Kirstin Woo, MD Palo Alto Foundation Medical Group May 5, 2009 Diabetes in Pregnancy Kirstin Woo, MD Palo Alto Foundation Medical Group May 5, 2009

Outline Physiologic changes in pregnancy Diabetes in pregnancy Organ systems affected Metabolic changes in pregnancy Diabetes in pregnancy Clinical implications Epidemiology/Types Screening and Diagnosis Management Future directions Now that we have considered the general differences between glucose metabolism in the pregnant and non-pregnant state, let us move on to the discussion of when glucose metabolism goes awry – diabetes in pregnancy.

Physiologic changes in pregnancy Cardiovascular system Respiratory system Gastrointestinal system Urinary system Endocrine system Genital Tract Skin Pregnancy affects nearly all systems in the body I will focus on the cardiovascular, respiratory and GI effects and then move on to the metabolic changes, since that relates more closely to diabetes in pregnancy

Physiologic changes in pregnancy: Cardiovascular Sodium and water retention Reduced systemic blood pressure (mean 105/60 mmHg in 2nd trimester) Increased cardiac output (30-50% rise) Increased blood volume (total body water increases 40%) Reduced systemic vascular resistance (vasodilitation PLUS high flow, low-resistance circuit of the uteroplacental circulation) Increased maternal heart rate (up 15-20 beats/min) As a result of increased blood volume and reduced systemic blood pressure, cardiac output increases significantly. In general, the heart is “working harder” through pregnancy, not to mention during labor, which means that women with preexisting heart conditions need to have special consideration when conceiving.

Physiologic changes in pregnancy: Respiratory Mechanical changes Diaphragm rises 4 cm Less negative intrathoracic pressure No impairments in diaphragmatic or thoracic muscle motion Lung compliance remains unaffected Physiologic changes Oxygen consumption increases 15-20 % 50% of this increase is required by the uterus Progesterone directly stimulates breathing 70% of women experience dyspnea (increased desire to breathe) The change in anatomy, especially later in pregnancy influences the shape and function of the thoracic (chest) cavity With a smaller volume, there is less negative pressure and therefore the volume inhaled with each breath is decreased. The muscle and lung tissue functions themselves remain the same.

Physiologic changes in pregnancy: Gastrointestinal Mechanical Pressure from growing uterus on stomach  reflux/heartburn Pressure from growing uterus on lower portion of colon and rectum  constipation Physiologic Relaxation of sphincter muscle between esophagus and stomach Progesterone (a smooth muscle relaxant) causes decreased GI motility and delayed gastric emptying

Normal glucose metabolism Glucose enters bloodstream from food source Insulin aids in storage of glucose as fuel for cells Insulin resistance is defined as insensitivity of cells to insulin, therefore resulting in increased levels of insulin and glucose in the bloodstream Let’s talk about the changes in metabolism that occur during pregnancy, specifically carbohydrate metabolism. First of all, normal glucose metabolism is depicted here. Glucose is absorbed from the stomach and small intestine and enters the bloodstream, then is transported to various organs. Insulin, secreted by the pancreas is required to permit entry of the glucose into the cell to be used.

Metabolic changes in pregnancy Caloric requirement for a pregnant woman is 300 kcal higher than the non-pregnant woman’s basal needs Placental hormones affect glucose and lipid metabolism to ensure that fetus has ample supply of nutrients Later in gestation with increased fetal growth, larger fluctuations in glucose and insulin occur as mother oscillates between fed and fasted states (during fasting, glucose is reserved for fetus)

Metabolic changes in pregnancy Lipid metabolism: Increased lipolysis (preferential use of fat for fuel, in order to preserve glucose and protein) Glucose metabolism: Decreased insulin sensitivity Increased insulin resistance

Metabolic changes in pregnancy Increased insulin resistance Due to hormones secreted by the placenta that are “diabetogenic”: Growth hormone Human placental lactogen Progesterone Corticotropin releasing hormone Transient maternal hyperglycemia occurs after meals because of increased insulin resistance

Metabolic changes in pregnancy Relative baseline hypoglycemia Proliferation of pancreatic beta cells (insulin-secreting cells) leads to increased insulin secretion Insulin levels are higher than in pregnant than nonpregnant women in fasting and postprandial states Hypoglycemia between meals and at night because of continuous fetal draw Blood glucose levels are 10-20% lower

Metabolic changes in pregnancy Lipid metabolism Increased serum triglyceride (300%) and cholesterol (50%) levels Spares glucose for fetus, since lipids do not cross the placenta Provides building blocks for increased steroid hormone synthesis

Outline Physiologic changes in pregnancy Diabetes in pregnancy Organ systems affected Metabolic changes in pregnancy Diabetes in pregnancy Clinical implications Epidemiology/Types Screening and Diagnosis Management Future directions Now that we have considered the general differences between glucose metabolism in the pregnant and non-pregnant state, let us move on to the discussion of when glucose metabolism goes awry – diabetes in pregnancy.

