Management of third-trimester diabetic pregnancies with the use of continuous subcutaneous insulin infusion therapy: A pilot study

Six women with juvenile-onset diabetes were managed as outpatients during the third trimester of pregnancy with continuous subcutaneous insulin infusion therapy. Twenty-four-hour metabolic profiles for plasma glucose, β-hydroxybutyrate, and triglycerides were monitored prior to, 1 week, 5 weeks, and 10 weeks after initiation of continuous subcutaneous insulin infusion therapy and compared with the metabolic profiles of 10 normal (nondiabetic) pregnant women. Near-normal metabolic profiles were achieved in these patients after 5 weeks of therapy in this pilot study. Patient motivation, compliance, and understanding of their illness were crucial in achieving the therapeutic goals of normoglycemia.     

Evaluation of serum ischemia-modified albumin levels in pregnant women with and without gestational diabetes mellitus

Objective. To investigate serum ischemia-modified albumin (IMA) levels in gestational diabetes mellitus and the effect of treatment with continuous subcutaneous insulin infusion on the biomarker. Methods. The gestational diabetes mellitus women in the second trimester were evaluated before and after the two kinds of treatments with continuous subcutaneous insulin infusion and medical nutrition therapy for 6 weeks. Maternal serum ischemia-modified albumin and metabolic parameters were measured at baseline and at the 6th week. Results.Serum ischemia-modified albumin levels and metabolic parameters were higher in patients with gestational diabetes mellitus at baseline than in controls. Ischemia-modified albumin levels were correlated with plasma glucose (p < 0.05). Variables of glycemic control and ischemia-modified albumin levels were significantly reduced at the 6th week. The effect of insulin treatment was generally better than diet therapy. Linear regression analysis showed that fasting plasma glucose was an independent determinant for IMA levels (β = 0.611, p = 0.035).Fetal outcome was similar except for macrosomia and Apgar score at 5 min. Conclusion.Serum ischemia-modified albumin levels were higher in gestational diabetes mellitus compared to normal pregnancy. Continuous subcutaneous insulin infusion consistently improved metabolic disorder control. Gestational diabetes mellitus women were associated to a higher risk of oxidative stress and pregnancy complications.     

Continuous subcutaneous insulin infusion (CSII) in pregnant diabetic patients

The efficacy of the insulin infusion pump (CSII) in pregnancy was examined in 12 diabetic patients and compared with intermittent insulin therapy (IIT). In patients poorly controlled on IIT constant and rapid equilibrium was achieved with CSII (mean of glucose levels: CSII versus IIT = 84 versus 137 mg/dl; S.D. = 36 versus 63 mg/dl; mean amplitude of glycemic excursion (MAGE) = 65 versus 112 mg/dl. In patients well controlled on IIT, CSII led to a reduction in the variation of glucose excursions (S.D. = 29 versus 36 mg/dl; MAGE = 48 versus 76 mg/dl). CSII generally produced a reduction of 20-37 per cent of daily insulin dose (in three cases there was an increase of dose with the achievement of glycemic control). Furthermore in CSII treated-patients amniotic glucose, insulin and C-peptide concentrations were found to be in the normal range (22.1 +/- 10.1 mg/dl; 5.2 +/- 2.7 microU/ml; 1.25 +/- 0.71 ng/ml, respectively). All infants were born at or near-term, had no macrosomia or neonatal problems. It is concluded that CSII is a highly efficient way to achieve normal glucose levels in pregnancy, not only in type I, but also in type II or gestational diabetes.     

Continuous subcutaneous insulin infusion. Improved blood glucose in pregnant diabetics

