US Pharm. 2007;32(10)(Diabetes suppl):17-20.

Gestational diabetes mellitus (GDM) is defined as onset or first recognition of carbohydrate intolerance during pregnancy; 1-3 this definition does not encompass women who are known to have diabetes prior to conception. Approximately 2% to 7% of all pregnancies are complicated by GDM, although the prevalence may be as high as 15% depending upon the population evaluated.1,2,4 Ethnic groups at greater risk for GDM include populations with an inherently higher rate of type 2 diabetes mellitus, such as African Americans, Hispanics, Native Americans, and those of South Asian, East Asian, or Pacific Islander descent.2,3,5 Unrecognized or inappropriately treated GDM can result in serious consequences, including fetal macrosomia and shoulder dystocia, neonatal hypoglycemia, hyperbilirubinemia and hypocalcemia, and an increased incidence of type 2 diabetes in the mother later in life.1,6 Appropriate identification and management of GDM is crucial to ensuring optimal outcomes for both the mother and neonate.

The full spectrum of metabolic abnormalities that contribute to hyperglycemia in GDM has not been fully elucidated. In general, human pregnancy is associated with insulin resistance; insulin sensitivity begins to decline in mid-pregnancy, progressively diminishing throughout the latter half of pregnancy.7,8 Insulin resistance in pregnancy has been attributed to a number of factors, including effects of human placental lactogen, human placental growth hormone, progesterone, prolactin, and cortisol.9,10 Recently, adipokines (proteins synthesized and secreted by adipocytes) such as leptin, tumor necrosis factor alpha, adiponectin, and resistin have also been implicated.8-10 Regardless of the cause, insulin resistance in pregnancy serves to decrease glucose utilization by the mother and facilitate the provision of energy substrate for the fetus.9,10 In normal pregnancy, insulin secretion may increase by as much as 200% to 250% to counteract the increased insulin resistance seen in late gestation.8 Insulin secretion in GDM is insufficient to offset the increased insulin resistance, and hy­perglycemia results.

In addition to impaired compensatory secretion of insulin, a number of other proposed mechanisms may play a role in GDM. Adiponectin is an endogenous insulin–sensitizing hormone that decreases hepatic glucose production and stimulates glucose uptake in skeletal muscle.8 Adiponectin levels are reduced in women with GDM, as compared to those without it.7,8 Additionally, glucose uptake in skeletal muscle of patients with GDM may be impaired due to defective insulin receptor signaling. Insulin resistance may also occur in adipose tissue due to downregulation of GLUT4, a glucose transport protein responsible for insulin-mediated glucose disposal. GLUT4 becomes downregulated in adipocytes of pregnant women, but the downregulation is more pronounced in women with GDM. 8 Further study is needed to fully characterize the scope of metabolic defects seen in GDM.

Screening and Diagnosis
Women who are severely obese or have a history of GDM, a strong family history of type 2 diabetes, impaired glucose tolerance, glucosuria, or a previous delivery of a large-for-gestation age infant are considered to be at high risk for GDM.1,11 After pregnancy is confirmed, individuals with these risk factors should be screened for GDM as soon as possible. If the initial screening is negative, follow-up testing should be performed between 24 and 28 weeks' gestation. Testing should also occur at 24 to 28 weeks' gestation for women at average risk for GDM. Women at low risk for GDM include those who meet all of the following criteria: age younger than 25 years, normal prepregnancy weight, normal weight at birth, ethnicity with a low prevalence of GDM, no family history of diabetes in first-degree relatives, no history of glucose intolerance, and no history of poor obstetric outcome.1,2,11 The benefit of screening for GDM in low-risk women is controversial.

Recommended screening for GDM consists of administration of a 50-g oral glucose load, followed by measurement of plasma glucose one hour later.1,2,12 A glucose threshold value of more than 140 mg/dL identifies approximately 80% of individuals with GDM, and a threshold of greater than 130 mg/dL increases the sensitivity to approximately 90%. According to the American Diabetes Association, use of either threshold for the screening test is acceptable. 1,2,13 Women with one-hour glucose values exceeding the screening test threshold are candidates for a diagnostic oral glucose tolerance test (OGTT). The OGTT involves administration of a 100-g glucose load and measurement of fasting plasma glucose and glucose levels at one, two, and three hours post–glucose ingestion.1-3,12 Specific diagnostic criteria can be found in Table 1. Although not as well validated as the 100-g OGTT, a 75-g OGTT with fasting, one-hour, and two-hour glucose measurements is an alternative diagnostic test.

