1. Division of Maternal Fetal Medicine Newark Beth Israel Medical Center
Diabetes in Pregnancy
Martin L Gimovsky MD
Division of Maternal Fetal Medicine
Newark Beth Israel Medical Center
Newark, New Jersey

2. Learning Points Importance - 17 million diabetics in US +
6 million undiagnosed, 6 – 8% of population
Pathophysiology - A diabetic has metabolic changes that adversely affect blood vessels
Pregnancy - Accelerates/predisposes these metabolic derangements.
Treatment - Seeks to minimize maternal and fetal/neonatal M&M by correcting/compensating for fluctuations in blood glucose.

3. Overview: Diabetes Hyperglycemic state fasting and/or postprandial
Due to relative/absolute deficiency of insulin
Results in significant changes in intermediary metabolism with striking clinical effects

4. Beta cells
Storage granules
Nucleus
Endoplasmic
reticulum

5. The Islet of a Type 1 Diabetic Beta Cells (Injured and then) Destroyed

6. Islet cells and Isle of Langerhans
Beta cells
in blue
Alpha cells
in red
Delta cells
unmarked

7. Type 2 and GDM Tissue becomes insulin resistant Hyperglycemia
Inhibits glucose uptake
Results in inadequate insulin response
Disrupts pulsatile insulin release
Enhances lipolysis in visceral fat
Increases FFA, increases insulin resistance
Impaired glucose tolerance  elevated FBS and increases PP hyperglycemia

8. Diabetes alters intermediary metabolism

9. Insulin Effects X Glucose, aa  glycogen Glycogen  glucose X
Protein synthesis
Protein catabolism
Glucose, amino acid uptake
 Inhibits glucose, amino acid uptake X X
Fatty acid synthesis
Fatty acid release X

10. Comparison of Diabetic Types

11. Diabetes in Pregnancy Common medical complication
2-5% (2.6%) of live births
90% are gestational diabetics, White class A1, A2 (GDM & NIDDM)
10% are overt diabetics, White class B-H (IDDM)

12. Diabetes and Pregnancy
Pregnancy is a “diabetogenic state.”
Placenta has passive control of glucose to fetus, but is impermeable to insulin.
Maternal intermediary metabolism is under control of hormonal influences that insure fetal needs for glucose are met.

13. Pregnancy as a Diabetogenic State
Increasing glucose (&insulin) demand  both maternal and fetal
Increasing insulin resistance  hormone driven
Maternal hyperglycemia  fetal excess of nutrients  fetal hyperglycemia & insulinemia, neonatal hypoglycemia
Teratogenesis
Catabolism consumes energy & oxygen
and  episodic fetal hypoxemia, results in fetal hypertension, cardiac remodeling, polycythemia, increased blood viscosity, heart failure, stillbirth

14. Insulin Resistance in Pregnancy
More insulin demand: Increased basal level and response to blood glucose, increased overall demand for glucose
Insulin is less efficient (resistance)
HCS, Prolactin, E&P
 Hyperglycemia
 Facilitate a continuous supply of glucose for placental transfer

15. Effect of Pregnancy Hormones on Maternal Carbohydrate Metabolism
HCS = decreases glucose tolerance
Prolactin = insulin resistance
Glucocorticoids = glycogenolysis, gluconeogenesis

16. Overview: Recognition
Clinical
Preclinical
IDDM, NIDDM (I,II)
Poly-dipsia, uria, phagia, glycosuria
Infections
Vascular damage
FBS > 140 mg/dL
Random BS > 200
GESTATIONAL(III)
Hyperglycemia first seen in pregnancy
Screening:
50 gram 1 hr > 140
Diagnosis:
100 gram GTT 2 abnormal values, or a single value > 200

17. Classification of Overt Diabetes (IDDM) in Pregnancy Hare and White, Diabetes Care 3:394 1980

18. Effects of Diabetes in Pregnancy
Fetal
Anomalies
Stillbirth
Macrosomia
Neonatal
Resp distress
Hypoglycemia
Hyperbilirubinemia
Hypocalcemia
Hypertrophic Cardiomyopathy
Maternal
Infections, DKA, HyperOsm
Vascular damage results in
Retinopathy
Benign
Neovascularization
Renal failure
Microalbuminuria <300
Nephropathy >300
Myocardial infarction
Neuropathy
Peripheral
Autonomic

