History

• Typically asymptomatic and detected with screening tests ^c1
• More severe hyperglycemia (at glucose levels that usually occur with overt diabetes) may cause the following symptoms:
  • Polydipsia ^c2
  • Polyuria ^c3
  • Polyphagia ^c4

Physical examination

• Gravid uterus; otherwise unremarkable ^c5

Causes

• Insulin resistance progressively increases throughout gestation ^c6
• Hyperglycemia develops when insulin resistance exceeds the compensatory insulin secretory capacity of pancreatic β-cells to maintain normoglycemia ^r14

Risk factors and/or associations

Primary diagnostic tools

• Routine screening for gestational diabetes is performed in all pregnant patients at 24 to 28 weeks of gestation
  • Consensus has not been reached regarding optimal strategy; either of the following approaches is acceptable: ^r6r21
    • Older and most widely used strategy in North America consists of 2 steps ^r11r20r22
      • Step 1: perform 1-hour 50-g oral glucose challenge test in all patients at 24 to 28 weeks of gestation
      • Step 2: if initial result is abnormal, perform 3-hour 100-g oral glucose tolerance test (2-hour 75-g test in Canada)^r22
    • Alternative 1-step strategy is recommended by the American Diabetes Association and has been adopted internationally ^r6r8r10
      • Perform 75-g oral glucose tolerance test in all patients at 24 to 28 weeks of gestation
        • This method may be associated with better perinatal outcomes compared with 2-step approach ^r23
• Early pregnancy screening for diabetes may be considered in patients at high risk for overt diabetes
  • Screening at initial prenatal tests for patients is as for nonpregnant patients (2-hour 75-g oral glucose tolerance test, fasting blood glucose, and/or hemoglobin A1C test) ^r6r11r20
    • Consider in pregnant patients of any age who are overweight (BMI of 25 kg/m² or higher, or 23 kg/m² or higher in Asian Americans) and have 1 or more additional risk factors, such as: ^r6r11
      • First-degree relative with diabetes
      • High-risk race or ethnicity (eg, African American, Hispanic, Native American, Pacific Islander, Asian American)
      • History of cardiovascular disease
      • Hypertension (blood pressure 140/90 mm Hg or higher or currently on therapy for hypertension)
      • Dyslipidemia (HDL cholesterol level less than 35 mg/dL and/or triglyceride level more than 250 mg/dL)
      • Polycystic ovary syndrome
      • Physical inactivity
      • Conditions associated with insulin resistance (eg, metabolic syndrome, nonalcoholic fatty liver disease, acanthosis nigricans)
      • Those who have previously given birth to an infant weighing more than 4000 g
      • Gestational diabetes in a previous pregnancy
      • Known impaired glucose metabolism
    • If glucose levels meet the criteria for diabetes as established for nonpregnant adults, the diagnosis is overt diabetes and not gestational diabetes ^r5r8
    • If results are not diagnostic of diabetes, test again at 24 to 28 weeks of gestation ^r8r22

