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    Gestational diabetes

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    Apr.15.2024

    Gestational Diabetes

    Synopsis

    Key Points

    • Gestational diabetes is any degree of glucose intolerance with onset or first recognition during pregnancy
    • Diagnosis is usually made with oral glucose tolerance test
    • Mainstay of treatment consists of lifestyle changes and, when necessary, insulin or oral hypoglycemic agents to achieve specified glycemic targets
    • Treatment of gestational diabetes can reduce the rate of adverse pregnancy outcomes,r1r2 including macrosomia, fetal adiposity, preeclampsia, and gestational hypertension
    • Patients with gestational diabetes are at higher lifetime risk for development of postpartum type 2 diabetesr3
    • Treatment of gestational diabetes is associated with improved health outcomes r4

    Urgent Action

    • Treat patients with severe hyperglycemia (ie, glucose levels indicative of overt diabetes) with insulin immediately

    Pitfalls

    • Hemoglobin A1C target in pregnancy is less than 6%r5 but should be pursued only if it can be achieved without significant hypoglycemia

    Terminology

    Clinical Clarification

    • Gestational diabetes (gestational diabetes mellitus) is any degree of glucose intolerance with onset or first recognition during pregnancy: diagnosis is typically applied to patients meeting criteria for diagnosis when tested between 24 and 28 weeks of pregnancy r6
    • Depending on the criteria used, gestational diabetes occurs in 13.4% to 14.6% of pregnancies r7
    • Patients who are diagnosed with diabetes at an early prenatal visit using standard diagnostic criteria are diagnosed with diabetes complicating pregnancy (this is usually type 2 diabetes) r6
    • Diagnostic criteria are based on results of oral glucose tolerance test; recommended diagnostic thresholds vary by professional society
      • Defining criteria of International Association of the Diabetes and Pregnancy Study Groupsr8r9 are used internationally and are endorsed by WHO,r10American Diabetes Associationr6, and Endocrine Societyr11
      • Defining criteria of American College of Obstetricians and Gynecologistsr12 and NIHr13 are used primarily in the United States

    Classification

    • Pregnant patients with gestational diabetes are categorized according to the White classification: r12r14
      • Class A1: diabetes diagnosed during pregnancy and controlled by diet
      • Class A2: diabetes diagnosed during pregnancy and requiring medication

    Diagnosis

    Clinical Presentation

    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 and Risk Factors

    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 r15

    Risk factors and/or associations

    Age
    • More common in patients older than 25 years c7
    Genetics
    • Polygenic influences contribute to risk r16r17c8
      • Increased risk of gestational diabetes in those with variants in TCF7L2, ABCC8, HKDC1, and BACE2 genes r16r18c9c10c11c12
    • Maternal history of gestational diabetes or family history of type 2 diabetes imparts strong risk c13c14
    Ethnicity/race
    • Higher rates of gestational diabetes are found in the following populations: r19
    Other risk factors/associations
    • Overweight or obesityr20 (BMI greater than 25 kg/m²) c19c20
    • Personal history of glucose intolerance or prior gestational diabetes c21c22
    • Family history of gestational or type 2 diabetes c23
    • Polycystic ovary syndrome c24
    • Acanthosis nigricans r21c25
    • Twin gestation c26
    • Hypertension c27
    • Long-term corticosteroid use c28
    • Previous birth of infant weighing more than 4000 g or with shoulder dystocia c29c30
    • Unexplained perinatal loss or malformation c31c32

