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

2. Definition of GDM

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

4. 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

5. Epidemiology of Diabetes

6. Prevalence of Diabetes 1994, 2002 and 2007

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

31. Adolescent Obesity

33. The Effects of the Supersizing of America

34. Heart Attack Grille – Chandler, AZ

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

36. Michaelangelo’s David: Before Touring the US

37. And after…..

38. Insulin Requirement

39. Insulin Requirement and Gestational Age

41. 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/ / Kg 167 units
9/7/ / Kg 320 units
10/5/ / Kg 710 units

43. Sequelae of Maternal Diabetes

44. 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)

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

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

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

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

49. 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

50. 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

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

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

53. Pregnancy #1 Female
Pregnancy #2 Male

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

55. 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 weeks

56. 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 wks
Two abnormal values = GDM
* 4th International Conference on GDM

57. 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.

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

59. 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 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
@ 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

60. 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:
Landon MB, Spong CY, Thorn E, et al. A Multicenter, Randomized Trial of Treatment for Mild Gestational Diabetes. N Engl J Med 2009;361:
Rowan JA, Hague WM, Gao W et al. Metformin versus Insulin for the Treatment of Gestational Diabetes N Engl J Med 2008;358:
Catalano PM, Farrell K, Thomas A, et al. Perinatal risk factors for childhood obesity and metabolic dysregulation. Am J Clin Nutr;90:

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

62. Treatment

63. 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

64. 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.

65. Oral Hypoglycemic Agents

66. Metformin and the Biquanides

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

68. 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

69. 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

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

71. 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)

72. 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%)

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

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

75. 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

76. 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.

77. Protocol Start with Metformin 500 mg bid: Add Glyburide 2.5 mg bid:
Increase 500 mg twice weekly until CBG goals are met
At 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:

78. 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
Can use 1/3 Glargine dose h.s. given as NPH.
03:00.