Laboratory

• Fasting plasma glucose or serum glucose test ^r8c33
  • Diagnostic of gestational diabetes: 92 to 125 mg/dL
  • Diagnostic of overt diabetes: 126 mg/dL or higher (same reference limit as general population) ^r6
• Random plasma glucose or serum glucose test ^c34
  • Diagnostic of overt diabetes: glucose of 200 mg/dL or higher (same reference limit as general population) ^r6
• Hemoglobin A1C test ^c35
  • Not recommended for diagnosis of gestational diabetes
  • May be used in lieu of plasma or serum glucose levels to diagnose overt diabetes; however, owing to increased RBC turnover, hemoglobin A1C level is usually lower in pregnant patients than in nonpregnant patients (reference ranges differ) ^r6
  • Diagnostic of overt diabetes: 6.5% or higher ^r6
  • Early pregnancy levels between 5.7% and 6.4% may predict subsequent development of gestational diabetes ^r24
• Oral glucose tolerance test ^c36
  • 2-hour 75-g oral glucose tolerance test (1-step testing strategy) ^r6
    • Perform at 24 to 28 weeks on all patients not previously diagnosed with gestational diabetes
    • Perform test on morning after patient completes both an overnight fast of at least 8 hours
    • Blood glucose is measured while fasting and at 1 and 2 hours after oral glucose challenge
    • Diagnostic of gestational diabetes ^r6
      • Fasting glucose of 92 mg/dL or higher
      • 1-hour postprandial glucose level of 180 mg/dL or higher
      • 2-hour postprandial glucose level of 153 mg/dL or higher
  • 1-hour 50-g oral glucose tolerance test, followed by 3-hour 100-g glucose tolerance test, if indicated (2-step testing strategy)
    • Perform at 24 to 28 weeks on all patients not previously diagnosed with diabetes
      • 1-hour 50-g oral glucose tolerance test ^c37
        • First step in 2-step strategy and can be performed without fasting; blood glucose is measured at 1 hour after oral glucose challenge
        • If 1 hour after glucose challenge test glucose level is, depending on criteria used, 130 mg/dL, 135 mg/dL, 140 mg/dL, or higher, proceed to step 2 (3-hour 100-g glucose tolerance test after fasting) ^r6r11
      • 3-hour 100-g glucose tolerance test
        • Second step in 2-step strategy; perform in patients whose 1-hour postprandial glucose level is, depending on criteria used, 130 mg/dL, 135 mg/dL, 140 mg/dL, or higher
        • Perform test on morning after patient completes both an overnight fast of at least 8 hours
        • Gestational diabetes may be diagnosed using one of the following diagnostic criteria:
          • Carpenter and Coustan criteria (recommended by American Diabetes Association and American College of Obstetricians and Gynecologists) ^r6r11
            • Glucose at 0 hour (fasting): 95 mg/dL
            • Glucose level at 1 hour: 180 mg/dL or higher
            • Glucose level at 2 hours: 155 mg/dL or higher
            • Glucose level at 3 hours: 140 mg/dL or higher
          • National Diabetes Data Group criteria (recommended by American College of Obstetricians and Gynecologists) ^r11
            • Glucose at 0 hour (fasting): 105 mg/dL
            • Glucose level at 1 hour: 190 mg/dL or higher
            • Glucose level at 2 hours: 165 mg/dL or higher
            • Glucose level at 3 hours: 145 mg/dL or higher
          • American Diabetes Association bases diagnosis on 2 or more of the abnormal results; however, American College of Obstetricians and Gynecologists allows for use of a single elevated result ^r6r11

Imaging

• Fetal ultrasonography
  • For patients in whom pregestational diabetes is suspected, begin fetal ultrasonographic surveillance in first trimester to monitor for congenital abnormalities ^c38
  • For patients with gestational diabetes, perform fetal ultrasonography between 28 and 36 weeks of gestation to estimate fetal weight and size ^c39
  • Information about fetal size is useful to identify any need for more intensive metabolic management,^r25 scheduled cesarean delivery, or early induction of labor
    • Fetal abdominal circumference above 75th percentile is indicative of fetal overgrowth

Most common

• Pregestational type 1 or type 2 diabetes ^c40c41d1
  • Persistence of hyperglycemia after delivery suggests unrecognized pregestational onset of type 1 or type 2 diabetes ^d2
  • To differentiate between gestational and type 1 or type 2 diabetes, perform standard laboratory testing for diabetes at 6 to 12 weeks after delivery. Test with 1 of 3 methods, using nonpregnant criteria^r6 (result must be confirmed by repeated testing; if 1 of the results is abnormal, diabetes likely predated pregnancy)
    • Fasting serum glucose level (126 mg/dL or higher is diagnostic of diabetes) ^r6
    • Hemoglobin A1C level (6.5% or higher is diagnostic of diabetes) ^r6
    • 2-hour 75-g oral glucose tolerance test (2-hour glucose level of 200 mg/dL or higher is diagnostic of diabetes) ^r6
• Nondiabetic hyperglycemia that develops either pregestationally or during pregnancy ^c42c43c44
  • May occur as an associated condition in the setting of other rare disorders, such as Cushing syndrome, acromegaly, or pheochromocytoma

Recommendations for specialist referral

• Refer all patients to a registered dietitian for individualized medical nutrition therapy
• Refer all patients to a diabetes educator for education on blood glucose monitoring
• Refer patients with gestational diabetes that requires pharmacotherapy to an endocrinologist; ideal management is in a multidisciplinary setting with endocrine and maternal-fetal medicine specialists

