Objectives. Diabetes in Pregnancy: A Growing Dilemma. Diabetes in the US 10/6/2015. Disclosure. The presenter has no conflicts to disclose

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1 Diabetes in Pregnancy: A Growing Dilemma Kathy O Connell, MN RN Perinatal Clinical Nurse Specialist University of Washington Medical Center Seattle, WA koconnll@uw.edu Objectives Describe pathophysiologic processes related to diabetes in pregnancy that increase risks for both mother/newborn Define current recommendations for screening and treatment of mothers who have diabetes complicating their pregnancies Discuss outcomes in infants exposed to maternal hyperglycemia during pregnancy Disclosure The presenter has no conflicts to disclose Diabetes in the US Total: 29.1 million people or 9.3% of the population have diabetes. Diagnosed: 21.0 million people. Undiagnosed: 8.1 million people (27.8% of people with diabetes are undiagnosed). all ages, 2012 Age-adjusted * percentage of people aged 20 years or older with diagnosed diabetes, by race/ethnicity, United States, Rate of new cases of type 1 and type 2 diabetes among people younger than 20 years, by age and race/ethnicity, *Based on the 2000 U.S. standard population. Source: National Health Interview Survey and 2012 Indian Health Service s National Patient Information Reporting System. <10 years years Source: SEARCH for Diabetes in Youth Study. NHW=non-Hispanic whites; NHB=non-Hispanic blacks; H=Hispanics; API=Asians/Pacific Islanders; AIAN=American Indians/Alaska Natives. * The American Indian/Alaska Native (AI/AN) youth who participated in the SEARCH study are not representative of all AI/AN youth in the United States. Thus, these rates cannot be generalized to all AI/AN youth nationwide. 1

2 Estimated costs Diabetes No Data <14.0% 14.0% 17.9% 18.0% 21.9% 22.0% 25.9% > 26.0% No Data <4.5% 4.5% 5.9% 6.0% 7.4% 7.5% 8.9% >9.0% CDC s Division of Diabetes Translation. National Diabetes Surveillance System available at Age-adjusted Prevalence of Obesity BMI> 30 (top)and Diagnosed Diabetes (bottom)among US Adults Total (direct and indirect) $ 245 billion/year Direct medical costs $ 176 billion After adjusting for population age and sex differences, average medical expenditures among people with diagnosed diabetes were 2.3 times higher than people without diabetes. Indirect $ 69 billion (disability, work loss, premature death). Washington State Diabetes: By County You are here Phy Physiology of Pregnancy A continuously feeding fetus in an intermittently feeding mom! 2

3 1 st half of pregnancy Early pregnancy: beta cell hyperplasia => increased insulin production Increased tissue sensitivity to insulin hyperinsulinemic state => increased lipogenesis and fat deposition in early pregnancy increased incidence of hypoglycemia in early pregnancy 2 nd half of pregnancy Accelerated growth of fetus (and placenta) maternal and placental diabetogenic hormones HPL Cortisol Estrogen/progesterone Prolactin Cont d Increasing insulin requirement as pregnancy progresses Progressive increase in insulin secretion Pregnancy related insulin resistance Hormonally mediated (as fetus/placenta grow) Cytokine secretion (from fetus/placenta) which modulates the balance between humoral (antibody)and cell based immune responses Rapid change to a catabolic phase in 2 nd half of pregnancy =>Lipolysis (fat breakdown) Change from carbohydrate to fat metabolism during fasting times (overnight) Fats become fuel source Fatty acids, triglycerides produced Ketones produced (DKA) Accelerated starvation Increase in hepatic glucose production MATERNAL FETAL Glucose Amino Acids FFA TGFA Ketones Insulin Glucagon Insulin Glucagon 3

