HAPO Study Rationale. Blinded Participants At Each Field Center

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1 Clinical Implications of IADPSG Recommendations on the Diagnosis & Treatment of Gestational Diabetes Mellitus 36 th Annual Congress The Korean Diabetes Association Busan BEXCO, Korea October 16-17, 2010 Boyd E Metzger, MD Northwestern University, Chicago, IL USA HAPO Study Rationale MATERNAL PLACENTA FETAL Overt diabetes clearly increases the risk of adverse pregnancy outcome. What level of glucose intolerance during pregnancy, short of diabetes, is associated with the risk of adverse outcome? INSULIN RELEASE GLUCOSE UTILIZATION HYPERGLYCEMIA ` BIRTHWEIGHT HYPOGLYCEMIA INSULIN HYPERGLYCEMIA HAPO Protocol 75 g OGTT weeks Fasting, 1 &2 hr plasma glucose 25,505 Unblinded at Field Center if OGTT Fasting >105/5.8&/or 2 hr >200/11.1 or random glucose >160/8.9 ~ 36 wks or <45/2.5 mmol/l 746(2.9%) unblinded: standard GDM care 23,316 Standard care for Field Center Cord glucose, C-peptide Neonatal glucose 1-2 hrs of age Anthropometrics by 72 hrs Length, HC, weight, skin fold x3 1443(5.7%) drop outs Blinded Participants At Each Field Center Bellflower Chicago Providence Cleveland Toronto Belfast Manchester Barbados Petah-Tiqva Beersheba Bangkok Brisbane Newcastle Singapore Hong Kong

2 HAPO Study s Primary outcomes Infants with birth weight > 90th percentile Delivery by primary Cesarean section Clinical neonatal hypoglycemia Neonatal hyperinsulinemia (elevated cord blood serum C-peptide concentration) Secondary outcomes Neonatal adiposity Preterm delivery (< 37 weeks gestation) Preeclampsia Shoulder dystocia/birth injury Neonatal morbidities HAPO: Potential Associations of Maternal Glucose with Pregnancy Relative Rate Relative Concentration of Glucose Plasma Glucose Concentration By Category Associations: Glucose & 1 s Category FPG (mg/dl) < > 100 (mmol/l) < > 5.6 Percent Hr* (mg/dl) < > 212 (mmol/l) < > Hr* (mg/dl) < > 178 (mmol/l) < > 9.9 *Percent/Category similar to FPG categories Adjusted Odds Ratios: Maternal Glycemia as Continuous Variable & Primary s Fasting 1-Hour 2-Hour Birthweight >90% 1.38 ( )* 1.46 ( ) 1.38 ( ) Primary C-section 1.11 ( ) 1.10 ( ) 1.08 ( ) Adjusted Odds Ratios: Maternal Glycemia as Continuous Variable & Secondary s Fasting 1-Hour 2-Hour Pre-term Birth (<37 wks) 1.05 ( )* 1.18 ( ) 1.16 ( ) Preeclampsia 1.21 ( ) 1.28 ( ) 1.28 ( ) Clinical Neo Hypo 1.08 ( ) 1.13 ( ) 1.10 ( ) Cord serum C-Peptide >90% 1.55 ( ) 1.46 ( ) 1.37 ( ) Shoulder Dystocia/Birth Injury Intensive neonatal care 1.18 ( ) 1.23 ( ) 1.22 ( ) 0.99 ( ) 1.07 ( ) 1.09 ( ) *Odds ratios for glucose level 1 SD (F=6.9/0.4; 1-hr=30.9/1.7; 2-hr=23.5/1.3 mg/dl/mmol/l) Quadratic (nonlinear association) p = Hyperbilirubinemia 1.00 ( ) 1.11 ( ) 1.08 ( ) *Odds ratios for glucose level 1 SD (F=6.9/0.4; 1-hr=30.9/1.7; 2-hr=23.5/1.3 mg/dl/mmol/l) 2

3 Adjusted for Confounders Maternal glucose perinatal outcome associations are independent of maternal age, BMI and family history of diabetes Associations did not differ among centers The results are applicable to all centers Results were used globally to develop outcome based criteria for classifying glucose metabolism in pregnancy HAPO: Potential Associations of Maternal Glucose with Pregnancy Relative Rate Relative Concentration of Glucose From Associations to Diagnostic Criteria Form a committee of experts to resolve issues & make recommendations A task assumed by the International Association of Diabetes in Pregnancy Study Groups (IADPSG) From Associations to Diagnostic Criteria: What Is the IADPSG? Affiliated Organizations DPSG of EASD JAPD (Japan) ADIPS (Australasia) West Coast USA DPSG DPSI (India) Canadian Special Interest Group for Diabetes and Pregnancy Associated Groups European Association of Perinatal Medicine; Society of Maternal Fetal Medicine (USA); ADA Pregnancy Council; SAREDIA IADPSG Workshop Conference Days 1 & 2 Presentations of data & discussion 220 delegates from ~40 countries Post conference regional caucuses Day 3 Consensus development session ~50 delegates: representing IADPSG groups or organizations including ACOG, ADA, EASD, WHO, IDF, CDC, or at large Steering Committee/ Writing Group appointed IADPSG Consensus Panel Activities After Pasadena Steering Committee/Writing Group Conference calls Review Additional data & analyses Reports to parent Consensus Panel Prepare draft of Diabetes Care manuscript Consensus Panel Reports from the Writing Group Review additional data analyses & provide feedback Questionnaire X 3 Meeting #2: Sorrento, Italy, March 25,

