US Pharm. 2011;36(5)(Diabetes suppl):3-6.

Gestational diabetes mellitus (GDM) has been defined as “glucose intolerance with first recognition during pregnancy.”1 GDM has a prevalence of 1% to 14%, affecting approximately 7% of all pregnancies.2-4 While it is well known that GDM puts the mother at risk for developing type 2 diabetes mellitus (T2DM) later in life, recent evidence indicates that perinatal morbidity (e.g., macrosomia, birth trauma, neonatal metabolic complications) increases with increasing maternal glucose levels.1,5,6 This led the American Diabetes Association (ADA) to alter its criteria for diagnosis of GDM in 2011.4,7

Risk Factors and Diagnosis

Certain characteristics predispose a pregnant patient to develop GDM. These characteristics include increasing maternal age, ethnicity, obesity, family history of diabetes, and past obstetric history.3

In the past, the ADA and the American College of Obstetrics and Gynecology recommended that all patients undergo risk assessment at the initial prenatal visit, with low-risk patients requiring no additional screening.2,3 To be considered low-risk, a patient had to meet all of the following characteristics: age less than 25 years; normal prepregnancy weight; not from an ethnic group with a high prevalence of GDM (e.g., African American, Native American, Hispanic); no known diabetes in first-degree relatives; and no history of abnormal glucose tolerance or of poor obstetric outcome.

Under the previous recommendations, average-risk patients were administered a 50-gram, 1-hour oral glucose challenge test between 24 and 28 weeks’ gestation.3,4 A glucose threshold of either >140 mg/dL or >130 mg/dL was used to determine the necessity of additional testing. Patients requiring additional screening were given a 100-gram oral glucose tolerance test (OGTT). To receive a diagnosis of GDM, a patient had to have two abnormal values out of a possible four.2,3

In January 2011, the ADA issued a new position statement on the diagnosis and classification of diabetes mellitus.4 The ADA’s position statement and standards of care recommend that all women not known to have diabetes undergo a 75-gram OGTT between 24 and 28 weeks’ gestation.4,7 Cutpoints for fasting, 1 hour, and 2 hours are provided. To be diagnosed with GDM, a patient must exceed just one of the following values: fasting glucose ³92 mg/dL; 1-hour glucose ³180 mg/dL; or 2-hour glucose ³153 mg/dL. The ADA expects the prevalence of GDM to increase based on these new criteria.4,7

Goals of Therapy

For patients with GDM, the main goal of treatment is to decrease pregnancy complications associated with hyperglycemia. These complications include macrosomia, shoulder dystocia, and other birth trauma or metabolic effects in the infant.8 To that end, optimal glycemic goals are a fasting glucose of 90 mg/dL to 99 mg/dL; 1-hour postprandial glucose <140 mg/dL; and 2-hour postprandial glucose 120 mg/dL to 127 mg/dL.8

Treatment

Daily self-monitoring of blood glucose (SMBG) appears to be more effective than simply monitoring a patient’s blood glucose at an office visit; however, the optimal frequency of SMBG has not been established for patients with GDM.2,3,8 Patients who self-monitor more frequently appear to experience fewer adverse outcomes (e.g., macrosomia).3,8 Patients can be encouraged to self-monitor up to four times per day using the blood-glucose goals provided above. Some evidence suggests that maintaining postprandial values at goal may be more important than fasting values.3 Once a patient consistently achieves blood-glucose goals, the provider may reduce the frequency of SMBG.8

Medical nutrition therapy (MNT) is a mainstay of treatment for patients with GDM.8 All GDM patients should receive nutritional counseling from a registered dietician.2,3,8 MNT should be individualized for each patient based on BMI, weight gain, and physical activity.2,8 MNT may need to be modified throughout the pregnancy in order to achieve normal glucose levels and avoid ketosis.2,3

At present, no data exist on optimal MNT and weight gain for patients with GDM.8 However, it is currently recommended that patients be trained in carbohydrate counting and in using food records to achieve postprandial blood-glucose goals. Emphasis should be placed on healthful food choices, portion control, and cooking practices that could be continued postpartum to help prevent the onset of T2DM.8

For obese patients (BMI >30 kg/m2), calorie restriction of 30% to 33% has been shown to decrease hyperglycemia and plasma triglycerides without increasing ketonuria.2,3 These patients should consume approximately 25 kcal per kilogram of actual weight per day. In addition, restricting carbohydrates in all GDM patients to no more than 35% to 40% of total daily calories can decrease maternal glucose levels and improve maternal and fetal outcomes.2

There is no consensus on the appropriate amount of weight gain in patients with GDM. The Institute of Medicine (IOM) has issued recommendations for all patients based on prepregnancy weight or BMI, with recommended weight gain ranging from 11 pounds to 40 pounds (TABLE 1).9 A recent study by Cheng et al involving 31,000 subjects with GDM demonstrated that patients with gestational weight gain exceeding IOM guidelines were more likely to have a high-birthweight baby, have a primary cesarean delivery, or experience preterm delivery. Patients with less weight gain than recommended were more likely to maintain glycemic control by diet only, but had a greater risk of having an infant who was small for gestational age.10 More information is necessary to determine more accurate guidelines for weight gain in patients with GDM.

Ketone testing is sometimes recommended in GDM patients with severe hyperglycemia or for detection of insufficient caloric or carbohydrate intake in patients who are restricting calories. Its effectiveness in terms of fetal outcomes has not been determined, however.2,8

Exercise or physical activity is recommended for GDM patients capable of participating.8 Cardiovascular exercise may improve glycemic control in GDM, which could eliminate the need for insulin in some patients.

