and delayed peak insulin response) at all time points investigated; this was also found when only nonobese glucose-tolerant women were examined. Low insulin secretion during pregnancy together with a high fasting plasma glucose level at the diagnostic OGTT in pregnancy and hyperglycemia during the postpartum OGTT were predictive for subsequent development of overt diabetes (logistic regression analysis). CONCLUSIONS: Women who develop GDM have a relative insulin secretion deficiency, the severity of which is predictive for later development of diabetes. Furthermore, our data indicate that their relatively reduced beta-cell function may be a significant pathogenic factor in relation to the high incidence of subsequent diabetes in women with GDM. This could be important in the design of follow-up programs for women with previous GDM.

Effects of contraceptive steroids on cardiovascular risk factors in women with insulin-dependent diabetes mellitus.

OBJECTIVE: We evaluated established cardiovascular risk factors within lipoprotein metabolism, hemostasis, and endothelial function in women with insulin-dependent diabetes mellitus who were using oral contraceptives. STUDY DESIGN: Twenty-five women with uncomplicated insulin-dependent diabetes mellitus, allocated to treatment with a monophasic combination of 30 micrograms ethinyl estradiol and 75 micrograms gestodene (treatment group, n = 12) or with nonhormonal contraception (control group, n = 13), were prospectively followed up for 12 months. Nonparametric methods were used for statistical evaluation. RESULTS: No statistical differences in the biochemical risk markers were noted between the two groups at the start of the study. In the treatment group serum levels of low-density lipoprotein cholesterol decreased, whereas the concentrations of total cholesterol, high-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, and triglycerides were unchanged. Within the coagulation system factor VII coagulant activity increased, while fibrinogen levels were unchanged. In the fibrinolytic system we found unchanged activities but decreased antigen concentrations of tissue plasminogen activator and plasminogen activator inhibitor. The concentration of von Willebrand factor increased, but no change in albumin excretion rates were found. In the control group no changes in any of the variables were observed. CONCLUSION: Intake of modern oral contraceptives does not deteriorate the cardiovascular risk profile in women with insulin-dependent diabetes mellitus, but our study indicates a risk of disturbances of the endothelial integrity, which needs further investigation.

Prevalence and predictive value of islet cell antibodies and insulin autoantibodies in women with gestational diabetes.

The objective of the present study was to investigate the predictive value of islet cell antibodies (ICA) and insulin autoantibodies (IAA) for development of diabetes in women with previous gestational diabetes (GDM). Two hundred and forty-one previous diet-treated GDM patients and 57 women without previous GDM were examined 2-11 years after the index pregnancy. In subgroups, plasma from the diagnostic OGTT during index pregnancy was analysed for ICA and IAA. Among the previous GDM patients, 3.7% had developed Type 1 diabetes and 13.7% Type 2 diabetes. Four (2.9%) of the 139 GDM patients tested for ICA were ICA-positive and three of these had Type 1 diabetes at follow-up, as well as three ICA-negative patients. The sensitivity, specificity, and predictive value of ICA-positivity for later development of diabetes were 50%, 99%, and 75%, respectively. None of the women was IAA-positive during pregnancy. In conclusion, the majority of the patients with GDM did not show evidence of ongoing autoimmune destruction of the beta cells during the index pregnancy. However, ICA-positive GDM patients had a high risk of developing Type 1 diabetes later in life.

Congenital malformations in offspring of diabetic women treated with oral hypoglycaemic agents during embryogenesis.

A markedly increased risk (50%) of congenital malformations in the offspring of women treated with oral hypoglycaemic agents during the first trimester has recently been reported. With this background, the medical records of a consecutive sample of 25 pregnant Type 2 diabetic women treated with oral hypoglycaemic agents during embryogenesis between 1966 and 1991 in the diabetic service of a university hospital, were studied retrospectively. None of the infants had major congenital malformations disclosed in the neonatal period (0%, 97.5% confidence interval 0.0-13.7%), but one minor congenital malformation was found (4.0%, 95% confidence interval 0.1-20.3%). Although this study, due to the limited number of pregnancies examined, does not exclude an association between treatment with oral hypoglycaemic agents at the time of embryogenesis and major congenital malformations in the offspring, the previously reported association was not confirmed. Thus we find no obvious indication for therapeutic abortions in patients who have accidentally been treated with oral hypoglycaemic agents during embryogenesis. On the contrary it seems reasonable to reassure these women with respect to their risk of having a malformed baby, stop the treatment with oral hypoglycaemic agents and initiate insulin treatment.

