Insulins and oral hypoglycemic agents in pregnancy

Numerous studies have established a direct relationship between maternal levels of glycemic control and neonatal outcomes for pregnancies complicated by diabetes. The past several years have seen the addition of insulin analogues as well as many new oral agents to the pharmacological armamentarium available to treat diabetes. Insulin analogs (both rapid and long acting) are of potential interest for women with insulin-requiring diabetes because of the improved control reported in non-pregnant individuals. Insulin lispro is the only insulin analog to be systematically studied in pregnancy. At this time, the majority of evidence suggests that insulin lispro does not cross the placenta and does not have adverse maternal or fetal effects during pregnancy in women with diabetes.

For women with gestational diabetes mellitus (GDM) and type 2 diabetes, which are characterized by insulin resistance and relatively decreased insulin secretion, treatment with oral hypoglycemic agents is generating much excitement. Most retrospective studies and the published clinical experience have failed to demonstrate an increased risk of neonatal hypoglycemia and other neonatal morbidities with glyburide or metformin. To date there has been only one randomized controlled trial utilizing glyburide, which found it to be safe and effective in the management of GDM. More intensive investigation regarding the safety and feasibility of oral agents in pregnancies complicated by type 2 diabetes is necessary.     

Insulins and oral hypoglycemic agents in pregnancy.

Numerous studies have established a direct relationship between maternal levels of glycemic control and neonatal outcomes for pregnancies complicated by diabetes. The past several years have seen the addition of insulin analogues as well as many new oral agents to the pharmacological armamentarium available to treat diabetes. Insulin analogs (both rapid and long acting) are of potential interest for women with insulin-requiring diabetes because of the improved control reported in non-pregnant individuals. Insulin lispro is the only insulin analog to be systematically studied in pregnancy. At this time, the majority of evidence suggests that insulin lispro does not cross the placenta and does not have adverse maternal or fetal effects during pregnancy in women with diabetes.For women with gestational diabetes mellitus (GDM) and type 2 diabetes, which are characterized by insulin resistance and relatively decreased insulin secretion, treatment with oral hypoglycemic agents is generating much excitement. Most retrospective studies and the published clinical experience have failed to demonstrate an increased risk of neonatal hypoglycemia and other neonatal morbidities with glyburide or metformin. To date there has been only one randomized controlled trial utilizing glyburide, which found it to be safe and effective in the management of GDM. More intensive investigation regarding the safety and feasibility of oral agents in pregnancies complicated by type 2 diabetes is necessary.     

Insulin glargine versus neutral protamine Hagedorn insulin for treatment of diabetes in pregnancy

We compared maternal and neonatal outcomes in diabetic pregnancies treated with either insulin glargine or neutral protamine Hagedorn (NPH) insulin. We performed a retrospective chart review of diabetic pregnant patients using the Diabetes Care Center of Wake Forest University during the years 2000 to 2005. Outcomes of interest included maternal hemoglobin A1C, average fasting and 2-hour postprandial blood sugars, mode of delivery, birth weight, 5-minute Apgar score < 7, umbilical artery pH < 7.20, incidence of neonatal hypoglycemia, and pregnancy complications. A total of 52 diabetic pregnant patients were included in this study. Twenty-seven women used insulin glargine. A total of 13 women used insulin glargine during the first trimester. Glycemic control was similar in women who used NPH insulin and insulin glargine, as determined by hemoglobin A1C levels and mean blood sugar values. There were no differences in mode of delivery, average birth weight, or neonatal outcomes. Maternal and fetal/neonatal outcomes appear similar in pregnant diabetic women who use either NPH insulin or insulin glargine in combination with a short-acting insulin analogue to achieve adequate glycemic control during pregnancy. Insulin glargine appears to be an effective insulin analogue for use in women whose pregnancies are complicated by diabetes.     

Pregnancy outcome in gestational diabetes.

OBJECTIVE: To assess maternal and neonatal outcomes of gestational diabetes mellitus (GDM) following glycemic screening and diabetic management, with special focus on concurrent GDM and pre-eclampsia. METHODS: A retrospective chart review of 782 women diagnosed with and treated for GDM at a Chinese university teaching hospital. Data on maternal and neonatal outcome, glycemic control, concurrent pre-eclampsia, and diabetic management were collected and analyzed. RESULTS: The incidence of GDM was 3.8%. Of the affected women, 62.9% were managed with diet only and the remainder received insulin treatment. Overall, 80.7% had good glycemic control. Poor glycemic control and concurrent pre-eclampsia correlated with maternal and neonatal complications. CONCLUSION: Aggressive management for tight glycemic control improves maternal and neonatal outcomes in women with GDM.     

