1. Evidence Based Guide to Gestational Diabetes
Robert Fraser
University of Sheffield.UK.

2. Treatments for Gestational Diabetes and Impaired Glucose Tolerance
( Cochrane Systematic Reviews 2003)
“ It is uncertain whether intensive treatment can influence birth weight and reduce perinatal morbidity i.e. is there any benefit to treating women with GDM or IGT in pregnancy?”

3. NICE: Antenatal Care Guidelines (2003)
“there is an absence of evidence to support routine screening for gestational diabetes mellitus and therefore it is not recommended”.

4. So - Is GDM a disease capable of causing adverse perinatal outcomes?
If so – is there effective treatment available?
If so – are there effective screening protocols?

6. ACHOIS Trial: Research Question
Does treatment of women with screen detected impaired glucose tolerance in pregnancy reduce perinatal morbidity, without increasing maternal physical and psychological morbidity?
What was the Research Question?
The primary research question was DID TREAMENT OF SCREEN DETECTED IGT in pregnancy reduce perinatal morbidity, without increasing maternal physical and psychological morbidity?
The study aimed to evaluate whether resources should be applied to the diagnosis and management of glucose intolerance in pregnancy.
The secondary research questions were whether?

7. ACHOIS results Intervention Routine Care Group Group n = 490 n = 510
RR (95%CI)
Any serious perinatal
7 (1%)
23 (4%)
0.33 (0.14 -
0.75)
complication
Perinatal
death
5 (1%)
n.s .
Induction of
189 (39%)
150 (29%)
1.36 (1.15 -
1.62)
Labour
LGA
68 (13%)
115 (22%)
0.62 (0.47 -
0.81)
Caesarean delivery
152 (31%)
162 (32%)
n.s .
Postnatal depression
23 (8%)
50 (17%)
0.46 (0.29 -
0.73)
n = 278
n = 295

8. ACHOIS Trial: Conclusions
“ Treatment of gestational diabetes reduces serious perinatal morbidity and may also improve the women’s health –related quality of life.”

9. NICHD Maternal Fetal Medicine Units : Prospective multicenter Randomised Treatment Trial of Mild Gestational Diabetes.
958 women with GDM by ADA criteria
(100g GTT)
Double blind randomisation.
Primary endpoint: Composite of PNM,and Neonatal Morbidity (Hyperbiliruinaemia, hypoglycaemia,hyperinsulinaemia,birth trauma)
(Landon et al 2009)

10. MFMU Network Trial results.
Treated GDM
n = 485
Untreated GDM
n = 473 RR p
Composite Outcome
149/460 (32.4%)
163/440
(37.0%)
0.87
( )
0.143
Birth Trauma
3/476
(0.63%)
6/455
(1.32%)
0.48
( )
0.332
Shoulder Dystocia
7/476
(1.5%)
18/455
(4.0%)
0.37
( )
0.019
Hypoglycaemia
62/381
(16.3%)
55/357
(15.4%)
1.06
( )
0.747

11. MFMU Network Trial Results
Treated GDM
Untreated GDM RR p
C Section
128/476 (26/9%)
154/455 (33.8%)
0.79
( )
0.021
Large for Gestational Age
34/477
(7.1%)
66/454
(14.5%)
0.49
( )
0.0003
Cord c-peptide >90th centile
75/423
(17.7%)
92/403
(22.8%)
0.78
( )
0.068

12. Two recently published RCTs suggest treatment of mild GDM is effective.
If GDM causes pathological outcomes which respond to treatment it follows that screening is justified.

13. Gestational Diabetes Mellitus
How should screening be performed?
Does GDM cause an increase in Congenital Malformations?
Can GDM management be more effective?
Does timing of delivery in GDM affect outcomes?

