Q: Why has there been a change in the standards of care for gestational diabetes mellitus?
With the obesity epidemic in this country, a greater number of women in their childbearing years are at risk for this continuum of metabolic syndrome, gestational diabetes mellitus (GDM), and type 2 diabetes mellitus (T2DM). GDM has long been defined as glucose intolerance with onset or first recognition during pregnancy.1 Compounding this definition are concerns that undiagnosed type 1 diabetes mellitus (T1DM) or T2DM may have been present at conception or that glucose intolerance may continue after pregnancy, developing into T2DM postpartum or prior to subsequent pregnancies.
In April 2011, the CDC reported that GDM occurs in 2% to 10% of pregnancies and is more likely in women who have a family history of diabetes, are obese, or are African-American, Hispanic/Latino American, or American Indian.2
Furthermore, in 2008, the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study demonstrated a continuous association of adverse pregnancy outcomes (maternal, fetal, and neonatal) with increasing maternal glucose levels, even at glycemic levels previously considered normal.3 In response, the International Association of Diabetes and Pregnancy Study Groups (IADPSG) developed revised recommendations for diagnosing GDM; these were published in 2010.4 Professional organizations such as the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE) are now incorporating these revisions into their guidelines.5,6
Q: What causes GDM?
After 20 weeks’ gestation, there is an approximately 50% increase in insulin resistance in all women, most likely resulting from elevated levels of reproductive/placental hormones and possibly cytokines. As levels rise for the duration of the pregnancy, insulin resistance continually increases.
Women with normal pancreatic function are able to secrete the additional insulin required (as much as 200% to 250% by late pregnancy) to maintain euglycemia. Women predisposed to insulin resistance prior to pregnancy have already begun taxing their pancreatic beta-cells for increased production. As insulin resistance increases during the second and third trimesters, they are less likely to meet the additional demands for insulin, with impaired insulin secretion resulting in a greater risk for hyperglycemia.7
Q: What are the risks of maternal hyperglycemia for the child?
Hyperglycemia during the first trimester, either due to uncontrolled T1DM or undiagnosed T2DM, may cause birth defects, including neural tube and cardiac malformations; it can also contribute to early fetal loss.8,9 Maternal hyperglycemia during the second and third trimesters, as seen with the onset of GDM, is also associated with an increased risk for other complications, and HAPO reported that these complications increased with rising glucose levels previously considered normal.4
According to Pedersen’s hypothesis, maternal hyperglycemia transfers across the placenta, inducing fetal hyperglycemia, compensatory fetal hyperinsulinemia, and consequently increased adipose deposition of nutrients, resulting in macrosomia—the most common complication of GDM.10 Fetal hyperinsulinemia can siphon glucose from the mother, known as steal phenomenon, creating the appearance of maternal euglycemia.11 For this reason, ultrasound surveillance is used to monitor for accelerated fetal growth.
An estimated fetal weight of more than 4,500 g carries a high risk for shoulder dystocia with vaginal delivery, so elective cesarean section is usually recommended.12 Common complications in the infant include neonatal hypoglycemia secondary to fetal hyperinsulinemia, polycythemia, hyperbilirubinemia, and an increased need for neonatal intensive care.4 Furthermore, uncontrolled maternal GDM results in offspring at risk for childhood obesity and impaired glucose tolerance, giving rise to the theory of fetal imprinting and perpetuating a vicious cycle.13-16
In light of worldwide weight trends and with obesity considered the number one risk factor for insulin resistance, which is characterized by elevated triglycerides and free fatty acids, Catalano is revisiting Pedersen’s hypothesis, adding that the availability of maternal lipids for fetal lipogenesis is a possible contributing factor to fetal fat accumulation.17 This could explain why pregnancies complicated by obesity carry many of the same risks, or compound the maternal-fetal risks, that are associated with hyperglycemia in pregnancy.18-20
Q: What are the risks of GDM for the mother?
The immediate risks are an increased incidence of cesarean section, preeclampsia, and preterm delivery.3 Since GDM falls within the continuum for developing T2DM, pregnancy serves as a “stress test” in women who are genetically predisposed. Women who develop GDM have about a 50% risk for developing T2DM within five to 10 years.21
Q: How is GDM diagnosed?