Therapeutic interventions available for the treatment of GDM include medical nutrition therapy and pharmacologic therapy. Potential pharmacologic options include insulin and glyburide. Metformin and rosiglitazone have both been shown to cross the placenta, and use of these agents in GDM is not recommended until further information on teratogenic potential and risk/benefit ratio in pregnancy can be ascertained.14-16 Initial studies with acarbose, an alpha-glucosidase inhibitor, have shown promise in the treatment of GDM, but limited data exist. Although acarbose exhibits minimal systemic absorption, the transplacental passage of this medication has not been thoroughly investigated.11,16 The adverse effect of gastrointestinal discomfort in the mother may limit the utility of acarbose in the treatment of GDM. Safety and efficacy of other agents used for diabetes, such as incretin mimetics, synthetic amylin analogs, meglitinides, glucagon-like peptide-1 agonists, and the dipeptidyl peptidase-4 inhibitors, have not been established in GDM. Regardless of the chosen mode of therapy, the ultimate goal is achieving glycemic control to prevent perinatal and maternal complications. Currently, no consensus exists regarding glycemic goals in GDM. Controlled trials are needed to establish optimal target ranges for glucose.

Medical Nutrition Therapy: Medical nutrition therapy (MNT) is the cornerstone of therapy for GDM, and the majority of women can be managed with MNT alone.1,17 The primary goal of MNT is to achieve adequate glycemic control while maintaining sufficient nutritional intake to support a healthy pregnancy. Patients with GDM have individualized requirements for MNT, depending on prepregnancy weight and micronutrient needs.11,17 As such, MNT is best managed by a registered dietitian or other health care practitioner skilled in the area of GDM. Success of MNT is measured by frequent monitoring of glucose levels and assessment of weight gain throughout the pregnancy. Weight gain should be appropriate for the stage of pregnancy, but should not be excessive.

In general, patients should limit carbohydrates to 35% to 40% of total calories and should distribute carbohydrate intake over three meals and two to four snacks per day. 1,14,18,19 In addition to the quantity of carbohydrates in the diet, the type of carbohydrate may also be important. Eating carbohydrates with a low glycemic index has been shown to lower postprandial glucose levels in nonpregnant patients with diabetes. However, to date, no studies have investigated the effects of glycemic index in women with GDM.17 Physical activity of 30 minutes per day is recommended as an adjunct to MNT in women with GDM.11,17 Women should closely monitor fetal activity and glucose levels pre- and post-exercise.

Insulin: Women who do not achieve glycemic control from MNT alone should be placed on insulin therapy.19 Recommendations for when to initiate insulin are provided in Table 2. Insulin is classified into four categories: rapid-acting, short-acting, intermediate-acting, and long-acting. Rapid-acting insulins are most appropriate for targeting postprandial glucose levels, and a basal-bolus regimen is recommended for patients with both elevated fasting and postprandial glucose.20 The pharmacokinetic properties of the various insulin preparations are found in Table 3.21-23

Of the insulin preparations, human regular insulin and human neutral protamine Hagedorn (NPH) insulin have been the most extensively studied in pregnancy. When compared to human regular insulin, the rapid-acting analogs lispro and aspart have demonstrated comparable safety and efficacy in the management of GDM.11,20 The two rapid-acting analogs may provide better postprandial glycemic control and may be associated with fewer hypoglycemic episodes. No data are available regarding the use of the rapid-acting analog glulisine in pregnancy. A few case reports describe the use of long-acting insulin glargine during pregnancy in women with type 1 diabetes; however, no results of randomized, controlled trials examining the use of insulin glargine in pregnancy are available.11,14,20,23 Likewise, controlled studies of the long-acting analog insulin detemir in pregnancy have not been performed. At this time, human NPH insulin remains the preferred basal insulin for patients with GDM.11

Insulin requirements generally increase as pregnancy progresses and are often much greater in morbidly obese women.13 As such, total daily dosing requirements for insulin should be based on body weight and gestational week. Insulin regimens should be individualized and adjusted to achieve glycemic targets.

