Diabetes in Pregnancy Ass. Pro. : S. Rouholamin

Objectives Discuss Gestational Diabetes Mellitus (GDM) and Treatment Recognize common problems of GDM in Pregnancy Discuss long term followup of Gestational Diabetes Mellitus (GDM) Discuss needs of pre-existing diabetes in pregancy

Gestational Diabetes Mellitus

Gestational Diabetes Reduced sensitivity to insulin in 2nd and 3rd trimesters “Diabetogenic State” when insulin production doesn’t meet with increased insulin resistance Hod and Yogev Diabetes Care 30:S180-S187, 2007 Crowther, et al NEJM 352:2477–2486, 2005 Langer, et al Am J Obstet Gynecol 192:989–997, 2005

Gestational Diabetes Human placental lactogen, leptin, prolactin, and cortisol result in insulin resistance Lack of diagnosis and treatment-increased risk of perinatal morbidities Hod and Yogev Diabetes Care 30:S180-S187, 2007 Crowther, et al NEJM 352:2477–2486, 2005 Langer, et al Am J Obstet Gynecol 192:989–997, 2005

Gestational Diabetes Occurs in 2-9% of pregnancies ~135,000 cases in U.S. annually Management can include insulin (usually preferred, better efficacy) or sulfonylureas (in very select cases) Am J Obstet Gynecol 192:1768–1776, 2005 Diabetes Care 31(S1) 2008 Diabetes Care 25:1862-1868, 2002

Gestational Diabetes and Type 2 Diabetes Risk Gestational Diabetes should be considered a pre-diabetes condition Women with gestational diabetes have a 7-fold future risk of type 2 diabetes vs.women with normoglycemic pregnancy Lancet, 2009, 373(9677): 1773-9

Gestational Diabetes-Screening Screen all very high risk and high risk Very high risk: Previous GDM, strong FH, previous infant >9lbs High risk: Those not in very high risk or low risk category

Gestational Diabetes-Screening Low Risk (all of following) Age <25 years Weight normal before pregnancy Member of an ethnic group with a low prevalence of diabetes Diabetes Care 31(S1) 2008

Gestational Diabetes-Screening Low Risk (all of following)(cont’d) No known diabetes in first-degree relatives No history of abnormal glucose tolerance No history of poor obstetrical outcome Diabetes Care 31(S1) 2008

Gestational Diabetes Screening 2 step approach oral glucose tolerance test (OGTT) 1) 50gm 1 hour OGTT 2) 100gm 2 hour OGTT

Gestational Diabetes-Screening GDM screening at 24–28 weeks: Two-step approach: 1) Initial screening: plasma or serum glucose 1 h after a 50-g oral glucose load Glucose threshold 140 mg/dl identifies 80% of GDM 130 mg/dl identifies 90% of GDM Diabetes Care 31(S1) 2008

Gestational Diabetes-Screening GDM screening at 24–28 weeks: Two-step approach (cont’d) 2) 3 hour OGTT* (100g glucose load) Fasting: >95 mg/dl (5.3 mmol/l) 1 h: >180 mg/dl (10.0 mmol/l) 2 h: >155 mg/dl (8.6 mmol/l) 3 h: >140 mg/dl (7.8 mmol/l) *2 of 4 Diabetes Care 31(S1) 2008

Gestational Diabetes Management Dietician Diabetes Educator Consider referral to Diabetologist or Endocrinologist Moderate Physical Activity ~30 minutes daily when appropriate Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus Diabetes Care 30:S251-S260, 2007

Preprandial: <95 mg/dl, and either: 1-h postmeal: <140 mg/dl or Glucose Control in GDM Preprandial: <95 mg/dl, and either: 1-h postmeal: <140 mg/dl or 2-h postmeal: <120 mg/dl and Urine ketones negative Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus. The Organizing Committee. Diabetes Care 21(2):B161–B167, 1998

Gestational Diabetes-Medications Patients who do not meet metabolic goals within one week or show signs of excessive fetal growth Insulin has been the usual first choice Sulfonylureas (glyburide) may be used in select patients Other diabetes medications not recommended in GDM Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus Diabetes Care 30:S251-S260, 2007 Langer et al N Engl J Med 343:1134–1138, 2000

Diabetes Medications Insulins-Safety Aspart, Lispro, NPH, R, Lispro protamine all Category B and used in pregnancy All other insulins Category C Human Insulins-Least Immunogenic Breastfeed-All insulins considered safe Data from Package Inserts

Gestational Diabetes-Management Fasting, pre-meal, 2-hour post-prandial blood glucose probably all important Mean blood glucose >105-115, greater perinatal mortality A1C in GDM probably not important Am J Obstet Gynecol 192:1768–1776, 2005 ADA Position Statement Pettit, et al Diabetes Care 3:458–464, 1980 Karlsson, Kjellmer Am J Obstet Gynecol 112:213–220, 1972 Langer, et al Am J Obstet Gynecol 159:1478–1483, 1988

Insulin Dosing-GDM Insulin dosing: Can use usual weight based dosing (i.e., 0.5 u/kg) Practical dosing can be to start 10 units NPH with evening meal Most will titrate to BID, with eventual addition of Regular or Rapid Acting BID

Alternate Insulin Dosing in GDM Regular or rapid acting (lispro or aspart) with meals, NPH at bedtime NPH + Regular or rapid acting in AM, regular or rapid acting at supper, NPH at bedtime Titrate insulin based on SBGM values, tested fasting, pre-meal, 2 hour post-meal, bedtime, occasional 3 AM.