    Diagnostic Procedures

    Primary diagnostic tools

    • Perform 2-hour 75-g oral glucose tolerance test in all pregnant patients at 24 to 28 weeks of gestation
      • 1-step strategy is recommended by the American Diabetes Association and has superseded the older 2-step approach based on a initial 1-hour 50-g oral glucose challenge test r6r9r11
      • Significantly increases the diagnosis of gestational diabetes; may be associated with better perinatal outcomes compared with 2-step approach r6r22
    • Early pregnancy screening (before 15 weeks) for overt diabetes or prediabetes is recommended in patients with certain risk factors r6
      • Screening tests are the same as for nonpregnant patients (2-hour 75-g oral glucose tolerance test, fasting blood glucose, and/or hemoglobin A1C test) r6r12r21
        • Includes pregnant patients of any age who are overweight (BMI of 25 kg/m² or greater, or 23 kg/m² or greater in Asian Americans) and have 1 or more additional risk factors, such as: r6r12
          • 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 patients with hypertension)
          • Dyslipidemia (HDL-C level less than 35 mg/dL and/or triglyceride level greater than 250 mg/dL)
          • Polycystic ovary syndrome
          • Physical inactivity
          • Conditions associated with insulin resistance (eg, metabolic syndrome, acanthosis nigricans, MASLD (metabolic dysfunction-associated steatotic liver disease, formerly nonalcohoic fatty liver disease)
          • 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 r6r9
        • If results are not diagnostic of diabetes, test again at 24 to 28 weeks of gestation r9r23
    • Consider universal early screening (before 15 weeks) for abnormal glucose metabolism (defined as fasting plasma glucose 110 to 125 mg/dL or A1C 5.9% to 6.4%) r6
      • Identifies individuals at higher risk of adverse maternal and neonatal outcomes, who are more likely to require insulin treatment, and who are at high risk of a later diagnosis of gestational diabetes r6
      • If results are negative, rescreen at 24 to 28 weeks r6
      • The benefit of immediate treatment for those with abnormal results is not well defined, but a recent randomized trial found a significant but modest reduction in a composite outcome of adverse neonatal events r24

    Laboratory

    • Fasting plasma glucose or serum glucose test r9c33
      • 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) r5
      • 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 r25
    • 2-hour 75-g oral glucose tolerance test r6c36
      • Perform at 24 to 28 weeks on all patients not previously diagnosed with gestational diabetes
      • Perform test on morning after patient completes 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

    Imaging

    • Fetal ultrasonography
      • For patients in whom pregestational diabetes is suspected, begin fetal ultrasonographic surveillance in first trimester to monitor for congenital abnormalities c37
      • For patients with gestational diabetes, perform fetal ultrasonography between 28 and 36 weeks of gestation to estimate fetal weight and size c38
      • Information about fetal size is useful to identify any need for more intensive metabolic management,r26 scheduled cesarean delivery, or early induction of labor
        • Fetal abdominal circumference above 75th percentile is indicative of fetal overgrowth

    Differential Diagnosis

    Most common

    • Pregestational type 1 or type 2 diabetes c39c40d1
      • 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 4 to 12 weeks after delivery. Test with 1 of 3 methods, using nonpregnant criteria (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 c41c42c43
      • May occur as an associated condition in the setting of other rare disorders, such as Cushing syndrome, acromegaly, or pheochromocytoma

    Treatment

    Goals

    • Primary goals of the metabolic aspect of treatment are to restore fasting and postprandial glucose levels to within reference ranges
    • Target glucose levels r5r12r27
      • Fasting: 95 mg/dL or less
      • 1-hour postprandial: 140 mg/dL or less
      • 2-hour postprandial: 120 mg/dL or less
    • Hemoglobin A1C levels
      • Target of less than 6% is optimal during pregnancy if it can be achieved without significant hypoglycemia r5r27
      • Use as a secondary measure of glycemic control in pregnancy, after blood glucose monitoring r5
        • Hemoglobin A1C levels fall during normal pregnancy owing to increased RBC turnover
        • Hemoglobin A1C levels do not capture postprandial hyperglycemia, which is the major factor underlying macrosomia
    • Goals of obstetric management are the following:
      • Deliver healthy neonates by reducing fetal adiposity, birth weight, and instances of large-for-gestational-age status r1r4r28
      • Avoid maternal complications r4

    Disposition

    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

    Treatment Options

    Lifestyle modifications (eg, medical nutrition therapy, exercise, weight management) are used as first line therapy r5