4 From Associations to Diagnostic Criteria IADPSG Consensus Panel considerations Choose outcomes for defining thresholds Relative importance of study outcomes Some outcomes are related Thresholds based on OR for LGA, fat, &/or hyperinsulinemic babies How much risk is too much? Statistical evidence & outcome frequencies considered in combination Importance of specific glucose measures: FPG, 1-hr & 2-hr OGTT Results of RCTs of treating mild GDM Frequency (%) >90th Percentile Fasting Plasma Glucose and s < >=100 Concentration (mg/dl) Birthweight % Body fat Cord C-peptide 1-Hour Plasma Glucose and s 2-Hour Plasma Glucose and s Frequency (%) >90th Percentile < >=212 Concentration (mg/dl) Birthweight % Body fat Cord C-peptide Frequency (%) >90th Percentile < >=178 Concentration (mg/dl) Birthweight % Body fat Cord C-peptide From Associations to Diagnostic Criteria for GDM IADPSG recommendations Threshold values for GDM as follows* Fasting: >92 mg/dl; 5.1 mmol/l 1-hr post 75 gm: >180 mg/dl; 10.0 mmol/l 2-hr post 75 gm: >153 mg/dl; 8.5 mmol/l *One or more abnormal value = GDM Frequencies of s: Glucose Values < or > Threshold % All Values < Threshold % Any > 92/180/153 Birthweight >90 th percentile Cord C-peptide >90 th percentile % Body fat >90 th percentile Preeclampsia Preterm birth (<37 weeks) Shoulder dystocia/birth injury Primary Cesarean section

5 From Associations to Diagnostic Criteria IADPSG Consensus Panel considerations Choose outcomes for defining thresholds Relative importance of study outcomes Some outcomes are related Thresholds based on OR for LGA, fat, &/or hyperinsulinemic babies How much risk is too much? Statistical evidence & outcome frequencies considered in combination Importance of specific glucose measures: FPG, 1-hr & 2-hr OGTT Results of RCTs of treating mild GDM Diagnosis of GDM in Pregnancy: Threshold Values Diagnosis of GDM & Proportion of HAPO Cohort with values > Threshold* Glucose Measure mg/dl mmol/l >threshold (%) FPG hr OGTT-PG hr OGTT-PG *GDM = 1 or more values > threshold From Associations to Diagnostic Criteria IADPSG Consensus Panel considerations Choose outcomes for defining thresholds Relative importance of study outcomes Some outcomes are related Thresholds based on OR for LGA, fat, &/or hyperinsulinemic babies How much risk is too much? Statistical evidence & outcome frequencies considered in combination Importance of specific glucose measures: FPG, 1-hr & 2-hr OGTT Results of RCTs on treatment of mild GDM Treatment of GDM Reduces Adverse * OUTCOME ROUTINE CARE (N = 510) INTERVENTION (N = 490) Birth Weight <.001 LGA 22% 13% <.001 Macrosomia 21% 10% <.001 Preeclampsia 18% 12% 0.02 SGA 7% 7% ns *Crowther CA, et al. NEJM 352: , 2005 P Treatment of GDM Reduces Adverse * Not treated NICHD RCT Treated BW >90 th percentile <0.001 C-peptide >95 th percentile NICU admission Shoulder Dystocia Preeclampsia *Landon MB et al. NEJM 361: , 2009 P Frequencies of s: Comparison of RCT & HAPO NICHD RCT FPG <95 Not treated Treated (1-hr >180; 2hr >155) FPG <95 (1-hr <180; 2-hr <155) BW >90 th percentile C-peptide >95 th percentile (>90 th %) 7.5 (>90 th %) NICU admission Shoulder Dystocia Preeclampsia

