Gestational Diabetes Mellitus

 US Pharm. 2009;34(9):43-48. 

Gestational diabetes mellitus (GDM) is a common medical complication associated with pregnancy. GDM is defined as any degree of glucose intolerance that occurs with pregnancy or is first discovered during pregnancy.¹ GDM imposes risks on both mother and fetus. Some of these risks continue throughout the lifetime of mother and child. Maternal complications include pre-eclampsia, hyperglycemic crisis, urinary tract infections that may result in pyelonephritis, need for cesarean sections, morbidity from operative delivery, increased risk of developing overt diabetes, and possibly cardiovascular complications later in life, including hyperlipidemia and hypertension. Mothers with GDM have a 50% chance of developing type 2 diabetes mellitus (T2DM) for the 20 years following their diagnosis of GDM. Maternal hyperglycemia causes increased glucose delivery to the fetus, resulting in fetal hyperinsulinemia and increased fetal growth. Complications of excessive fetal growth include birth trauma, increased cesarean deliveries, and the long-term risk of glucose intolerance and obesity. Other immediate fetal complications include hypoglycemia, hyperbilirubinemia, respiratory distress syndrome, cardiomyopathy, and hypocalcemia.^2-5 This plethora of risks demonstrates the importance of early risk stratification with appropriate screening and diagnosis and of therapeutic interventions that maintain optimal glycemic control.   

Epidemiology and Pathophysiology

GDM is the most common metabolic complication associated with pregnancy.⁶ GDM occurs in up to 14% of all pregnancies, resulting in approximately 200,000 cases annually in the United States.¹ As the occurrence of T2DM has increased over the past few decades, an increase in the incidence of GDM has also been observed. Between 1994 and 2002, the incidence of GDM doubled.⁷ The rise in GDM can likely be attributed to improved screening and diagnostic tools, as well as to the climbing rate of obesity in the U.S.³ Excessive caloric intake and sedentary lifestyles are the major causative factors contributing to obesity.

The main pathophysiologic defects that occur in GDM are the same as those observed with T2DM: marked insulin resistance and impairment of insulin secretion. The exact mechanisms responsible for these defects in GDM are not known.⁸ 

All pregnancies are associated with an increase in insulin resistance and increased pancreatic insulin secretion as the pregnancy progresses. Skeletal muscle is the body's main site of glucose disposal and becomes insulin resistant during pregnancy. This insulin resistance begins in mid pregnancy and continues until the end of gestation. Pregnancies are also associated with a 200% to 250% increase in insulin secretion to maintain euglycemia in the mother. These metabolic changes are normal and provide adequate nourishment to the fetus. When maternal insulin secretion is unable to meet increased demand secondary to marked resistance, GDM results.^3,8-10

The cause for pancreatic beta-cell dysfunction and accompanying decrease in insulin secretion in GDM is categorized into three groups. The three groups are: 1) autoimmune, 2) monogenic, and 3) occurring on the background of insulin resistance.⁸ Additional maternal factors such as obesity also contribute to this insulin resistance. The exact maternal influences and the extent of their contribution are still poorly understood.^8-10

Placental hormones contribute to insulin resistance and secretion as well. The placenta is capable of producing a milieu of hormones and cytokines independently. Placental cytokines such as tumor necrosis factor alpha (TNFa), resistin, and leptin are known to contribute to the insulin resistance of GDM. Important placental hormones include human chorionic somatomammotropin (HCS), cortisol, estrogen, progesterone, and human placental growth hormone (hPGH). HCS increases throughout pregnancy and stimulates maternal pancreatic insulin release. Placental overexpression of hPGH results in severe peripheral insulin resistance.^3,8-10 

It is thought that the cumulative effects of maternal and placental influences result in abnormalities in insulin signaling pathways, which lead to decreased glucose uptake and an increase in insulin resistance. The exact molecular processes of such remain unclear.^3,8-10  

Detection and Diagnosis

The 2004 American Diabetes Association (ADA) position statement provides the standards for screening and diagnosis of GDM that have been carried forward into the Standards of Medical Care in Diabetes--2009. Due to the potential negative health impacts GDM can inflict on both mother and baby, a risk assessment for GDM should be performed at the first prenatal visit. This risk assessment classifies women as very high risk, greater than low risk (average), or low risk.^1,11 Very high risk and low risk criteria are described in TABLE 1. Average risk is defined as not meeting the criteria for low risk, including very high-risk patients who are not found to have GDM upon initial screening.¹ Patients at very high risk for developing GDM should be screened as soon as pregnancy is confirmed using standard diagnostic testing. If this initial screening is negative, they are considered average risk and should be retested at 24 to 28 weeks of gestation using the one- or two-step approach. Women with average risk should be tested at 24 to 28 weeks of gestation. Those who meet all the criteria for low risk do not require testing.^1,11 (See FIGURE 1 for an algorithm.)