Sulfonylureas: Sulfonylureas work by increasing insulin secretion from the pancreas. None of the sulfonylureas are currently approved by the FDA for the treatment of GDM. Of the sulfonylureas, glyburide has been the most extensively investigated in the management of GDM.15 Langer et al. conducted a prospective study comparing the use of glyburide and insulin in women with GDM.24 Glyburide levels were undetectable in the cord blood, indicating minimal transfer across the placenta. In addition, glycemic control and perinatal outcomes were comparable between the two groups.24 Several retrospective reports have also documented the use of glyburide in GDM. Approximately 80% of subjects treated with glyburide achieved successful glycemic control, and the remainder required treatment with insulin therapy. 25 Based on these data, glyburide may be a reasonably safe alternative to insulin therapy for women with GDM. However, larger randomized studies are needed to fully assess neonatal outcomes and optimal dosing regimens.25 Glyburide is currently classified as pregnancy category C.22 Data are lacking regarding the use of glipizide and glimepiride in pregnancy. 15,22

Biguanides: The only drug in the biguanide class is metformin, which is FDA approved for use in type 2 diabetes, but not for use in GDM. Metformin acts by reducing hepatic glucose production, increasing peripheral glucose disposal, and reducing intestinal glucose absorption.15 Metformin is a pregnancy category B drug.22 When used in pregnant patients, metformin crosses the placenta readily, resulting in significant exposure to the fetus. As human studies are limited, it is unknown if metformin is teratogenic or beneficial to the fetus.16,22 To address issues concerning metformin, the Metformin in Gestational Diabetes (MiG) trial is an ongoing prospective, randomized multicenter trial designed to compare the use of metformin and insulin in women with GDM.26 The primary outcome measure of the trial is neonatal morbidity. In addition, the trial will assess maternal glycemic control and follow offspring for five years after delivery. Until data from studies such as the MiG trial are available, there is inadequate evidence to recommend metformin for the treatment of GDM. 11,15,16

Postpartum Care
Women with GDM have an increased risk of developing diabetes after giving birth.1,27 Finger-stick glucose should be measured in the immediate postpartum period to rule out persistent hyperglycemia and a diagnosis of diabetes.28 If early postpartum testing is negative, patients should have a follow-up 75-g OGTT six to 12 weeks after delivery.1,11,28 Because 35% to 60% of women with GDM will develop type 2 diabetes within 10 years, a repeat OGTT should be conducted in one year and at least every three years thereafter.11 Additionally, offspring of women with GDM are at risk of developing obesity and abnormal glucose tolerance. Children should have regular check-ups to evaluate height, weight, and blood glucose levels. 27

Pharmacist's Role

Pharmacists have a key role in helping to achieve optimal outcomes for patients with GDM. They can educate high-risk patients on the importance of obtaining screening for GDM as soon as possible after pregnancy is established. Patients at average risk should also be counseled on the benefits of screening for GDM at 24 to 28 weeks' gestation. For patients who are diagnosed with GDM, pharmacists may provide information on how to maximize diet and lifestyle modifications to achieve target glucose levels. Additionally, pharmacists should ensure that patients are educated on the appropriate technique for glucose monitoring. Pharmacists should inform patients of consequences of uncontrolled GDM and the importance of controlling blood glucose to minimize the risk of complications in the mother and fetus. Although only a minority of patients with GDM require insulin therapy, pharmacists should be prepared to advise these patients on proper administration and timing of insulin injections. Lastly, pharmacists should educate women with GDM on the significant risk of developing type 2 diabetes later in life and should emphasize the need for continued follow-up to assess the status of glucose metabolism.

GDM is characterized by onset or first recognition of glucose intolerance during pregnancy. The underlying mechanisms of insulin resistance in GDM are complex and have not yet been fully characterized. Glucose targets in GDM are more stringent compared with other types of diabetes; however, most patients with GDM can be successfully managed with a combination of MNT and exercise. For patients who fail to achieve adequate glucose control with MNT, pharmacologic therapy with insulin is indicated. Glyburide may be a reasonable alternative to insulin therapy in the management of GDM. Risks of uncontrolled GDM include fetal macrosomia, shoulder dystocia, and neonatal hypoglycemia. In addition, a significant number of women with GDM will later develop type 2 diabetes. By educating patients with GDM, pharmacists can have a significant impact on the health outcomes of both the mother and baby.


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