Drug therapy

• Insulin ^c45
  • Indicated for pregnant patients who meet criteria diagnostic of overt diabetes or for whom metabolic goals have not been met through lifestyle modification
  • Insulin is the preferred medication for treating hyperglycemia in gestational diabetes according to the American Diabetes Association ^r5
  • Usually administered as multiple daily injections but can be delivered with continuous subcutaneous infusion
    • Delivery methods appear to be equally effective; evidence does not support one over the other, but advances in technology may change this
  • Initiation of insulin ^r11
    • If insulin is used throughout the day in patients in whom fasting and postprandial hyperglycemia are present after most meals, a typical starting total dosage is 0.7 to 1 units/kg daily; this dosage should be divided with a regimen of multiple injections using long-acting or intermediate-acting insulin in combination with rapid-acting insulin ^r36
    • If there are only isolated abnormal values at a specific time of day, use insulin to target the specific time range during which hyperglycemia is observed
      • Examples: give a dose of intermediate-acting insulin at nighttime to avoid elevated morning fasting glucose levels; or, give a dose of rapid-acting insulin before breakfast to avoid elevated postprandial glucose levels
  • Insulin adjustments
    • Insulin usually needs to be continuously adjusted to achieve glycemic targets ^r20
      • Adjust insulin dosing on an individualized basis to keep fasting, preprandial, and 1- or 2-hour postprandial values within target ranges
    • At onset of labor, insulin requirements typically decrease but must be carefully monitored and adjusted
      • Discontinue insulin therapy in those patients with gestational diabetes (not type 1 diabetes) during labor or at delivery. Patients with type 1 diabetes always require exogenous insulin on board
  • Short-acting insulin
    • Regular insulin ^c46
      • For pregnant patients with gestational-onset diabetes not controlled by diet therapy alone
        • Insulin Regular (Recombinant) Solution for injection; Adults and Adolescents (pregnant females): Dosing must be individualized. For women with persistent fasting and postprandial hyperglycemia after most meals, initial total daily insulin requirements are roughly 0.7 to 1 units/kg/day. This dosage should be divided with a regimen of multiple injections using long-acting or intermediate-acting insulin in combination with short-acting insulin. If only isolated abnormal values are present at a specific time of day, focus the insulin regimen to correct the specific hyperglycemia. During labor, requirements change. Insulin is often discontinued during or after labor.
      • For pregnant patients with preexisting diabetes (before pregnancy)
        • Insulin Regular (Recombinant) Solution for injection; Adults and Adolescents (pregnant females): On average, insulin needs increase from a range of 0.7 to 0.8 units/kg of actual body weight/day in the first trimester to 0.8 to 1 units/kg/day in the second trimester, to 0.9 to 1.2 units/kg/day in the third trimester; individualize dosage. The daily dose is usually divided and administered in varying ratios of long-acting or intermediate-acting insulin: short-acting insulin, to fit individual patient needs. During labor and postpartum, hyperglycemia must be closely managed due to the changes in insulin requirements and variable calorie intake.
  • Rapid-acting insulin analogs
    • Insulin lispro ^c47
      • For pregnant patients with gestational-onset diabetes not controlled by diet therapy alone
        • Insulin Lispro Solution for injection; Adults and Adolescents (pregnant females): Dosing must be individualized. For women with persistent fasting and postprandial hyperglycemia after most meals, initial total daily insulin requirements are roughly 0.7 to 1 units/kg/day. This dosage should be divided with a regimen of multiple injections using long-acting or intermediate-acting insulin in combination with short-acting insulin. If only isolated abnormal values are present at a specific time of day, focus the insulin regimen to correct the specific hyperglycemia. During labor, requirements change. Insulin is often discontinued during or after labor.
      • For pregnant patients with preexisting diabetes (before pregnancy)
        • Insulin Lispro Solution for injection; Adults and Adolescents (pregnant females): On average, insulin needs increase from a range of 0.7 to 0.8 units/kg of actual body weight/day in the first trimester, to 0.8 to 1 units/kg/day in the second trimester, to 0.9 to 1.2 units/kg/day in the third trimester; individualize dosage. The daily dose is usually divided and administered in varying ratios of long-acting or intermediate-acting insulin: short-acting insulin, to fit individual patient needs. During labor and postpartum, hyperglycemia must be closely managed due to the changes in insulin requirements and variable calorie intake.
