1. Update in Diagnosis and Management
Gestational Diabetes
Update in Diagnosis and Management

2. Objectives Review basic physiology of gestational diabetes
Review fetal and maternal implications
Review current recommendations for screening for GDM
Review 3 important studies published within last 5 years that are driving current recommendations
Review recommendations from the 5th International Workshop-Conference on Gestational Diabetes Mellitus
Review use of insulin analogs in pregnancy
Review use of oral antihyperglycemic agents in pregnancy

3. Brief overview
Defined as carbohydrate intolerance that begins or is first recognized during pregnancy
Important because it impacts maternal health care both during and after pregnancy
Incidence varies, but most often reported as 5-7% of pregnant women; may be greater in some high-risk populations

4. Brief overview Insulin Resistance Insulin Output Normal pregnancy
Gestational Age (weeks)

5. Brief overview Insulin Resistance Insulin Output Gestational diabetes
Gestational Age (weeks)

6. Brief overview
Underlying risk factors include increased maternal age, obesity, h/o GDM in prior pregnancy, h/o large babies
Increased risk for development of hypertensive disorders, cesarean delivery, and developing diabetes later in life

7. Brief overview Pederson Hypothesis (1952) Maternal hyperglycemia
Fetal hyperglycemia
Fetal hyperinsulinemia
Pederson Hypothesis
(1952)

8. Brief overview
Fetal risks include adverse events related to macrosomia, ie, shoulder dystocia and birth injuries, neonatal hypoglycemia and hyperbilirubinemia
As rates of obesity increase, so do the rates of type 2 diabetes and GDM

9. Current recommendations for screening for GDM
Depends on who you ask!!
ADA
ACOG
WHO
4th International Workshop-Conference on GDM
National Diabetes Data Group
United States Preventive Services Task Force
5th International Workshop-Conference on GDM

10. Current recommendations for screening for GDM
Do risk assessment at first visit, with no screening for low risk
Low-risk ethnicity (Caucasian, European)
Age < 25
BMI < 25
No known diabetes in first degree relative
No h/o glucose intolerance
No h/o obstetric complications usually associated with GDM
4th International Workshop-Conference on Gestational Diabetes Mellitus, ADA, ACOG

11. Current recommendations for screening for GDM
High risk patients should be screened as early as possible and repeated at weeks if screening negative
Strong family history of diabetes
Prior history of GDM
Morbid obesity
Other manifestations of glucose intolerance
4th International Workshop-Conference on Gestational Diabetes Mellitus, ADA, ACOG

12. Current recommendations for screening for GDM
Patients of intermediate risk should be screened at 24 to 28 weeks
Recommended screening is 2-step approach, with 50-g 1-hr GCT followed by 2-hr or 3-hr 100-g OGTT
Threshold value for 1-hr GCT is 130 or 140 – either is acceptable
Threshold values for 3-hr OGTT are 95, 180, 155, 140, respectively; 2 values must be abnormal to diagnose GDM
4th International Workshop-Conference on Gestational Diabetes Mellitus, ADA, ACOG

13. Current recommendations for screening for GDM
WHO advocates universal screening utilizing a one-step 2-hr 75-g OGTT
Patient is diagnosed with GDM if fasting > 126 or 2-hr > 140
5th International Workshop-Conference on Gestational Diabetes Mellitus did not change recommendations set forth by 4th International Workshop-Conference on Gestational Diabetes Mellitus

14. Effect of Treatment of Gestational Diabetes Mellitus on Pregnancy Outcomes. Crowther, CA et al. NEJM, June 2005.
Hypothesis: Treatment of women with GDM will reduce the risk of perinatal complications
Prospective, randomized study of 1,000 women with GDM (490 in intervention group, 510 in routine-care group)
*Often referred to as Australian Carbohydrate Intoleranc Study (ACHOIS)

15. Eligible women had the following:
Effect of Treatment of Gestational Diabetes Mellitus on Pregnancy Outcomes. Crowther, CA et al. NEJM, June 2005.
Eligible women had the following:
Singleton or twin pregnancy
One or more risk factors for GDM or positive 50-g glucose challenge test (> 140)
75-g glucose-tolerance test at weeks with fasting glucose < 140 and glucose at 2 hours was *
*When study was initiated, women meeting this criteria were classified as having glucose intolerance of pregnancy by WHO, but in 1998 WHO classified any glucose level above normal as indicative of GDM