Diabetes in Pregnancy: Clinical Implications Obstetric complications: Increased incidence of miscarriage Congenital malformations Incidence 4X higher than in general population Most significant remaining cause of fetal death is congenital malformation Association with hypertensive disorders of pregnancy Gestational hypertension Preeclampsia It has long been recognized that poorly controlled diabetes causes a multitude of obstetric complications

Diabetes in Pregnancy: Clinical implications Shoulder dystocia Fetal macrosomia

Diabetes in Pregnancy: Clinical Implications Obstetric complications (cont’d.): Preterm delivery Intrauterine fetal demise Traumatic delivery (e.g., shoulder dystocia) Operative vaginal delivery vacuum-assisted forceps-assisted

Diabetes in Pregnancy: Clinical Implications Fetal macrosomia Disproportionate amount of adipose tissue concentrated around shoulders and chest Respiratory distress syndrome Neonatal metabolic abnormalities: Hypoglycemia Hyperbilirubinemia/jaundice Organomegaly Polycythemia Perinatal mortality Long term predisposition to childhood obesity and metabolic syndrome Other perinatal complications involve both long and short term exposure to high levels of serum glucose.

Outline Physiologic changes in pregnancy Diabetes in pregnancy Organ systems affected Metabolic changes in pregnancy Diabetes in pregnancy Clinical implications Epidemiology/Types Screening and Diagnosis Management Future directions Now that we have considered the general differences between glucose metabolism in the pregnant and non-pregnant state, let us move on to the discussion of when glucose metabolism goes awry – diabetes in pregnancy.

Diabetes in Pregnancy: Epidemiology Preexisting diabetes complicates ~1 % of pregnancies in US (>8 million women) 154,000 (4%) of all pregnancies are affected by diabetes 135,000 (88%) due to GDM 12,000 (8%) due to Type 2 DM 7,000 (4%) due to Type 1 DM

Diabetes in Pregnancy: Epidemiology Geographic disparities exist in the state of California with the highest rates of GDM reported in the counties of Alameda, Amador, Colusa, Glenn, Monterey, Santa Clara and Yolo

Diabetes in Pregnancy: Classification Criterion White Classification gestational diabetes, insulin not required A1 gestational diabetes, insulin required A2 age of onset >= 20 years (maturity onset diabetes) B1 duration < 10 years, no vascular lesions B2 age of onset 10-19 years of age C1 duration 10-19 years, no vascular lesions C2 age of onset < 10 years of age D1 duration >= 20 years D2 benign retinopathy D3 calcified arteries of legs D4 calcified arteries of pelvis (no longer sought) E nephropathy F many failures G cardiopathy H proliferating retinopathy R renal transplant T Priscilla White developed this classification system to assess maternal and fetal risk and differentiate between preexisting diabetes and gestational diabetes

Diabetes in Pregnancy: Types Gestational Diabetes Mellitus (GDM) Type A1: abnormal oral glucose tolerance test (OGTT) but normal blood glucose levels during fasting and 1-2 hours after meals; diet modification is sufficient to control glucose levels Type A2: abnormal OGTT compounded by abnormal glucose levels during fasting and/or after meals; additional therapy with insulin or other medications is required Pregestational Diabetes Mellitus Type 1: autoimmune process that destroys pancreatic b cells Type 2 (“lifestyle diabetes”): acquired insulin resistance related to obesity

Pregestational Diabetes: Types 1 and 2 Type 1 is characterized by lack of insulin (a production problem) Type 2 is characterized by plentiful insulin that is not able to do its job effectively (a function problem – i.e., lack of response, hence the term “insulin resistance”)