The benefit of early treatment without rescreening in women with a history of gestational diabetes

Objective: In this center, women with a history of gestational diabetes (GDM) are treated without rescreening from early pregnancy in any subsequent pregnancies, commencing with a low glycemic diet and insulin if and when indicated. The objective of this study was to see if this practice reduced the incidence of macrosomia compared with the index pregnancy. Method: The analysis was confined to women who required insulin in the subsequent pregnancy. Results: Among 369 women who were prospectively identified with a history of previous GDM, 95 required insulin – the study cohort. Insulin treatment was commenced at an earlier gestation in the subsequent pregnancy. The incidence of macrosomia was significantly less in the subsequent pregnancy in the group of women who required insulin in both pregnancies (p = 0.02). Conclusion: This data suggests early treatment is of benefit to this high-risk group in the reduction of macrosomia.     

Perinatal outcomes in pregnancies complicated by type 1 diabetes mellitus

Abstract

The aim of this study was to explore the risk of perinatal outcomes in pre-gestational type 1 diabetes mellitus (T1DM) compared to gestational diabetes mellitus (GDM) and pregnancy without diabetes and to examine the association of glycemic level of third-trimester gestation with perinatal outcomes in T1DM. We included 69 pre-gestational T1DM, 1398 cases of GDM, and 1304 control pregnancies and collected data regarding demographics, obstetric, and perinatal outcomes from the hospital discharge database. Relative to the pregnancies without diabetes, women with T1DM encountered increasing risk of polyhydramnios, preterm delivery, and cesarean section. These adverse outcomes were also common in GDM, although with relatively lower adjusted ORs. The weights of babies delivered by women with T1DM were more intend to be large for gestational age, as well as to be less than 2.5?kg relative to those without diabetes. Poorly controlled hemoglobin A1c in late pregnancy was significantly associated with an increased risk of preterm birth in T1DM (adjusted odds ratio 2.01, 95%confidence interval 1.1–3.6). Women with T1DM have considerably increased risks of adverse perinatal outcomes, which appear more prevalent than the perinatal outcomes in women with GDM. Thus, a specific routine is required for pregnancy in T1DM to improve the glycemic control and obstetric care.     

The role of adding metformin in insulin-resistant diabetic pregnant women: a randomized controlled trial

Purpose

The aim of the present study is to assess the impact of adding oral metformin to insulin therapy in pregnant women with insulin-resistant diabetes mellitus.

Methods

The current non-inferiority randomized controlled trial was conducted at Ain Shams University Maternity Hospital. The study included pregnant women with gestational or pre-existing diabetes mellitus at gestations between 20 and 34 weeks, who showed insulin resistance (defined as poor glycemic control at a daily dose of ≥1.12 units/kg). Recruited women were randomized into one of two groups: group I, including women who received oral metformin without increasing the insulin dose; and group II, including women who had their insulin dose increased. The primary outcome was maternal glycemic control. Secondary outcomes included maternal bouts of hypoglycemia, need for another hospital admission for uncontrolled diabetes during pregnancy, gestational age at delivery, mode of delivery, birth weight, birth trauma, congenital anomalies, 1- and 5-min Apgar score, neonatal hypoglycemia, need for neonatal intensive care unit (NICU) admission and adverse neonatal outcomes.

Results

A total number of 154 women with diabetes mellitus with pregnancy were approached; of them 90 women were eligible and were randomly allocated and included in the final analysis. The recruited 90 women were randomized into one of two groups: group I (metformin group) (n = 46), including women who received oral metformin in addition to the same initial insulin dose; and group II (control group) (n = 44), including women who had their insulin dose increased according to the standard protocol. The mean age of included women was 29.84 ± 5.37 years (range 20–42 years). The mean gestational age at recruitment was 28.7 ± 3.71 weeks (range 21–34 weeks). Among the 46 women of group I, 17 (36.9 %) women reached proper glycemic control at a daily metformin dose of 1,500 mg, 18 (39.2 %) at a daily dose of 2,000 mg, while 11 (23.9 %) received metformin at a daily dose of 2,000 mg without reaching proper glycemic control and needed raising the dose of insulin dose.