Decreased alpha-fetoprotein in amniotic fluid and maternal serum in diabetic pregnancy.

OBJECTIVE: To determine a reference level for alpha-fetoprotein (AFP) in the amniotic fluid (AF) in pregnant women with insulin-dependent diabetes mellitus in order to suggest an explanation for the observed decrease in maternal serum AFP. METHODS: Alpha-fetoprotein was measured in AF, maternal serum, or both in the second trimester in 287 pregnant women with insulin-dependent diabetes mellitus. Retrospectively, these AFP values were correlated with glycosylated hemoglobin (HbA1C) levels, early fetal growth delay, and congenital malformations. RESULTS: The median concentration of AFAFP was 0.89 multiples of the normative median (MoM) (n = 280; 95% confidence interval [CI] 0.88-0.93 MoM); the maternal serum AFP (MSAFP) value was 0.78 MoM (n = 155; 95% CI 0.77-0.84 MoM). A statistically significant but weak positive correlation was found between HbA1C and MSAFP (r2 = 0.033, P = .03), but the correlation with AFAFP was not statistically significant. The levels of AFP did not correlate with early fetal growth delay. One neural tube defect, but none of the 11 other major malformations, was detected by AFP screening. CONCLUSIONS: A physiologic basis for the decreased AFAFP and MSAFP levels is still obscure. Screening for congenital malformations in diabetic pregnancies should include both a mid-gestation ultrasound scan and MSAFP measurement. However, routine amniocentesis does not seem to be indicated. Concentrations of AFAFP may be corrected for the observed decrease.

Insulin receptor binding and tyrosine kinase activity in skeletal muscle from normal pregnant women and women with gestational diabetes.

OBJECTIVE: To ascertain whether the decreased glucose tolerance and insulin resistance found in normal and gestational diabetic pregnancy might be associated with changes in insulin receptor function. METHODS: Eight nonpregnant healthy women (nonpregnant controls), eight healthy pregnant women (pregnant controls), and eight women with gestational diabetes were investigated. All were non-obese. Muscle biopsies were obtained from the vastus lateralis muscle, and insulin binding and tyrosine kinase activities in partially purified skeletal muscle insulin receptors were studied. The pregnant controls were investigated in late pregnancy, and the women with gestational diabetes were investigated at the time of diagnosis of gestational diabetes. A further examination was carried out 2 months after delivery. RESULTS: Insulin binding at tracer insulin concentration (60 pmol/L) was diminished in women with gestational diabetes compared to nonpregnant controls (P < .05), whereas normal pregnant women did not differ from the other two groups. Postpartum, no differences in insulin binding were found between the groups. Basal and maximal tyrosine kinase activities toward the exogenous substrate poly(Glu4Tyr1) were the same in nonpregnant controls, pregnant controls, and women with gestational diabetes. Postpartum, no differences in tyrosine kinase activity were found among the groups. Moreover, no significant differences in insulin binding or tyrosine kinase activity were found comparing pregnancy and postpartum values within the groups. CONCLUSION: The insulin resistance found in normal and gestational diabetic pregnancy is not likely to be caused by a defective insulin receptor tyrosine kinase, whereas decreased insulin receptor binding might have some pathogenic importance in gestational diabetes.

Predictive factors for the development of diabetes in women with previous gestational diabetes mellitus.

OBJECTIVES: The purpose of this study was to determine the incidence of diabetes in women with previous dietary-treated gestational diabetes mellitus and to identify predictive factors for development of diabetes. STUDY DESIGN: Two to 11 years post partum, glucose tolerance was investigated in 241 women with previous dietary-treated gestational diabetes mellitus and 57 women without previous gestational diabetes mellitus (control group). RESULTS: Diabetes developed in 42 (17.4%) women with previous gestational diabetes mellitus (3.7% insulin-dependent diabetes mellitus and 13.7% non-insulin-dependent diabetes mellitus). Diabetes did not develop in any of the controls. Predictive factors for diabetes development were fasting glucose level at diagnosis (high glucose, high risk), preterm delivery, and an oral glucose tolerance test result that showed diabetes 2 months post partum. In a subgroup of previous patients with gestational diabetes mellitus in whom plasma insulin was measured during an oral glucose tolerance test in late pregnancy a low insulin response at diagnosis was found to be an independent predictive factor for diabetes development. CONCLUSIONS: Women with previous dietary-treated gestational diabetes mellitus have a considerably increased risk of later having diabetes. Follow-up investigations are therefore important, especially in those women with previous gestational diabetes mellitus in whom the identified predictive factors are present.