    • Insulin aspart ^c48
      • For pregnant patients with gestational-onset diabetes not controlled by diet therapy alone
        • Insulin Aspart (Recombinant) Solution for injection; Adults and Adolescents (pregnant females): Dose guidelines vary and must be individualized. For women with persistent fasting and postprandial hyperglycemia after most meals, initial suggested daily insulin requirements are roughly 0.7 to 1 units/kg/day. This dosage should be divided with a regimen of multiple injections using long-acting or intermediate-acting insulin in combination with short-acting insulin. If only isolated abnormal values are present at a specific time of day, the insulin regimen should be focused to correct the specific hyperglycemia. During labor, requirements change. Insulin is often discontinued during or after labor.
      • For pregnant patients with preexisting diabetes (before pregnancy)
        • Insulin Aspart (Recombinant) Solution for injection; Adults and Adolescents (pregnant females): On average, insulin needs increase from a range of 0.7 to 0.8 units/kg of actual body weight/day in the first trimester to 0.8 to 1 units/kg/day in the second trimester, to 0.9 to 1.2 units/kg/day in the third trimester; individualize dosage. The daily dose is usually divided and administered in varying ratios of long-acting or intermediate-acting insulin: short-acting insulin, to fit individual patient needs. During labor and postpartum, hyperglycemia must be closely managed due to the changes in insulin requirements and variable calorie intake.
  • Intermediate-acting insulin ^c49
    • May be used in combination with regular insulin for longer-acting glycemic control.
    • Insulin Suspension Isophane (NPH) (Recombinant) Suspension for injection; Adults and Adolescents (pregnant females): Dosing must be individualized. For women with persistent fasting and postprandial hyperglycemia after most meals, initial total daily insulin requirements are roughly 0.7 to 1 units/kg/day. This dosage should be divided with a regimen of multiple injections using long-acting or intermediate-acting insulin in combination with short-acting insulin. If only isolated abnormal values are present at a specific time of day, focus the insulin regimen to correct the specific hyperglycemia. During labor, requirements change. Insulin is often discontinued during or after labor.
  • Long-acting insulin analogs
    • For pregnant patients with preexisting diabetes (before pregnancy)
    • Insulin detemir ^c50
      • Insulin Detemir (Recombinant) Solution for injection; Adults and Adolescents (pregnant females): Dose guidelines vary and must be individualized. Initial suggested daily insulin requirements: 0.3 to 0.7 units/kg/day; requirements usually increase during second and third trimesters (0.8 units/kg/day or more). During labor, requirements decrease; usually return to normoglycemia several days postpartum. Insulin is often discontinued during or after labor.
    • Insulin glargine ^c51
      • Insulin Glargine for injection; Adults and Adolescents (pregnant females): Dose guidelines vary and must be individualized. Initial suggested daily insulin requirements: 0.3 to 0.7 units/kg/day; requirements usually increase during second and third trimesters (0.8 units/kg/day or more). During labor, requirements decrease; usually return to normoglycemia several days postpartum. Insulin is often discontinued during or after labor.
• Oral hypoglycemic medications ^c52
  • Indicated for pregnant patients whose metabolic goals are not met with lifestyle approaches alone, for those who decline insulin, and for those in whom insulin administration may not be safe
  • Glyburide ^c53
    • Glyburide’s glycemic control is comparable with that of insulin, but glyburide may cross the placenta and lacks long-term safety data ^r37
      • Glyburide Oral tablet; Adults (pregnant females): 1.25 mg PO twice daily initially, titrated by no more than 5 mg/day PO each week, up to 10 mg PO twice daily, has been studied. Recommended Max: 10 mg PO twice daily. Long-term safety is not established; not a first-line treatment for gestational diabetes mellitus (GDM) or pregnant patients with pre-existing type 2 diabetes mellitus (T2DM) per ACOG and the ADA.
  • Metformin hydrochloride ^c54
    • Metformin Hydrochloride Oral tablet; Adult females: 500 mg PO once nightly for 1 week, then titrate to 500 mg PO twice daily. May further titrate the daily dose by 500 mg every 1 to 2 weeks to attain glycemic targets. Max: If needed, up to 2.5 to 3 grams/day PO, given in 2 or 3 divided doses has been studied; metformin is not the first-line choice for women with GDM.

