Gestational Diabetes and the Oral Hypoglycemic Agents Zane A. Brown, MD Professor Department of Obstetrics and Gynecology University of Washington

Definition of GDM

Gestational Diabetes Glucose intolerance with onset or first recognition during pregnancy Glucose intolerance frequently antedates pregnancy but is generally first diagnosed at 24-28 weeks Diabetes Care 1998, 21 (Suppl 2):B161-B167

Women at HIGH risk for GDM Obese (BMI > 30) Family history of 1st degree relatives with DM Ethnicity - Latina, Native American, African American, Asian, Pacific Islander Impaired glucose tolerance in prior pregnancies

Epidemiology of Diabetes

Prevalence of Diabetes 1994, 2002 and 2007

Obesity Trends* Among U.S. Adults 1985 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14%

Obesity Trends* Among U.S. Adults 1986 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14%

Obesity Trends* Among U.S. Adults 1987 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14%

Obesity Trends* Among U.S. Adults 1988 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14%

Obesity Trends* Among U.S. Adults 1989 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14%

Obesity Trends* Among U.S. Adults 1990 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14%

Obesity Trends* Among U.S. Adults 1991 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19%

Obesity Trends* Among U.S. Adults 1992 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19%

Obesity Trends* Among U.S. Adults 1993 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19%

Obesity Trends* Among U.S. Adults 1994 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19%

Obesity Trends* Among U.S. Adults 1995 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19%

Obesity Trends* Among U.S. Adults 1996 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19%

Obesity Trends* Among U.S. Adults 1997 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% ≥20%

Obesity Trends* Among U.S. Adults 1998 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% ≥20%

Obesity Trends* Among U.S. Adults 1999 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% ≥20%

Obesity Trends* Among U.S. Adults 2000 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% ≥20%

Obesity Trends* Among U.S. Adults 2001 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

Obesity Trends* Among U.S. Adults 2002 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

Obesity Trends* Among U.S. Adults 2003 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

Obesity Trends* Among U.S. Adults 2004 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

Obesity Trends* Among U.S. Adults 2005 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

Obesity Trends* Among U.S. Adults 2006 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

Obesity Trends* Among U.S. Adults 2007 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

Obesity Trends* Among U.S. Adults 2008 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

Adolescent Obesity

The Effects of the Supersizing of America

Heart Attack Grille – Chandler, AZ

All you can eat!!! Fried in PURE LARD 8000 calories

Michaelangelo’s David: Before Touring the US

And after…..

Insulin Requirement

Insulin Requirement and Gestational Age

21 y.o Cauc. G5 P2 SAB2. DM since 12 y.o. Diet – anything and everything Metformin 3 grams/24 hours. Humalog + NPH until 9/7/10 U500 + NPH since 9/7/10 Date Gest. Age Weight Daily Ins. 7/20/10 24 3/7 101 Kg 167 units 9/7/10 31 3/7 140 Kg 320 units 10/5/10 35 3/7 148 Kg 710 units

Sequelae of Maternal Diabetes

Fetal Risks from Maternal Diabetes Congenital Malformations Group B Strep colonization Macrosomia and birth trauma Hypoglycemia, hyperbilirubinemia, hypocalcemia, increased insulin resistance Late consequences (e.g. adult obesity)

Pre-Gestational Diabetes Structural Functional Anthropometric Pre-Gestational Diabetes Gestational Diabetes Weeks of Pregnancy From: Norbert Frenkel

Relationship of Fetal Insulin with Fetal Adiposity Lean Obese Catalano, PM et al. Diabetes Care, June 2009;32(6):1076-80. Relationship of Fetal Insulin with Fetal Adiposity

HOMA-IR Indices in Fetuses of Lean and Obese Mothers Catalano, PM et al. Diabetes Care, June 2009;32(6):1076-80.

Catalano, PM et al. Diabetes Care, June 2009;32(6):1076-80.