16. Effect of Treatment of Gestational Diabetes Mellitus on Pregnancy Outcomes. Crowther, CA et al. NEJM, June 2005.
Intervention group:
Individualized dietary advice
Self-monitored blood glucose levels 4x/day
Insulin therapy for FBS > 99 or 2-hr postprandial > 126
Routine-care group:
Providers unaware of diagnosis of glucose intolerance
Care c/w clinical care in which screening for GDM is not available

17. Effect of Treatment of Gestational Diabetes Mellitus on Pregnancy Outcomes. Crowther, CA et al. NEJM, June 2005.
Outcome
Intervention Group
Routine-Care Group
Adjusted P value
Infants
Total Number
506
524
Serious perinatal complications
7 (1%)
23 (4%)
0.04
Women
Total Number
490
510
Labor induction
189 (39%)
150 (29%)
<0.001
Cesarean delivery
152 (31%)
164 (32%)
0.73

18. Number needed to treat to prevent serious complication was 34
Effect of Treatment of Gestational Diabetes Mellitus on Pregnancy Outcomes. Crowther, CA et al. NEJM, June 2005.
Conclusions
Treatment of women with GDM (glucose intolerance) reduced the rate of serious perinatal complications from 4% to 1%
Number needed to treat to prevent serious complication was 34
Benefits were associated with increased rate of labor induction, but not an increased rate of C/S

19. Hyperglycemia and Adverse Pregnancy Outcomes (HAPO). NEJM. May, 2008.
Hypothesis: maternal hyperglycemia less severe than overt DM will still increase risk for adverse pregnancy outcomes
25,505 pregnant women at 15 centers in 9 countries underwent 75-g oral glucose-tolerance testing at weeks gestation

20. Hyperglycemia and Adverse Pregnancy Outcomes (HAPO). NEJM. May, 2008.
Data remained blinded if FBS < 105 and 2-hr glucose was < 200
Only women whose data were blinded and who did not undergo any additional glucose testing outside the HAPO study were included for analysis
Primary outcomes were BW > 90th percentile, primary C/S, clinically diagnosed hypoglycemia, and cord-blood serum C-peptide > 90th percentile (fetal hyperinsulinemia)

21. Hyperglycemia and Adverse Pregnancy Outcomes (HAPO). NEJM. May, 2008.
Secondary outcomes were delivery before 37 weeks, shoulder dystocia or birth injury, need for NICU, hyperbilirubinemia, and preeclampsia

22. Hyperglycemia and Adverse Pregnancy Outcomes (HAPO). NEJM. May, 2008.
Glucose categories defined:
2-hr
<90
91-108
>178
1-hr
<105
>212
FBS
<75
75-79
80-84
85-89
90-94
95-99
>100 1 2 3 4 5 6 7

23. Birth weight > 90th percentile
HAPO. NEJM. May 2008: Frequency of primary outcomes across the Glucose Categories
Birth weight > 90th percentile
Frequency (%)
Glucose category

24. HAPO. NEJM. May 2008: Frequency of primary outcomes across the Glucose Categories
Cord-Blood Serum C-Peptide > 90th Percentile
Frequency (%)
Glucose category

25. HAPO. NEJM. May 2008: Frequency of primary outcomes across the Glucose Categories
Primary Cesarean Section
Frequency (%)
Glucose category

26. HAPO. NEJM. May 2008: Frequency of primary outcomes across the Glucose Categories
Clinical Neonatal Hypoglycemia
Frequency (%)
Glucose category

27. HAPO. NEJM. May 2008: Frequency of primary outcomes across the Glucose Categories

28. Hyperglycemia and Adverse Pregnancy Outcomes (HAPO). NEJM, May, 2008.
Conclusions
With increasing maternal glucose levels, the frequency of each primary outcome increased, although less so for clinical neonatal hypoglycemia than for the others
Secondary outcomes of preeclampsia, shoulder dystocia or birth injury, premature delivery, NICU admit, and hyperbilirubinemia also showed significant positive associations with maternal glycemia

29. Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. July 2007
Efforts at diagnosis and management of GDM are supported (preferably with onset of treatment by 30 weeks gestation)
Identification and intensive management of GDM is associated with a decrease in mortality and morbidity in infants
With appropriate therapy, the likelihood of IUFD is not detectably higher than in the general population
Morbidity, however, can be increased and will likely remain an issue until optimal management of the altered intrauterine environment is understood and appropriate interventions are implemented

30. Maternal glycemia Target glucose concentrations:
Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. July 2007.
Goals and surveillance
Maternal glycemia
Target glucose concentrations:
FBS < 96
1 hr PP < 140
2 hr PP < 120
Daily SMBG using meters appears to be superior to less frequent monitoring in the clinic

31. Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. July 2007.
Goals and surveillance
Assessment of fetal response utilizing ultrasound measurements, particularly of fetal abdomen, in second and early third trimesters can provide useful information
Less intensified management may be allowed with normal growth (fetal AC < 75th percentile for GA)

32. Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. July 2007.
MNT and physical activity
Medical nutrition therapy remains cornerstone of treatment for GDM; however, relatively little information available to allow evidence-based recommendations regarding specific nutritional approaches such as total calories and nutrient distribution to the management of GDM

33. MNT best prescribed by registered dietician
Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. July 2007.
MNT and physical activity
MNT best prescribed by registered dietician
Food plans should be culturally appropriate
Adjust amount and type of carbohydrate to achieve target for PP glucose concentrations
No data on optimal weight gain for women with GDM
Physical activity of 30 min/day is recommended for individuals capable of participating

34. Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. July 2007.
Intensified medical therapy
Insulin remains cornerstone in treatment of patients who fail to maintain glycemic goals with MNT
Insulin analogs offer advantages of improved glucose control with immunogenic rates similar to human insulin

35. Rapid-acting insulin analogs (RAIA)
Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. July 2007.
Intensified medical therapy
Rapid-acting insulin analogs (RAIA)
Lispro (Humalog) and Aspart (Novolog)
Achieve more rapid insulin peak and have been shown to provide better post-prandial glucose control
Multiple studies have demonstrated improved PP glucose control with RAIA vs human regular insulin with no increased risk of complications, such as retinopathy or teratogenic effect

36. Long-acting insulin analogs
Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. July 2007.
Intensified medical therapy
Long-acting insulin analogs
Glargine (Lantus) and Detemir (Levomir)
Lantus provides peak-less duration of action around 24 hrs, translating to less glucose variability and lower risk of nocturnal hypoglycemia
Levomir also with peak-less but less longer duration of action, about 12 hrs; provides similar benefits as Lantus

37. Long-acting insulin analogs: safety
Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. July 2007.
Intensified medical therapy
Long-acting insulin analogs: safety
Currently classified as Category C by FDA
Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women, or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus.
Compares to NPH which is Category B and is onlybasal insulin that has received FDA approval for treating GDM specifically
Review article Nov 2007: “long-acting insulin analogs do not yet have sufficient safety evaluation in clinical studies to warrant their use during pregnancy”
Recent placental perfusion study published in Mar 2010 showed Lantus does not cross the human placenta

38. Oral antihyperglycemic agents
Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. July 2007.
Intensified medical therapy
Oral antihyperglycemic agents
Glyburide acts by promoting production of insulin in the pancreas
Langer, et al. NEJM 2000: Randomized, prospective study comparing glyburide and insulin in women with GDM
Conclusion: In women with GDM, glyburide is a clinically effective alternative to insulin therapy.

39. Oral antihyperglycemic agents
Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. July 2007.
Intensified medical therapy
Oral antihyperglycemic agents
Metformin is thought to act by inhibiting liver’s production of glucose; appears to increase insulin sensitivity/reduce insulin resistance
Rowan, et al. NEJM 2008: Randomized, prospective study comparing metformin and insulin in GDM
Conclusion: In women with GDM, metformin (alone or with supplemental insulin) is not associated with increased perinatal complications as compared with insulin. The women preferred metformin to insulin treatment.

40. Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. July 2007.
Obstetric management
Fetal surveillance
Ultrasound screening for congenital anomalies recommended for women with GDM who present with A1C > 7.0% or FPG > 120
Data insufficient to determine whether surveillance beyond self-monitoring of fetal movements is indicated in women with GDM who continue to meet targets of glycemic control with MNT regimens alone and in whom fetal growth is normal

41. Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. July 2007.
Obstetric management
Maternal surveillance
Risk for PTD may be increased with untreated GDM
Use of steroids to enhance fetal lung maturity should not be withheld because of GDM but intensified monitoring of glucose levels is indicated with possible need for (increased) insulin
Risk for hypertensive disorders increased with GDM
Blood glucose monitoring should be continued during labor with insulin or glyburide as necessary to correct maternal hyperglycemia

42. Timing and route of delivery
Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. July 2007.
Obstetric management
Timing and route of delivery
No data supporting delivery of women with GDM prior to 38 weeks in absence of objective evidence of maternal or fetal compromise
Lung maturity amnio not indicated in well-controlled patients who have indications for induction or C/S as long as reasonable certainty of dates

43. Timing and route of delivery
Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. July 2007.
Obstetric management
Timing and route of delivery
Delivery of LGA fetus in setting of GDM is associated with increased risk of birth injury compared with nondiabetic population
Strategies to reduce this risk include liberal policy toward C/S; however, no controlled trials available to support this approach

44. Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. July 2007.
Post partum/long term
Studies show that after GDM, 35-60% of women develop Type 2 diabetes within 10 years
Glucose tolerance testing should be performed 6-12 weeks after delivery in GDM women who do not have diabetes immediately PP
Optimal testing frequency for diabetes long term has not been established

45. A Multicenter, Randomized Trial of Treatment for Mild Gestational Diabetes. Landon, MB, et al. NEJM, Oct 2009.
Hypothesis: Treatment of mild GDM improves pregnancy outcomes.
Prospective, randomized study of 958 women (485 in treatment group, and 473 in control group)
Treatment group received nutritional counseling, diet therapy, and insulin if required
Control group received usual prenatal care

46. Eligible women had the following:
A Multicenter, Randomized Trial of Treatment for Mild Gestational Diabetes. Landon, MB, et al. NEJM, Oct 2009.
Eligible women had the following:
Abnormal 1-hr 50-g glucose challenge with glucose between
Abnormal 3-hr GTT with FBS < 95 and 2 of 3 glucose measurements that exceeded thresholds for 1-hr (180), 2-hr (155), or 3-hr (140)

47. A Multicenter, Randomized Trial of Treatment for Mild Gestational Diabetes. Landon, MB, et al. NEJM, Oct 2009.
Primary outcome was composite outcome that included perinatal mortality, hypoglycemia, hyperbilirubinemia, neonatal hyperinsulinemia, and birth trauma

48. A Multicenter, Randomized Trial of Treatment for Mild Gestational Diabetes. Landon, MB, et al. NEJM, Oct 2009.
Neonatal secondary outcomes included BW > 4000 gm, LGA, SGA, NICU admit, and RDS
Maternal secondary outcomes included weight gain, gestational HTN, preeclampsia, cesarean delivery, labor induction, and shoulder dystocia

49. A Multicenter, Randomized Trial of Treatment for Mild Gestational Diabetes. Landon, MB, et al. NEJM, Oct 2009.
Outcome variable
Treatment Group (N=485)
Control Group (N = 473)
P value
GA at birth (wk)
39.0
38.9
0.87
Composite end point
32.4%
37%
0.14

50. A Multicenter, Randomized Trial of Treatment for Mild Gestational Diabetes. Landon, MB, et al. NEJM, Oct 2009.
Neonatal Secondary Outcome Variable
Treatment Group (N=485)
Control Group (N=473)
P value
Birth weight
3302 gm
3408 gm
<0.001
BW > 4000 gm
5.9%
14.3%
LGA
7.1%
14.5%
Preterm delivery
9.4%
11.6%
0.27
SGA
7.5%
6.4%
0.49
NICU admit
9.0%
0.19
RDS
1.9%
2.9%
0.33

