成大醫院 內科部 內分泌新陳代謝科 歐弘毅醫師 認識妊娠糖尿病 成大醫院 內科部 內分泌新陳代謝科 歐弘毅醫師

Standards of Medical Care in Diabetes—2011 “Standards of Medical Care in Diabetes—2011” contains all of the current and key clinical recommendations of the American Diabetes Association (ADA) These standards of care are intended to provide clinicians, patients, researchers, payors, and other interested individuals with the components of diabetes care, general treatment goals, and tools to evaluate the quality of care While individual preferences, comorbidities, and other patient factors may require modification of goals, targets that are desirable for most patients with diabetes are provided These standards are not intended to preclude clinical judgment or more extensive evaluation and management of the patient by other specialists as needed The recommendations included are screening, diagnostic, and therapeutic actions that are known or believed to affect health outcomes of patients with diabetes favorably The slides are organized to correspond with sections within the “Standards of Medical Care in Diabetes—2011” While not every section in the document is represented, these slides do incorporate the most salient points from the Position Statement These standards of care are revised annually by the ADA’s multidisciplinary Professional Practice Committee, incorporating new evidence; subsequently, they are reviewed and approved by the Executive Committee of ADA’s Board of Directors Reference American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care 2011;34(suppl 1):S11-12. Available online at http://care.diabetesjournals.org/content/34/Supplement_1

Epidemiology and risk factors A global increase in the prevalence of obesity and type 2 diabetes The incidence of GDM is increasing In the US: 2.2~9% of pregnancies Taiwan: GDM=2.03%, G-IGT=6.99% Asian Risk factors (high risks) Advanced maternal age ↑40y/o > 35~39y/o > ↓35y/o Severe obesity Inter-pregnancy BMI gain Hypertension Strong family history of type 2 DM Previous history of GDM, IGT Parity Prepregnancy BMI parity Am Fam Physician. 2009 Jul 1;80(1):57-62. 北市醫學雜誌2005 ; 2 (2):132-137

Gestational Diabetes Mellitus Gestational diabetes mellitus (GDM) Carbohydrate intolerance with onset or first recognition during pregnancy GDM occurs around 24-28 weeks into pregnancy Screening (24~28 wk) 50-g non-fasting one-hour glucose challenge 130 mg/dL (7.20 mmol/L): 90% sensitivity 140 mg/dL (7.75 mmol/L): 80% sensitivity 100-g oral glucose tolerance test Fasting< 95 mg/dL (5.25 mmol/L) 1-hr< 180 mg/dL (10.00 mmol/L) 2-hr< 155 mg/dL (8.60 mmol/L) 3-hr< 140 mg/dL (7.75 mmol/L) 75-g oral glucose tolerance test Fasting< 95 mg/dL (5.25 mmol/L) 1-hr< 180 mg/dL (10.00 mmol/L) 2-hr< 155 mg/dL (8.60 mmol/L) Am Fam Physician. 2009 Jul 1;80(1):57-62. Diabetes Care. 2007 Jul;30 Suppl 2:S251-60

Recommendations: Detection and Diagnosis of GDM (1) Screen for undiagnosed type 2 diabetes at the first prenatal visit in those with risk factors, using standard diagnostic criteria (B) In pregnant women not previously known to have diabetes, screen for GDM at 24-28 weeks gestation, using a 75-g OGTT and the diagnostic cutpoints in Table 6 (B) Recommendations for the detection and diagnosis of gestational diabetes mellitus (GDM) are summarized on two slides; this slide (Slide 1 of 2) includes: As the ongoing epidemic of obesity and diabetes has led to more type 2 diabetes in women of childbearing age, the number of pregnant women with undiagnosed type 2 diabetes has increased[24] Because of this, it is reasonable to screen women with risk factors for type 2 diabetes for diabetes at their initial prenatal visit, using standard diagnostic criteria; women with diabetes found at this visit should receive a diagnosis of overt, not gestational, diabetes ADA. III. Detection and Diagnosis of GDM. Diabetes Care 2011;34(suppl 1):S15. References American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care 2011;34(suppl 1):S15. Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care 2002;25:1862-1868.