14. Screening for GDM by Risk Factors
( Helton 1997)
Obesity, FH Diabetes, Previous pregnancy failure,
Previous macrosomia.
Sensitivity 69%
Specificity 68%
PPV %
(High risk ethnic minority groups)

15. Screening for GDM by 50g Glucose Challenge Test
50g glucose in 150 ml H2O: Unprepared subject at weeks gestation
Positive Test – Plasma Glucose >7.8 mmol/l
Sensitivity 79%
Specificity 87%
PPV %
( O’Sullivan 1973)

16. Diagnostic Screening by 75g glucose load after overnight fast
Community based population screening in Southern Sweden
2 h value only recorded:
interpreted by WHO Criteria
( Aberg 2001)

17. ADA: Low Risk Criteria for GDM
Age < 25yrs
Normal weight
From low prevalence ethnic group
Can be excluded from screening

19. HAPO Study 23,325 women were recruited at random.
75g OGTT at weeks gestation.
Results unblinded if FPG > 5.8 mmol/l
0r 2 hr >11.1 mmol/l.
If symptomatic may have Random Plasma
Glucose at weeks – unblinded if >8.9mmol/l.

20. HAPO Study-Primary Outcomes
Caesarean delivery
Increased Fetal Size
Neonatal Hypoglycaemia
Fetal Hyperinsulinism

21. HAPO: Glucose Categories (mmol/l)1 2 3 4 5 6 7
Fasting n
<4.2
4035
-4.4
7501
-4.7
6168
-4.9
2741
-5.2
1883
-5.5
672
>5.5
217
1 hour
<5.8
3721
-7.3
6806
-8.6
5483
-9.5
2378
-10.7
1601
-11.7
560
>11.7
183
2 hour
<5.0
4043
-6.0
7503
-6.9
6164
-7.7
2744
-8.7
1884
-9.8
>9.8

22. Frequency of Primary Outcomes across the Glucose Categories
Figure 1. Frequency of Primary Outcomes across the Glucose Categories. Glucose categories are defined as follows: fasting plasma glucose level - category 1, less than 75 mg per deciliter (4.2 mmol per liter); category 2, 75 to 79 mg per deciliter (4.2 to 4.4 mmol per liter); category 3, 80 to 84 mg per deciliter (4.5 to 4.7 mmol per liter); category 4, 85 to 89 mg per deciliter (4.8 to 4.9 mmol per liter); category 5, 90 to 94 mg per deciliter (5.0 to 5.2 mmol per liter); category 6, 95 to 99 mg per deciliter (5.3 to 5.5 mmol per liter); and category 7, 100 mg per deciliter (5.6 mmol per liter) or more; 1-hour plasma glucose level - category 1, 105 mg per deciliter (5.8 mmol per liter) or less; category 2, 106 to 132 mg per deciliter (5.9 to 7.3 mmol per liter); category 3, 133 to 155 mg per deciliter (7.4 to 8.6 mmol per liter); category 4, 156 to 171 mg per deciliter (8.7 to 9.5 mmol per liter); category 5, 172 to 193 mg per deciliter (9.6 to 10.7 mmol per liter); category 6, 194 to 211 mg per deciliter (10.8 to 11.7 mmol per liter); and category 7, 212 mg per deciliter (11.8 mmol per liter) or more; and 2-hr plasma glucose level - category 1, 90 mg per deciliter (5.0 mmol per liter) or less; category 2, 91 to 108 mg per deciliter (5.1 to 6.0 mmol per liter); category 3, 109 to 125 mg per deciliter (6.1 to 6.9 mmol per liter); category 4, 126 to 139 mg per deciliter (7.0 to 7.7 mmol per liter); category 5, 140 to 157 mg per deciliter (7.8 to 8.7 mmol per liter); category 6, 158 to 177 mg per deciliter (8.8 to 9.8 mmol per liter); and category 7, 178 mg per deciliter (9.9 mmol per liter) or more.
The HAPO Study Cooperative Research Group. N Engl J Med 2008;358: 22