19. Monitoring Blood Sugar
Blood glucose levels both fasting and postprandial are the key indicators
AGP ambulatory blood glucose profile
SMBG self monitored blood glucose
HbA1c glycosylated hemoglobin 4-6 week intervals

20. Normal glucose tolerance in pregnancy
Mean BS 85, range
120
AGP 70
Relatively flat, narrow limits

21. IDDM in Third Trimester 3 Injection Regimen Mean 137, Range 100 - 165
Wider limits, increase in mean value

22. Overview: Management of Diabetes
Dietary modifications
Caloric content, distribution of food types, frequency of meals, snacks in context of “Glycemic Index, Load”
Interventional Exercise
Insulin
Oral hypoglycemics

23. Dietary Modification

24. Considerations in Diabetic Diet
Kcal/kg/d (30 kcal/kg/d)
CHO=50%, Protein 25%, Fat 25% (ADA 2002)
Decrease kcal for BMI > 30, increase for BMI<25 (ADA 2002)
Low glycemic foods (slow absorption)
Avoid nocturnal hypoglycemia
Avoid ketonemia

25. Glycemic Index
Pro: Measures how rapidly BG is elevated in response to eating a specific food.
Con: Values not necessarily reflective of how foods are really consumed
Total calories may be more important

26. RCT: diet + exercise > diet alone
Bung et al, 1993

27. Glycemic Response to Exercise: Nonpregnant and Pregnant
Exercise lowers BG further and faster in pregnancy
Nonpregnant
Pregnant

28. Insulin preparations vary by time to peak action and total duration of action
Lispro- 1h/2h
Regular- 2h/4h
NPH- 4h/8h
Ultralente- 8h/20h
Insulin pen

29. Oral Hypoglycemics First generation:
Sulfonylureas (diabinase)-freely crossed placenta
 High level in neonate
Severe & prolonged hypoglycemia
Sporadic reports of anomalies

30. Oral Hypoglycemics Fast Acting Secretagogues, and Sensitizers
Second Generation (Pregnancy category B)
Glyburide, Glipizide, Glimepride
Biguanides Metformin
Fast Acting Secretagogues, and Sensitizers
Short duration of action

31. Oral Hypoglycemics Glyburide Rx of adult onset diabetes
Transplacental dose small
No known fetotoxicity, teratogenicity
Effect is mildly hypoglycemic to gravida and fetus
Dosed by BMI >< mgs, 5 mgs
Similar effect to a 70:30 mix (NPH:Reg)

32. Control: Insulin vs Glyburide
Langer et al: Comparison of glyburide and insulin in women with GDM. NEJM 2000;343:
Insulin
N=203
Glyburide
N=201
Mean glucose
FBS, Pre, Postpr
114,104,104
116,108,107
Hba1c 1T
Hba1c 3T
5.7%
5.4
5.6%
5.5
Dose
85+/ -48 units
9 +/- 6 mgs
Results
No difference
in neonatal or PN outcome

33. Glyburide vs Insulin Langer et al 2000
LGA
12% 13
Anomalous 2
> 4 delivery 7 4
NN low BS
NICU admit
RDS/pulmonary 9 6 8

34. Glyburide After ADA Diet Failure Carolinas Medical Center, 2004
4/5 gravidas were controlled, 1/5 insulin
Neonatal Outcome
23% had hypoglycemic episode
11% had polycythemia
38% were LGA (> 90th centile)
13% were macrosomic (> 4000 gm)
7% needed (any) respiratory support

35. Glycemic Control: Fetal Outcomes Summary, multiple studies
Indicator
Threshold/Goal
Perinatal Mortality
Mean BS < 115 mg/dL
Spontaneous Abortion
HgA1c < 7%
Malformations
Postprandial < 140
Macrosomia
Mean BS < 100
Neonatal Metabolic Problems
Mean neonatal BS > 1 SD below the mean

36. Malformations
Postprandial BS < 140 mgs/Dl

37. Perinatal Mortality
Mean BS < 115 mg/Dl

38. Neonatal Morbidity in Diabetic Pregnancy
GDM (III)
Type I
Type II
Hyperbilirubin
29% 55 44
Hypoglycemia 9 29 24
RDS 3 8 4
Cardiomyopathy 1 2
Polycythemia
Neonatal BG > 1 SD below the mean
Neonatal hypoglycemia =