Currently, there are two methods of screening for GDM: the one-step approach and the two-step approach, both detailed in TABLE 2.^1,11 The Hypoglycemia and Adverse Pregnancy Outcome study revealed adverse outcomes associated with hyperglycemia less severe than these current cutoffs.¹² Given these findings, an international group consisting of multiple obstetric and diabetes organizations, including the ADA, are working on a consensus to standardize the diagnostic tests to use and the rational diagnostic cutoff points for GDM.^1,12 

Glycemic Goals and Treatment

The Fifth International Workshop-Conference on Gestational Diabetes Mellitus made recommendations for the following maternal capillary glucose concentration goal: preprandial ≤95 mg/dL and either 1-hour postprandial ≤140 mg/dL or 2-hour postprandial of ≤120 mg/dL.^1,3 Identifying and aggressively managing GDM may decrease morbidity and mortality in infants.³ Although nonpharmacologic therapy is the root of all GDM treatments, there are pharmacologic options such as insulin and oral antihyperglycemic agents available when nonpharmacologic therapy is not adequate. 

Monitoring of Maternal Glycemia

The ADA's gestational diabetes position statement of 2004 encourages women to conduct daily self-monitoring of blood glucose (SMBG).¹¹ The exact methods for maternal glucose monitoring, including devices used and frequency and timing of blood collection, are not yet clear and remain an area of active research. The ADA 2009 Standards of Care suggests that the methods and frequency of blood glucose monitoring be designed around the needs of the individual patient.¹ The goal is to maintain euglycemia and avoid complications associated with hyperglycemic and hypoglycemic episodes. It is most commonly suggested that patients with GDM perform SMBG three to four times daily. The ADA 2009 Standards of Care does not comment on postprandial versus fasting or preprandial SMBG levels specifically. The ADA simply states that to achieve postprandial glucose goals, postprandial SMBG may be appropriate. A study by De Veciana et al concluded that SMBG in patients with GDM should consist of fasting, preprandial, and postprandial readings.¹³ These result in improved glycemic control in women with GDM who require insulin and lead to reduced complications for both mother and child. In particular, postprandial blood glucose levels that are utilized to alter therapy are associated with fewer incidences of macrosomia, fewer cesarean deliveries, and overall improved glycemic control.¹³

Areas of current research include studies that are comparing continuous glucose-monitoring systems to SMBG. A small study by Kestila et al showed that continuous glucose-monitoring systems detect more episodes of hyperglycemia that require medication than those detected by SMBG, leading to the conclusion that further well-designed trials are now needed to evaluate whether continuous glucose-monitoring initiation of medications to treat hyperglycemia results in fewer macrosomial and perinatal complications.¹⁴ Another study made medical management decisions based on information gathered from continuous glucose-monitoring systems that often included otherwise undetected and possibly dangerous postprandial hyperglycemia and overnight hypoglycemia.¹⁵

Providing initial education to the patient on the proper use of the blood glucose meter, assessment of the patient's SMBG technique, and periodic reassessment thereafter are also advised.¹ Additional advantages to patients with GDM  who perform SMBG include the sense of self-empowerment and the ability to react and treat abnormal blood glucose levels such that risks of complications are reduced both for the mother and her baby.¹⁶ 

Nonpharmacologic Treatment Modalities

Medical nutrition therapy (MNT) is the standard of care for all patients with GDM. There are no specific nutritional recommendations since they must be individualized.³ MNT includes caloric and nutritional provisions to meet the minimum needs of the pregnancy and to achieve the maternal blood glucose goals without weight loss or excessive weight gain.^3,11 MNT is best initiated and managed by a registered dietitian or qualified individual with experience in GDM management.³ The Institute of Medicine report recommends a small gain of 15 pounds for obese patients and up to 40 pounds for underweight patients.¹⁷ However, there are no standardized  recommendations for optimal MNT and weight gain for women with GDM in the medical literature.³ Additional nonpharmacologic treatments include initiating or continuing  30 minutes of physical activity daily for women with no medical or obstetric contraindications.^3,11   

Pharmacologic Treatment Modalities

Pharmacotherapy consideration is based on measures of maternal blood glucose with or without assessment of fetal growth characterisitics.¹¹ By utilizing ultrasound measurements of the fetal abdomen in the second and early third trimesters and repeating these every 2 to 4 weeks, management can be guided.³ The ADA recommends insulin therapy when there are signs of excessive fetal growth or maternal glycemic goals are not maintained.³ The ADA defines failure to maintain goals when SMBG levels result in fasting plasma glucose (FPG) >105 mg/dL, 1-hour postprandial >155 mg/dL, or 2-hour postprandial >130 mg/dL.¹¹ 

Insulin: Insulin is the only FDA-approved medication for the treatment of gestational diabetes and has been the mainstay of treatment when MNT is not enough.^3,18 Human insulin (neutral protamine Hagedorn [NPH] and regular insulin) is the least immunogenic of the available insulin preparations; however, lispro and aspart develop antibodies at rates and titers comparable to human regular insulin. Lispro and aspart have shown clinical efficacy, minimal transfer across the placenta, and no evidence of teratogenesis while improving postprandial glucose excursions compared to human regular. Randomized, controlled trials (RCTs) have not been done with glulisine (short-acting insulin) or any of the long-acting insulins. When longer acting agents are needed, NPH insulin can be used as an intermediate-acting insulin.³   

