Disclosures. Diagnosis and Management of Diabetes in Pregnancy. I have nothing to disclose. Type 1. Overview GDMA1

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1 Diagnosis and Management of Diabetes in Pregnancy Kirsten Salmeen, MD Assistant Professor Department of Obstetrics, Gynecology & Reproductive Sciences Maternal-Fetal Medicine Disclosures I have nothing to disclose Overview Type 1 GDMA1 Pre-DM/ Type 2 GDMA2 Impact of Hyperglycemia Testing Management Postpartum 1

2 PREGNANT NON-PREGNANT PREGNANT NON-PREGNANT Glucose & Insulin GLUCOSE Normal Pregnancy: - Fasting HYPO glycemia INSULIN - Postprandial HYPER glycemia - HYPER insulinemia Normal Glucose In Pregnancy: Non Diabetics Cunningham et al. Williams Obstetrics, 23rd Edition Hernandez Diabetes Care 2011 Glucose & Insulin Pregnancy Glucose & Insulin The Fetus Pregnancy = Pancreatic Stress Test Human placental lactogen blocks peripheral uptake and use of glucose in the mother Insulin sensitivity is > 50% lower Transfer of glucose across placenta is by facilitated diffusion via glucose transport proteins Glucose is the primary substrate for fetal growth The fetus makes its own insulin Hyperinsulinemia likely drives excess fetal growth 2

3 Overview Pregnancy Outcomes in GDM Impact of Hyperglycemia Testing Management Postpartum Approximate Overall % Relative Risk/Odds Ratio Macrosomia 20 RR ~1.4 Pre-Eclampsia 15 RR ~1.7 Cesarean Section Varies RR ~ 1.2 Shoulder Dystocia 3-5 OR ~ 1.2 IUFD ~ 0.05 RR ~ 2 HAPO Study Cooperative Research Group N Engl J Med 2008 Schmidt M Diabetes Care 2001 Wendland E BMC Pregnancy Childbirth 2012 Hyperglycemia & Pregnancy Outcomes Hyperglycemia & Pregnancy Outcomes 50 gram, 1-hour Preeclampsia (%) Macrosomia (%) Cesarean Section (%) < 100 mg/dl mg/dl mg/dl > 134 mg/dl P-value for trend Fasting Glucose Macrosomia (%) < 72 mg/dl mg/dl mg/dl 14.1 > 82 mg/dl 20.5 Sermer et al AJOG 1995 Sermer et al AJOG

4 Outcome (%) Birth weight 4000 g Birth weight 4500 g Fasting < 74 Fasting Fasting Fasting 83 Odds Ratio 95% CI LGA PIH/PreE Shoulder Dystocia Hyperglycemia & Pregnancy Outcomes Outcome (%) Birthweight 4000 g Birthweight > 4500 g 2 hour < hour hour hour 130 Odds Ratio 95% CI LGA PIH/PreE Shoulder Dystocia Hyperglycemia & Pregnancy Outcomes Jensen AJOG 2001 Jensen AJOG 2001 HAPO Glucose Levels Does hyperglycemia without overt diabetes during pregnancy increase risk of adverse pregnancy outcomes? Blinded study of ~25,000 women at 15 centers in 9 countries Primary outcomes: birthweight > 90%ile for GA, primary CD, neonatal hypoglycemia, cord-blood C-peptide level > 90%ile Primary predictor: Levels of hyperglycemia Level Fast (mg/dl) 1 hr (mg/dl) 2 hr (mg/dl) 1 < HAPO Study Cooperative Research Group N Engl J Med 2008 HAPO Study Cooperative Research Group N Engl J Med

5 HAPO Results Impacts of Macrosomia Maternal Weight Prolonged Labor (%) Excess Bleeding (%) CD (%) g 0.9% g g > 5000 g HAPO Study Cooperative Research Group N Engl J Med 2008 Boulet SL et al. Am J Obstet Gynecol. 2003;188(5):1372-8; Acker et al. Obstet Gynecol. 1985;66:762; Nesbitt et al. Am J Obstet Gynecol. 1998;179:476; Sandmire et al. Int J Gynaecol Obstet. 1988;26:65; Overland E et al. Am J Obstet Gynecol. 2009;200(5): g Impacts of Macrosomia Fetal 4,000 4,499 g 4,500 4,999 g 5,000 g Outcome % % OR CI % OR CI % OR CI 5 min Apgar 3 Assisted ventilation 30 min Birth injury Neonatal Mortality Rate* LGA Impacts of Macrosomia - Childhood P = 0.56 AGA LGA P = AGA Cumulative hazard (risk) function for development of metabolic syndrome according to birth weight. Boulet AJOG 2003 * Per 1,000, < 28 days Gillman Pediatrics

