Gestational Diabetes: A Comprehensive ReviewWHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC). The prevalence of gestational diabetes mellitus (GDM) continues to rise in the face of the obesity epidemic affecting up to 14% of the population. It is the most common clinical issues facing obstetricians and gynecologists and their patients. Diabetes is classified as type 1 or type 2 according to whether the patient requires insulin injections to avoid ketoacidosis. Gestational diabetes mellitus (GDM) has been characterized as carbohydrate intolerance that begins or is first diagnosed during pregnancy. Reported prevalence in the United States ranges from 1% to 14% with 2-5% being the most common figure. Approximately 7% of all pregnancies are complicated by GDM, resulting in more than 200,000 cases annually. The offspring of women with GDM are prone to such adverse events as macrosomia with its potential complications and hyperbilirubinemia. Newborns of women with GDM are at increased risk for operative delivery, shoulder dystocia, and birth-trauma. The purpose to this document is to provide a comprehensive review of understanding of gestational diabetes mellitus (GDM) and provide management guidelines. Because the risk factors for GDM (particularly obesity) are independent risk factors for fetal macrosomia, the role of maternal hyperglycemia has been widely debated. Considerable controversy remains regarding the exact relationship of these complications to maternal hyperglycemia. Women with GDM are more likely to develop maternal and fetal complications. Whether the relationship with GDM is casual or not, clinicians should be aware of these risks. In addition, women with GDM have an increased risk of developing diabetes later in life. Definition:Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy. The definition applies whether insulin or only diet modification is used for treatment and whether or not the condition persists after pregnancy. It does not exclude the possibility that unrecognized glucose intolerance may have antedated or begun concomitantly with pregnancy (1). A fasting plasma glucose level >126 mg/dL (7.0 mmol/L) or a casual plasma glucose >200 mg/dL (11.1 mmol/L) meets the threshold for the diagnosis of diabetes, if confirmed on a subsequent day, and precludes the need for any glucose challenge. In the absence of this degree of hyperglycemia, evaluation for GDM in women with average or high-risk characteristics should follow one of two approaches: One-step approach: perform a diagnostic oral glucose tolerance test without plasma or serum glucose screening. The one-step approach may be cost effective in high-risk patients or populations. Two-step approach: perform an initial screening by measuring the plasma or serum glucose concentration 1 hour after a 50-g oral glucose load (glucose challenge test) and perform a diagnostic oral glucose tolerance test on that subset of women exceeding the glucose threshold value on the glucose challenge test. When, the two-step approach is employed, a glucose threshold value >140 mg/dL (7.8 mmol/L) identifies approximately 80% of women with GDM, and the yield is further increased to 90% by using a cutoff >130 mg/dL (7.2 mmol/L). Current Screening Practices:All pregnant patients should be screened for GDM, whether by patient's history, clinical risk factors, or laboratory screening test to determine blood glucose levels. A number of studies have demonstrated that the prevalence of GDM increases with advancing gestation (2). It has been customary to recommend the 50-g, 1-hour oral glucose challenge test be administered at 24-28 weeks of gestation. This arbitrary recommendation results from an attempt to balance two competing interests. Insulin resistance increases as pregnancy progresses, therefore, testing later in pregnancy will result in a higher yield of abnormal tests. However, the later the abnormality is diagnosed, the less time will be available for intervention. Although many practitioners choose to screen high-risk patients early in pregnancy, the benefit of early treatment of women with GDM identified early in pregnancy has not been demonstrated but rather has been accepted on a theoretical basis. Patients who had GDM in a previous pregnancy have a 33-35% likelihood of recurrence in a subsequent pregnancy. The screening test commonly used in the United States is the 50-g, 1-hour glucose challenge, using a pure glucose load of 50 g in 150 mL of fluid. Glucose polymer solutions, which provide a lower osmotic load for a given glucose load, appear to be associated with fewer gastrointestinal symptoms and have been demonstrated to yield fair correlation with monomeric glucose solutions. The use of jelly beans instead of a pure glucose challenge has been shown to be better tolerated, but this method has poor sensitivity (40%) when compared with glucose polymer solutions (80-90%) (3). Among patients with GDM, for whom the function of the screening test is most critical, either higher or similar values are reported when the test is administered in the fasting state. Therefore, given the lack of evidence that fasting improves the accuracy of the screening test and the fact that fasting may pose significant logistic problems, the 50-g, 1-hour screening test may be administered without regard to the time elapsed since the last meal. Office-based glucose testing is not recommended because of the difficulty in complying with required federal standards for testing. The original description of the