Conclusion

Adding metformin to insulin therapy in women with insulin-resistant diabetes mellitus with pregnancy seems to be effective in proper glycemic control in a considerable proportion of women, along with benefits of reduced hospital stay, reduced frequency of maternal hypoglycemia as well as reduced frequency of neonatal hypoglycemia, NICU admission and neonatal respiratory distress syndrome.     

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.     

妊娠期糖尿病口服降糖药的应用评价

妊娠期糖尿病患者是2型糖尿病的高危人群,两者存在发病机制的关联性和病程的续贯性。治疗原则相同,通过饮食、运动和药物治疗控制血糖。妊娠患者在选择治疗药物时,应考虑到对胎儿的影响。传统观点视胰岛素为治疗妊娠期糖尿病的唯一选择,口服降糖药可透过胎盘致胎儿低血糖、畸形等且远期影响不明确,所以其临床应用受到限制。妊娠期口服降糖药的动物实验和临床研究显示,二甲双胍、格列本脲及阿卡波糖未发现致畸作用。目前降糖药治疗妊娠期糖尿病还处于不成熟阶段,评价其治疗价值仍需大量临床资料积累和前瞻性研究。     

妊娠期糖尿病口服降糖药的应用评价

妊娠期糖尿病患者是2型糖尿病的高危人群,两者存在发病机制的关联性和病程的续贯性。治疗原则相同,通过饮食、运动和药物治疗控制血糖。妊娠患者在选择治疗药物时,应考虑到对胎儿的影响。传统观点视胰岛素为治疗妊娠期糖尿病的唯一选择,口服降糖药可透过胎盘致胎儿低血糖、畸形等且远期影响不明确,所以其临床应用受到限制。妊娠期口服降糖药的动物实验和临床研究显示,二甲双胍、格列本脲及阿卡波糖未发现致畸作用。目前降糖药治疗妊娠期糖尿病还处于不成熟阶段,评价其治疗价值仍需大量临床资料积累和前瞻性研究。     

The postprandial glucose profile in the diabetic pregnancy

OBJECTIVE: A controversy exists regarding the time to monitor blood glucose in the diabetic pregnancy (60 or 120 minutes after meals). Using a novel approach that provides continuous measurement of blood glucose, we sought to determine postprandial glucose profile in the diabetic pregnancy. STUDY DESIGN: Subjects were connected to a continuous glucose monitoring system for 72 consecutive hours. A continuous glucose monitoring system measures the interstitial glucose levels in subcutaneous tissue every 5 minutes. Women were instructed to record the time of each meal during the study period. For each meal, the first 240 minutes were analyzed. RESULTS: Sixty-five women participated in the study: 26 women were treated by diet alone; 19 women received insulin therapy, and 20 women had type 1 diabetes mellitus. The time interval from meal to peak postprandial glucose levels was similar in all the evaluated types of diabetic pregnancies and in good and poor control insulin-treated patients with gestational diabetes mellitus (approximately 90 minutes). Failure to return to preprandial glucose values within a 3-hour observation period was identified in approximately 50% of the patients. A similar postprandial glucose peak time was obtained for breakfast, lunch, and dinner in all study groups. Postprandial hypoglycemia events were noted in approximately 10% of the meals and occurred about 160 minutes after mealtime. CONCLUSION: The time interval for postprandial glucose peak in diabetic pregnancies is approximately 90 minutes after meals throughout the day and is not affected by the level of glycemic control. This information should be considered in the treatment of diabetes mellitus in pregnancy.     

Glyburide in gestational diabetes – prediction of treatment failure

Objective.?To identify factors predicting failure of glyburide treatment in women with gestational diabetes mellitus (GDM).

Methods.?A retrospective study of all women with GDM that were treated with glyburide in a single tertiary referral center. Patients were switched from glyburide to insulin if they failed to achieve glycemic goals, and were then classified as glyburide failure.

Results.?Overall, 124 women with GDM treated with glyburide were included in the study, of which 31 (25%) failed to achieve glycemic control. Women in the failure group were characterized by a higher weight gain during pregnancy, higher rates of GDM on previous pregnancies, and a glucose challenge test (GCT) result. On multivariate logistic regression analysis, a GCT value of >200?mg/dl (OR=7.1, 95% CI 2.8–27.6) and weight gain ≥12?kg (OR=3.9, 95% CI 1.2–13.0) were the only significant and independent predictors of glyburide failure. Most women who were successfully treated with glyburide required a daily dose of 5?mg or less and the time required to achieve glycemic control in these cases was 12.4±4.9 days (range 5–24 days). Of the women who failed to achieve glycemic control with gluburide, 26/31 were switched to insulin, of them only 12 (46%) achieved desired level of glycemic control.