    • Lifestyle measures alone may be sufficient for many patients (approximately 70%-85%) r29
    • Medications are added if needed to achieve treatment targets

    Metabolic surveillance is an essential component of management r5

    • Most patients with gestational diabetes should monitor fasting and postprandial capillary blood glucose levels as a strategy to achieve optimal metabolic control
    • Insulin-treated patients in particular must monitor capillary blood glucose levels while fasting and at 1 or 2 hours after eating to guide adjustment of insulin doses
      • Continuous glucose monitoring has been shown to aid in optimization of glycemia in pregnancy complicated by type 1 diabetes; however, there is insufficient data to support its use in patients with gestational diabetes r5r30

    Intensified metabolic therapy, using pharmacotherapy, is required in the following situations: r5

    • Maternal metabolic goals are not met (when more than 25% of glucose monitoring values are above fasting/preprandial or postprandial targets)
    • Obstetric fetal ultrasonography finds signs of excessive fetal growth (ie, abdominal circumference above 75th percentile, macrosomia)

    Choice of pharmacotherapy

    • First line pharmacotherapy (when required) is insulin r5r12
      • Indicated for pregnant patients who meet criteria diagnostic of overt diabetes or for whom metabolic goals have not been met through lifestyle modification
      • Insulin can provide tight glycemic control, does not cross placenta, and has an extensive history and safety record r12r28
      • Insulin is the preferred medication for treating hyperglycemia in gestational diabetes according to the American Diabetes Association r5
      • Insulin is always required for patients with type 1 diabetes and is typically required for management of patients who have pregestational type 2 diabetes
      • 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
    • Oral hypoglycemic agents are used as alternatives only when insulin administration may be unsafe or unfeasible r5r31
      • Indicated for pregnant patients whose metabolic goals are not met with lifestyle approaches alone and who decline insulin or those in whom insulin administration may not be safe
      • Known to cross the placenta and concerns persist among many experts regarding long-term safety and possible adverse developmental programming effects associated with oral hypoglycemic agents r32
        • Exposure in utero may produce an adverse metabolic/obesogenic phenotype in offspring
      • Preferred oral agent is also controversial
        • American Diabetes Association cautiously suggests use of either metformin or glyburide (glibenclamide) as alternatives to insulin r5
        • American College of Obstetricians and Gynecologists, American Association of Clinical Endocrinology, Diabetes Canada, and Society for Maternal-Fetal Medicine suggest use of metformin in preference to glyburide r12r21r27r33
        • Studies have shown that metformin and glyburide have comparable effects on glycemia and incidence of adverse effects,r35 but more recent evidence suggests that glyburide does not yield equivalent outcomes compared with insulin or metformin r12r34
        • Both glyburide and metformin failed to provide adequate glycemic outcomes in approximately a quarter of patients with gestational diabetes according to individual randomized controlled trials r5
    • Aspirin can be used to lower the risk of preeclampsia
      • Pregnant individuals with type 1 or type 2 diabetes should be prescribed low-dose aspirin starting at 12 to 16 weeks gestation r5
      • May be indicated in individuals with gestational diabetes who have 1 high-risk factor for preeclampsia (eg, hypertension, autoimmune disease) or multiple moderate-risk factors (eg, nulliparous, obesity, aged 35 years or older)

    Delivery

    • Patients with good glycemic control and no complications may deliver at term r12
      • Those with control by diet and exercise may be managed expectantly until 40 6/7 weeks
      • Those with control by pharmacotherapy should have delivery between 39 0/7 and 39 6/7 weeks
    • Timing of delivery in patients with poorly controlled diabetes is controversial r12r23
      • Take into consideration risk of prematurity versus risk of stillbirth
      • Induction of labor between 37 0/7 weeks and 38 6/7 weeks is reasonable, with earlier delivery reserved for patients whose condition is refractory to inpatient treatment and those with abnormal results on antepartum fetal testing
    • Mode of delivery should take into consideration estimated fetal size r12
      • Scheduled cesarean delivery may be considered when estimated fetal weight is 4500 g or more (to minimize risk of birth trauma associated with macrosomia)
    • Manage intrapartum blood glucose levels (to avoid maternal hyperglycemia and neonatal hypoglycemia)
      • Suggested blood glucose target range is 72 to 126 mg/dL r11r21