The effect of continuous subcutaneous insulin infusion (c.s.i.i.) on the control of blood-glucose concentration and outcome of pregnancy was assessed in two pregnant diabetics (class B and class C White classification) who were poorly controlled with conventional insulin therapy. The insulin pump was carried in a holster and enabled the patients to ambulate freely. The patients were able to refill the syringe, to augment the infusion rate at mealtime and to change the implantation site of the needle weekly, and thus, were able to leave the hospital. Daily glucose profiles were assessed 1-3 times a week, and the infusion rate was readjusted accordingly. Twenty-four hours glucose profiles were obtained from both patients during inpatient conventional insulin regimens, and then, during c.s.i.i. which was maintained for 41 and 145 days, respectively. Mean 24 hours glucose concentrations were reduced from 156 to 113 mg/100 ml, mean fasting glucose from 152 to 106 mg/100 ml, and mean diurnal variation (maximal excursion) from 75 to 65 mg/100 ml. The favourable results achieved with the c.s.i.i. enabled both patients to reach the 18th week of gestation and to deliver healthy non-macrosomic infants, who had uneventful and morbid-free neonatal periods. Since the c.s.i.i. supplies insulin in a more physiological manner than twice daily regimens, better control of blood sugar and body fuel metabolism may be achieved. By extending the therapy to the early stages of pregnancy, or if possible to pre-conceptional period, reduced perinatal mortality and morbidity may be anticipated.     

Insulin secretion and insulin sensitivity in normal pregnancy and gestational diabetes mellitus.

The purpose of this study was to evaluate insulin sensitivity, beta-cell function and islet-cell-directed autoimmunity in pregnant women with normal glucose tolerance and gestational diabetes mellitus (GDM). A total of 21 women with normal glucose tolerance and 21 women with GDM were evaluated at 24-36 weeks' gestation. Insulin resistance and beta-cell function were evaluated using the continuous infusion of glucose with model assessment (CIGMA) method, which aims to give a near-physiological stimulus and to evaluate the endogenous insulin and glucose response. Islet-cell autoantibody was positive in one woman with GDM, and glutamic acid decarboxylase autoantibodies were negative in both groups. The calculated CIGMA insulin resistance (CIGMA IR) was 2.04 +/- 1.74 and 1.08 +/- 1.22 in patients with GDM and in control subjects, respectively (p < 0.05). CIGMA percentage beta-cell values were 64.04 +/- 44.55% and 87.07 +/- 52.77% in patients with GDM and control subjects, respectively (p > 0.05). Decreased insulin sensitivity in late pregnancy was more evident in lean GDM subjects with mild hyperglycemia who did not require insulin therapy, and beta-cell function was partially preserved in this group of patients.     

Continuous subcutaneous insulin therapy during early pregnancy

Intensive metabolic control of diabetes is probably important during formation of the embryo early in pregnancy. The purpose of this study was to determine the efficacy and complications of continuous subcutaneous insulin infusion therapy during the fifth to the tenth week of gestation. Twenty-four insulin-dependent subjects were trained to use blood glucose self-monitoring and the Auto Syringe portable insulin infusion pump (AS6C). Regular insulin was administered as a basal infusion of 18 +/- 8 U/24 hours (+/- SD) (12.2 +/- 3.9 mU . kg-1 . h-1) and as bolus injections of 6 +/- 3 U before meals and 1.2 +/- 1 U before snacks. Reasonable control of fasting (119 +/- 30 mg/dL) and postprandial (133 +/- 34 mg/dL) hyperglycemia was achieved, accompanied by an average of 2.2 +/- 1.5 symptomatic hypoglycemic episodes per week. The frequency of complications with this new therapy declined as the authors gained experience in teaching the system. The persistence of good diabetic control in many of the subjects after they returned to conventional insulin therapy points to the need for a controlled trial of continuous subcutaneous insulin infusion therapy versus intensive conventional therapy in pregnancy.     

Intensive insulin therapy in pregnancy: Strategies for successful implementation in pregestational diabetes mellitus

The role of intensive insulin therapy (IIT) in the reduction of long-term diabetes-related complications is well established. Normal blood glucose level prior to and during pregnancy is critical in reducing both short- and long-term morbidity and mortality in mother and infant. IIT in pregnancy, though occasionally challenging, is necessary to achieve and maintain normal blood glucose level during pregnancy. Current knowledge and recent advances in insulin formulations and delivery systems have improved our ability to achieve glycemic targets in pregnancy while limiting maternal and fetal morbidity. The objective of this review is to discuss contemporary strategies for successful use of IIT in pregnancy.     