Conclusion.?Most women with GDM achieved desired level of glycemic control under glyburide treatment.     

New technologies for the management of pregestational diabetes mellitus

Purpose of the Review: The purpose of this review is to understand new modalities available to treat and manage type 1 and type 2 diabetes during pregnancy. Recent Findings: The use of new insulin analogs and oral agents, as well as new technologies to deliver insulin and monitor glucose during pregnancy remains controversial. This review will outline the advantages and disadvantages, as well as the safety profiles of these new medications and therapeutic options. Summary: There are many effective treatments for diabetes during pregnancy. New insulin analogs seem to be safe to use in pregnancy and offer the potential for better glycemic control compared with older agents. Oral hypoglycemic medications also seem to be safe and may be an option for a select group of pregnant patients with type 2 diabetes. Insulin pumps and continuous glucose monitoring systems may be beneficial in certain patients, but adequate data are not yet available in terms of outcomes and cost-effectiveness to support widespread use. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After participating in this CME activity, physicians should be better able to revise glycemic goals for pregnant patients with pregestational diabetes to be in line with our current understanding of glycemic profiles in normal pregnant women. Use new insulin analogs to treat pregnant women with abnormalities in glucose homeostasis and choose which patients will benefit from advanced technologies for diabetes management, such as insulin pumps and continuous glucose monitoring systems.     

New strategies for glucose control in patients with type 1 and type 2 diabetes mellitus in pregnancy

Over the past 5 decades, perinatal outcome in pregnancies complicated by diabetes mellitus has improved dramatically due in large part to better maternal glycemic control. Self-blood glucose monitoring in combination with flexible or intensive insulin treatment including the use of newer insulin analogs and insulin pump therapy has dramatically improved glucose control in most pregnancies complicated by diabetes. In developing an insulin regimen, careful attention must be paid to both basal and prandial insulin needs. Every effort must be made to avoid hypoglycemia and prevent ketoacidosis. A team approach including the patient, diabetes nurse educator, nutritionist, and social worker is ideal.     

Predictive value of early pregnancy glycohemoglobin in the insulin-treated diabetic patient

The influence of early pregnancy glycemic control as measured by hemoglobin A1c concentration and the incidence of congenital anomalies and spontaneous abortions were evaluated in women presenting for prenatal care with insulin-treated diabetes in a population whose glycemic control was poor. Thirty-one abnormal outcomes were seen in 83 pregnancies (37%). There were 22 spontaneous abortions and nine major congenital anomalies. No woman with an early pregnancy hemoglobin A1C value less than 9.5% had an infant with a congenital anomaly and a single woman experienced a spontaneous abortion (4%). Conversely, in women with an early pregnancy hemoglobin A1C value greater than or equal to 9.5%, congenital anomalies occurred in 24% and spontaneous abortion in 35%. Outcomes of pregnancies in type 1 and type 11 diabetic women were comparable. A strong statistical relationship between hemoglobin A1C and adverse pregnancy outcomes was demonstrated. These results strongly suggest that poor glycemic control during early pregnancy adversely influences pregnancy outcomes; the greater the degree of poor control, the greater the impact on pregnancy outcome. The data further justify the need for preconceptional control in diabetic woman and for careful evaluation of the fetus during pregnancy in the woman with insulin-treated diabetes.     

The effect of maternal obesity on pregnancy outcomes in women with gestational diabetes

Objective.?To examine the impact of maternal obesity on maternal and neonatal outcomes in pregnancies complicated with gestational diabetes mellitus (GDM).

Methods.?Women with singleton pregnancies and GDM enrolled in an outpatient GDM education, surveillance and management program were identified. Maternal and neonatal pregnancy outcomes were compared for obese (pre-pregnancy BMI?≥?30?kg/m²) and non-obese (pre-pregnancy BMI?<?30?kg/m²) women and for women across five increasing pre-pregnancy BMI categories.