As a result of the obesity and diabetes epidemics in this country, increasing numbers of women have undiagnosed T2DM with pregnancy.22 For this reason, the new guidelines recommend using standard diabetes screening for women with risk factors for T2DM at the first prenatal visit. Women who test positive are given a diagnosis of diabetes and should begin diabetes self-management education and therapeutic intervention, when indicated, without delay. AACE recommends that A1C be used as a screening test, due to potential interfering factors not related to glycemia, and that the diagnosis of diabetes be based on plasma glucose readings.6
Using HAPO data, the IADPSG proposed a new set of GDM diagnostic criteria in 2010, which has been adopted by ADA and AACE in 2011.3-6 Following the new standards, all women not previously diagnosed with diabetes should be screened at 24 to 28 weeks’ gestation using a 75-g, 2-h oral glucose tolerance test (OGTT) after an 8-h overnight fast. The diagnosis of GDM is made if there is one abnormal plasma glucose value: fasting glucose ≥ 92 mg/dL, 1-h glucose ≥ 180 mg/dL, or 2-h glucose ≥ 153 mg/dL.
Q: What are the goals for self-monitoring of blood glucose (SMBG) in pregnancy?
HAPO revealed that fasting and postprandial hyperglycemia all predicted risk for macrosomia, fetal hyperinsulinemia, and cesarean delivery.3 ADA and AACE concur with the recommendations from the Fifth International Workshop-Conference on Gestational Diabetes that SMBG goals for women with GDM are as follows: preprandial ≤ 95 mg/dL and either 1-h postprandial ≤ 140 mg/dL or 2-h postprandial ≤ 120 mg/dL.5,6,23
SMBG is recommended at least three times daily for pregnant women taking insulin, but ADA also recommends that monitoring be dictated by the needs and goals of the patient.5 For women with T1DM and T2DM who become pregnant, ADA and AACE concur with a recent consensus statement recommending avoidance of excessive hypoglycemia while aiming for glycemic goals of: preprandial, bedtime, and overnight glucose, 60 to 99 mg/dL, peak postprandial glucose, 100 to 129 mg/dL, and A1C < 6%.5,6,24
Q: What is the best therapy for women with GDM?
Although more women will be diagnosed with GDM using the 2011 guidelines, therapeutic lifestyle changes and medical nutrition therapy (diet) will be key elements in their management, as demonstrated in the Maternal-Fetal Medicine Units Network and the Australian Carbohydrate Intolerance Study in Pregnant Women trials.25,26 Women should not arbitrarily restrict calories, as ketosis can result from simply an overnight fast, and maternal ketones have been shown to impair the IQ of offspring.27,28
In many cases, diet alone, while preventing ketonuria, may control postprandial plasma glucose, but diet-control is less successful when fasting hyperglycemia develops. When SMBG does not meet the established goals, ADA, AACE, and the American College of Obstetricians and Gynecologists (ACOG) concur that insulin is the first-line therapy, either via multiple daily injections or continuous subcutaneous insulin infusion.5,6,12
Regular and neutral protamine hagedorn (NPH) insulin, both of which are classified as pregnancy category B, have been the mainstay therapy. Recently, rapid-acting insulin aspart has been approved for use in pregnancy, and lispro is considered a treatment option for patients with GDM by AACE and the 2008 Expert Review of Obstetrics and Gynecology on the Management of GDM.6,29 Likewise, 70/30 aspart mix and 75/25 lispro mix are now pregnancy category B. For basal insulin, detemir appears to be safe during pregnancy in early studies, while glargine, though used, has no conclusive reports on safety30,31; both remain pregnancy category C.
Recent studies have indicated that pregravid BMI should also be considered by clinicians who treat GDM. Results showed overweight women with GDM that is well controlled on diet alone had a 50% greater risk for delivering a macrosomic infant than did normal-weight patients with GDM, and this risk increased twofold for obese women. Of note, overweight and obese women with GDM that was well controlled on insulin had no increased risk for fetal macrosomia, compared to the reference group.32
The oral medications metformin (pregnancy category B) and glyburide, the most widely studied sulfonylurea (pregnancy category C), have been shown to be effective alternatives to insulin without adverse effects in some women.6 However, the studies have been limited.
Long-term effects on children exposed to these medications in utero are yet to be determined, and randomized, prospective studies using oral diabetic medications in pregnancy, with long-term follow-up of mothers and offspring, are needed. (Consequently, in our practice, we only use insulin therapy for GDM.)
Q: What is the follow-up for women diagnosed with GDM?
Due to the prevalence of T2DM in women with GDM, ADA, AACE, and ACOG concur with the recommendations from the Fifth International Workshop-Conference on Gestational Diabetes that a 75-g, 2-h OGTT be administered six to 12 weeks after delivery in women with GDM who do not have diabetes immediately postpartum.5,6,12,23 Thereafter, ADA recommends resuming routine screening every three years, with more frequent testing depending on initial results and risk status.5 Education regarding diet, weight loss, and exercise should be presented as lifestyle changes and adopted by the entire family, since the infant is also at risk for obesity and the metabolic syndrome.
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