Current Recommendations for Managing Diabetes in Pregnancy Practical Ways to Achieve Targets in Diab

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Current Recommendations for Managing Diabetes in
PregnancyPractical Ways to Achieve Targets in
Diabetes CareBarbara Davis Center for Diabetes
and Childrens Diabetes Foundation at
DenverAugust 14, 2005

• Lois Jovanovic, MD

Director and Chief Scientific Officer Sansum
Diabetes Research Institute Santa Barbara,
California
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Pre-gestational Diabetes Complications Diagnosis
and Treatment

• Retinopathy Dilated retinal exam frequent
  follow-up
• Nephropathy 24 hour urine for Crcl, total
  proteinuria, microalbuminuria
• Hypertension BP lt120/80 mmHG (no ACE-I or
  ARBs)
• Hypothyroidism TSH lt 2.5 and FT4 gt1.0
• ASCVD Normal Stress Test with beat to beat
  variability

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Preconception Care of Established
DiabetesPreventing Retinopathy Progression

• Rapid normalization of blood glucose during
  pregnancy can trigger retinopathy progression
• A preconception dilated eye exam should be
  performed by an ophthalmologist
• Retinal status should be stabilized prior to
  conception
• Reassess retinal status each trimester (more
  frequently if retinopathy is present)

American Diabetes Association. Diabetes Care.
200427(suppl 1)S76-S78
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Diabetes in Early Pregnancy (DIEP) Trial
Prevalence of Major Fetal Complications
Control
Prevalence rate ()
Diabetes lt21 days postconception
10
9.0
P0.032
Diabetes gt21 days postconception
9
8
7
P0.027
6
4.9
5
4
2.1
3
2
1
0
Early-entry control
Early-entry diabetes
Late-entry diabetes
Mills JL et al. N Engl J Med. 1988318671-676
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Neonatal Outcomes Human Regular Insulin Use
During Pregnancy
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Neonatal Malformations Are Not Related to Type
of Insulin
15.8
Regular human insulin
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Congenital malformation rate ()
Insulin lispro
14
12
10
7.9
P0.79
8
6.6
P0.16
6
3.8
4
2
0
GDM
Preexisting diabetes
N213
N97
Bhattacharyya A et al. Q J Med. 200194255-260
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Malformations Are Related to Glucose Not Type of
Insulin
Wyatt JW, Frias JL, Hoyme HE, Jovanovic L, et al.
Congenital anomaly rate in offspring of
pre-gestational diabetic women treated with
insulin lispro during pregnancy. Diabetic
Medicine 212001-2007, 2004.
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A. Standardized Maximum Glycosylated Protein
B. Standardized Maximum Fructosamine
IDDM Pregnancies
Nondiabetic Pregnancies
Jovanovic L et al. In Press, Diabetes Care 2005
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Prevalence of Diabetes in Pregnancyin the United
States of America

• 4.5 millions births per year
• 240,000 T2DM 6,000 T1DM pregnancies 135,000
  GDM

Diabetes 8
Non-diabetes 92
American Diabetes Association. Diabetes Care.
199821(Suppl. 2).
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Enrollment and Outcomes
Crowther, C. et al. N Engl J Med
20053522477-2486
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Primary Clinical Outcomes among the Infants and
Their Mothers
Crowther, C. et al. N Engl J Med
20053522477-2486
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Secondary Outcomes among the Infants
Crowther, C. et al. N Engl J Med
20053522477-2486
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Fetal Hyperglycemia

• Glucose

Stimulates fetal pancreas
Insulin
Placenta
Fetal Hyperinsulinemia
IgG-antibody-bound Insulin
Mother
Fetus
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Macrosomia
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Magnetic Resonance Image of Pregnancy
Complicated by Diabetes
Normoglycmia
Hyperglycmia
Jovanovic L et al. Am J Perinatol. 199310432-437
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38 Weeks Gestation
28 Weeks Gestation
120
110
5.6 mmol/L
100
90
Blood glucose (mg/dL)
80
70
3.3 mmol /L
60
50
40
8 AM
9 AM
10 AM
12 PM
1 PM
2 PM
4 PM
6 PM
8 PM
9 PM
10 PM
12 AM
2 AM
4 AM
6 AM
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Relationship Between Number of Blood Glucose
Determinations and A1C
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"Hyperglycemic Peaks" Risk of Macrosomia
60 50 40 30 20 10 0
Risk of Macrosomia
80
90
100
110
120
130
140
150
160
170
180
Blood Glucose 1 hour after beginning the meal
(mg/dL)
Jovanovic L et al. Maternal postprandial blood
glucose levels and infant birth weight The
Diabetes in Early Pregnancy Study. Am J Obstet
Gynecol. 1991164103.
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The U-Shaped CurveBirth Weight vs. Risk of Type
2 Diabetes
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20
15
Percent
10
5
0
1500
2500
3500
4500
Birth weight (grams)
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What is the Optimal Diet for Pregnant Diabetic
Women to Prevent Neonatal Macrosomia?
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MiniMed Continuous Glucose Monitoring System
(CGMS)
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Glucose Sensor Profile Unrecognized "Peaks"
11.1 mmol /L
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Total Amount of Time Per Day Hyperglycemic (In
Hours)
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Interstitial Fluid Glucose Sensors
GlucoWatch
DexCom
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Indications for Insulin Therapy in GDM

