Insulin therapy in patients with GDM A Amouzegar

Insulin therapy in patients with GDM A. Amouzegar MD Research Institute for Endocrine Sciences

Agenda • • Definition and prevalence Who should be screened Comparison of diagnostic classification Insulin therapy

Definition and prevalence • Gestational diabetes mellitus is defined as any degree of glucose intolerance with onset or first recognition during pregnancy • Approximately 7% of all pregnancies are complicated by GDM, resulting in more than 200, 000 cases annually • The prevalence may range from 1 to 14% of all pregnancies, depending on the population studied and the diagnostic tests employed • American Diabetes Association. Clinical practice recommendations 2001: gestational diabetes mellitus. Diabetes Care 2001; 24: Suppl 1: S 77 -S 79.

Detection and diagnosis • Risk assessment for GDM should be undertaken at the first prenatal visit • Women with clinical characteristics consistent with a high risk of GDM (marked obesity personal history of GDM, glycosuria, or a strong family history of diabetes) should undergo glucose testing as, soon as feasible

Cont • If they are found not to have GDM at that initial screening, they should be retested between 24 and 28 weeks of gestation • Low-risk status requires no glucose testing, but this category is limited to those women meeting all of the following characteristics: • Age 25 years, Weight normal before pregnancy Member of an ethnic group with a low prevalence of GDM, No known diabetes in first-degree relatives, No history of abnormal glucose tolerance, no history of poor obstetric outcome

• A fasting plasma glucose level 126 mg/dl or a casual plasma glucose 200 mg/dl meets the threshold for the diagnosis of diabetes, if confirmed on a subsequent day

Two-step approach: • Perform an initial screening by measuring the plasma or serum glucose concentration 1 h after a 50 -g oral glucose load (GCT)and perform a diagnostic OGTT on that subset of women exceeding the glucose threshold value on the GCT • A glucose threshold value 140 mg/dl identifies approximately 80% of women with GDM, and the yield is further increased to 90% by using a cutoff of 130 mg/dl

Diagnosis • With either approach, the diagnosis of GDM is based on an OGTT • Diagnostic criteria for the 100 -g OGTT are derived from the original work of O’Sullivan and Mahan, modified by Carpenter and Coustan

Diagnosis of GDM with a 100 -g oral glucose load Fasting 95 mg/dl 1 -h 180 mg/dl 2 -h 155 mg/dl 3 -h 140 mg/dl

The study was planned to clarify the risks of adverse outcomes associated with various degrees of maternal glucose intolerance less severe than that in overt diabetes mellitus

• METHODS: total of 25, 505 pregnant women at 15 centers in nine countries underwent 75 -g OGTT at 24 to 32 w of gestation • Primary outcomes were birth weight above the 90 th percentile for gestational age, primary cesarean delivery, clinically diagnosed neonatal hypoglycemia and cord-blood serum C-peptide level above the 90 th percentile • Secondary outcomes were delivery before 37 weeks of gestation, shoulder dystocia or birth injury, need for intensive neonatal care, hyperbilirubinemia, and preeclampsia

Frequency of Primary Outcomes across the Glucose Categories Hyperglycemia and Adverse Pregnancy Outcomes NEJM 2008

Adjusted Odds Ratios for Associations between Maternal Glucose as a Categorical Variable and Primary Outcomes*

Adjusted Odds Ratios for Associations between Maternal Glycemia as a Continuous Variable and Primary and Secondary Perinatal Outcomes. * Among the primary outcomes, odds ratios for an increase in the glucose level by 1 SD were highest for birth weight greater than the 90 th percentile (range, 1. 38 to 1. 46) and cord-blood serum C-peptide level above the 90 th percentile (range, 1. 37 to 1. 55)

Conclusion: • The data presented here show associations between increasing levels of fasting, 1 -h, and 2 -h plasma glucose obtained on OGTT and birth weight above the 90 th percentile and cord blood serum C-peptide level above the 90 th percentile, with weaker associations between glucose levels and primary cesarean delivery and clinical neonatal hypoglycemia • We also found positive associations between increasing plasma glucose levels and each of the five secondary outcomes examined

• These results have led to careful reconsideration of the diagnostic criteria for GDM • After deliberations in 2008– 2009, the International Association of Diabetes and Pregnancy Study Groups (IADPSG), an international consensus group with representatives from multiple obstetrical and diabetes organizations, including ADA, developed revised recommendations for diagnosing GDM

• The group recommended that all women not known to have diabetes undergo a 75 -g OGTT at 24– 28 weeks of gestation

Screening for and diagnosis of GDM • The OGTT should be performed in the morning after an overnight fast of at least 8 h. • The diagnosis of GDM is made when any of the following plasma glucose values are exceeded: • Fasting 92 mg/dl • 1 h 180 mg/dl • 2 h 153 mg/dl