screening test used venous whole blood, but laboratories have switched from whole blood to plasma or serum samples. Detection and Diagnosis:Risk assessment for GDM should be undertaken at the first prenatal visit. Women with clinical characteristics consistent with a high-risk of GDM (marked obesity, personal history of GDM, glycosuria, or a strong family history of diabetes) should undergo glucose testing as soon as feasible. If they are found not to have GDM at that initial screening, they should be retested between 24 and 28 weeks of gestation. With either one-step approach or two-step approach, the diagnosis of GDM is based on the oral glucose tolerance test (GTT). Although a threshold of 140 mg/dL after 50-g 1-hour glucose challenge test was recommended in the past, the most recent position statement of the American Diabetes Association ascribes a sensitivity of approximately 80% to this cutoff and 90% sensitivity with a threshold of 130 mg/dL, leaves the choice open (4). Because the precise cost-benefit ratio of diagnosing GDM remains unresolved, either threshold is acceptable. Diagnostic criteria for the 100-g GTT are derived from Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. It is summarized below (5): Status Plasma or Serum Glucose Level Plasma Level Fasting mg/dL mmol/L mg/dL mmol/L One hour 180 10.0 190 10.6 Two hours 155 8.6 165 9.2 Three hours 140 7.8 145 8.0 A positive diagnosis requires that two or more thresholds be met or exceeded. The test is administered in the morning after an overnight fast. Patients should not smoke before the test and should be instructed to follow an unrestricted diet, consuming at least 150 g of carbohydrate per day for at least 3 days prior to the test. This should avoid carbohydrate depletion, which could cause spuriously high values on the GTT. Patients with only one abnormal value have been demonstrated to manifest increased risk for macrosomic infants and other morbidities. However, because the relationship between carbohydrate metabolism, macrosomia, and other morbidity is a continuum, and because not all of this morbidity arises from carbohydrate intolerance, it should be anticipated that no threshold will identify all patients at risk. Management of Gestational Diabetes Mellitus (GDM):Maternal metabolic surveillance should be directing hyperglycemia severe enough to increase risks to the fetus. Daily self-monitoring of blood glucose appears to be superior to intermittent office monitoring of plasma glucose. For women treated with insulin, limited evidence indicates that postprandial monitoring is superior to pre-prandial monitoring (6). However, the success of either approach depends on the glycemic targets that are set and achieved. Urine glucose monitoring is not useful in GDM. Urine ketone monitoring may be useful in detecting insufficient caloric or carbohydrate intake in women treated with calorie restriction. Maternal surveillance should include blood pressure and urine protein monitoring to detect hypertensive disorders. Increased surveillance for pregnancies at risk for fetal demise is appropriate, particularly when fasting glucose levels exceed 105 mg/dL (5.8 mmol/L) or pregnancy progresses past term. The initiation, frequency, and specific techniques used to assess fetal well-being will depend on the cumulative risk the fetus bears from GDM and any other medical/obstetric conditions present. Assessment for asymmetric fetal growth by ultrasonography, particularly in early third trimester, may aid in identifying fetuses that can benefit from maternal insulin therapy. Programs of moderate physical exercise have been shown to lower maternal glucose concentrations in women with GDM. Although the impact of exercise on neonatal complications awaits rigorous clinical trials, the beneficial glucose-lowering effects warrant a recommendation that women without medical or obstetrical contraindications be encouraged to start or continue a program of moderate exercise as a part of treatment of GDM. The rate of obesity among patients with gestational diabetes is high (approximately 30%) and that no significant differences are found in some studies in pregnancy outcomes between the groups, obese and morbidly obese gestational diabetic women (15). The rate of insulin treatment was high in both groups, but higher in the morbidly obese, and when insulin treatment was initiated, rates of fetal macrosomia and metabolic complications in the newborns were lower. Primarily, it has been demonstrated that good diabetes control leads to good outcomes even in obese and morbidly obese women. Active rather than expectant management of labor at term for women with gestational diabetes may reduce rates of macrosomia and related complications. Further randomized controlled trials and observational studies with a broader range of outcomes are needed for sufficient evidence to inform clinical practice (16). Nutritional Counseling:All women with GDM should receive nutritional counseling, by a registered dietitian when possible, consistent with the recommendations by the American Diabetes Association. Individualization of medical nutritional therapy depending on maternal weight and height is recommended. Medical nutritional therapy should include nutrients to meet the needs of pregnancy and should be consistent with the maternal with the maternal blood glucose goals that have been established. The American Diabetes Association also recommends an average of 30 kcal/kg/d based on pre-pregnant body weight for non-obese