    Postpartum management r21

    • Recommend breastfeeding immediately after delivery (to prevent neonatal hypoglycemia) and encourage mother to continue it for at least 4 months
      • Breastfeeding reduces adverse outcomes (eg, childhood obesity and diabetes, maternal type 2 diabetes and hypertension) r36
    • Recommend weight loss to achieve BMI in reference range (to reduce risk of development of type 2 diabetes or gestational diabetes in a subsequent pregnancy)

    Drug therapy

    • Insulin c44
      • Initiation of insulin r12
        • If insulin is used throughout the day in patients in whom fasting and postprandial hyperglycemia are present (after most meals), the insulin dose should be divided with a regimen of multiple injections using long-acting or intermediate-acting insulin in combination with rapid-acting insulin r37
        • 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 r21
          • 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 c45
          • For pregnant patients with gestational-onset diabetes not controlled by diet alone
            • Insulin Regular (Recombinant) Solution for injection; Adolescents: 0.7 to 1 units/kg/day subcutaneously is the typical starting total daily insulin dose using a regimen of multiple injections of long- or intermediate-acting insulin plus short-acting insulin in cases where fasting and postprandial hyperglycemia are present. Focus the regimen to correct the specific hyperglycemia if there are only isolated abnormal blood glucose values at a particular time of day. Adjust dose based on blood glucose.
            • Insulin Regular (Recombinant) Solution for injection; Adults: 0.7 to 1 units/kg/day subcutaneously is the typical starting total daily insulin dose using a regimen of multiple injections of long- or intermediate-acting insulin plus short-acting insulin in cases where fasting and postprandial hyperglycemia are present. Focus the regimen to correct the specific hyperglycemia if there are only isolated abnormal blood glucose values at a particular time of day. Adjust dose based on blood glucose.
          • For pregnant patients with preexisting diabetes (before pregnancy)
            • Insulin Regular (Recombinant) Solution for injection; Adolescents: 0.7 to 0.8 units/kg in the first trimester, 0.8 to 1 units/kg/day in the second trimester, and 0.9 to 1.2 units/kg/day in the third trimester is the typical total daily insulin dose using a regimen of multiple injections of long- or intermediate-acting insulin plus short-acting insulin. Adjust dose based on blood glucose and glycemic control goal. Base dose on actual body weight.
            • Insulin Regular (Recombinant) Solution for injection; Adults: 0.7 to 0.8 units/kg in the first trimester, 0.8 to 1 units/kg/day in the second trimester, and 0.9 to 1.2 units/kg/day in the third trimester is the typical total daily insulin dose using a regimen of multiple injections of long- or intermediate-acting insulin plus short-acting insulin. Adjust dose based on blood glucose and glycemic control goal. Base dose on actual body weight.
      • Rapid-acting insulin analogs
        • Insulin lispro c46
          • For pregnant patients with gestational-onset diabetes not controlled by diet alone
            • Insulin Lispro Solution for injection; Adolescents: 0.7 to 1 units/kg/day subcutaneously is the typical starting total daily insulin dose using a regimen of multiple injections of long- or intermediate-acting insulin plus short-acting insulin in cases where fasting and postprandial hyperglycemia are present. Focus the regimen to correct the specific hyperglycemia if there are only isolated abnormal blood glucose values at a particular time of day. Adjust dose based on blood glucose.
            • Insulin Lispro Solution for injection; Adults: 0.7 to 1 units/kg/day subcutaneously is the typical starting total daily insulin dose using a regimen of multiple injections of long- or intermediate-acting insulin plus short-acting insulin in cases where fasting and postprandial hyperglycemia are present. Focus the regimen to correct the specific hyperglycemia if there are only isolated abnormal blood glucose values at a particular time of day. Adjust dose based on blood glucose.
          • For pregnant patients with preexisting diabetes (before pregnancy)