Questions have been raised regarding the • benefits of treating “mild” gestational diabetes mellitus

Study conducted to assess whether the treatment of gestational diabetes would reduce perinatal complications and to assess the effects of treatment on maternal outcome, mood, and quality of life

• Methods: We randomly assigned women between 24 and 34 weeks’ gestation who had gestational diabetes to receive dietary advice, blood glucose monitoring, and insulin therapy as needed (the intervention group) or routine care • Primary outcomes among the infants were a composite measure of serious perinatal complications • (defined as one or more of the following: death, shoulder dystocia, bone fracture, and nerve palsy), admission to the neonatal nursery, and jaundice requiring phototherapy

Primary Clinical Outcomes among the Infants and Their Mothers. * The rate of serious perinatal outcomes among the infants (defined by one or more of the following: death, shoulder dystocia, bone fracture, and nerve palsy) was significantly lower in the intervention group than the routine-care group NNT=34

Secondary Outcomes among the Infants. *

Secondary Clinical Outcomes among the Women. *

Conclusion: • Results indicate that treatment of GDM in the form of dietary advice, blood glucose monitoring, and insulin therapy as required for glycemic control reduces the rate of serious perinatal complications, without increasing the rate of cesarean delivery

The present randomized trial was performed to determine whether treatment of women with mild gestational diabetes mellitus reduces perinatal and obstetrical complications

• METHODS: total of 25, 505 pregnant women at 15 centers in nine countries underwent 75 -g OGTT at 24 to 32 w of gestation • Primary outcomes were birth weight above the 90 th percentile for gestational age, primary cesarean delivery, clinically diagnosed neonatal hypoglycemia and cord-blood serum C-peptide level above the 90 th percentile • Secondary outcomes were delivery before 37 weeks of gestation, shoulder dystocia or birth injury, need for intensive neonatal care, hyperbilirubinemia, and preeclampsia

Primary Perinatal Outcome. * No significant difference between the treatment group and the control group in the frequency of the composite primary perinatal outcome (32. 4% and 37. 0%, respectively; relative risk, 0. 87; 97% confidence interval [CI], 0. 72 to 1. 07; P = 0. 14 There were no perinatal deaths in either group. The individual rates of neonatal hypoglycemia, hyperbilirubinemia, birth trauma, and elevated cord-blood C-peptide level did not differ significantly between the two groups

Secondary Neonatal Outcomes. * The mean birth weight and neonatal fat mass, as well as the frequency of large-for gestational age infants and of infants with a birth weight of 4000 g or greater, were significantly reduced in thentreatment group as compared with the control group In contrast, the frequency of small-for-gestational age infants and the frequency of admission to the neonatal intensive care unit did not differ significantly between the groups

Maternal Outcomes The rates of labor induction were similar between the treatment and control groups; however, cesarean delivery was significantly less common among women in the treatment group than among women in the control group (26. 9% vs. 33. 8%, P = 0. 02)

Conclusion • This randomized trial showed that treatment of mild GDM did not reduce the frequency of the composite primary perinatal outcome, it did lower the risks of fetal overgrowth, shoulder dystocia, cesarean delivery, and preeclampsia

Glucose target • We suggest insulin administration if blood glucose concentrations reach the values below on two or more occasions within a two-week interval despite dietary therapy • Fasting blood glucose concentration ≥ 90 mg/d. L • One-hour postprandial blood glucose concentration ≥ 120 mg/d. L • Jovanovic L, Pettitt DJ. Treatment with insulin and its analogs in pregnancies complicated by diabetes. Diabetes Care 2007; 30 Suppl 2: S 220

• The target maternal capillary glucose concentrations recommended by the Fifth International Workshop Conference on GDM are • Preprandial glucose concentration ≤ 95 mg/d. L • One hour postprandial glucose concentration ≤ 149 mg/d. L) OR Two hour postprandial glucose concentration ≤ 120 mg/d. L • American Diabetes Association. Standards of medical care in diabetes--2009. Diabetes Care 2009; 32 Suppl 1: S 13

• The American College of Obstetricians and Gynecologists suggest administration of insulin to reduce the risk of macrosomia when • Fasting glucose concentration ≥ 95 mg/d. L or 1 h postprandial glucose >130 to 140 mg/d. L or 2 h-postprandial blood concentration ≥ 120 mg/d. L

Insulin therapy • The dose of insulin varies in different populations because of varied rates of obesity, ethnic characteristics, and other demographic criteria, but the majority of studies have reported a total insulin dose ranging from 0. 7 to 2 units per kilogram (present pregnant weight) to achieve glucose control