4 Structural Functional Anthropometric Pre-Gestational Diabetes Gestational Diabetes From: Norbert Freinkel Weeks of Pregnancy Maternal Obesity ~ 33% of pregnancies complicated by maternal obesity! Metabolic syndrome (choose 3) Hyperlipidemia Hypertension Elevated fasting BS Elevated triglycerides Low HDL Source: NIH Impacts quality of oocytes and embryos Fetal programming Predisposition begins in utero Susceptibility to adult disease in response to exposure Over nutrition during pregnancy Epigenetic changes Changes in the biochemical structure of DNA that alter gene expression Affected by both inherited and environmental triggers Origins of adult diseases (HTN, T2D, CVD) Impact both embryonic and fetal development Resulting in: permanent structural/functional damage Damage to cellular structures May manipulate cellular responses to stimuli Over nutrition: Programs the developing fetus to anticipate excessive nutrient availability after birth» Increases adiposity in offspring» Increases inflammation in offspring» Elevates fasting insulin levels» Increases insulin resistance 4

5 What if nutrients are appropriate after birth? Normal diet postnatally Offspring maintained adverse metabolic profile and epigenetic changes into adulthood. What about pregnancy outcomes after bariatric surgery? (compared with matched controls) Lower risk of GDM» 1.9% v 6.8% Lower risk of LGA babies» 8.6% v 22.4% Higher risk of SGA babies» 15.6% v 7.6% Similar risk of preterm birth» 10% v 7.5% Higher risk of stillbirth or NND» 1.7% v.7% No significant differences in congenital malformations Johansson K et al. NEJM 2015 Diabetes as a complication of pregnancy type 1 - autoimmune destruction of pancreatic islet cells (~10%) type 2 enhanced insulin resistance (β cell dysfunction) (~90%) Limited (or NO) pancreatic reserve Increasing hormonal secretion Increasing insulin resistance Type 2 Diabetes: Can have insulin resistance with normal insulin secretion Changes can be seen years before onset of overt disease Insulin resistance => precursor to β cell dysfunction Treating insulin resistance can lower dysfunction and slow the onset of the disease Risk factors 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 5

6 Plasma Glucose (mg/dl) Gestational Diabetes Because of the number of pregnant women with undiagnosed type 2 diabetes, it is reasonable to test women with risk factors for type 2 diabetes at their initial prenatal visit, using standard diagnostic criteria women with diabetes in the first trimester would be classified as having type 2 diabetes GDM is diabetes diagnosed in the 2 nd or 3 rd trimester that is not clearly overt diabetes ADA Classification and Diagnosis of Diabetes: studies reviewed Diabetes care, Volume 34, July Plasma Glucose Variation Over 24 Hrs Pregnant, Normal, Non-Diabetic at 28 and 38 wks Screening Screen at first visit: EITHER all women or only those with risk factors using FPG, RPG or A1C (not rapid) include in prenatal labs 100 A1C < 5.7 FPG < 92 mg/dl OR RPG < 126 mg/dl A1C OR FPG > 92 mg/dl OR RPG > 126 mg/dl A1C > 6.4 OR FPG > 126 mg/dl OR RPG > 200 mg/dl 80 s No Dx DM; perform universal wks Dx GDM; treat now Dx type 2 DM; treat now AM 2PM 6PM 10PM 2AM 6 AM Time Obtain fasting & 2 hour 75 gm OGTT (or 50 gm) Consider ordering with 3 rd trimester labs Treat GDM if ONE or more values > the following: Fasting: 92, 1hr 180, 2hr 153 6

7 ACOG and ADA recommendations for BS goals (2013) Assess BS at either 1or 2 hours postprandially BS <140 at 1 hour BS <120 at 2 hours Diabetes care, Volume 34, July 2011 Authors Recommendation Treatment Exercise Medical nutrition therapy Medications Oral» Metformin» Glyburide insulin 7