Long Term Problems with Having an Overweight Fetus Obesity in pregnancy causes fetal metabolic dysregulation Adult Obesity, type 2 DM Fetal/Newborn Obesity Diet/Activity Diet/Activity Childhood Obesity

Sequelae of Maternal Hyperglycemia Long Term Maternal Hyperglycemia Organ Damage Congenital Anomalies Fetal Hyperglycemia Macrosomia/ Metabolic Dysregulation Fetal Hyperinsulinism Respiratory Distress Hematologic and Biochemical Sequelae Stillbirth Neonatal Hyperinsulinism Neonatal Hypoglycemia

HgA1C and Malformations Periconceptional A1c % Diabetes Care 2007;30:1920.

HgA1C and Adverse Outcomes Diabetes Care 2006;29(12):2612.

Pregnancy #1 Female Pregnancy #2 Male

Current Recommendations* Screening for Gestational Diabetes Current Recommendations* *4th Int. Congress on GDM

Screening for Diabetes at First Prenatal Visit Screen at FIRST visit with risk factors such as ethnicity, obesity, family history or h/o macrosomia 50 gram OGTT: if <140 mg/dl at one hour: Screen again at 24-28 weeks

Screening for Diabetes at 24-28 weeks If 1 hr screen > 140 and ≤180 mg/dl Schedule 3 hr GTT* for the following day Fasting <95 1 hour <180 2 hour <155 3 hour <140 One abnormal value, treat with diet. Retest at 32-34 wks Two abnormal values = GDM * 4th International Conference on GDM

Screening for Diabetes in Pregnancy If 1 hr Glucose is > 180 = GDM Do not order a 3 hour GTT Capillary glucose meters are valuable in management but do not have the diagnostic accuracy for screening.

Proposed Recommendations* Screening for Gestational Diabetes Proposed Recommendations* IADPSGC 2010

Screening Protocol Risk factors for undiagnosed type 2 diabetes/prediabetes during pregnancy: -history of gestational diabetes, macrosomia, unexplained stillbirth, malformed infant -family history of overt diabetes among first degree relatives -high risk ethnic groups: African American, American Indian, Hispanic/Latina, Asian/Pacific Islander, South East Asian, East Indian -obesity (BMI > 30) -medications that adversely affect normoglycemia -H/O prediabetes, PCOS Screen EITHER all women or only those with above risk factors at first visit using FPG, RPG or A1C (not rapid)… include in prenatal labs A1C <5.7 A1C 5.7-6.4 OR FPG > 92 mg/dl OR RPG > 126 mg/dl A1C > 6.4 OR FPG > 126 mg/dl OR RPG > 200 mg/dl No Dx DM; perform universal testing @ 24-28 wks Dx GDM; treat now Dx type 2 DM; treat now Obtain fasting & 2 hour 75 gm. OGTT (not 50 gm.) Consider ordering with 3rd trimester labs Treat GDM if ONE or more values > the following: Fasting: 92, 1hr 180, 2hr 153

Important Supporting Papers International Association of Diabetes and Pregnancy Study Groups Consensus Panel. Recommendations on the Diagnosis and Classification of Hyperglycemia in Pregnancy. Diabetes Care 2010;33:676-82 The HAPO Study Cooperative Research Group. Hyperglycemia and Adverse Pregnancy Outcomes. N Engl J Med 2008;358:1991-2002 Landon MB, Spong CY, Thorn E, et al. A Multicenter, Randomized Trial of Treatment for Mild Gestational Diabetes. N Engl J Med 2009;361:1339-48 Rowan JA, Hague WM, Gao W et al. Metformin versus Insulin for the Treatment of Gestational Diabetes N Engl J Med 2008;358:2003-15 Catalano PM, Farrell K, Thomas A, et al. Perinatal risk factors for childhood obesity and metabolic dysregulation. Am J Clin Nutr;90:1303-13

Why bother with hand written log sheets? Why not just download the meter?