Results.?A total of 3798 patients were identified. Maternal obesity was significantly associated with the need for oral hypoglycemic agents or insulin, development of pregnancy-related hypertension, interventional delivery, and cesarean delivery. Adverse neonatal outcomes were also significantly increased including stillbirth, macrosomia, shoulder dystocia, need for NICU admission, hypoglycemia, and jaundice. When looking across five increasing BMI categories, increasing BMI was significantly associated with the same adverse maternal and neonatal outcomes.

Conclusion.?In women with GDM, increasing maternal BMI is significantly associated with worse maternal and neonatal outcomes.     

Diabetic pregnancy outcomes in mothers treated with basal insulin lispro protamine suspension or NPH insulin: a multicenter retrospective Italian study

Objective: The aim of this study was to study the efficacy and safety of long-acting insulin analog insulin lispro protamine suspension (ILPS) in diabetic pregnant women.

Methods: In a multicenter observational retrospective study, we evaluated pregnancy outcome in 119 women affected by type 1 diabetes and 814 with gestational diabetes (GDM) treated during pregnancy with ILPS, compared with a control group treated with neutral protamine hagedorn (NPH) insulin.

Results: Among type 1 diabetic patients, fasting blood glucose at the end of pregnancy was significantly lower in ILPS-treated than in NPH-treated patients. HbA1c levels across pregnancy did not differ between groups. Caesarean section and preterm delivery rates were significantly lower in the ILPS-women. Fetal outcomes were similar in the ILPS and NPH groups. Among GDM women, fasting blood glucose at the end of pregnancy was significantly lower in ILPS-treated than in NPH-treated patients. Duration of gestation was significantly longer, caesarian section and preterm delivery rates were lower in the ILPS-treated group. In addition, there were significantly fewer babies with an excessive ponderal index or neonatal hypoglycemic episodes in the ILPS group than in the NPH group.

Conclusions: Association of ILPS with rapid-acting analogs in pregnancy is safe in terms of maternal and fetal outcomes.     

125I insulin receptor binding characteristics on umbilical cord blood erythrocytes from normal and diabetic pregnancies

Umbilical cord blood erythrocyte insulin receptor characteristics of 13 normal and 14 diabetic pregnancies were evaluated to elucidate the effect of maternal diabetes on fetal insulin binding. Specific insulin binding to erythrocytes was similar in the two populations. However, in comparison to infants of nondiabetic women, infants of diabetic mothers exhibited a fourfold decrease in receptor affinity and a fourfold increased number of receptor sites in spite of significant hyperinsulinemia. The in utero infant of a diabetic mother therefore functions with a comparatively low affinity/high capacity insulin binding system that allows it to maintain normal insulin sensitivity in the presence of hyperinsulinemia. This altered, but balanced, mechanism may play an important role in glycemic homeostasis in utero and in the development of neonatal hypoglycemia.     

Insulin secretion at the diagnosis of gestational diabetes is lower in multiparas than in primiparas

Gestational diabetes mellitus (GDM) has heterogeneous ethiopathogenesis, pathophysiology and clinical features. OBJECTIVES: The aim of the study was to evaluate some of anthropometric parameters, clinical features and indices of insulin resistance and beta cell function in GDM women in first pregnancy and in GDM women in third and following pregnancies. MATERIAL AND METHODS: 877 GDM women, aged 18-48 years were studied. Both groups were compared according to age, BMI before pregnancy, week of GDM diagnosis, weight gain during pregnancy, fasting blood glucose, fasting serum insulin level, HbA1c, insulin resistance and beta-cell function indices. All parameters except BMI were evaluated at GDM diagnosis. RESULTS: Multiparas were older, with higher BMI and lower beta-cell function indices. CONCLUSION: At the moment of GDM diagnosis, insulin secretion evaluated by HOMA indices are lower in multiparas in comparison to primaparas.     

孕前糖尿病合并妊娠临床管理新进展

孕前糖尿病合并妊娠母儿不良结局增加。孕前糖尿病孕妇计划妊娠是避免和减少胎儿先天畸形等的重要一步。推荐的糖化血红蛋白控制目标孕前为<6.5%,孕期为<6.0%。糖尿病合并症的筛查及管理至关重要,血压控制目标应更谨慎,尤其是有糖尿病肾脏疾病者。对于1型糖尿病患者,孕期动态血糖监测有助于改善血糖控制水平。胰岛素是孕期糖尿病患者的一线治疗方案。优化血糖控制和药物治疗方案,并密切关注并发症,能够降低孕前糖尿病合并妊娠的母儿不良结局风险,并确保孕前、妊娠期间和产后的糖尿病管理质量。