6 Overview Increasing blood glucose (even without overt diabetes) is associated with worsening pregnancy outcomes including macrosomia, pre-eclampsia and cesarean section in an approximately linear fashion. Impact of Hyperglycemia Testing Treatment Postpartum When to test? Initial Visit: Overweight/obese History of gestational diabetes or glucose intolerance Prior LGA infant Family history of type 2 DM Maternal age > 35 High-risk ethnic groups (non-caucasian) PCOS Weeks: Everyone else High-risk patients who screened negative earlier How are average-risk patients screened for GDM in your practice? A. Two step testing (1-hour, 50 gram glucose loading test followed by fasting 3-hour, 100 gram loading test if needed) at weeks B. One step testing (fasting 2-hour, 75 gram loading test at weeks 57% C. Fasting blood sugar and/or hemoglobin A1c in the first trimester D. A and C E. B and C T w o s t e p t e s t... O n e s t e p t e s t... 13% F a s t i n g b l o o d... 2% A a n d C 21% B a n d C 7% 6

7 GDM Testing Controversy What defines disease? F hr hr F hr hr HAPO Study Cooperative Research Group. N Engl J Med A. > 15% B. > 20% In your opinion, what primary cesarean section rate defines disease? > 1 5 % > 2 0 % 30% 35% C. > 25% Testing for 1 abnormal value D. > 30% 12% More Sensitive, Less Specific > 2 5 % 24% > 3 0 % One-Step Carpenter Coustan Universal Screening Early Screening Hemoglobin A1c MORE women WITHOUT disease test positive Sensitivity v Specificity Two-Step National Diabetes Data Group Risk-Based Screening Week Screening No Hemoglobin A1c No f/u for 1 abnormal value Less Sensitive, More Specific LESS women WITHOUT disease test positive 7

8 One-Step vs. Two-Step Testing Prenatal Outcomes and Screening Strategies One-Step Fasting, 75 g, 1 & 2 hr serum glucose measurement 1+ abnormal value GDM GDM prevalence ~ 20% Two-Step Step 1: Non-Fasting, 50 g, 1 hr serum glucose measurement 130/140 mg/dl Step 2 Step 2: Fasting, 100 g, 3 hr glucose test 2+ abnormal values GDM GDM prevalence ~ 5-10% CC IAD- PSG Control *Primary Cesarean *Shoulder Dystocia GDM by CC (%) GDM by IADPSG (%) Normal Glucose Tolerance (%) *PPH * Not statistically significant Ethridge Obstet Gynecol 2014 Prenatal Outcomes and Screening Strategies Pregnancy outcomes among 1,750 women diagnosed with GDM by Carpenter- Coustan criteria and 1,526 women diagnosed by IADPSG criteria. GDM Rate by CC = 10.6% GDM rate by IADPSG = 35.5% GDM % 2-Step CC Criteria NGT % P: GDM vs NGT GDM % IADPSG Criteria NGT % P: GDM vs NGT Gest HTN Delivery Vaginal CD Forceps LGA Outcome Prenatal Outcomes and Screening Strategies Odds of Outcome compared to 1 hr, 50 g < 140 mg/dl OGTT Negative (N=526) IADPSG (N=155) CDA (N=358) * Composite 0.9 ( ) 1.4 ( ) 1.4 ( ) PIH/Pre-E 0.9 ( ) 3.0 ( ) 1.2 ( ) CD 1.1 ( ) 1.4 ( ) 1.3 ( ) LGA (> 90%ile) 1.2 ( ) 1.8 ( ) 1.5 ( ) * Composite of: hypertensive disorders, shoulder dystocia, 3 rd or 4 th degree laceration, LGA, NICU admission, neonatal: respiratory complication, hypoglycemia, jaundice CDA Guidelines: 1 hr, 50 g > hr, 75 g < 95/191/160 Duran Diabetes Care 2014 Mayo AJOG

9 One-Step vs. Two-Step Alternative Testing Strategies IADPSG criteria increases rates of GDM IADPSG GDM is associated with pregnancy outcomes similar to CC GDM If treating CC GDM improves outcomes (it does), diagnosing and treating IADPSGdefined GDM seems clinically appropriate Fasting plasma glucose as a predictor for GDM (by IADPSG criteria) Performance Measures Cut-off for fasting plasma glucose (mg/dl) Positive Test (%) Sensitivity (%) Specificity (%) Positive Predictive Value (%) Negative Predictive Value (%) Trujillo Diab Res Clin Prac 2014 Alternative Testing Strategies Jelly Beans A1c 6.5 DM2 A1c Pre-Diabetes A1c < 5.7 Normal 5.6% 5.4% 5.1% 4.9% 4.7% 4.4% Non-Preg 1 st Tri 2 nd Tri 3 rd Tri Brach jelly beans, mixed assortment 28 jellybeans = 50 g simple sugar 50 g Glucose Beverage Jelly Beans Calculated Value 95% CI Calculated Value 95% CI HbA1c % Average HbA1c Values Non-Diabetic Women Non- Pregnant (5.2) 1 st Trimester (5.0) 2 nd Trimester (4.9) 3 rd Trimester (5.1) Sensitivity 80% 28-99% 40% 5-85% Specificity 82% 75-88% 85% 77-90% Positive Predictive Value 15% 4-34% 9% 1-29% Negative Predictive Value 99% % 97% 93-99% O Connor Clin Chem Lab Med 2012 Lamar AJOG