Treatment

Initiating Treatment Initiate treatment either as in-patient or out-patient. Choice depends on gestational age, intelligence, social support and choice of Rx. Medical Evaluation - Renal, Thyroid, Autoimmune, Hemodynamics CBG measurements AC and 1 hr PC, HS and 03:00 Nutritional Counseling – Consistency, Consistency and more Consistency Social Work Evaluation – Partners abandon ship when going gets tough. Diabetes education - Requires several hours to cover everything Effects of Diabetes on Pregnancy Effects of Pregnancy on Diabetes Conduct and place of Prenatal Care (e.g. frequency of visits, testing) Timing and route of delivery Costs and charges (what is her co-pay?) Obstetrical evaluation - Gestational dating, Ultrasound anatomy, GBS culture, Antepartum testing

Diet vs Insulin or Oral Agents Start medication if  30% of Capillary Blood Glucose levels above goals while on diet. Fasting >90 mg/dl 1 hour postprandial > 140 mg/dl May not have time to fail on oral agents.

Oral Hypoglycemic Agents

Metformin and the Biquanides

Metformin Non pregnant elimination half life: 6.2 hours Clearance accelerated as pregnancy progresses Pregnancy category B

Metformin Crosses the placenta but no adverse fetal effects (MiG trial) May decrease pre-eclampsia by decreasing insulin resistance May decrease spontaneous abortion in PCOS patients May protect against breast, colon, lung cancer

Metformin  Starting dose: 500 mg bid and increase twice weekly. (Rapid increase  GI Symptoms)  Maximum dose: 3000 mg daily  How supplied: 500, 850, 1000 mg tablets  (also supplied as SR)  Hypoglycemia minimal concern

Metformin Black box warning: Lactic Acidosis - 0.03 cases/1000 patient years - Not related to dose or duration

Metformin in GDM Trial Centers in Australia and New Zealand 751 women with GDM enrolled 733 completed study 363 assigned to Metformin (46.3% with supplemental Insulin) 500 mg bid starting dose 2500 mg/day maximum dose 370 assigned to Insulin Rowan et al NEJM 2008;358:19 (May 8, 2008)

Metformin in GDM Trial No differences in Neonatal Primary Composite Outcomes Hypoglycemia, Birth Trauma, Respiratory Distress, Neonatal Depression, Preterm Birth, Phototherapy, etc No differences in Neonatal Secondary Outcomes GA at birth, BW, Measurements, UC Insulin Levels, etc No clinically significant differences in Maternal Secondary Outcomes Significantly better control with Metformin (but not clinically significant) Patients preferred Metformin (77% vs 27%)

Glyburide Peak: ~4 hours Non Pregnant Elimination half life: ~10 hours Clearance increases as pregnancy progresses Breastfeeding not affected

Glyburide Pregnancy category B (Probably will change) Not detected in cord blood (Langer 2000) Is detected in cord blood (Hebert 2008)

Glyburide Start with 2.5 mg qd or bid Taken ~ 30 minutes before meals Use 1.25 mg with small or sensitive patients Increase by 2.5 mg every 2-3 days Maximum dose 20 mg/day (Probably higher) Hypoglycemia education - as if on insulin Obstetrical management - as if on insulin

Metformin or Glyburide? Start treatment with Metformin if: Obese and likely to be insulin resistant If PCOS patient who became pregnant while on Metformin, may continue.

Protocol Start with Metformin 500 mg bid: Add Glyburide 2.5 mg bid: Increase 500 mg twice weekly until CBG goals are met At 2500-3000 mg/day and goals not met: Add Glyburide 2.5 mg bid: Increase by 2.5 mg twice weekly until CBG goals are met At Glyburide 20 mg/day and Metformin 3 grams/day and goals not met:

Protocol Add Insulin Glargine h.s. (e.g. 20 units) and stop Glyburide: Increase 2-4 units (or more) every day to attain goals Admit the night before IOL or C/S and d/c Metformin and Insulin Glargine: Use insulin infusion as necessary to maintain CBG between 90-140 Can use 1/3 Glargine dose h.s. given as NPH. CBG @ 03:00.