            • Insulin Lispro Solution for injection; Adolescents: 0.7 to 0.8 units/kg in the first trimester, 0.8 to 1 units/kg/day in the second trimester, and 0.9 to 1.2 units/kg/day in the third trimester is the typical total daily insulin dose using a regimen of multiple injections of long- or intermediate-acting insulin plus short-acting insulin. Adjust dose based on blood glucose and glycemic control goal. Base dose on actual body weight.
            • Insulin Lispro Solution for injection; Adults: 0.7 to 0.8 units/kg in the first trimester, 0.8 to 1 units/kg/day in the second trimester, and 0.9 to 1.2 units/kg/day in the third trimester is the typical total daily insulin dose using a regimen of multiple injections of long- or intermediate-acting insulin plus short-acting insulin. Adjust dose based on blood glucose and glycemic control goal. Base dose on actual body weight.
        • Insulin aspart c47
          • For pregnant patients with gestational-onset diabetes not controlled by diet alone
            • Insulin Aspart (Recombinant) Solution for injection; Adolescents: 0.7 to 1 units/kg/day subcutaneously is the typical starting total daily insulin dose using a regimen of multiple injections of long- or intermediate-acting insulin plus short-acting insulin in cases where fasting and postprandial hyperglycemia are present. Focus the regimen to correct the specific hyperglycemia if there are only isolated abnormal blood glucose values at a particular time of day. Adjust dose based on blood glucose.
            • Insulin Aspart (Recombinant) Solution for injection; Adults: 0.7 to 1 units/kg/day subcutaneously is the typical starting total daily insulin dose using a regimen of multiple injections of long- or intermediate-acting insulin plus short-acting insulin in cases where fasting and postprandial hyperglycemia are present. Focus the regimen to correct the specific hyperglycemia if there are only isolated abnormal blood glucose values at a particular time of day. Adjust dose based on blood glucose.
          • For pregnant patients with preexisting diabetes (before pregnancy)
            • Insulin Aspart (Recombinant) Solution for injection; Adolescents: 0.7 to 0.8 units/kg in the first trimester, 0.8 to 1 units/kg/day in the second trimester, and 0.9 to 1.2 units/kg/day in the third trimester is the typical total daily insulin dose using a regimen of multiple injections of long- or intermediate-acting insulin plus short-acting insulin. Adjust dose based on blood glucose and glycemic control goal. Base dose on actual body weight.
            • Insulin Aspart (Recombinant) Solution for injection; Adults: 0.7 to 0.8 units/kg in the first trimester, 0.8 to 1 units/kg/day in the second trimester, and 0.9 to 1.2 units/kg/day in the third trimester is the typical total daily insulin dose using a regimen of multiple injections of long- or intermediate-acting insulin plus short-acting insulin. Adjust dose based on blood glucose and glycemic control goal. Base dose on actual body weight.
      • Intermediate-acting insulin c48
        • May be used in combination with regular insulin for longer-acting glycemic control.
        • Isophane insulin (neutral protamine Hagedorn)
          • For pregnant patients with gestational-onset diabetes not controlled by diet alone
            • Insulin Suspension Isophane (NPH) (Recombinant) Suspension for injection; Adolescents: 0.7 to 1 units/kg/day subcutaneously is the typical starting total daily insulin dose using a regimen of multiple injections of long- or intermediate-acting insulin plus short-acting insulin in cases where fasting and postprandial hyperglycemia are present. Focus the regimen to correct the specific hyperglycemia if there are only isolated abnormal blood glucose values at a particular time of day. Adjust dose based on blood glucose.
            • Insulin Suspension Isophane (NPH) (Recombinant) Suspension for injection; Adults: 0.7 to 1 units/kg/day subcutaneously is the typical starting total daily insulin dose using a regimen of multiple injections of long- or intermediate-acting insulin plus short-acting insulin in cases where fasting and postprandial hyperglycemia are present. Focus the regimen to correct the specific hyperglycemia if there are only isolated abnormal blood glucose values at a particular time of day. Adjust dose based on blood glucose.