10 Overview Impact of Hyperglycemia Testing Treatment Postpartum Hyperglycemia is associated with worse pregnancy outcomes. Does intervention help? Treatment of GDM Crowther et al: RCT of treatment for gestational diabetes 958 women with OGT: fasting < 140 & 2 hr received dietary intervention, glucose monitoring, and insulin therapy if indicated 473 received routine care *Any serious perinatal complication Treatment of GDM Intervention Group N= 490 (%) Routine Care N= 510 (%) Adjusted RR or Treatment Effect Adjusted p-value ( ) 0.01 Admission to NICU ( ) 0.04 Macrosomia ( ) < Neonatal hypoglycemia ( ) 0.16 Preeclampsia ( ) 0.02 Cesarean Delivery ( ) 0.73 * One or more of: death, shoulder dystocia, bone fracture, nerve palsy Crowther et al. N Engl J Med

11 Anxiety & GDM Treatment of GDM * ** * * * * Landon et al: RCT of treatment of mild GDM 958 patients with fasting glucose < 95, but 2 or more abnormal values on 3 hour (1 hr > 180, 2 hr > 155, 3 hr > 140) 485 were treated (37 required insulin) 473 had usual care (2 required insulin) Crowther NEJM 2005 Scores for the SF-36 can range from 0 (worst) to 100 (best). Treatment of GDM Treatment of GDM Intervention Group N = 485 (%) Control Group N = 473 (%) Relative Risk p-value NICU Admission ( ) 0.19 Macrosomia ( ) < Neonatal Hypoglycemia ( ) 0.32 Shoulder Dystocia ( ) 0.02 Blood Sugar Monitoring (biofeedback) Choices for Treatment: Dietary modification & exercise Oral agents Insulin therapy Cesarean Delivery ( ) 0.02 Preeclampsia or GHTN ( ) 0.01 Landon et al. N Eng J Med

12 Treatment of GDM Blood Sugar Monitoring Weekly (N=675) Daily (N=315) p Vaginal Delivery 67.1% 63.2% 0.22 Shoulder Dystocia 1.9% 1.6% 0.71 Birth Weight 3,690 g 3,536 g < LGA 34.4% 23.1% < Treatment of GDM Diet No evidence to-date to support a specific diet. Carb-restriction (< 40%) seems to improve outcomes Usual advice: kcal/kg/day, limit carbs to < 40% of total calories, 20% protein, 40% fat. Exercise data is lacking with regards to pregnancy outcomes Hawkins Obstet Gynecol 2009 Han et al. Cochrane Database of Systematic Reviews 2013, Issue 3. Major et al. Obstet Gynecol 1998;91: Avoiding Ketosis Severe carb restriction can result in ketosis resulting from breakdown of fatty acids in absence of sufficient carbohydrates Ketosis may be associated with behavioral and intellectual abnormalities in offspring Rizzo et al: Children s developmental scores correlated inversely with 3 rd trimester beta-hydroxybutyrate levels Onyeije et al: Maternal ketonuria associated with increased risk of oligohydramnios, nonreactive NST, fetal heart rate decelerations In your practice, for patients who fail diet/exercise management of diabetes, what is your preferred first-line agent? A. Metformin B. Glyburide C. Insulin 19% 59% 22% Rizzo et al. N Engl J Med 1991;325: Onyeije et al. Am J Obstet Gynecol. 2001;184(4): M e t f o r m i n G l y b u r i d e I n s u l i n 12