individuals. For obese women (BMI >30kg/m2), a 30-33% calorie restriction (to ~25 kcal/kg actual weight per day) has been shown to reduce hyperglycemia and plasma triglycerides with no increase in ketonuria. Restriction of carbohydrates to 35-40% of calories has been shown to decrease maternal glucose levels and improve maternal and fetal outcomes (7). One concern about caloric restriction is that, although glucose levels may decrease, there is possibility that it may cause starvation ketosis. Supplemental dietary fiber may prove glycemic control in women with type-2 diabetes. Role of insulin in the management of GDM:Insulin is the pharmacologic therapy that has most consistently been shown to reduce fetal morbidities when added to medical nutritional therapy. Selection of pregnancies for insulin therapy can be based on measures of maternal glycemia with or without assessment of fetal growth characteristics. One traditional approach has been to add insulin if medical nutritional therapy does not maintain fasting plasma glucose below 105 mg/dL or 2-hour values below 120 mg/dL or both (8). These thresholds have been extrapolated from recommendations for managing pregnancy in women with pre-existing diabetes. Women with higher fasting glucose levels are more likely to require insulin therapy to achieve optimal glucose control than women with lower fasting glucose levels. Measurement of the fetal abdominal circumference early in the third trimester can identify a large subset of infants with no excess risk of macrosomia in the absence of maternal insulin therapy. This approach has been tested primarily in pregnancies with maternal fasting serum glucose levels < 105 mg/dL (5.8 mmol/L). Human insulin should be used when insulin is prescribed, and serum maternal blood glucose should guide the doses and timing of the insulin regimen. The use of insulin analogs has not been adequately tested in GDM. A frequent question is how long to attempt dietary management before adding insulin. One study suggested diet be tried for 2 weeks before adding insulin if the initial fasting plasma glucose was 95 mg/dL or less (9). No particular insulin regimen or insulin dose has been demonstrated to be superior for GDM. Generally, it is easiest for patient to start with the simplest regimen and work up to a more complex regimen as needed. Regardless of the starting dosage, subsequent dosage adjustments should be based on the blood glucose levels at particular times of day. Because free insulin apparently does not cross the placenta, all types of insulin have been used in patients with GDM. Insulin lispro (Humalog), an analog of human insulin with a single amino acid substitution, has a more rapid onset of action than regular insulin and may be useful in improving postprandial glucose concentrations. Role of oral anti-diabetic agents in management of GDM:Oral glucose-lowering agents have generally not been recommended during pregnancy. The early-generation sulfonylureas crossed the placenta and had the potential to stimulate the fetal pancreas, leading to fetal hyperinsulinemia. There also was concern about the potential for teratogenicity, although diabetes itself is teratogenic, and it is difficult to distinguish the effects of the treatment from those of the disease. Glyburide, a second-generation sulfonylurea, was compared with insulin in a randomized trial among patients with GDM who failed to achieve adequate glycemic control with diet alone (10). Glucose control was similar, and the glyburide group had pregnancy outcomes similar to those of insulin group, including rates of cesarean delivery, preeclampsia, macrosomia (>4 kg), and neonatal hypoglycemia. Cord serum analyses showed no detectable glyburide in the infants. Glyburide is more likely to fail in women diagnosed earlier in pregnancy, of older age and multiparity, and with higher fasting glucoses, suggesting that earlier glucose intolerance and a reduced capacity to respond to an insulin secretagogue may distinguish this group (11). At this time, no other oral agent has been shown to be safe and effective in GDM, and further study is recommended before the use of newer oral hypoglycemic agents can be supported for use in pregnancy. Glyburide is not FDA approved for the treatment of GDM. Metformin is a logical treatment for women with gestational diabetes mellitus, but randomized trials to assess the efficacy and safety of its use for this condition are lacking. Metformin improves insulin sensitivity, probably by activating AMP kinase, and is not associated with weight gain or hypoglycemia. Reported outcomes of its use during pregnancy have been favorable except for one small, retrospective cohort study that showed increased rates of perinatal loss and preeclampsia as compared with insulin treatment. The investigators in the Metformin in Gestational Diabetes (MiG) Trial concluded; in women with gestational diabetes mellitus, metformin (alone or with supplemental insulin) is not associated with increased perinatal complications as compared with insulin. The women preferred metformin to insulin treatment (14). Timing and route of delivery in pregnancies complicated by GDM:GDM is not in itself an indication for cesarean delivery or for delivery before 38 completed weeks of gestation. Prolongation of gestation past 38th weeks increases the risk of fetal macrosomia without reducing cesarean rates, so that delivery during the 38th week is recommended unless obstetric considerations dictate otherwise (12). When GDM