          • For pregnant patients with preexisting diabetes (before pregnancy)
            • Insulin Suspension Isophane (NPH) (Recombinant) Suspension for injection; Adolescents: 0.7 to 0.8 units/kg in the first trimester, 0.8 to 1 units/kg/day in the second trimester, and 0.9 to 1.2 units/kg/day in the third trimester is the typical total daily insulin dose using a regimen of multiple injections of long- or intermediate-acting insulin plus short-acting insulin. Adjust dose based on blood glucose and glycemic control goal. Base dose on actual body weight.
            • Insulin Suspension Isophane (NPH) (Recombinant) Suspension for injection; Adults: 0.7 to 0.8 units/kg in the first trimester, 0.8 to 1 units/kg/day in the second trimester, and 0.9 to 1.2 units/kg/day in the third trimester is the typical total daily insulin dose using a regimen of multiple injections of long- or intermediate-acting insulin plus short-acting insulin. Adjust dose based on blood glucose and glycemic control goal. Base dose on actual body weight.
      • Long-acting insulin analogs
        • Insulin glargine c49
          • For pregnant patients with gestational-onset diabetes not controlled by diet alone
            • Insulin Glargine Solution for injection; Adolescents: 0.7 to 1 units/kg/day subcutaneously is the typical starting total daily insulin dose using a regimen of multiple injections of long- or intermediate-acting insulin plus short-acting insulin in cases where fasting and postprandial hyperglycemia are present. Focus the regimen to correct the specific hyperglycemia if there are only isolated abnormal blood glucose values at a particular time of day. Adjust dose based on blood glucose.
            • Insulin Glargine Solution for injection; Adults: 0.7 to 1 units/kg/day subcutaneously is the typical starting total daily insulin dose using a regimen of multiple injections of long- or intermediate-acting insulin plus short-acting insulin in cases where fasting and postprandial hyperglycemia are present. Focus the regimen to correct the specific hyperglycemia if there are only isolated abnormal blood glucose values at a particular time of day. Adjust dose based on blood glucose.
          • For pregnant patients with preexisting diabetes (before pregnancy)
            • Insulin Glargine Solution for injection; Adolescents: 0.7 to 0.8 units/kg in the first trimester, 0.8 to 1 units/kg/day in the second trimester, and 0.9 to 1.2 units/kg/day in the third trimester is the typical total daily insulin dose using a regimen of multiple injections of long- or intermediate-acting insulin plus short-acting insulin. Adjust dose based on blood glucose and glycemic control goal. Base dose on actual body weight.
            • Insulin Glargine Solution for injection; Adults: 0.7 to 0.8 units/kg in the first trimester, 0.8 to 1 units/kg/day in the second trimester, and 0.9 to 1.2 units/kg/day in the third trimester is the typical total daily insulin dose using a regimen of multiple injections of long- or intermediate-acting insulin plus short-acting insulin. Adjust dose based on blood glucose and glycemic control goal. Base dose on actual body weight.
    • Oral hypoglycemic medications c50
      • Glyburide c51
        • Glyburide Oral tablet; Adolescents: 2.5 mg PO once daily, initially. Increase the dose by 2.5 to 5 mg/day weekly as needed. Usual Max: 20 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
        • Glyburide Oral tablet; Adults: 2.5 mg PO once daily, initially. Increase the dose by 2.5 to 5 mg/day weekly as needed. Usual Max: 20 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Metformin c52
        • Metformin Hydrochloride Oral tablet; Adolescents: 500 mg PO once nightly for 1 week, then 500 mg PO twice daily. May increase the dose further if needed up to 2.5 to 3 g/day divided in 2 or 3 doses.
        • Metformin Hydrochloride Oral tablet; Adults: 500 mg PO once nightly for 1 week, then 500 mg PO twice daily. May increase the dose further if needed up to 2.5 to 3 g/day divided in 2 or 3 doses.
    • Aspirin
      • Aspirin Oral tablet; Adolescents: 81 mg PO once daily starting at 12 weeks gestation. Consider 162 mg PO once daily with pre-existing diabetes mellitus.
      • Aspirin Oral tablet; Adults: 81 mg PO once daily starting at 12 weeks gestation. Consider 162 mg PO once daily with pre-existing diabetes mellitus.