6 Diagnosis of Overt Diabetes Mellitus in Pregnancy: Threshold Values Diagnosis of Overt Diabetes Mellitus in Pregnancy Measure of glycemia Consensus threshold FPG A1C >126 mg/dl (7.0 mmol/l) >6.5% (DCCT/UKPDS standardized) Random plasma glucose (RPG) >200 mg/dl (11.1 mmol/l) confirmed* *Confirm RPG with FPG or A1C Diagnosis of GDM in Pregnancy: Threshold Values Diagnosis of GDM & Proportion of HAPO Cohort with values > Threshold* Glucose Measure mg/dl mmol/l >threshold (%) FPG hr OGTT-PG hr OGTT-PG *GDM = 1 or more values > threshold Strategy for detection and diagnosis of hyperglycemic disorders in pregnancy First Prenatal Visit: Test for overt DM Fasting plasma glucose, HbA1c or random plasma glucose on all or only high risk women Results indicate overt diabetes Treatment and follow-up as for pre-existing diabetes Results not diagnostic of overt diabetes FPG >92 mg/dl (<126 mg/dl) = GDM FPG <92 mg/dl: test for GDM between weeks gestation with a 75 gm OGTT Strategy for detection and diagnosis of hyperglycemic disorders in pregnancy weeks gestation:test for GDM 2-hr 75-g OGTT on all not previously diagnosed with overt DM or GDM Overt DM = FPG >126 mg/dl (7.0 mmol/l) GDM = 1 or more values > thresholds for FPG, 1-hr & 2-hr PG Normal = all OGTT values < thresholds Other Considerations Timing of the initial test for overt DM As early as possible in order to initiate treatment to minimize adverse outcomes Indeterminate results Insufficient data to recommend generalized OGTT to diagnose overt diabetes prior to weeks Treatment for the expanded population of women with Type 2 DM & GDM 6

7 USA: Diabetes & Prediabetes - Diagnosed And Undiagnosed Increasing Incidence of GDM: N California Year % Diabetes + 19% Pre diabetes = approximately 30% of adult US population So 17-18% GDM rate is consistent with current population trends *All White A - A Hisp Asian *Adjusted for age & race/ethnicity; Adjusted for age *From: Ferrara A, et al.: Obstet Gynecol 103:526-33, 2004 Prevalence of GDM & Preexisting DM: S California * Age-adjusted Percentage of U.S. Adults Who Were Obese or Who Had Diagnosed Diabetes Obesity (BMI 30 kg/m 2 ) Year GDM * Preexisting Diabetes Combined No Data <14.0% % % % >26.0% Diabetes *Adjusted for age & race/ethnicity; trend < Adjusted for age & race/ethnicity; trend = *From: Lawrence JM et al. Diabetes Care 31: , 2008 No Data <4.5% % % % >9.0% CDC s Division of Diabetes Translation. National Diabetes Surveillance System available at Increasing Prevalence of Obesity (BMI >25) in Korea* Men Women Total 1995^ 11.7% 18.0% 13.9% % 28.1% 26.2% % 29.4% 30.6% *Maternal & Fetal in Women with Type 2 vs. Type 1 DM A systematic review & meta analysis Despite a milder glycemic disturbance, women with type 2 DM had no better perinatal outcomes than those with type 1 indicating that type 2 DM in pregnancy is a serious condition. *D M Kim et al. Obesity Reviews 6:117-21, 2005 ^Self-reported data *Balsells M et al. J Clin Endocrinol Metab 94: ,

8 FPG & RISK OF MALFORMATIONS IN GDM OR TYPE 2 DM T2DM: risk of major congenital anomalies similar that in T1DM Risk for congenital anomalies in T2DM is related to maternal glycemic control Treatment of Type 2 During Pregnancy Most are overweight or obese Optimal weight gain? Potential for use of oral medication is limited Human insulin or analog insulin? Careful postpartum follow-up is necessary Treatment Paradigm for GDM Most are overweight or obese Optimal weight gain? Likelihood of successful MNT is good Pharmacological therapy in minority Insulin or analogs use is well established Use of metformin or glyburide a subject for debate Postpartum follow-up Opportunity for DM prevention Contraception & subsequent pregnancy Funding for the HAPO Study NICHD & NIDDK The American Diabetes Association Additional support Diabetes UK Bernick Family Foundation Other sources Acknowledgments Steering Committee Data Monitoring Committee Boyd Metzger: Clin Coord Center PI Steven Gabbe: Chair Alan Dyer: Data Coord Center PI Gary Cutter Elisabeth Trimble: Central Lab PI John Hare Don Coustan: N American Reg Director Lynne Wagenknecht David Hadden: European Reg Central Laboratory Director Elisabeth Trimble, PI Moshe Hod: Mid East/Asia Reg Director Brian Sheridan Jeremy Oats: Australasia Reg Terry Lappin Director Selby Nesbitt Bengt Persson: Consultant Mike Smye Lynn Lowe, Project Manager, ex Colin Burgess officio Acknowledgments Field Center & PI Bangkok, Thailand Chaicharn Deerochanawong Barbados, West Indies Anselm Hennis (Yvonne Rotchell) Beersheba, Israel Arnon Wiznitzer/Moshe Mazor Belfast, Northern Ireland, UK David Hadden Bellflower, CA, USA David Sacks Brisbane, Queensland, Australia David McIntyre Chicago, IL, USA Sharon Dooley Cleveland, OH, USA Patrick Catalano Hong Kong, China C Y Li Manchester, England, UK Kennedy Cruickshank/M Maresh Newcastle, NSW, Australia Julia Lowe Petah Tiqva, Israel Rony Chen Providence, RI, USA Marshall Carpenter Singapore, Singapore George Yeo Toronto, ON, Canada Elaine Herer/Anne Kenshole (Kofi Amankwah) 8

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