Gestational Diabetes (GDM) Definition: Insulin resistance/ glucose intolerance first diagnosed during pregnancy Prevalence: 1-14% of all pregnancies Indicates predisposition to later development of Type 2 Diabetes Chance of recurrence in future pregnancies: 30-84% Within 10-20 years after delivery, approximately 50% of women who had gestational diabetes will develop type 2 diabetes Varies by ethnicity – in the Hispanic population, up to 50% develop type 2 diabetes within 5 years of diagnosis of gestational diabetes Prevalence is wide-ranging and variable depending on ethnic makeup of the population. Also, patients’ first presentation may be during pregnancy

GDM: Risk factors Maternal age >25 years Body mass index >25 kg/m2 Race/Ethnicity Latina Native American South or East Asian, Pacific Island ancestry Personal/Family history of DM History of macrosomia

Gestational Diabetes (GDM) Risk factors play into increased pre-conception insulin resistance Adding on insulin resistance of pregnancy because of estrogen/progesterone and placental hormones creates a hyperinsulinemic state

Outline Physiologic changes in pregnancy Diabetes in pregnancy Organ systems affected Metabolic changes in pregnancy Diabetes in pregnancy Clinical implications Epidemiology/Types Screening and Diagnosis Management Future directions Now that we have considered the general differences between glucose metabolism in the pregnant and non-pregnant state, let us move on to the discussion of when glucose metabolism goes awry – diabetes in pregnancy.

GDM: Screening Screening test Screening thresholds 50 gm 1-hour glucose challenge test (GCT) Screening thresholds 130mg/dL: 90% sensitivity (23% screen positive) 140mg/dL: 80% sensitivity (14% screen positive) If patient screens positive, she goes on to take a 3-hour glucose tolerance test (GTT) 50 grams of glucola are drunk, followed by a serum measurement of glucose one hour later 2/3 of obgyns use 140 cutoff 1/3 of obgyns use 130-135 cutoff

National Diabetes and Data Group GDM: Diagnosis Fasting blood glucose >126mg/dL or random blood glucose >200mg/dL 100 gm 3-hour glucose tolerance test (GTT) with 2 or more abnormal values Carpenter and Coustan National Diabetes and Data Group Fasting 95 mg/dL 105 mg/dL 1 hour 180 mg/dL 190 mg/dL 2 hour 155 mg/dL 165 mg/dL 3 hour 140 mg/dL 145 mg/dL C/C criteria capture 54% more patients than NDDG criteria

Outline Physiologic changes in pregnancy Diabetes in pregnancy Organ systems affected Metabolic changes in pregnancy Diabetes in pregnancy Clinical implications Epidemiology/Types Screening and Diagnosis Management Future directions Now that we have considered the general differences between glucose metabolism in the pregnant and non-pregnant state, let us move on to the discussion of when glucose metabolism goes awry – diabetes in pregnancy.

Management: Glycemic control Significant benefit of insulin therapy Prior to insulin use, perinatal mortality was 65% After introduction of insulin therapy, perinatal mortality declined to 5%

Management: Glycemic control Glycosylated Hemoglobin A1C (Hgb A1C) level should be less than or equal to 6% Levels between 5 and 6% are associated with fetal malformation rates comparable to those observed in normal pregnancies (2-3%) Goal of normal or near-normal glycosylated hemoglobin (Hgb A1C) level for at least 3 months prior to conception Hgb A1C concentration near 10% is associated with fetal anomaly rate of 20-25% In the normal 120-day life span of the red blood cell, glucose molecules join hemoglobin, forming glycated hemoglobin. In individuals with poorly controlled diabetes, increases in the quantities of these glycated hemoglobins are noted. Once a hemoglobin molecule is glycated, it remains that way. A buildup of glycated hemoglobin within the red cell reflects the average level of glucose to which the cell has been exposed during its life cycle. Measuring glycated hemoglobin assesses the effectiveness of therapy by monitoring long-term serum glucose regulation. The HbA1c level is proportional to average blood glucose concentration over the previous four weeks to three months. Some researchers state that the major proportion of its value is related to a rather short term period of two to four weeks.