13 Treatment of GDM Glyburide Treatment of GDM Oral Agents 400 women, GDM requiring medication, randomized to Glybruide or insulin. Glyburide (sulfonylurea) Increases insulin release from beta cells in pancreas Metformin (biguanide) Increases insulin sensitivity, decreases gluconeogenesis Langer et al. N Engl J Med 2000;343: Neonatal Outcome Langer et al. N Engl J Med 2000 Treatment of GDM Glyburide Glyburide (N=201) Insulin (N=203) P Value LGA 12% 13% 0.76 Birth Weight 3256 g 3194 g 0.28 Hypoglycemia 9% 6% 0.25 Maternal Blood Glucose < 40 mg/dl 2% 20% 0.03 Preeclampsia 6% 6% 1 Cesarean Section 23% 24% NS Langer: Secondary data analysis of RCT Glyburide and insulin are equally efficient for treatment of GDM in all levels of disease severity. Fasting plasma glucose on oral GTT Langer et al. Am J Obstet Gynecol Treatment of GDM Glyburide < 95 mg/dl > 95 mg/dl Insulin Glyburide Insulin Glyburide LGA 7.7% 8.8% 17.8% 18.4% Macrosomia 2.0% 6.3% 8.0% 9.2% Composite Outcome* 25.3% 27.5% 30.7% 29.1% * At least one of: metabolic complications, LGA/macrosomia, neonatal ICU admission > 24 hrs, need for respiratory support. 13

14 Glyburide Timing of Administration Glyburide should be administered minutes before a meal Glyburide crosses the placenta Downsides of Glyburide Rochon et al: Retrospective cohort study of 235 women Odds of Glyburide failure were 2.84 ( ) times higher among patients with glucose challenge test 200 mg/dl Neonates born to successfully Glyburide-treated mothers were more likely to go to the ICN as compared to women with Glyburide-failures (33% vs 10%, p = 0.037). Jacobson et al: Retrospective study comparing outcomes between 236 Glyburide-treated patients and 268 insulin-treated patients Patients treated with Glyburide had higher incidence of preeclampsia (12% vs 6%, p = 0.02, aor 2.32) Neonates more likely to receive phototherapy (9% vs 5%, p < 0.05) Caritis et al. Obstet Gynecol. 2013;121: Schwartz et al. Abstract SMFM. Am J Obstet Gynecol 2003;S25. Rochon et al. Am J Obstet Gynecol. 2006;195: Jacobson et al. Am J Obstet Gynecol. 2005;193: Trends in Glyburide Use Metformin Proportion of Patients on Glyburide Glyburide use increased from 7.4% to 64.5% from 2000 to Rowan et al: RCT of 751 women to compare Metformin & insulin in the treatment of GDM. Primary outcome was composite of neonatal complications Rate of primary outcome was equal in both groups 46% required supplemental insulin. More women in the metformin group than in the insulin group would choose to receive their assigned treatment again (76.6% vs 27.2%, p < 0.001). Castillo Obstet Gynecol 2014 Rowan et al. N Engl J Med. 2008;358: Moore et al. Obstet Gynecol. 2010;115:

15 Treatment of GDM - Metformin Treatment of GDM - Metformin Moore: RCT of 149 women comparing Metformin to Glyburide. Generally similar outcomes Failure rate for metformin was 2.1 x higher than Glyburide. Rowan et al. N Engl J Med. 2008;358: Moore Obstet Gynecol 2010 Insulin Oral Agents vs. Insulin Meta-analysis of oral hypoglycemics vs insulin: No difference in birthweight Type Onset Peak (hours) Duration (hours) Insulin Lispro/Aspart 1-15 min 1-2 hrs 4-5 hrs NPH 1-3 hrs 5-7 hrs hrs Insulin Glargine (Lantus) 1 hr None 24 hrs Insulin Detemir (Levemir) 1-2 hrs None 24 hrs Pooled Weighted Mean Difference FAVORS ORAL AGENTS 0 FAVORS INSULIN Dhulkotia AJOG

16 Oral Agents vs Insulin Meta-analysis of oral hypoglycemics vs insulin: No difference in CS Rates Induction of Labor Rosenstein: Infant mortality rates at 39 weeks are lower than overall mortality risk of expectant management. FAVORS ORAL AGENTS FAVORS INSULIN Dhulkotia AJOG 2010 Rosenstein et al. Am J Obstet Gynecol. 2012;206:309.e1-7. Overview Impact of Hyperglycemia Testing Treatment Postpartum Postpartum Impact of Activity Each 100 min/wk increase in moderate-intensity physical activity reduced the risk of DM2 by 9%. Bao JAMA Intern Med

17 Postpartum Impact of Activity Effect of Life Style on Risk of DM RR for Type 2 DM associated with TV watching: 0-5 hrs = hrs = hrs = 1.41 > 20 hrs = 1.77 Bao JAMA Intern Med 2014 Ratner J Clin Endocrinol Metab 2008 Conclusions Conclusions The goal of blood sugar testing is to identify women at increased risk for poor perinatal outcomes and provide intervention where possible Given the low risk of intervention and the high-potential for gain, the most sensitive testing strategy should be considered Testing strategy must be tailored to patients/population Dietary intervention is often adequate treatment Oral antihyperglycemics are an appropriate alternative to insulin Careful attention to diet and exercise in the postpartum period reduces the long term risk of type 2 diabetes 17

18 Thank You! 18