Overweight and obese in gestational diabetes: the impact on pregnancy outcome

OBJECTIVE: We sought to investigate the relationship between prepregnancy weight, treatment modality (diet or insulin), level of glycemic control, and pregnancy outcome. STUDY DESIGN: We recruited women with gestational diabetes (GDM) from inner city prenatal clinics. All women were instructed in the use of an intensified management protocol using memory reflectance meters. Outcomes were analyzed according to maternal prepregnancy body mass index (BMI, kg/m 2 ) categories: normal weight (BMI 18.5-24.9), overweight (BMI 25-29.9), and obese (BMI > or =30), and by diet or insulin therapy and glycemic control (mean blood glucose <100 mg/dL = good control). Pregnancy outcome variables included a composite outcome (at least 1 of the following: neonatal metabolic complications, large-for-gestational age or macrosomic infants, NICU admission for >24 hours, and the need for respiratory support) (not including oxygen therapy). In addition to composite outcome, a bivariate analysis was performed for each single variable, including preeclampsia and cesarean section delivery. RESULTS: Four thousand and one women were enrolled. Obese women who achieved targeted levels of glycemic control had comparable pregnancy outcomes to normal weight and overweight women only when they were treated with insulin. Normal weight women treated with diet therapy who achieved targeted levels of glycemic control had good outcomes, but obese women treated with diet therapy who achieved targeted levels of glycemic control, nevertheless, had a 2- to 3-fold higher risk for adverse pregnancy outcome when compared with overweight and normal weight patients with well-controlled GDM. Women with GDM who failed to achieve established levels of glycemic control had significantly higher adverse pregnancy outcomes in all 3 maternal weight groups. CONCLUSION: In obese women with BMI > or =30 with GDM, achievement of targeted levels of glycemic control was associated with enhanced outcome only in women treated with insulin.     

Intensive insulin therapy in pregnancy: strategies for successful implementation in pregestational diabetes mellitus.

The role of intensive insulin therapy (IIT) in the reduction of long-term diabetes-related complications is well established. Normal blood glucose level prior to and during pregnancy is critical in reducing both short- and long-term morbidity and mortality in mother and infant. IIT in pregnancy, though occasionally challenging, is necessary to achieve and maintain normal blood glucose level during pregnancy. Current knowledge and recent advances in insulin formulations and delivery systems have improved our ability to achieve glycemic targets in pregnancy while limiting maternal and fetal morbidity. The objective of this review is to discuss contemporary strategies for successful use of IIT in pregnancy.     

Continuous subcutaneous insulin infusion vs intensive conventional insulin therapy in pregnant diabetic women: a systematic review and metaanalysis of randomized, controlled trials

The objective of the study was to study the effects of continuous subcutaneous insulin infusion (CSII) vs multiple-dose insulin (MDI) therapy on glycemic control and pregnancy outcome in diabetic women. Randomized, controlled trials comparing CSII vs MDI in pregnant diabetic women were included after an electronic database search. Studies were rated for quality independently by 2 reviewers in accordance with the Quality of Reporting of Metaanalyses statement. Summary weighted mean difference and odds ratio were estimated for insulin dose, birthweight, gestational age, mode of delivery, hypoglycemic/ketotic episodes, worsening retinopathy, neonatal hypoglycemia, and rates of intrauterine fetal death. Six randomized clinical trials met the inclusion criteria. Pregnancy outcomes and glycemic control were not significantly different among treatment groups. Higher number of ketoacidotic episodes and diabetic retinopathy found in the CSII group did not reach statistical significance. This systematic review does not show any advantage or disadvantage of using CSII over MDI in pregnant diabetic women. Large multicenter, randomized, controlled trials addressing the quality of life/cost effectiveness are required.     

Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus

OBJECTIVE: This study prospectively evaluated the longitudinal changes in insulin sensitivity, insulin response, and endogenous (primarily hepatic) glucose production and suppression during insulin infusion in women with normal glucose tolerance (control) and gestational diabetes mellitus before and during a planned pregnancy. STUDY DESIGN: Eight control subjects and 7 subjects in whom gestational diabetes mellitus developed were evaluated with an oral glucose tolerance test, an intravenous glucose tolerance test, and hyperinsulinemic-euglycemic clamp with infusion of [6,6 (2)H2 ]glucose before conception and at 12 to 14 and 34 to 36 weeks' gestation. Insulin response was estimated as the area under the curve during the intravenous glucose tolerance test. Basal endogenous glucose production was estimated from isotope tracer dilution during steady state with [6,6 (2)H2 ]glucose and suppression during insulin infusion. Insulin sensitivity to glucose was defined as the glucose infusion rate required to maintain euglycemia during steady-state insulin infusion. Body composition was estimated with hydrodensitometry. Data were analyzed with 2-way analysis of variance with repeated measures for 2 groups. RESULTS: There were increases in first-phase (P =.006) and second-phase (P =. 0001) insulin responses in both groups with advancing gestation, but the increase in second-phase response was significantly greater (P =. 02) in the gestational diabetes mellitus group than in the control group. Basal glucose production increased significantly (P =.0001) with advancing gestation, and there was resistance to suppression during insulin infusion in both groups (P =.0001). There was less suppression of endogenous glucose production however, in the gestational diabetes mellitus group than in the control group (P =. 01). Insulin sensitivity decreased with advancing gestation in both groups (P =.0001), and there was lower insulin sensitivity in the gestational diabetes mellitus group than in the control group (P =. 04). Significant decreases in insulin sensitivity with time (P =. 0001) and between groups (P =.03) remained when the data were adjusted for differences in insulin concentration or residual hepatic glucose production. CONCLUSION: Obese women in whom gestational diabetes mellitus develops have a significant increase in insulin response but decreases in insulin sensitivity and suppression of hepatic glucose production during insulin infusion with advancing gestation with respect to a matched control group. These metabolic abnormalities in glucose metabolism are the hallmarks of type 2 diabetes, for which these women are at increased risk in later life.     

Endocrine pancreatic sensitivity to glucose in women with gestational diabetes

To study whether gestational diabetes is the result of abnormal endocrine pancreatic adaptation to pregnancy, alpha- and beta-cell sensitivity to glucose was determined during pregnancy and post partum in seven women of normal weight who had gestational diabetes. Glucose was infused intravenously in quantities producing similar increases in plasma glucose in pregnancy and post partum, and the plasma glucose curves obtained closely resembled those found during an oral glucose tolerance test. The insulin response to the infusion was 3.5 times greater in pregnancy (P less than .02), whereas glucagon was suppressed similarly in pregnancy and post partum. These findings resemble previous ones in normal women. It is concluded that pancreatic alpha and beta cells adapt similarly to pregnancy in women with gestational diabetes and in normal women.     

Fetal growth in women managed with insulin pump therapy compared to conventional insulin

OBJECTIVE: Fetal hyperinsulinaemia secondary to maternal hyperglycaemia is considered to be the driving force behind excessive fetal growth. We hypothesised that insulin pump therapy (continuous subcutaneous insulin infusion, CSII) would improve maternal glycaemic control and normalise fetal growth parameters. To this end, this study compares maternal glycaemic control and fetal growth of women receiving insulin pump therapy with those receiving conventional insulin therapy. STUDY DESIGN: Prospective non-randomised study of 42 women with pre-existing diabetes attending a joint obstetric diabetic clinic. Each woman was offered the choice of commencing insulin pump therapy or remaining on a conventional insulin regime. Estimated fetal weight and fetal growth velocity were calculated from routinely collected third trimester ultrasound biometry and expressed as standard deviation (Z) scores. RESULTS: Eighteen women commenced insulin pump therapy. There was no difference in pre-conception glycosylated haemoglobin A1c concentrations (HbA1c) between pump and conventional therapy groups (mean HbA1c 7.62 versus 8.01; p=0.49) or third trimester glycaemic control (mean HbA1c 6.63 versus 6.44; p=0.51). Women using pump therapy had similar mean growth velocity Z scores (1.5 versus 1.36; p=0.83), similar mean estimated fetal weight Z scores prior to delivery (2.80 versus 2.16; p=0.16) and similar mean birthweight Z scores (2.09 versus 2.00; p=0.86) compared to women using conventional insulin therapy. CONCLUSION: This small, non-randomised study suggests that the use of insulin pump therapy offers no benefit in terms of normalising fetal growth velocity, fetal size, birthweight or improving maternal glycaemic control compared to conventional insulin therapy.     