• If insulin is required because the fasting blood glucose concentration is high, an intermediate -acting insulin, such as NPH insulin, is given before bedtime • We suggest an initial dose of 0. 2 unit/kg body weight

• If postprandial blood glucose concentrations are high, we suggest insulin aspart or insulin lispro before meals at a dose calculated to be 1. 5 units per 10 grams carbohydrate in the breakfast meal and 1 unit per 10 grams carbohydrate in the lunch and dinner meals • Jovanovic L, Pettitt DJ. Treatment with insulin and its analogs in pregnancies complicated by diabetes. Diabetes Care 2007; 30 Suppl 2: S 220

• If both preprandial and postprandial blood glucose concentrations are high or if the woman's postprandial glucose levels can only be blunted if starvation ketosis occurs, then we suggest initiating a six injection per day regimen • We give a total dose of 0. 7 unit/kg up to week 12, 0. 8 unit/kg for weeks 13 to 26, 0. 9 unit/kg for weeks 26 to 36, and 1. 0 unit/kg for weeks 36 to term. • In a severely obese woman, the initial doses of insulin may need to be increased to 1. 5 to 2. 0 units/kg to overcome the combined insulin resistance of pregnancy and obesity • Jovanovic L, Pettitt DJ. Treatment with insulin and its analogs in pregnancies complicated by diabetes. Diabetes Care 2007; 30 Suppl 2: S 220

• The insulin is divided according to the following schedule: 50 % as NPH insulin (given in three equal doses before breakfast, before lunch and before dinner) and 50 %as three preprandial rapid-acting insulin injections • This regimen improved glycemic control and perinatal outcome compared to a twice-daily regimen • Jovanovic L, Pettitt DJ. Treatment with insulin and its analogs in pregnancies complicated by diabetes. Diabetes Care 2007; 30 Suppl 2: S 220.

Type of insulin • The three rapid acting insulin analogs (lispro, aspart, glulisine) are comparable in immunogenicity to human Regular insulin, but only lispro and aspart have been investigated in pregnancy and shown to have acceptable safety profiles, minimal transfer across the placenta, and no evidence of teratogenesis • . Jovanovic L, Pettitt DJ. Treatment with insulin and its analogs in pregnancies complicated by diabetes. Diabetes Care 2007; 30 Suppl 2: S 220.

• Neonatal outcomes are similar to those of women treated with regular insulin. Evid Rep Technol Assess (Full Rep). 2008 These two insulin analogs both improve postprandial excursions compared to human Regular insulin and are associated with lower risk of delayed postprandial hypoglycemia

• Long-acting insulin analogs (insulin glargine, insulin detemir) have not been studied extensively in pregnancy, however, a multinational trial on the safety and efficacy of insulin detemir for the treatment of type 1 diabetic women is almost complete. Based on available data, we prefer use of human NPH insulin as part of a multiple injection regimen in pregnant women. Jovanovic L, Pettitt DJ. Treatment with insulin and its analogs in pregnancies complicated by diabetes. Diabetes Care 2007; 30 Suppl 2: S 220. • There are good data supporting the safety and effectiveness of NPH in pregnancy and doses can be adjusted frequently and quickly in response to changing requirements in pregnant women

In Summary • Risk assessment for GDM should be undertaken at the first prenatal visit • There are continuous associations of maternal glucose levels below those diagnostic of diabetes with increased adverse pregnancy outcomes • Treatment of women with mild gestational diabetes mellitus reduces perinatal and obstetrical complications

cont • The target preprandial glucose concentration ≤ 95 mg/d. L and 2 hpostprandial glucose concentration ≤ 120 mg/d. L • An effective treatment regimen consists of dietary therapy, self blood glucose monitoring, and the administration of insulin if target blood glucose values are not met with diet alone

NUTRITIONAL THERAPY • All patients with GDM should receive nutritional counseling by a registered dietitian (when possible) upon diagnosis and be placed on an appropriate diet • The major components to consider when creating a nutritional plan for women with GDM are caloric allotment, carbohydrate intake, and calorie distribution

Calorie allotment • Is based upon ideal body weight and calculated based on current weight of the pregnant woman • The suggested caloric intake is approximately • 30 kcal /kg current weight /d in who has BMI 22 to 25 • 24 kcal per kg current weight / day in overweight pregnant women (BMI 26 to 29) • 12 to 15 kcal per kg current weight / day for obese pregnant women (BMI >30) • 40 kcal per kg current weight per day in pregnant women who are less than BMI 22

• Carbohydrate intake is restricted to 33 to 40 percent of calories, with the remainder divided between protein (about 20 percent) and fat (about 40 percent) • With this calorie distribution, 75 to 80 percent of women with GDM will achieve normoglycemia