Gestational Diabetes: Diagnosis, Treatment Long Term Management, and Followup Eric Lind Johnson, M.D. Assistant Professor Department of Family and Community Medicine University of North Dakota School of Medicine And Health Sciences Assistant Medical Director Altru Diabetes Center Grand Forks, ND

Objectives Discuss Gestational Diabetes Mellitus (GDM) and Treatment Recognize common problems of GDM in Pregnancy Discuss long term followup of Gestational Diabetes Mellitus (GDM)

Gestational Diabetes Mellitus

Gestational Diabetes Reduced sensitivity to insulin in 2 nd and 3 rd 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: , 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):

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

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 Gestational Diabetes-Screening 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

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 > , 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.

Gestational Diabetes Complications

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:Outcomes Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Study 28,000 women Four primary outcomes: 1) weight above the 90th percentile for gestational age 2) primary cesarean delivery 3) clinical neonatal hypoglycemia 4) cord-blood serum C-peptide level above the 90th percentile (fetal hyperinsulinemia) NEJM (358) 2008

Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) Five secondary outcomes 1)premature delivery (before 37 weeks) 2)shoulder dystocia or birth injury 3)need for intensive neonatal care 4)hyperbilirubinemia 5)preeclampsia Gestational Diabetes:Outcomes NEJM (358) 2008

HAPO Primary and Secondary Outcomes NEJM (358) 2008

Gestational Diabetes: Post-natal GDM is a prediabetes syndrome Some women will have frank type 2 diabetes presenting in pregnancy Blood glucose testing first few days after delivery Kitzmiller, et al Diabetes Care 30:S225-S235, 2007

GDM Post-natal and Long Term Followup

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

Case Study 28 y/o caucasian female 2 nd pregnancy 1 st 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) 2 hour: 160 (>155) 3 hour: 149 (>140) 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

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 > 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 1 st 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):

5 Reasons to perform glucose tolerance testing after pregnancies complicated by GDM: 1) The substantial prevalence of glucose abnormalities detected by 3 months postpartum. 2) Abnormal test results identify women at high risk of developing diabetes over the next 5–10 years (15-50% risk) 3)Ample clinical trial evidence in women with glucose intolerance that type 2 diabetes can be delayed or prevented by lifestyle interventions or modest and perhaps intermittent drug therapy. Kitzmiller, et al Diabetes Care 30:S225-S235, 2007 Kim et al Diabetes Care 25: , 2002 Lauenborg, et al Diabetes Care 27: , 2004

5 Reasons to perform glucose tolerance testing after pregnancies complicated by GDM: cont’d 4) Women with prior GDM and IGT or IFG have CVD risk factors. Interventions may also reduce subsequent CVD, which is the leading cause of death in both types of diabetes. GDM 71% higher risk of future CVD-other risk factors (HTN, lipids, smoking) assessed and managed 5) Identification, treatment, and planning pregnancy in women developing diabetes after GDM should reduce subsequent early fetal loss and major congenital malformations. Kitzmiller, et al Diabetes Care 30:S225-S235, 2007 Shah, et al Diabetes Care 31: , 2008

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

Diagnosis Guidelines CategoryFPG (mg/dL) Normal <100 Impaired Fasting Glucose (IFG)100 – 125 Diabetes >126** OR A1C >6.5 ** On 2 separate occasions American Diabetes Association

Initial Type 2 Diabetes Treatment Current guidelines (ADA/EASD, AACE) recommend metformin at diagnosis in additional to lifestyle management Diabetes Educator/Dietician Eye Exam Evaluation of cholesterol and blood pressure

Key References Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus Diabetes Care July :S251-S260 American Diabetes Association Consensus Statement Pre-existing DM in Pregnancy Diabetes Care May 2008 vol. 31 no American Diabetes Association: Clinical Practice Recommendations: International Diabetes Federation:

Summary GDM: Meet targets, avoid hypoglycemia, reduce risk of complications GDM is a pre-diabetes syndrome Many women with GDM will go on to have repeat GDM or type 2 DM and have CVD risk

Acknowledgements William Zaks, M.D., Ph.D., Assistant Medical Director Altru Diabetes Center Grand Forks, ND Slide and Content Review

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