1. Normal physiology of pregnancy First trimester-Increased insulin sensitivity. Late 2 nd and 3 rd trimester insulin resistance possible associated with increasing levels of unknown placental hormone(s) which correlate(s) with placental mass.

2. Pathophysiology of GDM Insulin resistance Reduced insulin secretion GDM is characterized by baseline preconception:

3. Low risk- no screening? No longer! Low risk ethnic group ( European American) No Family Hx of DM2 Age <25 Weight normal before pregnancy No hx of abnormal glucose metabolism No hx of poor obstetrical outcome Normal maternal birth weight

4. High Risk Obesity Previous history of GDM Glycosuria Strong family hx of DM (1 st degree relative) Impaired OGTT or IFG Previous baby with > 9 lb birth wt.

5. Diagnostic OGTT (2 abnormal values)???-  HAPO 100gm OGTT criteria O’Sullivan whole blood mg / dl NDDG conversion Plasma mg/dl Carpenter & Coustan Plasma mg/dl Fasting9010595 1 hour165190180 2 hour145165155 3 hour125145140

6. HAPO 23,316 women 75 gm OGTT at 24-32 weeks: fasting, 1hr, and 2 hr glucose obtained Results unblinded and excluded if 2hr >200 mg/dl or if fasting > 105 mg/dl, any 160 mg/dl Only those that stayed blinded and did not undergo further testing were analyzed NEJM 2008:358:1991-2002

7. HAPO Diagnostic GDM Guidelines 1 step testing 2 hour 75 gram GTT Only 1 abnormal value required Fasting 92 mg/dl (5.1 mmol/L) 1 Hour 180 mg/dl (10 mmol/L) 2 Hour 153 mg/dl (8.5 mmol/L) Guidelines based on outcomes ie macrosomia, cord C peptide, preeclampsia etc Diabetes Care 2010; 33:676-682

8. Maternal Glucose vs Primary Outcomes Copyright 2009 ADA. Published online at http://care.diabetesjournals.org/cgi/content/full/dc09-1848/DC1.http://care.diabetesjournals.org/cgi/content/full/dc09-1848/DC1

9. Maternal 1 hr Glucose vs Primary Outcomes Copyright 2009 ADA. Published online at http://care.diabetesjournals.org/cgi/content/full/dc09-1848/DC1.http://care.diabetesjournals.org/cgi/content/full/dc09-1848/DC1

10. Maternal 2 hr Glucose vs Primary Outcomes Copyright 2009 ADA. Published online at http://care.diabetesjournals.org/cgi/content/full/dc09-1848/DC1.http://care.diabetesjournals.org/cgi/content/full/dc09-1848/DC1

11. All HAPO Outcomes- normal vs 1 abnormal glucose Copyright 2009 ADA. Published online at http://care.diabetesjournals.org/cgi/content/full/dc09-1848/DC1.http://care.diabetesjournals.org/cgi/content/full/dc09-1848/DC1

12. Treatment of Mild GDM Landon et al 2009; 361:1339-48 Study group 958 women in 24 th to 31 st week gestation. Inclusion criteria- Fasting glucose 180, or 2 hr >155 or 3 hr >140 Randomization- 485 to treatment group and 473 to control group (blinded) Treatment group targets: fasting <95, 2 hr <120 mg/dl

13. Results Landon et al NEJM 2009; 361; 1339-1448 p<0.001, <0.001, 0.003, 0.02, 0.02, 0.01 respectively below Outcome variable Treatment Control Birth wt 3302 gms 3408 gms Birth wt > (4000 g) 5.9 % 14.3 % Fat mass gms 427 464 Cesarean delivery 26.9 % 33.8 % Shoulder dystocia 1.5 % 4.0 % Preeclampsia/G HTN 8.6 % 13.6 %

14. A Comparison of Glyburide and Insulin in Women with GDM Langer, et al. NEJM 2000;343:1134-1138 404 women with GDM Recruited 11-33 weeks gestation Singleton pregnancies Dietary therapy for all subjects 201  Glyburide (2.5-20mg/day; mean 9mg/day) 203  Insulin, TID dosing Blood Glucose Goals: –Testing 7x/day –Mean 90-105 –Fasting 60-90 –Preprandial 80-95 –2 Hr Postprandial <120

15. A Comparison of Glyburide and Insulin in Women with GDM Langer, et al. NEJM 2000;343:1134-1138 82% on Glyburide reached BG goals 88% on Insulin reached BG goals 4% on Glyburide required Insulin No difference in preeclampsia and c-section rates Maternal Hypoglycemia (<40mg/dL) –4 vs 41 (2% vs 20%) in Glyburide treatment vs Insulin 12 random patients –Simultaneous maternal and cord blood levels of Glyburide measured –Maternal concentrations 50-150 ng/ml –Cord concentrations were undetectable

16. Langer, et al. NEJM 2000;343:1134-1138 50% increase in Neonatal hypoglycemia and hyperbilirubinemia though not significant

17. Predicting which patients might have better control on Glyburide Fasting  110 associated with higher failure –Conway et al. J Matern Fetal Neonatal Med 2004;15:51-55 Failure more likely if diagnosed earlier in pregnancy, older age, multiparous, higher mean fasting glucose –Kahn et al. Obstet Gynecol 2006;107:14303-1309 GLT  200 predicted failure –Rochon et al. AJOG 2006;195:1090-1094

18. Metformin vs Insulin for the Treatment of Gestational Diabetes Rowan et al. NEJM 2008;358:2003-2015. 751 women with GDM at 20-33 weeks randomly assigned to open treatment with Metformin (and insulin if needed) or to insulin Primary outcome was a composite of –Neonatal hypoglycemia –Respiratory distress –Need for phototherapy –Birth trauma –5 min Apgar < 7 –Prematurity

19. Metformin vs Insulin for the Treatment of Gestational Diabetes Rowan et al. NEJM 2008;358:2003-2015. Secondary outcomes –Neonatal anthropometric measurements –Maternal glycemic control –Maternal hypertensive complications –Postpartum glucose tolerance –Acceptability of treatment

20. Enrollment of Subjects Rowan JA et al. N Engl J Med 2008;358:2003-2015

22. Metformin vs Insulin for the Treatment of Gestational Diabetes Rowan et al. NEJM 2008;358:2003-2015.