39. Maternal Morbidity Class DM A1, A2 B, C D,F,R PIH 10% 8 16 Chronic HBP17
DKA 8% 7 9
C/S
12% 44 57

40. Guidelines for Diabetic Pregnancy
Preconception
Optimal glycemic control
Folic acid x 3 months, GC
1st Trimester
Fetal Viability CRL
2nd Trimester
Fetal Development Level 2 scan
Fetal growth baseline 24 weeks MMS
3rd Trimester
Fetal Growth and Well-being
Kick 28wks NST/BPP
36 weeks EFW, Deliver at with amnio, without

41. Preconception Counseling
Maternal medical risks
Fetal and neonatal risks
Obstetric complications
Family/social supports
Economic

42. Diabetes and Obesity

43. Fetal surveillance first 28 weeks
1st Trimester
Dx: up to 20% GDM
Fetal viabilty
Accurate dates
2nd Trimester
Mult marker screen
Level 2 scan, Fetal cardiac echo
24 weeks fetal growth
28 fetal kick counts

44. Diabetic Ketoacidosis
Type 1 diabetic, 2nd trimester
Infections
Limited prenatal care
Unrecognized new onset of diabetes
Inadequate insulin  excessive hepatic glucose production

45. Diabetic Ketoacidosis

46. Treatment of DKA
Recognition: hyperventilation, dehydration, hypotension, fruity odor to breathe, elevated BS, + serum ketones 1:4
Infection, poor compliance, unrecognized onset of DM
Treatment: Vigorous fluid resuscitation (NS) until base deficit is < -4; anion gap is < 12
Small bolus (10u) then continuous infusion of low dose insulin 5u/hr; Potassium 20 meq/hr, bicarbonate replacement < 1 amp, pH < 7.2

47. 3rd Trimester Fetal growth by 32 week scan,
Fetus may be IUGR or LGA, EFW
Fetal Testing: wks BPP, NST 2X
Comorbidity with PIH, Chronic HBP
Timing of delivery: term or close
Confirmation of fetal lung maturity

48. Fetal Demise in-Utero
Increased glucose is catabolized consumes energy & oxygen.
The greater the fluctuation in BS, the more fetal hyperglycemia & hyperinsulinemia
Decrease testing intervals in A2 or >, test twice weekly after weeks
Can reduce the risk

49. Comorbidity with Hypertension Blood Pressure during Gestation

50. Fetal Growth Abnormalities in Diabetic Pregnancy by White Class California Diabetes Project, 1991
GDM
Class A,B,C
Class D,F,R
Total
>90th%
22% 31 22 24
<10th% 4 5

51. Big Babies Macrosomia – > 4500 gms ACOG, >4250 Langer
Infants of diabetics (IDM) – 15-45% macrosomic
Large for Gestational Age (LGA) > 90th%
30% diabetes in pregnancy, 70% are constitutional
Hard to predict fetal weight, easy to measure neonatal weight

52. Traumatic Birth & Shoulder Dystocia
Risk is > for diabetic fetus/neonate, at any EGA
Suspected macrosomia- size>dates by FH, EFW> 4500 gms (Tech Bull # 30, 2001)
Induction or prophylactic C/S unlikely to reduce the rate of permanent injury
By ultrasound EFW above 4500, actual bwt for ½ is within 10% of estimate
At EFW 4500 gms, then estimate 333 – 1667 C/S to prevent a single permanent Erb’s palsy

53. Respiratory Distress Syndrome
Abnormal timing of phospholipid production delay in PG+
Higher levels of myoinositol  persistence of PI+
PG/PI less favorable at same EGA
Effect is magnified with mean plasma glucose > 110 mgs
< 38.5 wks w/amnio; >38.5 with > 3% PG

54. Intrapartum Decisions
@ 40 wks with good 38 with PG:PI
Active phase must be adequate
Protracted descent best managed by C/S
Avoid mid-pelvic operative delivery absolutely
Outlet/low pelvic delivery with great care
Liberal use of C/S

55. Conclusions
Regulation of blood glucose needs to begin prior to conception for best result.
Treatment includes diet, exercise, oral hypoglycemics and insulin.
Comorbidities- Obesity, HBP, CAD
Fetal growth and well being, timing of delivery require attention in 3rd trimester.