23. HAPO Study Concensus on revised diagnostic criteria.
Risk factor positive; if FPG >7.0mmol/l,or random glucose above 11.1mmol/l, or
HB A1c >6.5% consider as likely overt diabetes and treat accordingly.
Or if universal blood testing : 75g load
Fasting plasma glucose >5.1mmol/l
And/or 1hr level >10.0mmol/l
??include 2hr > 8,5mmol/l

24. Ultrasound Diagnosis of Lumbar Myelomeningocoele

25. Congenital Malformation Rates - Sheffield Audit
Type 1/2
GDM/IGT
TOP for congenital malformations 4 1
Major malformations at birth 12 7
Percent major malformations
(7.6%)
(2.0%)
Minor malformations at birth

26. Congenital Malformations in Gestational Diabetes
Major Congenital Malformations
(%)
Type I diabetes (95% CI)
5.9 (3.2 – 9.8)
Type 2 diabetes
4.4 (2.4 – 7.3)
Gestational diabetes
1.4 (0.9 – 2.0)
but
New onset Type 2 in GDM group
(13% of 1822)
4.6 (2.3 – 8.2)
(Farrell et al 2002)

27. Glucose Levels in Gestational Diabetes
Patterns of Malformations and Relationships to Initial Maternal Fasting Serum
Glucose Levels in Gestational Diabetes
No Malformations
Major Malformations
Aneuploidy
n = 3895
n = 143
n = 21
Initial FPG
level mmol/L
± SD
6.4 ± 2.0
8.0 ± 3.1
6.4 ± 2.1
(Schaefer-Graf et al 2000)

29. The Relationship between Birth Weight Ratio and mean HbA1c in Pregnancy

30. Amniotic Fluid Insulin at Delivery

31. 50 40 30
Insulin mu/l 20 10 25 30 35 40 45
Weeks of Pregnancy
Weiss 1986

32. Percentage of LGA in infants according to Quintiles of Carbohydrate Intake in GDM
>243
LGA
5 (37%)
2 (12%)
4 (25%)
0 (0%)
SGA
2 (13%)
1 (6%)
Romon et al 2001

33. Gestational Diabetes; can a low glycemic index diet reduce the need for insulin? A randomised trial.
63 women randomised to low GI diet or conventional High Fibre diet.
Low GI 9/31 (29%) required insulin.
High Fibre 19/32 (59%)required insulin
(P= 0.023)
(Moses et al 2009)

34. RCT of Glycaemic Parameters ± Fetal Ultrasound to Determine Insulin Therapy in GDM
98 women with FGP 5.8 – 6.7 mmol/L
Experimental group – insulin only if AC ≥ 70th centile or Plasma Glucose > 6.7 mmol/L
Control group – all received insulin
(targets: preprandial ≤ 5.0, 2h postprandial ≤ 6.7)
(Kjos et al 2001)

35. RCT of Glycaemic Parameters ± Fetal Ultrasound to Determine Insulin Therapy in GDM
Outcomes
Controls
Experimental Group
Insulin Rx
100%
62%
Birthweight
3.27 Kg ± 0.5
3.37 ± 0.5
BWT >90th centile
6.3%
8.3%
Neonatal Morbidity
25%

36. Pre-prandial vs Post-prandial BG monitoring in Insulin treated GDM
RCT 66 women with GDM by ADA Criteria : Diagnosed before 30 weeks.
Pre-prandial Group : Insulin adjusted to keep fasting glucose mmol/L
and pre-prandial 3.3 – 5.9 mmol/L
Post-prandial Group: Insulin adjusted to keep fasting glucose mmol/L
and 1hr post prandial < 7.8 mmol/l
Veciana et al 1995

37. Pre-prandial vs Post-prandial BG monitoring in GDM
Target control met
86.0 ± 4.1%
88.0 ± 5.2%
Insulin dose U/day
76.8 ±21.4
100.4 ± 29.5
0.003
Final HbA1c
8.1 ± 2.2 %
6.5 ± 1.4%
0.006
Veciana et al 1995