• Fasting blood glucose concentration gt 90 mg/dl
  (5.0 mmol/L)
• and/or
• 1-hour postprandial blood concentration gt 120
  mg/dl (6.7 mmol/L)

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Physiological Serum Insulin Secretion Profile
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Breakfast
Lunch
Dinner
50
Plasma Insulin µU/ml)
25
400
800
1200
1600
2000
2400
400
800
Time
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Insulin Antibodies Relate to Diabetes Duration
and Do Not Impact Glucose Control
8000
Insulin antibody titer IgG (?U/mL)
r0.73
6000
4000
2000
1000
800
600
400
200
100
5
0
10
15
20
25
Years of treatment with conventional insulin
Jovanovic LG et al. Diabetes Care. 1984768-71
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Postprandial Hyperglycemia
140 120 100 80 60 40 20
Lispro insulin Human regular insulin
Plasma glucose (mg/dL)
0 50 100 150
200
Time (min)
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Maternal Hyperglycemia - 1Hour Postprandial
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Change in HbA1c
Lispro insulin Human regular insulin
5.5 5.4 5.3 5.2 5.1 5.0 4.0
Baseline Endpoint
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Insulin Antibody Findings
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Postprandial Glycemic Control inGDM NovoLog vs
Regular Insulin
Study group 15 insulin-requiring women with
GDM meal testing before initiation of
basal/bolus therapy
Insulin (?U/mL)
C-peptide (ng/dL)
Glucose (mg/dL)
100
8
7
80
6
5
60
4
40
3
2
20
1
0
0
-60
0
60
120
180
240
-60
0
60
120
180
240


Jovanovic et al. Diabetes 51 (suppl 2) abstrac
1784-2002

Time (minutes)
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Insulin Treatment and Antibodies
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Insulin PreparationsAdvantages and Disadvantages
During Pregnancy
Advantages
Disadvantages

• Delayed and prolonged
• action profile does not
• match mealtime needs

• Inexpensive

Regularhuman insulin Lispro Aspart Glulisine N
PH Glargine Detemir

• Action profile matches
• well with mealtime needs

• Limited objective data
• verifying safety in pregnancy

• Long experience verifies
• safety in pregnancy

• Peak action profile
• requires multiple injections
• for smooth 24-hour effect

• Flatter 24-hour profile
• allows fewer injections

• No objective data verifying
• safety in pregnancy

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Evidence that Drug Does Crosses The Placenta

• Sufonylureas Yes No None
• Second generation x x
• Bigunides
• Metformin x
• Meglitinides
• Repaglinide and x
• Netaglimide x
• Alpha glucosidase inhibitors
• Acarbose x
• Thiazolidienediones X

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Insulin Requirements for Pregnant Diabetic Women
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Six Injections/Daily Insulin AlgorithmNPH Three
Times Premeal Aspart or Lispro
Plasmainsulin
2400
400
2400
1600
2000
1200
800
NPH
NPH
NPH
NPH
Time
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Bolus and Variable Basal RateCSII Program
Infusion rate
3 U
2 U
1 U
400
1600
2000
2400
1200
800
2400
Time
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Neonatal Hypoglycemia Is Inversely Related to
Maternal Hyperglycemia at Delivery
Glucose(mg/dL)
250
Type 1 DM
200
Type 2 DM
Gestational DM
150
100
50
0
Maternal Glucose
Neonatal Glucose
Adapted from Jovanovic L et al. Am J Med.
198375607-612
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Labor and Delivery

• Labor is exercise
• Exercise requires glucose substrate
• Exercise obviates the insulin requirement
• Frequent fetal monitoring, blood glucose testing
  hourly, maintenance of blood glucose less than
  90 mg/dl
• JOVANOVIC L. Glucose and insulin requirements
  during labor and delivery the case for
  normoglycemia in pregnancies complicated by
  diabetes. Endocrine Practice 1040-45, 2004.

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Insulin Protocol for Labor and Delivery in
Type 1 Diabetic Women on Insulin Pumps Basal
insulin infusion rate 1/2 half on MDI
Discontinue the NPH insulin GLUCOSE ADJUSTMEN
TSlt70 mg/dL Dl0NS for10 to 15 minutes rate 100
ml/hr) 71-100 mg/dL D5NS/l00 ml/hr101-120
mg/dL NS/l00 ml/hr______________________________
___________________gt 121 mg/dL NS plus Regular
insulin IV or bolus analog sc/hr As Percent of
Big I121-140 mg/dL NS/l00 ml/hr Plus 3
Big I gt141 mg/dL NS/l00 ml/hr Plus 6 Big
I ____________________________________________
______ Big I The Total Daily Insulin
Requirement Note at Term it is 1.0 units per
kilogram per day. Thus 3 of this dose would be
3 units in a 100 kilogram woman at term
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Thank You