Does intensive glycemic control in diabetic pregnancies result in normalization of other metabolic fuels?

Intensive treatment of insulin-dependent diabetes mellitus during pregnancy often normalizes plasma glucose levels. However, it is unclear whether this adversely affects other metabolic fuels that are essential to normal fetal growth and development. Metabolic studies were conducted after the subjects ingested a standardized mixed meal during each trimester in 7 normal and 15 insulin-dependent diabetic pregnant women. The latter were treated with continuous subcutaneous insulin infusion or multiple injections, which were adjusted to achieve strict glucose control throughout pregnancy. Insulin, alanine, branched-chain amino acids, triglycerides, free fatty acids, and ketones were measured every 15 to 30 minutes before a standardized breakfast and for 150 minutes after the breakfast. Patients with insulin-dependent diabetes mellitus were studied while they received their unusual insulin dosages. Fasting glucose levels (87 +/- 7 mg/dl) and glucose levels 150 minutes after the meal (112 +/- 11 mg/dl) were near normal. However, normoglycemia was achieved at the expense of increased plasma insulin levels (area under insulin response curves, p less than 0.01, vs nondiabetic curves). Nevertheless, fasting and post-prandial plasma branched-chain amino acids, alanine, and free fatty acids were similar in both groups. Fasting cholesterol, triglyceride, and ketone levels were also normalized. We conclude that normalization of circulating amino acids and lipids in conjunction with correction of hyperglycemia may contribute to favorable outcomes in infants of intensively treated diabetic mothers.     

Glucose kinetics in nondiabetic and diabetic women during the third trimester of pregnancy

Glucose kinetics were measured with 78% enriched D-[U-13C] glucose by the prime constant infusion technique during the third trimester of pregnancy in nine nondiabetic women, nine insulin-dependent diabetic women, six gestational diabetic women, and five control women (nonpregnant, nondiabetic) after an overnight fast. The patients not dependent on insulin were diagnosed as diabetic by oral glucose tolerance tests with the use of O'Sullivan and Mahan's criteria as modified by Carpenter and Coustan during the third trimester. The turnover studies were repeated post partum (6 weeks to 5 months after delivery) in 14 of the 24 pregnant subjects. All pregnant groups had a progressive fall in plasma glucose concentration during the study, but there was a steady state of plasma glucose concentration during the turnover period. In comparison to the control subjects, both the pregnant nondiabetic and pregnant insulin-dependent diabetic women had significantly higher plasma insulin concentrations throughout the study (p less than 0.05). There were no differences in the glucose turnover rate between any of the pregnant groups (1.7 +/- 0.2 mg . kg-1 min-1 in pregnant nondiabetic women; 1.5 +/- 0.2 mg . kg-1 min-1 in pregnant insulin-dependent diabetic women; and 2.1 +/- 0.4 mg . kg-1 min-1 in gestational diabetic women) and the control group of women (1.8 +/- 0.2 mg . kg-1 min-1) (mean +/- SEM). When the pregnant patients were studied post partum, the glucose turnover rate was similar when referenced to body weight; however, because of a 9.6% to 14.5% fall in weight post partum, the absolute values were higher in the pregnant women. We conclude that, in the basal state after an overnight fast, (1) both nondiabetic and diabetic patients accelerated their glucose turnover rate during pregnancy to provide for increased maternal and fetoplacental metabolic requirements, and (2) in the diabetic subjects the nearly normal plasma glucose and insulin concentrations and other metabolic parameters, as well as the glucose turnover rate, suggested good metabolic control during pregnancy in most of the insulin-dependent and in all of the gestational diabetic patients.     

Pregnancy outcome in patients with insulin-dependent diabetes mellitus with preconceptional diabetic control: a comparative study

Forty-four of 75 pregnant women with juvenile-onset insulin-dependent diabetes, who attended a preconceptional clinic, were seen regularly by a diabetologic team. Glycemic control was obtained by intensified insulin therapy and monitored by blood glucose self-monitoring. When these patients were compared with a group of 31 nonattenders of the preconceptional clinic, in the former normoglycemia and normal hemoglobin A1 values were achieved before conception, whereas in the latter good control was reached by the second trimester. This group had also more maternal complications, such as preeclampsia, and higher cesarean section rates. Congenital anomalies were 9.6% among offspring of nonattenders, while none occurred in those with preconceptional counseling. We confirm the evidence accumulated in the recent literature that congenital malformations in pregnancy complicated by diabetes may be linked to disturbances in maternal metabolism during the period of embryogenesis. Consequently we concur with the recommendation that tight diabetic control is required before the patient attempts to conceive.     

