1. Diabetes in Pregnancy
Ass. Pro. : S. Rouholamin

2. 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

3. Gestational Diabetes Mellitus

4. 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

5. 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

6. 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

7. 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):

8. 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

9. 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

10. 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

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

12. 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

13. 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 Diabetes Care 31(S1) 2008

14. 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

15. 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

16. 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

17. 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

18. 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

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

20. 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.

21. 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

22. 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

23. 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

24. 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

25. Diabetes in Pregnancy: Clinical implications
Shoulder dystocia
Fetal macrosomia

26. 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

27. 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.

28. 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

29. 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

30. 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.

31. 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

32. Management: Glycemic Control
Blood glucose goals during pregnancy
Fasting < 95mg/dL
1-hr postprandial < mg/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

33. Management: Nutrition
Caloric requirements:
Normal body weight 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

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

35. 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

36. 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

37. 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 weeks, depending on glycemic control
Ultrasound to assess growth at 36 weeks
Delivery at weeks
Practice varies by institution, but the general principle of detecting fetal macrosomia and avoiding IUFD applies

38. 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)

39. 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

40. 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

41. 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

42. 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)

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

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

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

46. 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

47. 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

48. 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

49. 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

50. 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

51. 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

52. 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):

53. 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

54. 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: , 2008

55. 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: , 2008
Kitzmiller, et al Diabetes Care 31: , 2008

56. 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: , 2008
Kitzmiller, et al Diabetes Care 31: , 2008

57. 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: , 2008
Kitzmiller, et al Diabetes Care 31: , 2008

58. 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

59. 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

60. 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

61. 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