Glyburide: Although glyburide is not FDA approved for GDM, there is supporting evidence that it can be used as an adjunct to MNT and exercise when additional therapy is needed.^3,19 Glyburide is the only sulfonylurea that has shown minimal placenta transfer and has not shown an association with excess neonatal hypoglycemia.³ A recent meta-analysis looked at three RCTs comparing glyburide and insulin to find no statistically significant differences in maternal outcomes, glycemic control, cesarean deliveries, neonatal outcomes, neonatal hypoglycemia, or infant birth weight.²⁰   

Other Therapies: Other treatment options currently being studied include metformin and acarbose. Metformin does cross the placenta, and the last stance of the ADA at the Fifth International Workshop-Conference on Gestational Diabetes Mellitus was that there is not enough evidence to recommend metformin.³ Since releasing this statement, an RCT has been published comparing metformin with insulin. Of the 363 women in the metformin group, 46.3% needed supplemental insulin, 7.4% had the metformin stopped prior to delivery, and 8.8% had gastrointestinal side effects requiring dose adjustments. The overall composite of neonatal complications (neonatal hypoglycemia, respiratory distress, need for phototherapy, birth trauma, 5-minute Apgar score, and preterm birth) did not find statistically significant differences between metformin and insulin; however, the individual components found differences with less severe hypoglycemia in the metformin group (3.3% vs. 8.1%) and more preterm births in the metformin group (12.1% vs. 7.6%). Secondary outcomes found metformin to have lower blood glucose 1 week after randomization and lower 2-hour postprandial blood glucose throughout the study until delivery.²¹ There is a high frequency of gastrointestinal side effects with acarbose, and the safety and potential placenta passage have not been fully evaluated although systemic absorption is minimal.³ A preliminary RCT gives hope for further evaluations on these matters.²² 

Postpartum Considerations

Due to the fact that women diagnosed with GDM and their children have a lifelong risk of developing diabetes, it is important to implement preventive strategies to reduce this risk after the birth of the child.²³ The majority of women with GDM go on to develop diabetes with a nearly linear increase in the cumulative incidence during the first 10 years postpartum across all ethnic groups.³ Factors that promote insulin resistance such as obesity add to the risk of developing T2DM after GDM, while the markers of islet cell-directed autoimmunity may increase the risk of type 1 diabetes.¹¹ The mother should be tested 6 to 12 weeks postpartum using nonpregnant OGTT (oral glucose tolerance test) criteria and every 1 to 2 years thereafter.^1-3 Children of women with GDM have increased risk of obesity, glucose intolerance, and diabetes as early as adolescence.¹¹ Children born to mothers diagnosed with GDM during their gestation should be tested at age 10 years or at the onset of puberty, whichever occurs first, if they are overweight and have one of the following risk factors: family history of type 2 diabetes, race/ethnicity (Native American, African American, Latino, Asian American, or Pacific Islander), or signs of insulin resistance or conditions associated with insulin resistance. The preferred test in children is fasting plasma glucose and should be scheduled every 3 years.¹ The National Diabetes Education Program provides actions to minimize the risk of developing diabetes for both mother and child at www.ndep.nih.gov. These steps include breast-feeding, reaching prepregnancy weight within 6 to 12 months with additional weight loss if needed, healthy eating, portion control, and staying active. Children can lower their risk of developing diabetes if they maintain a healthy weight. Parents should help them make healthy food choices and be active for at least 1 hour each day. This active and healthy lifestyle should be adopted by the entire family.²³ 

Pharmacist's Role

The primary role of the pharmacist in GDM management is patient education. Education for a woman with GDM can include dietary counseling, technique and demonstration of insulin utilization, and use of SBGM. Patients should be educated on the symptoms of hypoglycemia (plasma glucose <70 mg/dL), such as shakiness, dizziness, sweating, hunger, headaches, pale skin, sudden mood or behavior changes, clumsy or jerky movements, seizures, difficulty paying attention, confusion, or tingling sensations around the mouth when using insulin or sulfonylureas.²⁴ Patients should also be educated on the proper treatment for hypoglycemic episodes. Pure glucose is the preferred treatment; however, ingestion of glucose or carbohydrate-containing foods will work.¹ Additional education pertains to lifestyle measures that patients can employ for optimal management of GDM and for reducing the postpartum long-term complications that may affect both mother and child.   

Conclusion

GDM is a condition that should be treated aggressively, as uncontrolled cases can result in detrimental effects on both mother and child. Fortunately, when controlled, patients with GDM can experience relatively healthy pregnancies. As such, long-term health complications can be reduced for both mother and child. Insulin has traditionally been used to treat GDM. However, current research is analyzing the safety and efficacy of oral agents such as glyburide and metformin. Oral agents may offer attractive alternatives to patients with GDM, which may reasonably result in increased patient compliance. See summary algorithm in FIGURE 1. 

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