Management: Overview Home self glucose monitoring Nutrition therapy Home self glucose monitoring Medical therapy if glycemic control not achieved with diet/exercise Subcutaneous insulin Oral hypoglycemic agents (Glyburide, Metformin) Antenatal monitoring Main goal is glycemic control, first by lifestyle adjustments (diet and exercise) and then by medication if necessary

Management: Glycemic Control Blood glucose goals during pregnancy Fasting < 95mg/dL 1-hr postprandial < 130-140mg/dL 2-hr postprandial am < 120mg/dL 2 am < 120mg/dL Nocturnal glucose level should not go below 60 mg/dL Abnormal postprandial glucose measurements are more predictive of adverse outcomes than preprandial measurements

Management: Nutrition Caloric requirements: Normal body weight - 30-35 kcal/kg/day Distributed 10-20% at breakfast, 20-30% at lunch, 30-40% at dinner, up to 30% for snacks (to avoid hypoglycemia) Caloric composition: 40-50% from complex, high-fiber carbohydrates 20% from protein 30-40% from primarily unsaturated fats

Management: Subcutaneous Insulin Therapy Insulin requirements increase rapidly, especially from 28 to 32 weeks of gestation 1st trimester: 0.7-0.8 U/kg/d 2nd trimester: 0.8-1 U/kg/d 3rd trimester: 0.9-1.2 U/kg/d Recall that the introduction of insulin therapy significantly reduced perinatal mortality

Management: Subcutaneous Insulin Therapy Recall that the introduction of insulin therapy significantly reduced perinatal mortality “Regular” insulin = Humalog, Novalog

Management: Oral Hypoglycemic Agents Glitazones (Avandia, Actos) Sensitize muscle and fat cells to accept insulin more readily Decrease insulin resistance Sulfonylureas Augment insulin release 1st generation Concentrated in the neonate  hypoglycemia 2nd generation (Glyburide) Low transplacental transfer Biguanide (Metformin, aka Glucophage) Increases insulin sensitivity Crosses placenta Recall that the introduction of insulin therapy significantly reduced perinatal mortality

Management Summary: Pregestational Diabetes Referral to perinatologist and/or endocrinologist Multidisciplinary approach Regular visits with nutritionist Hgb A1C every trimester Fetal Echocardiogram Level II ultrasound Opthamologist Baseline kidney and liver function tests

Management Summary: Pregestational Diabetes Optimize glycemic control – frequent insulin dose adjustments Type 1: often have insulin pump Type 2: subcutaneous insulin Fetal monitoring starting at 28-32 weeks, depending on glycemic control Ultrasound to assess growth at 36 weeks Delivery at 38-39 weeks Practice varies by institution, but the general principle of detecting fetal macrosomia and avoiding IUFD applies

Management Summary: GDM Begin with diet / walk after each meal If borderline/mild elevations, consider metformin (start at 500 mg daily) Counsel about increased PTD rates Unlikely pre-existing DM If elevations start out moderate to severe or metformin fails, proceed to subcutaneous insulin therapy NPH (long acting) Humalog/Novalog (short acting)

Management Intrapartum Attention to labor pattern, as cephalopelvic disproportion may indicate fetal macrosomia Careful consideration before performing operative vaginal delivery Hourly blood glucose monitoring during active labor, with insulin drip if necessary Notify pediatrics if patient has poorly controlled blood sugars antepartum or intrapartum

Management Postpartum For patients with pregestational diabetes, halve dose of insulin and continue to check blood glucose in immediate postpartum period For GDM patients who required insulin therapy (GDMA2), check fasting and postprandial blood sugars and treat with insulin as necessary For GDM patients who were diet controlled (GDMA1), no further monitoring nor therapy is necessary immediately postpartum

Management Postpartum For all GDM patients, perform 75 gram 2-hour OGTT at 6 week postpartum visit to rule out pregestational diabetes Most common recommendation is for primary care physician to repeat 2-hour OGTT every three years

Diabetes in Pregnancy: Future directions ACOG recommendations on oral hypoglycemic agents will be updated as more safety and efficacy data become available Further development of programs for patient and provider education Example: California Diabetes and Pregnancy Program (CDAPP) consultants develop, update and disseminate Sweet Success: Guidelines for Care which provides standards of practice for diabetes and pregnancy

References ACOG practice bulletin. Gestational Diabetes. Obstet Gynecol 2001;93:525-34 ADA position statement. Standards of Medical Care in Diabetes. Diabetes Care 2006;29:S4-42 Crowther CA et al. N Engl J Med 2005;352:2477-86 Casey BM et al. Obstet Gynecol 1997;90:867-73 Yang X et al. Diabetes Care 2002;9:1619-24 UpToDate.com Thanks to Dr. Bertha Chen and Dr. Aaron Caughey for sharing their slides