Continuous glucose monitoring and insulin pump therapy for diabetes in pregnancy

Continuous glucose monitoring (CGM) systems and continuous subcutaneous insulin infusion (CSII) systems, or insulin pumps, offer great promise for improved glycemic control during pregnancy. Combined, these two devices could potentially constitute an artificial pancreas, where real-time blood glucose readings are relayed to an insulin pump that uses a personalized algorithm to decide how much insulin is needed by the patient’s body. However, the promise of these two systems have not yet been proven individually or in combination in controlled clinical trials to improve pregnancy outcomes. Such trials are urgently needed before the widespread use of these devices in pregnancy can be justified.     

Spontaneous abortion in patients with insulin-dependent diabetes mellitus: the effect of preconceptional diabetic control

Fifty-nine of 94 pregnant women with juvenile-onset insulin-dependent diabetes who attended a preconceptional clinic were periodically examined by a diabetologic team. Glycemic control was obtained by intensified insulin therapy and monitored by blood glucose self-monitoring. These women were compared with the 35 pregnant women who did not receive preconceptual glycemic control. The initial glucose and maternal hemoglobin A1 values of the latter group experiencing spontaneous abortions were significantly higher (p less than 0.001) when compared with women receiving preconceptional diabetologic counseling whose pregnancies continued beyond 22 weeks' gestation. The frequency of spontaneous abortions among patients not seen before pregnancy was significantly higher (p less than 0.001), in contrast to attending women, whose rate represented the normal rate in the general population. We confirm the evidence accumulated in the recent literature that poor metabolic control around conception and in the early weeks of pregnancy may be the determining factor favoring abortion.     

Benefits, risks, costs, and patient satisfaction associated with insulin pump therapy for the pregnancy complicated by type 1 diabetes mellitus

OBJECTIVE: Glycemic control, perinatal outcome, and health care costs were evaluated among women with type 1 diabetes mellitus who began insulin pump therapy during pregnancy (group 1, n = 24), were treated with multiple insulin injections (group 2, n = 24), or were already using an insulin pump before pregnancy (group 3, n = 12). Patient satisfaction and continuation of pump therapy post partum were assessed. STUDY DESIGN: A retrospective review of maternal and neonatal medical records was performed, and a questionnaire was sent to patients after delivery. Patients in groups 1 and 2 were matched for age, age at onset and duration of diabetes mellitus, White class, and date of delivery. RESULTS: No differences in glycosylated hemoglobin A levels were observed among groups 1, 2 or 3 in the first, second, or third trimester. Patients in group 1 started pump therapy at a mean of 16.8 weeks' gestation, and 17 (70.8%) began therapy as outpatients. No deterioration in glycemic control was noted during the 2- to 4-week period after the start of pump treatment. Among the women in group 1 eight had at least one episode of severe hypoglycemia before starting pump therapy, but only one had such an episode after this treatment was begun. Two episodes of ketoacidosis occurred in group 1, and no episodes occurred in groups 2 and 3. No significant differences in perinatal outcomes or health care costs were observed among groups 1, 2, and 3. After delivery 94. 7% of the women in group 1 continued to use the pump because it provided better glycemic control and a more flexible lifestyle. Postpartum glycosylated hemoglobin A values were 7.2% in group 1 and 9.1% in group 2, a significant difference. CONCLUSIONS: Insulin pump therapy was initiated during pregnancy without a deterioration of glycemic control and was associated with maternal and perinatal outcomes and health care costs comparable to those among women who were already using the pump before pregnancy or who received multiple-dose insulin therapy. Women who began pump therapy in pregnancy were highly likely to continue pump use after delivery and preferred the flexible lifestyle that this treatment allowed.