Nondrug and supportive care

• Medical nutrition therapy ^c55
  • Cornerstone of metabolic management with oversight by a registered dietitian (familiar with the management of gestational diabetes) ongoing throughout pregnancy ^r38
  • Adjust initial caloric prescription (35-38 kcal/kg of ideal body weight) as needed to maintain weight gain within the range appropriate for the prepregnancy weight ^r39
  • Moderate caloric restriction^r40 (25% below level of standard diets) results in some correction of hyperglycemia ^c56
  • Dietary composition that best optimizes perinatal maternal and fetal outcomes is not known ^r38
    • Type of diet employed does not appear to affect most maternal outcomes (eg, hypertensive disorders of pregnancy, type 2 diabetes) or neonatal outcomes (eg, large-for-gestational-age status, mortality, morbidity, neurosensory disability) ^r41
    • Small reduction in rates of cesarean delivery has been observed in patients who consume a DASH diet (Dietary Approaches to Stop Hypertension) ^r41
    • Other short-term outcomes are similar, comparing strategies such as low-moderate glycemic index diet versus moderate glycemic index diet, DASH diet versus control diet, low-carbohydrate diet versus high-carbohydrate diet, and high-unsaturated-fat diet versus low-unsaturated-fat diet ^r41
  • Macronutrient requirements
    • Dietary Reference Intake for all pregnant patients, including those with gestational diabetes, specifies a minimum of 175 grams of carbohydrates, a minimum of 71 grams of protein (or 1.1 g/kg/day protein), and 28 grams of fiber ^r5
    • Available evidence does not identify the ideal amount (grams or percent of total calories) of carbohydrates to achieve glycemic targets
• Exercise ^c57
  • May improve glycemic control^r42r43 when performed at moderate intensity at least 3 times per week^r42
  • Moderate exercise is safe and effective in reducing both fasting and postprandial blood glucose levels^r5 in patients with gestational diabetes
    • Moderate exercise is defined as 20-minute intervals of cardiovascular training at a target heart rate approximately 70% of maximum heart rate
    • Examples of moderate intensity physical activity include brisk walking, water aerobics, stationary cycling, resistance training, and household chores ^r44
  • Patients with gestational diabetes on insulin must take precautions to avoid hypoglycemia ^r45
• Effectiveness of lifestyle changes ^c58
  • Patients participating in lifestyle changes of dietary modifications and physical activity are more likely to achieve postpartum weight goals 1 year after pregnancy ^r46
  • Patients participating in lifestyle changes of dietary modifications and physical activity have reduced risk of delivering large-for-gestational-age neonates and greater likelihood that neonates will have less adiposity ^r46
  • A Cochrane review found that lifestyle changes have beneficial effects on maternal health and reduce the risk of infants being large for gestational age ^r47

At-risk populations

• Screen patients at high risk of overt diabetes before pregnancy or at first prenatal visit as well as at 24 to 28 weeks
  • This includes patients who are overweight or obese and have 1 or more of the following: ^r6r11
    • Physical inactivity
    • First-degree relative with diabetes
    • African American, Asian, Native American, Pacific Islander, or Hispanic ethnicity ^c75c76c77
    • Previous delivery of a macrosomic infant (weighing 4 kg or more)
    • Previous gestational diabetes
    • Hypertension (140/90 mm Hg) or therapy for hypertension
    • Low HDL cholesterol level (35 mg/dL or lower) or high triglyceride level (more than 250 mg/dL)
    • Polycystic ovary syndrome
    • History of cardiovascular disease
    • Other conditions associated with insulin resistance
    • Known impaired glucose metabolism

Screening tests

• Glucose tolerance test ^c78c79c80
  • 2-hour, 75-g oral glucose tolerance test is most widely recommended by the International Association of the Diabetes and Pregnancy Study Groups and American Diabetes Association ^r6r8
  • 1-hour, 50-g oral glucose challenge test is recommended by the American College of Obstetricians and Gynecologists, with a 3-hour test to follow for those with an abnormal initial result ^r11