51. A Multicenter, Randomized Trial of Treatment for Mild Gestational Diabetes. Landon, MB, et al. NEJM, Oct 2009.
Maternal Secondary Outcome Variable
Treatment Group (N=476)
Control Group (N=455)
P value
Induction of labor
27.3%
26.8%
0.86
Cesarean delivery
26.9%
33.8%
0.02
Shoulder dystocia
1.5%
4.0%
Preeclampsia/HTN
8.6%
13.6
0.01
BMI at delivery
31.3
32.3
<0.001
Weight gain (kg)
2.8
5.0

52. A Multicenter, Randomized Trial of Treatment for Mild Gestational Diabetes. Landon, MB, et al. NEJM, Oct 2009.
Conclusions
Although treatment of mild GDM did not reduce the frequency of the composite primary outcome, it did lower the risks of fetal overgrowth, shoulder dystocia, cesarean delivery, and preeclampsia

53. Summary Screening/diagnosis No new guidelines at present
WHO endorses universal screening with single step, arguing that the 2-step process introduces additional barrier to care
Discussions continue around use of fasting, random glucose, or A1C at initial visit, but no consensus at present

54. Summary Measure of glycemia Threshold Fasting glucose > 126 mg/dl
To diagnose overt diabetes (preexisting) in pregnancy
Measure of glycemia
Threshold
Fasting glucose
> 126 mg/dl
A1C
> 6.5%
Random glucose
> 200 mg/dl
International Association of Diabetes and Pregnancy Study Groups, 2009

55. Summary Glucose measure Glucose threshold FPG 92 mg/dl
Diagnosis of GDM (75-g OGTT)
Glucose measure
Glucose threshold
FPG
92 mg/dl
1-hr plasma glucose
180 mg/dl
2-hr plasma glucose
153 mg/dl
*One or more of these values must be met or exceeded for diagnosis of GDM
International Association of Diabetes and Pregnancy Study Groups, 2009

56. Summary First prenatal visit 24-28 weeks
Measure FPG, A1C, or random glucose on all or only high-risk women
If results indicate overt diabetes as per Table 1, treat and f/u as for preexisting diabetes
If results are not diagnostic of overt diabetes and FPG > 92 but < 126, diagnose as GDM; if FPG < 92, test for GDM at weeks
24-28 weeks
2-hr 75-g OGTT after overnight fast on all women not previously found to have overt diabetes or GDM
Overt diabetes if FPG > 126
GDM if one or more values equals or exceeds thresholds
Normal if all values on OGTT less than thresholds
International Association of Diabetes and Pregnancy Study Groups, 2009

57. Summary Medical management of GDM includes following:
Nutritional therapy
Exercise
Self-monitoring of glucose at home
If diet and exercise fail, oral hyperglycemic agent or insulin
Glyburide “preferred” but metformin safe
Short-acting insulin analogs should be standard, and long-acting analogs not far behind, if not already here
Goal: Euglycemia!!

58. Summary 2-hr 1-hr FBS 1 2 3 4 5 6 7 <90 91-108 109-125 126-139
>178
1-hr
<105
>212
FBS
<75
75-79
80-84
85-89
90-94
95-99
>100 1 2 3 4 5 6 7

59. Summary Fetal surveillance with GDM
Increased surveillance of fetal well-being suggested if oral agent or insulin necessary, or abnormal fetal growth evident on ultrasound
Optimal timing of delivery remains uncertain, but would consider delivery by 39 weeks if evidence of poor glucose control and/or abnormal fetal growth noted
Allow usual indications for delivery management if diet controlled with normal growth and well-being

60. Summary Postpartum management
Assess fasting and/or 2-hr PP in first day or two after delivery – no further treatment necessary if normal (majority of GDM)
If fasting and/or 2-hr PP abnormal, continue oral agent or insulin
Screen for Type 2 diabetes at 6-week postpartum visit
Council patients regarding dietary and behavioral changes necessary to minimize risk of developing overt diabetes later in life

61. Summary Time Test Purpose Post-delivery (1-3 d) Postpartum visit
Metabolic assessments after GDM
Time
Test
Purpose
Post-delivery (1-3 d)
Fasting or random glucose
Detect persistent, overt diabetes
Postpartum visit
75-g 2-h OGTT
PP classification of glucose metabolism per ADA
1 year postpatum
Assess glucose metabolism
Annually
Fasting plasma glucose
Tri-annually
Prepregnancy
5th Annual Workshop-Conference on GDM