    Nondrug and supportive care

    • Medical nutrition therapy c53
      • 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 restrictionr40 (25% below level of standard diets) results in some correction of hyperglycemia c54
      • 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) r41r42
        • Small reduction in rates of cesarean delivery has been observed in patients who consume a DASH diet (Dietary Approaches to Stop Hypertension) r42
        • 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 r42
        • Academy of Nutrition and Dietetics guidelines recommend pregnant patients with a healthy BMI follow a customized meal plan that distributes total daily carbohydrate intake over three main meals and two or more snacks, with each meal separated by at least two, but no more than 12 hours r38r41
      • Overweight and obese patients should follow a calorie-restricted diet that includes sufficient calories and carbohydrates to avoid maternal ketosis 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 c55
      • May improve glycemic controlr43r44 when performed at moderate intensity at least 3 times per weekr44
      • Moderate exercise is safe and effective in reducing both fasting and postprandial blood glucose levels in patients with gestational diabetes r5
        • 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 r45
      • Patients with gestational diabetes on insulin must take precautions to avoid hypoglycemia r46
    • Effectiveness of lifestyle changes c56
      • Patients participating in lifestyle changes of dietary modifications and physical activity are more likely to achieve postpartum weight goals 1 year after pregnancy r47
      • 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 r47
      • A Cochrane review found that lifestyle changes have beneficial effects on maternal health and reduce the risk of infants being large for gestational age r48

    Monitoring

    • Antepartum
      • Blood glucose monitoring c57
        • Required for patients treated with insulin during pregnancy
        • Patient monitors glucose levels fasting or postprandially; patients with preexisting diabetes using insulin pumps or basal-bolus therapy must test preprandially as well
          • Preprandial measurements aid in selecting dose of rapid-acting insulin for the next interval
          • Postprandial measurements with hyperglycemic results indicate the need to adjust insulin doses or meal sizes
          • Note that in normal pregnancy, fasting levels of blood glucose are lower than in the nonpregnant state owing to insulin-independent glucose uptake by fetus and placenta
        • Results should be analyzed and acted on ideally by a specialist (eg, endocrinologist, maternal-fetal medicine specialist) in conjunction with registered dietitian
        • Continuous glucose monitoring when used in addition to traditional pre- and postprandial blood glucose monitoring, can help achieve hemoglobin A1C goals and reduce macrosomia and neonatal hypoglycemia in pregnancy complicated by type 1 diabetes; however, there is insufficient data to support its use in patients with gestational diabetes r5
      • Hemoglobin A1C c58
        • Monitor serially at 4- to 8-week intervals until term is reached
      • Fetal surveillance r12c59
        • Fetal assessment beginning at 32 weeks of gestation is recommended in patients with past or present poor glycemic control, which includes all those treated with pharmacotherapy; frequency and type of testing vary
        • Ultrasonography to estimate fetal weight late in third trimester in all patients
    • Postpartum r12
      • Screen for diabetes at 4 to 12 weeks postpartum with a fasting 2-hour 75-g oral glucose tolerance test using nonpregnancy criteria r5c60
      • Repeat diabetes screening every 1 to 3 years provided that initial postpartum result has normalized