is well controlled and dates are well documented, respiratory distress syndrome at or beyond 39 weeks of gestation is rare enough that routine amniocentesis for pulmonary maturity is not necessary. At earlier gestational ages, or when control is poor or undocumented, pulmonary maturity should be assessed before induction. However, when early delivery is planned because of maternal or fetal compromise, the urgency of induction should be considered in the decision to perform amniocentesis. Cesarean delivery rates are higher in women with GDM compared with controls, and the difference is not entirely attributable to fetal macrosomia. It would appear reasonable to recommend that patients with GDM be counseled regarding possible cesarean delivery without labor when the estimated fetal weight is 4,500 g or greater. When the estimated weight is 4,000-4,500 g, additional factors such as the patient's past delivery history, clinical pelvimetry, and the progress of labor may be helpful to consider in determining mode of delivery. With an estimated fetal weight greater than 4,500 g, prolonged second stage of labor or arrest of descent in the second stage is an indication for cesarean delivery. Because of the higher likelihood of shoulder dystocia at a given birth weight in the pregnancies of women with diabetes, it may be best to apply the above recommendation to an estimated fetal weight greater than 4,000 g for GDM. Operative deliveries from the midpelvis should be avoided in patients with GDM who have an estimated fetal weight of 4,000 g or more and a prolonged second stage of labor. Postpartum Care & Contraception:Women with a history of GDM are at increased risk for developing diabetes (generally type-2 diabetes) later in life. Current recommendations for the diagnosis and classification of diabetes in the non-pregnant state are based on the recommendations of an expert committee of the American Diabetes Association (13). Maternal glycemic status should be performed at least 6 weeks after delivery. If glucose levels are normal postpartum, reassessment of glycemia should be undertaken at a minimum of 3-year intervals. Women with impaired fasting glucose (110-125 mg/dL) or impaired glucose tolerance test (75-g, 2-hour plasma glucose levels 140-199 mg/dL) should be tested for diabetes annually. These patients should receive intensive medical nutritional therapy and should be placed on an individualized exercise program because of their very high risk for development of diabetes. All patients with prior GDM should be educated regarding lifestyle modifications that lessen insulin resistance, including maintenance of normal body weight through medical nutrition therapy and physical activity. Patients should be advised to seek medical attention if they develop symptoms suggestive of hyperglycemia. Medications that worsen insulin resistance (e.g., glucocorticoids, nicotinic acid) should be avoided if possible. Breastfeeding should be encouraged in women with GDM. In women with either type 1 or type 2 diabetes without vascular disease, use of combination hormonal contraception does not adversely affect metabolic control, promote vascular disease, or increase risk of cardio-vascular disease (14). Use of combination hormonal contraceptive methods does not increase risk of type 2 diabetes in women with prior gestational diabetes. In women with diabetes with vascular involvement, use of combination hormonal contraceptive methods is contraindicated. Based on theoretical concerns, American College of Obstetricians and Gynecologists (ACOG) recommends that use of combination hormonal contraceptives in women with diabetes should be limited to non-smoking, otherwise healthy women who are younger than 35 and have no evidence of hypertension, neuropathy, or retinopathy. For women with diabetes with or without vascular disease or hypertension, use of intrauterine contraceptive devices or progestin-only contraceptive methods is not contraindicated. Offspring of women with GDM should be followed closely for the development of obesity and/or abnormalities of glucose tolerance. Summary:The screening test generally should be performed on venous plasma or serum samples using well-calibrated and well-maintained laboratory instruments. The laboratory screening test should consist of a 50-g, 1-hour oral glucose challenge at 24-28 weeks of gestation, which may be administered without regard to the time of the last meal. A screening test threshold of 140 mg/dL has 10% less sensitivity than a threshold of 130 mg/dL but fewer false-positive results; either threshold is acceptable. Available evidence does not support a recommendation for or against moderate caloric restriction in obese women with GDM. However, if caloric restriction is used, the diet should be restricted by no more than 33% of calories. When medical nutritional therapy has not resulted in fasting glucose levels less than 95 mg/dL or 1-hour postprandial values less than 130-140 mg/dL or 2-hour postprandial values less than 120 mg/dL, insulin should be considered. The role for oral anti-diabetic agents is controversial. For women with GDM and an estimated fetal weight of 4,500 g or more, cesarean delivery may be considered because it may reduce the likelihood of permanent brachial plexus injury in the infant. Low-dose estrogen-progestogen oral contraceptives may be used in women with prior histories of GDM, as long as no medical contraindications exist. Suggested Reading:
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