38. Pre-prandial vs Post-prandial BG monitoring
Maternal outcomes
Pre prandial
n = 33
Post prandial p
Pre eclampsia
2 (6%) ns
GA at delivery
(weeks)
37.6 ± 3.8
37.9 ± 1.4 CS
13 (39%)
8 (24%)
3° Tear
8(24%)
3 (9%) ns
Veciana et al 1995

39. Pre-prandial vs Post-prandial BG monitoring in GDM
Neonatal outcomes
Pre-prandial
n=33
Post-prandial
RR p
(95% CI)
Birth Wt
3848 ± 434
3469 ± 668
0.01
LGA
14 (42%)
4 (12%)
( )
SGA
1 (3%) ns
Shoulder dystocia
6 (18%) ns
( )
Hypoglycaemia
(<1.6mmol/L)
7 (21%) ns
( )
Veciana et al 1995

40. A Comparison of Glyburide (glibenclamide) and Insulin in Women with GDM
404 GDM randomised to Glyburide 2.5 mg od rising to 20 mg/day – then commenced on insulin (n=8, 4%) or insulin 0.7 u/Kg with weekly adjustment
(Langer 2000)

41. A Comparison of Glyburide and Insulin in Women with GDM
GHb %
5.5
5.4 ns
LGA %
12.0
13.0
Cord Serum Insulin ( µU/ml)
15 ±(SD)13
15 ± 21
Langer 2000

42. A Comparison of Glyburide and Insulin in Women with GDM
RDS/TTN % 8 6 ns
Hypoglycaemia requiring IV dextrose % 14 11
SCBU admission % 7
Congenital Anomalies % 2

44. Metformin versus Insulin for the Treatment of Gestational Diabetes (MiG)
New England Journal of Medicine :

45. MiG Study Randomised to Insulin or Metformin
If targets not met with Metformin
alone – up to 2500mg/day) – insulin added

46. MiG STUDY Metformin Group Insulin Group n = 363 n = 370 195
Metformin alone
168
Metformin and Insulin

47. MiG Study Primary Outcomes
Metformin Group
n = 363
Insulin Group
n = 370 RR
(95% CI)
Neonatal Hypoglycaemia
77 (18.5%)
99 (24.7%)
0.95 (0.92 – 0.98)
RDS
4 (1.1%)
5 (1.4%)
n.s.
Shoulder Dystocia
6 (1.7%)
11 (3.0%)
NICU admission
68 (18.7%)
78 (21.1%)
0.97 (0.90 – 1.04)

48. MiG Study Secondary Outcomes
Metformin Group
n = 363
Insulin Group
n = 370 p
Maternal Weight
(from enrolment to 6 weeks post-partum)
-8.1 ± 5.1 Kg
-6.9 ± 5.3 Kg
0.006

49. Timing of Delivery in Gestational Diabetes

50. Insulin requiring diabetes in pregnancy: A randomised trial of active induction of labour and expectant management
200 subjects (187 GDM 13 Type 2)
Randomised at 38 weeks gestation
Active group: Induction within 5 days
Expectant group: Twice weekly CTG and weekly Amniotic Fluid Volume measurement until labour
(Kjos et al 1993)

51. RCT of active induction of labour and expectant management
BWT >90th centile
10%
23%
(p = 0.02)
CS rate
25%
31%
(ns)
Shoulder Dystocia 0% 3%
Spontaneous labour
22%
44%
(Kjos et al 1993)

55. MiG Hypothesis
In women with gestational diabetes metformin treatment, compared to insulin, will:
Result in similar perinatal outcomes
Improve insulin sensitivity in the mother and baby
Be associated with improved treatment acceptability

56. MiG Study 751 women with GDM: Considered for Insulin therapy
if Fasting Capillary Glucose >5.4 mmol/l
or 2h postprandial >6.7 mmol/l