Screening for and Diagnosis of GDM Perform a 75-g OGTT, with plasma glucose measurement fasting and at 1 and 2 h, at 24-28 weeks of gestation in women not previously diagnosed with overt diabetes Perform OGTT in the morning after an overnight fast of at least 8 h GDM diagnosis: when any of the following plasma glucose values are exceeded Fasting ≥92 mg/dl (5.1 mmol/l) 1 h ≥180 mg/dl (10.0 mmol/l) 2 h ≥153 mg/dl (8.5 mmol/l) GDM carries risks for the mother and neonate1 The Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study,2 a large-scale (25,000 pregnant women) multinational epidemiologic study, demonstrated that risk of adverse maternal, fetal, and neonatal outcomes continuously increased as a function of maternal glycemia at 24–28 weeks, even within ranges previously considered normal for pregnancy. For most complications, there was no threshold for risk. These results have led to careful reconsideration of the diagnostic criteria for GDM After deliberations in 2008–2009, the International Association of Diabetes and Pregnancy Study Groups (IADPSG), an international consensus group with representatives from multiple obstetrical and diabetes organizations, including ADA, developed revised recommendations for diagnosing GDM. The group recommended that all women not known to have diabetes undergo a 75-g OGTT at 24–28 weeks of gestation Additionally, the group developed diagnostic cut points for the fasting, 1-h, and 2-h plasma glucose measurements that conveyed an odds ratio for adverse outcomes of at least 1.75 compared with the mean glucose levels in the HAPO study Current screening and diagnostic strategies, based on the IADPSG statement,3 are outlined in Table 6, which is summarized on this slide ADA. III. Detection and Diagnosis of GDM. Diabetes Care 2011;34(suppl 1):S15. Table 6. References American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care 2011;34(suppl 1):S15. Table 6. Metzger BE, Lowe LP, Dyer AR, et al, for the HAPO Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med 2008;358:1991–2002. Metzger BE, Gabbe SG, Persson B, et al, for the International Association of Diabetes and Pregnancy Study Groups Consensus Panel. International Association of Diabetes and Pregnancy Study Groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 2010;33:676–682.

Recommendations: Detection and Diagnosis of GDM (2) Screen women with GDM for persistent diabetes 6-12 weeks postpartum (E) Women with a history of GDM should have lifelong screening for the development of diabetes or prediabetes at least every three years (E) Recommendations for the detection and diagnosis of gestational diabetes mellitus (GDM) are summarized on two slides; this slide (Slide 2 of 2) includes: Women with a history of GDM have a greatly increased subsequent risk for diabetes2; therefore, they should be screened for diabetes 6-12 weeks postpartum, using nonpregnant oral glucose tolerance test (OGTT) criteria, and should be followed for the development of diabetes or prediabetes (see Section II, “Testing for Diabetes in Asymptomatic Patients”) Information on the National Diabetes Education Program campaign to prevent type 2 diabetes in women with GDM can be found at: http://ndep.nih.gov/media/NeverTooEarly_Tipsheet.pdf ADA. III. Detection and Diagnosis of GDM. Diabetes Care 2011;34(suppl 1):S15. References American Diabetes Association. Standards of medical care in diabetes—2011. Diabetes Care 2011;34(suppl 1):S15. Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care 2002;25:1862-1868.

Management of gestational diabetes mellitus GDM is associated with adverse pregnancy outcome For maternal For fetal Pre-eclampsia Large for gestational age Cesarean delivery Future risk of diabetes Macrosomia Shoulder dystocia Clavicle fracture Neonatal hypoglycemia Malformation Perinatal mortality Shoulder dystocia 進一步造成手臂神經受損 Maternal capillary glucose goals for GDM Preprandial ≤ 95 mg/dL (5.3 mmol/L) AND 1-hr post-meal ≤ 140 mg/dL (7.8 mmol/L) OR 2-hr post-meal ≤ 120 mg/dL (6.7 mmol/L)