8 MATERNAL Glucose Amino Acids FFA TGFA Ketones Insulin Glucagon FETAL Insulin Glucagon Diet v Insulin v Oral Agents Start medication if 30% of CBG levels are above goals while on diet fasting > 90 mg/dl 1 hour postprandial > 120 mg/dl May not have enough time to try a diet or fail on oral agents Metformin/Glyburide Metformin Metformin in GDM Trial Crosses the placenta but no apparent adverse fetal effects (MiG trial) May decrease pre-eclampsia by decreasing insulin resistance May decrease spontaneous abortion in PCOS patients Long term, may protect against breast, colon, lung and pancreatic cancer 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 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%) Metformin Starting dose: 500 mg bid and increase twice weekly. (Rapid increase GI Symptoms) Maximum dose: mg daily How supplied: 500, 850, 1000 mg (generic) (also supplied as SR in 500 and 750 mg) Hypoglycemia minimal concern 8

9 Plasma Glucose (mg/dl) Glyburide Peak: ~4 hours Non Pregnant Elimination half life: ~10 hours Clearance increases as pregnancy progresses Breastfeeding not affected Pregnancy category B (Probably will change) Not detected in cord blood (Langer 2000) Is detected in cord blood (Hebert 2008) CONCLUSIONS AND RELEVANCE Newborns from privately insured mothers treated with glyburide were more likely to experience adverse outcomes than those from mothers treated with insulin. Given the widespread use of glyburide, further investigation of these differences in pregnancy outcomes is a public health priority Plasma Glucose Variation Over 24 Hrs Pregnant, Normal, Non-Diabetic at 28 and 38 wks s AM 2PM 6PM 10PM 2AM 6 AM Time 27 clinical sites, 350 women with GDM, 1416 women without GDM Conclusions: Women with GDM are at increased risk of developing diabetes In women with a history of GDM in the DPP/Diabetes prevention program outcomes study: both lifestyle and metformin reduced progression to diabetes in a 10 year follow up period Among women without GDM: lifestyle but not metformin reduced progression to diabetes What s on the horizon? The gut microbiome but, that s another story entirely! 9

10 References: American College of Obstetricians and Gynecologists: Practice Bulletin Gestational Diabetes Mellitus. Author. American Diabetes Association. Aroda, VR et al. The effect of lifestyle intervention and metformin on preventing or delaying diabetes among women with and without gestational diabetes: The diabetes prevention program outcomes study 10 year follow up. J Clinical Endocrinology and Metabolism. 2014; doi: /jc Catalano PM et al. Fetuses of Obese Mothers Develop Insulin Resistance in Utero. Diabetes Care. 2009; 32 (6) June Catalano PM et al. Perinatal risk factors for childhood obesity and metabolic dysregulation. American Journal of Clinical Nutrition : Catalano, PM; Hauguel-De Mouzon, S. Is it time to revisit the Pedersen hypothesis in the face of the obesity epidemic?. American Journal of Obstetrics and Gynecology. 2011; June 2011: Camelo-Castillo, W et al. Association of Adverse Pregnancy Outcomes wth Glyburide vs Insulin in Women with Gestational Diabetes. JAMA Pediatrics. 2015; 169 (5): Chiswick C, et al. Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double blind, placebo-controlled trial. The Lancet-Diabetes Endocrinology. 2015; July 10, 2015 Fernandez-Twinn,D et al. Intergenerational epigenetic inheritance in models of developmental programming of adult disease. Seminars in Cell and Developmental Biology. 2015; accessed online. Hernandez, TL et al. Patterns of Glycemia in Normal Pregnancy: Should the Current therapeutic targets be challenged? Diabetes Care; 2011June Segovia, S et al. Maternal obesity, inflammation and developmental programming. Biomed Research International. 2014; ID Smith, C; Ryckman,K. Epigenetic and developmental influencs on the risk of obesity, diabetes and metabolic syndrome. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2015: Obesity and Gestational Diabetes Mellitus Pathways for Programming in Mouse, Monkey and Man- where do we go next? The 2014 Norbert Freinkel Award Lecture. Diabetes Care; 2015; 38: Johannson, K et al. Outcomes of Pregnancy after Bariatric Surgery. NEJM. 2015; 372 (9) Landon, MB et al. The relationship between maternal glycemia and Perinatal outcome. Obstetrics & Gynecology. 2011; 117 (2) part