GDM Complications Macrosomia Fractures Shoulder dystocia Nerve palsies (Erb’s C5-6) Neonatal hypoglycemia Pregnancy outcomes can be very poor with HTN/nephropathy Gabbe, Obstetrics: Normal and Problem Pregnancies 2002

Gestational Diabetes: Post-natal Fasting glucose rechecked 6-12 weeks following delivery Every 6 months thereafter to be screened for type 2 diabetes Higher risk of developing Type 2 Diabetes Kitzmiller, et al Diabetes Care 30:S225-S235, 2007

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

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.

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

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

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: 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

Case Study 28 y/o caucasian female 2nd pregnancy 1st pregnancy at age 22, term male infant, 10 lbs 2oz, normal delivery “Thinks had high blood sugar” Very high risk (>9 lb infant, possible GDM)

Case Study No other significant medical history No tobacco Physical Exam: VS normal 5’ 2” 210 lbs BMI 38.4 Remainder consistent with 12 weeks gestation

Case Study 26 weeks, no problems, maybe slightly large for dates 12 lb weight gain Went directly to 3 hour GTT (100g)

Case Study FBG: 94 ( > 95) 1 hour: 192 (>180) 3 of 4 values abnormal= GDM

Case Study Referred to Diabetes Educator and Dietician SMBG: FBG, pre-meal, 2 hour post-prandial, HS, 3 am prn Meal Plan No contraindications to exercise, encouraged to walk 15 min/daily

Preprandial: <95 mg/dl, and either: 1-h postmeal: <140 mg/dl or Glucose Control in GDM Preprandial: <95 mg/dl, and either: 1-h postmeal: <140 mg/dl or 2-h postmeal: <120 mg/dl and Urine ketones negative Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus. The Organizing Committee. Diabetes Care 21(2):B161–B167, 1998

Case Study Returns one week later Has been following meal plan “90% of time” Has walked 15 minutes 2 times Has 4 FBG > 100 6 other values above target

Case Study Referred to Diabetes Educator for insulin start NPH 10 units, 3 units Insulin aspart BID Phone followup q 3 days Continues appropriate clinic appointments

Case Study 1-2 SMBG values out of target 1st week 3 weeks later, FBG, 2 hour post lunch and 2 hour post supper elevated about ~50% of time NPH increased in PM (or could move to HS), insulin aspart added at lunch (2 or 3 units) and increased at supper

Case Study Normal vaginal delivery at 38 weeks 8lb 10oz healthy female infant Patients FBS day after delivery 90 Enrolled in Diabetes Prevention Program Converted to type 2 diabetes 2 years later Had lap-band 4 years later

Gestational Diabetes Mellitus Risk of Type 2 Diabetes Meta analysis: 20 studies 675,455 women 7-fold increase in risk of type 2 diabetes following gestational diabetes vs. normoglycemic pregnancy Post pregnancy surveillance important Bellamy, L. et al. Lancet, 2009, 373(9677): 1773-9

Type 2 Diabetes Prevention Lifestyle- over 50% reduction of future type 2 diabetes Bariatric (Lap-Band-future preg?)- strong consideration in BMI >40 or >35 with co-morbid conditions Future treatments/prevention- no current medication role, possible in future

Pre-Existing Diabetes and Pregnancy Pre-conception counseling (Diabetes Educator and Dietician included) Recommended pre-conception A1C as close to normal (6.0%) without signficant hypoglycemia More Type 2 patients in child bearing years (diagnosed at younger age) Kitzmiller, et al Diabetes Care 31:1060-1079, 2008

Preconception Counseling Whenever possible, organize multidiscipline patient-centered team care for women with preexisting diabetes in preparation for pregnancy. Women with diabetes who are contemplating pregnancy should be evaluated and, if indicated, treated for diabetic nephropathy, neuropathy, and retinopathy, as well as cardiovascular disease (CVD), hypertension, dyslipidemia, depression, and thyroid disease. (Celiac?) Lawrence, et al Diabetes Care 31:899-904, 2008 Kitzmiller, et al Diabetes Care 31:1060-1079, 2008

Preconception Counseling Medication use should be evaluated before conception, since drugs commonly used to treat diabetes and its complications may be contraindicated or not recommended in pregnancy, including statins, ACE inhibitors, angiotensin II receptor blockers (ARBs), and most noninsulin therapies. Aspirin should also be stopped. Continue multidiscipline patient-centered team care throughout pregnancy and postpartum. Lawrence, et al Diabetes Care 31:899-904, 2008 Kitzmiller, et al Diabetes Care 31:1060-1079, 2008

Preconception Counseling Educate pregnant diabetic women about the strong benefits of Long-term CVD risk factor reduction Breastfeeding Effective family planning with good glycemic control before the next pregnancy Lawrence, et al Diabetes Care 31:899-904, 2008 Kitzmiller, et al Diabetes Care 31:1060-1079, 2008

Pre-existing Type 2 Diabetes Pregnancy Oral agents are not used in pre-existing type 2 diabetes in pregnancy Convert to insulin, similar to GDM insulin dosing

Pre-existing Type 2 Diabetes Pregnancy If already on insulin, continue Insulin needs increase as pregnancy progresses Controversy: Switch glargine or detemir to NPH? Continue lispro, aspart, or R if using

Pre-existing Type 1 Diabetes and Pregnancy All continue on insulin Controversy: glargine or detemir converted to NPH? Continue Regular/Rapid Acting If on pump, continue

Summary Start insulin if not meeting goals after one week in GDM Pre-existing type 2, convert to insulin Pre-existing type 1, continue insulin Meet targets, avoid hypoglycemia