Non-pharmacological management Diet management Medical nutritional therapy Specific nutrition procedures in the treatment of an illness, injury or disease condition Low-glycemic index diet Objective Investigation of the effect of a low–glycemic index (LGI) versus a conventional high-fiber diet on pregnancy outcomes, neonatal anthropometry, and maternal metabolic profile in GDM Method 99 women (26~42y/o, BMI=24 ± 5 kg/m2) diagnosed with GDM at 20–32 weeks’ gestation Protein (15–25%), fat (25–30%), and carbohydrate (40–45%) LGI (target GI ≤50) High-fiber content and moderate GI 第二型糖尿病則須改變飲食及運動習慣，控制體重以降低胰島素阻抗性，並減少飲食中的飽和脂肪、膽固醇和鈉鹽，以改善血脂及血壓。 Both diet strategies produced comparable pregnancy outcomes in women with GDM An LGI diet appears to be a safe alternative to the traditional pregnancy diet and expands the range of dietary strategies that can be offered. Result Data→ No significant between LGI and HF Diabetes Care. 2011 Nov;34(11):2341-6.

Non-pharmacological management In type 2 diabetes Regular physical activity enhances insulin sensitivity, facilitates weight loss, and improves glucose control Type of exercise for pregnancy with GDM 20 minutes of supervised aerobic training 3 days a week Lower fasting, post-pramdial glucose level and HbA1c Lower glucose response to a glucose challenge Delay in the requirement of insulin Pre-pregnancy BMI> 25 can less likely to require insulin A sensible level of light and moderate intensity physical activity until latter stages of the pregnancy Walking for 20~30 minutes each day Antenatal exercise classes Vasc Health Risk Manag. 2009;5(1):153-64

Pharmacological management Post-prandial monitoring Gold standard of insulin therapy Choice of drugs Bad compliance Frequency Oral anti-hyperglycemic agents Sulfonylurea Metformin Α-glucosidase inhibitors

Pharmacological management-insulin The dosage of insulin increases over the third trimester of pregnancy→the end of pregnancy, insulin can drop Significant hypoglycemia is uncommon in insulin-treated GDM Insulin therapy in GDM Fast-acting (regular insulin) Intermediate-acting (isophane insulin) Rapid-acting (insulin lisopro, aspart) → as effective and safe as human insulin Long-acting (insulin glargine) →not really clear →as safe as NPH for fetal outcome Concern Human insulin does not cross the placenta Anti-insulin antibodies pass the placenta →influence of fetal birth-weight

Pharmacological management-insulin Frequency of insulin therapy for GDM Randomized controlled open label trial Objective To compare perinatal outcome and glycemic control in pregnant diabetic patients receiving two insulin regimens Method Twice daily regimen GDM:138, pre-DM: 58 Morning dose: 2/3 (2/3 RI+1/3 NPH), evening dose: 1/3 Four times daily regimen GDM:136, pre-DM: 60 Pre-meal 30min: Novopen, bedtime: NPH Result Adequate glycemic control (<104.5 mg/dL (5.8 mmol/L)) Four times daily regimen: 91.3% Twice daily regimen: 74.3% Four times daily regimen can decrease risks Neonatal hypoglycemia Neonatal hyperbilirubinemia In order to improve glycemic control and the perinatal outcome Given insulin four times daily regimen is better than twice daily regimen BMJ. 1999 Nov 6;319(7219):1223-7.

Pharmacological management-OHA Oral anti-hyperglycemia agents were not recommended during pregnancy Assumption that these drugs cross the placenta Teratogenic early in development Neonatal hypoglycemia Anti-hyperglycemia agent for use during lactation Tolbutamide: approved by American Academy of Pediatrics AAP= 美國小兒科學會 J Perinat Neonatal Nurs. 2002 Sep;16(2):40-53

Pharmacological management-OHA J Perinat Neonatal Nurs. 2002 Sep;16(2):40-53

Pharmacological management-OHA Glyburide Randomized trial without blinding → as effective as insulin for GDM Objective To compare glyburide and insulin therapy on safety and efficacy for the pregnant women with GDM as the alternative therapy Method 404 women with gestational diabetes Insulin group: 0.7 unit/kg Glyburide group: initial: 2.5mg→5 mg→ 20mg Result No significant differences in mean blood sugar 4% glyburide group required insulin therapy No significant differences in fetal outcome N Engl J Med. 2000 Oct 19;343(16):1178-9.

