If you are a pharmacist who deals with patients, expect to deal with gestational diabetes.
If you are a pharmacist who deals with patients, expect to deal with gestational diabetes (GDM). About 14% of U.S. pregnancies result in GDM, although the incidence can vary dramatically based on local demographics and eating patterns. As the median BMI of the U.S. population increases, so does the prevalence of GDM.
Kristi Kelley“As a society, we are overweight, which contributes directly to GDM,” said Kristi Kelley, PharmD, BCPS, CDE, clinical assistant professor, Pharmacy Practice, Auburn University Harrison School of Pharmacy. “If patients in your area are more obese than national averages, you will probably see more moms with GDM. Other risk factors include a history of GDM during prior pregnancies, any family history of diabetes, and the usual ethnic risks for diabetes that you would look for regardless of pregnancy.”
GDM may be an increasingly common problem, but the possible consequences to both mother and baby can be lifelong and severe, even fatal.
On the maternal side, the most common complications of GDM are hypertension and a 50% risk of developing either GDM in later pregnancies or type 2 diabetes later in life, or both. Other negative outcomes include preeclampsia and cesarean section.
On the fetal side, the most common complication of GDM is macrosomia, defined by the American College of Obstetricians and Gynecologists (ACOG) as birth weight greater than 4,500 g (9 lbs, 15 oz). Greater than normal birth size gives rise to birth trauma to both mother and infant, including shoulder dystocia and the need for C-section delivery. Other negative outcomes for the child include hypoglycemia, hyperbilirubinemia, death from birth trauma, and greatly increased risk for obesity and diabetes later in life.
GDM is simply glucose intolerance with onset or initial diagnosis during pregnancy, Kelley said. It includes type 1 diabetes as well as type 2 diabetes that was previously undetected or first presents during pregnancy. For many women, GDM is type 2 diabetes that either begins during pregnancy or, increasingly, predates pregnancy but was never diagnosed because the woman was never tested for glucose intolerance.
In addition to increasing obesity, a second reason GDM rates have soared in recent years has to do with more widespread testing. Standard prenatal care now includes blood glucose testing as part of the standard blood panel for all pregnant women.
Standard screening for GDM should take place between 24 and 28 weeks, according to ACOG and other bodies. Women who are recognized as being at higher risk as a result of previous GDM, family history of diabetes, or obesity, or who have already given birth to a child with macrosomia may be appropriate for even earlier screening. If the initial screen was negative for GDM, high-risk women who have been screened early should be screened again between 24 and 28 weeks.
How to screen for GDM has been the subject of much debate over the decades. The American Diabetes Association (ADA) accepts hemoglobin A1c testing, fasting plasma glucose (FPG), oral glucose-tolerance testing (OGTT), and random plasma glucose testing as appropriate tests for diabetes in the general population. Any positive result should be subject to a second confirmation test.
Screening criteria are tighter for GDM. Both ADA and ACOG recommend a 100 g OGTT exclusively to confirm diagnosis. As a practical matter, ADA, the International Diabetes Federation (IDF), and Britain's National Institute for Health and Care Excellence (NICE) recommend a one-step screening and diagnosis using OGTT alone. A single 100 g OGTT is intrusive enough for many busy women, Kelley noted, and any step that can reduce the nuisance factor for women is likely to increase participation.
GDM management is relatively straightforward. Most guidelines focus on lifestyle modification, diet, and exercise. Pharmacotherapy focuses on just three agents.
Donald Coustan“Insulin is the tried-and-true agent for maintaining euglycemia in GDM,” said ADA spokesman Donald R. Coustan, MD, professor of Obstetrics and Gynecology at Warren Alpert Medical School of Brown University. “Insulin does not cross the placental barrier. Two oral antidiabetic drugs are often prescribed in pregnancy, metformin and glyburide, and a third, acarbose, has been reported in small studies but is not widely used.”
Different guidelines offer different glucose testing and treatment goals. There is broad agreement that elevated postprandial glucose is more predictive of negative outcomes, especially fetal macrosomia, than are preprandial levels. Guidelines generally recommend that mothers with GDM self-monitor fasting (<95 mg/dL) and postprandial (<140 mg/dL one hour or <120 mg/dL two hour) glucose levels. A1c monitoring is not useful for managing GDM in women who do not have preexisting diabetes.
Many moms with GDM will end up on medication, but neither insulin nor oral agents should be the first-line therapy for most women. Diet and exercise are initial interventions.
Between 75% and 80% of GMD can be managed with lifestyle modifications alone, Kelley said. Results can vary dramatically, depending on external factors such as the mom’s support network, her own attitudes and beliefs toward pregnancy and health, the availability of appropriate diet and exercise information, and the availability of an appropriate nutritional and activity infrastructure.
“One of the biggest issues is the persistent belief that a pregnant mom is eating for two,” she said. “The reality is that a mom needs to eat a balanced and healthy diet and that hunger levels can fluctuate widely. If you are hungry and eating more than three meals a day, be smart about it and don’t load up on carbs. Eating a gallon of ice cream is a little much. And as a pharmacist, you are the ideal health professional to deliver that message.