    Complications and Prognosis

    Complications

    • Continuous associations exist between detrimental perinatal outcomes and maternal hyperglycemia at levels lower than standard diagnostic thresholds for gestational diabetes or overt diabetes r49
    • Neonatal complications r50r51r52
      • Large for gestational age and macrosomia c61
        • Shoulder dystocia c62d3
        • Birth trauma c63
        • Operative delivery
      • Respiratory distress
      • Neonatal jaundice c64d4
      • Neonatal hypoglycemia c65
      • Childhood obesity c66d5
      • Preterm birth
      • Stillbirth r51
    • Maternal complications
      • Hypertension c67d6
      • Preeclampsia c68d7
      • Polyhydramnios
      • Increased risk for cesarean delivery c69
      • Hypoglycemia secondary to treatment
    • Tighter blood glucose targets (fasting blood glucose 90 mg/dL or less, 1-hour postprandial 133 mg/dL or less, 2-hour postprandial 121 mg/dL or less) did not reduce the risk of having a large-for-gestational-age neonate compared to less tight targets (fasting blood glucose 99 mg/dL or less, 1-hour postprandial 144 mg/dL or less, 2-hour postprandial 126 mg/dL or less) but did reduce the risk of perinatal death, birth trauma, or shoulder dystocia in a randomized trial r53
      • Tighter control was associated with an increase in serious maternal morbidity (the composite of major hemorrhage, coagulopathy, embolism, and obstetric complications)

    Prognosis

    • Patients with gestational diabetes are at increased lifetime risk (relative risk of 7.4) for development of postpartum overt type 2 diabetes compared with patients with normoglycemic pregnancies r54r55
      • Note that patients with previous gestational diabetes should be screened for diabetes at least every 3 years r6
    • Children born to patients with gestational diabetes have somewhat elevated risk for insulin resistance, metabolic syndrome, cardiovascular disease, and obesity in subsequent decades, although supporting evidence is limited r56r57
    • Treatment of gestational diabetes is associated with improved health outcomes r58

    Screening and Prevention

    Screening

    Screening for hyperglycemia in pregnancy is recommended in asymptomatic pregnant patients r58c70c71c72

    • Screen all patients at 24 to 28 weeks of gestation

    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: r6r12
        • Physical inactivity
        • First-degree relative with diabetes
        • African American, Asian, Native American, Pacific Islander, or Hispanic ethnicity c73c74c75
        • Previous delivery of a macrosomic infant (weighing 4000 g or more)
        • Previous gestational diabetes
        • Hypertension (140/90 mm Hg) or therapy for hypertension
        • Low HDL-C level (35 mg/dL or lower) or high triglyceride level (higher 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 c76c77c78
      • 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 r6r9
      • Previously a 1-hour, 50-g oral glucose challenge test was recommended by the American College of Obstetricians and Gynecologists, with a 3-hour test to follow for those with an abnormal initial result r12

    Prevention

    • Measures to reduce risk of gestational diabetes include diet modification, physical activity, and participation in structured sessions on lifestyle counseling conducted by specifically trained nurses and dietitians r5r59
      • Specific dietary recommendations include consumption of healthful foods (eg, vegetables, fruit, whole-grain products rich in fiber, low-fat dairy products, vegetable fats high in unsaturated fatty acids, fish, low-fat meats) and lower intake of sugar-rich foods r40
      • Specific physical activity recommendations include a minimum of 150 minutes of moderate-intensity activity per week r40
      • Combined interventions that begin before 20 weeks of pregnancy in obese patients or patients with history of earlier gestational diabetes can reduce risk of gestational diabetes by 39% r40
      • Cochrane review of dietary supplementation with myo-inositol (a common sugar) found significant reductions in incidence of gestational diabetes, hypertensive disorders of pregnancy, and preterm birth, but concluded the evidence was insufficient to currently support routine adoption r60
    • Patients planning pregnancy should strive to attain and maintain optimal body weight and to exercise regularly r59c79c80
      • Physical activity in pregnancy provides a slight protection against development of gestational diabetes r61r62
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