Pharmacological management-OHA Metformin Randomized trial without blinding Objective To assess the efficacy and safety of the use of metformin for pregnant women with GDM Method 751 women with GDM at 20 to 33 weeks of gestation to open treatment with metformin or insulin Metformin group: 500mg QD/BID→ Max: 2500mg/day Insulin group: prescribed according to usual practice Outcome Primary outcome: Neonatal hypoglycemia, respiratory distress, jaundice, birth trauma, 5-minute Apgar score< 7, or prematurity Secondary outcomes Neonatal anthropometric measurements, maternal glycemic control, maternal hypertensive complications, postpartum glucose tolerance, and acceptability of treatment N Engl J Med. 2008 May 8;358(19):2003-15.

Pharmacological management-OHA Result Primary outcomes→ Not significantly difference (P = 0.95) 32.0% in the metformin group 32.2% in the insulin group Secondary outcomes→ Not significantly difference Adverse effect No significant differences between the treatment groups None of the serious adverse events were considered Metformin, alone or with supplemental insulin, is an effective and safe treatment option for women with GDM Meet the usual criteria for starting insulin Metformin is more acceptable to women with GDM N Engl J Med. 2008 May 8;358(19):2003-15.

Pharmacological management-OHA Acarbose Not absorbed from the gut, unlikely to affect the fetus An open, randomized clinical trial Objective To compare neonatal results from patients with GDM who were treated with insulin, glyburide and acarbose Method 70 pregnant women diagnosed with GDM Insulin group (n=27): RI+NPH 0.7→0.8→0.9 IU/kg Glyburide group (n=24): 5 mg→ Max 20 mg Acarbose group (n=19): 50mg→ Max 300mg Result Not achieve glucose level Glyburide: 5 (20.8%) Acarbose: 8 (42.1%) Hypoglycemia in neonates Insulin: 1 (3.7%) Glyburide: 8 (33.3%) Acarbose: 1 (5.2%) Reducing post-prandial glucose almost the same as insulin in GDM High frequency of abdominal cramping Absorbed systemically, safety, potential trans-placenta need more evaluation J Perinat Med. 2005;33:519–523

Pharmacological management-OHA Recommendation The evidence of acarbose used in GDM must be evaluated in larger and more studies Metformin Glyburide J Perinat Neonatal Nurs. 2002 Sep;16(2):40-53

Pharmacological management-OHA Comparison between glyburide and metformin Randomized trial without blinding Objective To compare the efficacy of metformin with glyburide for glycemic control in gestational diabetes. Method 149 pregnant women at 11~33 weeks gestation with GDM Metformin group (n=75): 500mg/day→2000mg/day Glyburide group (n=74): 2.5mg,BID→ 10mg, BID Result Blood Glucose Levels Not achieve: metformin= 34.2% glyburide= 16.2% Neonatal outcome No significant difference Metformin Glyburide Not achieve 26 (34.7%) 12 (16.2%) Hypoglycemia 2 (2.7%) 1 (1.4%) Pre-eclampsia 3 (4%) The use of glyburide and metformin as single-agent therapies The failure rate of metformin was 2.1 times higher than the failure rate of glyburide in GDM The failure of oral anti-hyperglycemia agents should required insulin therapy Obstet Gynecol. 2010 Jan;115(1):55-9.

Follow-up of gestational diabetes mellitus Postpartum management Most cases resolve with delivery Linear increase in cumulative incidence during first 10 years after pregnancy Increased risk of developing diabetes after GDM Impaired glucose tolerance Increased HbA1c at GDM Low high-density lipoprotein cholesterol Age> 35 y/o Postpartum hyperglycemia Continue medical nutrition therapy If necessary, pharmacologic treatment (insulin, glyburide, glipizide are safe) No diabetes after postpartum Glucose tolerance testing 6~12 weeks Repeat at 1 year and then every 3 years CMAJ. 2008 Jul 29;179(3):229-34.

Take home message GDM occurs around 24-28 weeks into pregnancy, which may significantly affect both maternal and fetal outcomes. The goals of management of GDM Preprandial ≤ 95 mg/dL (5.3 mmol/L) AND 1-hr post-meal ≤ 140 mg/dL (7.8 mmol/L) OR 2-hr post-meal ≤ 120 mg/dL (6.7 mmol/L) When GDM happened, diet and activity management are the first ways to control the glucose level. The gold standard of pharmacologic management of GDM is insulin therapy, but recently found that metformin and glyburide can also be used to control the glucose level.

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