“A lot of pregnant women simply don’t have access to a dietician and a personalized meal plan,” she continued. “Pharmacists are the healthcare professionals people see most frequently, and we are the healthcare professionals people trust the most. We can help them eat smarter and urge them to go back for more management help when it is needed.”
The ADA also sees pharmacists as important players on the GDM team. As the medication experts, pharmacists can and should counsel moms about various aspects of their medications, Coustan said.
“For example, many patients with diabetes are under the false impression that insulin must be refrigerated or it will go bad,” he explained. “And while insulin should be stored in the refrigerator before initial use, once in use it should be kept at room temperature and is stable for up to 28 days. That means, among other things, that moms can take insulin with them when they go out to eat or when they travel.”
Another important message pharmacists can deliver has to do with the pharmacodynamics and pharmacokinetics of insulin and glucose. Insulin taken by the mother does not cross the placenta and can be used without concern for adverse drug effects on the fetus, he said. Glucose, by contrast, readily crosses the placental barrier and can stimulate the fetus to overproduce its own insulin, the primary cause of many fetal complications of GDM.
“Pharmacists can also anticipate that insulin requirements will increase as pregnancy progresses and reassure moms that this is to be expected,” he added. “You can help patients remember that the real goal is to titrate insulin dosage to maintain circulating insulin levels as close to normal without causing hypoglycemia. Managing GDM is more than taking the same does of insulin at the same time every day.”
When it comes to evidence, there are three primary choices in drug treatment for GDM: insulin, metformin, and glyburide. Little or no safety data on fetal development and outcomes exists for other oral and non-insulin injectable agents. Because the risks outweigh potential benefits, these other agents are generally not recommended for use during GDM.
Insulin is often recommended as first-line therapy because it does not cross the placental barrier. Both metformin and glyburide are pregnancy category B (no adverse evidence in pregnant women and no fetal risk demonstrated in animal studies), but long-term safety data in pregnancy are lacking, said Kelley.
ACOG has stated that insulin and oral agents are equally efficacious and either can be used as first-line therapy. ADA recommends insulin, noting that short-term data support use of both metformin and glyburide, but that long-term safety data are lacking.
NICE recommends metformin over insulin as first-line therapy. Insulin is recommended as an add-on to metformin if needed or as a replacement if metformin is contraindicated. Glyburide is the choice if metformin is ineffective or cannot be tolerated, or if the patient declines insulin.
Use of insulin can be problematic, and not just because so many people would prefer to avoid injections. There are decades of data on older insulins in pregnancy; less data exist for analogs; and there are no data on the most recent formulations. All insulins are pregnancy category B except glulisine, glargine, and inhaled formulations, which have little to no data on use during pregnancy.
“If there is an option to use an agent with evidence, I would go that route,” Kelley said. “It really comes down to personal preference by the prescriber and the patient.”
It is reasonable to select from regular, NPH, or analog insulins for patients who need insulin therapy for GDM, she said. If cost is an issue, either regular or NPH insulin may be a more appropriate choice. The convenience of mealtime dosing may tip the balance toward one of the rapid-acting analogs, while long-acting analogs may be an advantage when hypoglycemia is a concern. Insulin pens may be easier for some patients. Emerging safety data could affect decisions in all these categories in coming years.
Dosing recommendations during pregnancy are not specific to GDM, she said. By the time insulin is needed during GDM, many patients are at the end of the second trimester or later. Because insulin resistance increases during pregnancy, total daily dosing is usually between 0.8 and 0.9 units in insulin per kg of body weight.
“Metformin and glyburide are both reasonable options for GDM,” Kelley said. “They are both pregnancy category B and on a par with insulin for many patients.”
Current evidence indicates that dosing principles for both metformin and glyburide during GDM are similar to those in use for management of type 2 diabetes. Good candidates for metformin include mothers who decline to take insulin, who are in their first episode of GDM, and who have lower BMI as well as lower OGTT levels at screening. Good candidates for glyburide include mothers who decline to take insulin, who have progressed to at least week 25 in their pregnancy, who have lower OGTT levels at screening, and who are carrying a single fetus.
“The presence of GDM is a powerful risk factor for future type 2 diabetes,” Coustan said. “It also presents an opportunity for prevention of future diabetes.”
Women who used insulin to manage their GDM can exhibit wide fluctuations in blood glucose levels during the hours after delivery. So can their babies. Both mother and infant require close monitoring. Depending on the glucose environment in which they developed, infants may be at risk for hypoglycemia after birth.
Maternal insulin needs may decline significantly in the hours after delivery. The decline may continue, especially if the mother is breastfeeding. The need for oral medications may also decline with delivery and may not be needed at all.
Women with GDM should be screened for diabetes one to two months after delivery, Coustan said. A 75-g two-hour OGTT is the most sensitive screen for prediabetes. A positive diagnosis also offers the best chance for prevention as well as for counseling about diabetes risks in future pregnancies.
Women with a history of GDM who have prediabetes with both elevated fasting glucose and elevated two-hour plasma glucose will develop type 2 diabetes at a rate of 15% per year if untreated. Lifestyle intervention emphasizing diet and exercise can cut that rate in half. Weight loss of about seven% of total body weight can also ameliorate the increased risks of diabetes later in life.