Medical Therapy: Insulin

An estimated 30% to 40% of GDM patients are placed on insulin therapy when MNT fails.11 Insulin has the most data to support its use in the treatment of GDM. Patients should attempt dietary therapy for at least 2 weeks before adding insulin. There are no recommendations for how many times glucose values should exceed target before insulin is added.3

No particular insulin dose or regimen has demonstrated superiority at this time. Typically, the patient starts with a simple regimen and increases its complexity, if needed. It would be appropriate to begin with once-daily or twice-daily neutral protamine Hagedorn (NPH). Practitioners should make dose adjustments based on blood-glucose levels.3 A common regimen would include a combination of rapid-acting insulin and intermediate-acting insulin taken twice a day.12 Note that insulin requirements typically increase throughout pregnancy.2,13

Short-Acting Insulin: In the past, short-acting insulin analogues were not assessed in pregnant patients. Recent studies evaluating their use have been published. Insulin lispro and insulin aspart are now considered pregnancy category B and thought to be as effective and safe as regular insulin for use in pregnant patients.11,14-18 They are particularly effective for patients with postprandial hyperglycemia and tend to cause fewer episodes of hypoglycemia than regular insulin, without evidence of increased diabetic complications.11,16-18 Insulin glulisine has not yet been evaluated in pregnant patients and is still considered pregnancy category C; its use is not currently recommended.19

Long-Acting Insulin: Using human NPH insulin as part of a multiple-injection regimen in pregnant patients is typically preferred. Safety and efficacy data on the use of NPH in pregnancy are available. Doses may be titrated based on a patient’s glucose logs. Insulin glargine and insulin detemir have not been studied extensively in pregnancy, and their use cannot be recommended at this time; they are currently pregnancy category C.16,20,21

Oral Agents: Oral hypoglycemic drugs such as metformin and sulfonylureas have been a therapy mainstay for patients with T2DM. They are often the first drugs prescribed for patients diagnosed with T2DM. For a number of years, insulin has been the drug of choice when dietary management fails to achieve adequate glucose control in a patient with GDM. Recently, both patients and practitioners have been seeking a treatment for GDM that has fewer burdens than insulin therapy (patient discomfort, cost of supplies, and inconvenience of injections). Some physicians have turned to oral agents to accomplish this.

Glyburide: Glyburide, a second-generation sulfonylurea, has recently gained popularity for use in patients whose GDM is inadequately controlled by diet alone. In the past, glyburide was not used because it was thought to potentially harm the fetus, causing congenital malformations, hyperbilirubinemia, neonatal hypoglycemia, and neural-tube defects.22 Some studies have noted that these outcomes occur primarily with the first-generation sulfonylureas and that some newer-generation sulfonylureas (e.g., glyburide) have minimal transfer through the placenta, with little—if any—effect on the fetus.22,23

In one of the main trials to show the efficacy of glyburide in GDM, Langer et al compared glyburide with insulin for the treatment of GDM.23 No significant between-group difference was found in the frequency of newborns who were large for gestational age, weighed >4,000 g, had lung complications, were admitted to a neonatal ICU, had hypoglycemia, or had fetal anomalies. Based on these findings, some physicians are considering glyburide therapy for patients with GDM, and the drug can be dosed at 2.5 mg to 20 mg per day.23

Metformin: This biguanide is often used as first-line therapy for nonpregnant patients with T2DM in doses ranging from 500 mg to 2,550 mg per day. Because it increases insulin sensitivity, it seems to be a reasonable choice for patients with GDM where there is a relative decrease in insulin sensitivity.24 However, the information available for this indication is limited. There is some concern about using metformin for GDM, since the drug has been associated with a higher incidence of preeclampsia and perinatal mortality compared with insulin and sulfonylureas.25 Also, a study by Moore et al concluded that, compared with patients taking glyburide, those taking metformin were twice as likely to fail therapy.24 For these reasons, some physicians are hesitant to attempt metformin therapy in patients with GDM, and the drug is not approved for this indication.

Postpartum Management

The management of GDM after delivery is extremely important. In 90% of GDM patients, glucose intolerance is corrected upon delivery.26 However, these patients are at risk for developing T2DM later in life; in fact, 15% to 60% will develop it within 5 to 15 years postdelivery.26 Patients should be screened for continuous glucose intolerance between 6 to 12 weeks postpartum using the standard OGTT for nonpregnant patients. Regular screenings should be performed a minimum of every 3 years thereafter.7

Some studies have determined that certain factors put GDM patients at greater risk for developing T2DM later in life. A study by Pallardo et al found a positive association between prepregnancy BMI and the development of T2DM, while in a study by Jang et al, prepregnancy weight eventually advanced to full-blown disease.27,28 Löbner et al reported a nearly fivefold increased risk of T2DM development in patients who used insulin to control their diabetes during pregnancy, versus patients controlled through diet alone.29 Because DM is a major contributor to morbidity and mortality, it is extremely important to regularly assess patients for the disease, starting shortly after delivery and continuing over the coming years.

Conclusion

In the United States, GDM affects many pregnancies each year. This disease can be managed by diet, insulin, and possibly oral antidiabetic agents. Because each patient is unique, the choice of drug therapy must be tailored to the individual. As practitioners, pharmacists should encourage their patients with GDM to do their best to incorporate lifestyle modifications. Pharmacists must also assess these patients regularly for the development of glucose intolerance or T2DM. By so doing, they will ensure that patients diagnosed with GDM have the knowledge they need to help themselves and their unborn children.

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