Normal physiology of pregnancy
• First trimester-Increased insulin sensitivity.
• Late 2nd and 3rd trimester insulin
resistance possible associated with
increasing levels of unknown placental
hormone(s) which correlate(s) with
placental mass.
Pathophysiology of GDM
GDM is characterized by baseline
preconception:
• Insulin resistance
• Reduced insulin secretion
Low risk- no screening?
No longer!
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Low risk ethnic group (European American)
No Family Hx of DM2
Age <25
Weight normal before pregnancy
No hx of abnormal glucose metabolism
No hx of poor obstetrical outcome
Normal maternal birth weight
High Risk
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Obesity
Previous history of GDM
Glycosuria
Strong family hx of DM (1st degree
relative)
• Impaired OGTT or IFG
• Previous baby with > 9 lb birth wt.
Diagnostic OGTT (2 abnormal
values)???- HAPO
100gm
OGTT
criteria
O’Sullivan NDDG
whole blood conversion
Plasma
mg/dl
mg/dl
Carpenter &
Coustan
Plasma
mg/dl
Fasting
90
105
95
1 hour
165
190
180
2 hour
145
165
155
3 hour
125
145
140
HAPO
• 23,316 women
• 75 gm OGTT at 24-32 weeks: fasting, 1hr, and 2
hr glucose obtained
• Results unblinded and excluded if 2hr >200
mg/dl or if fasting > 105 mg/dl, any <45 mg/dl,
random >160 mg/dl
• Only those that stayed blinded and did not
undergo further testing were analyzed
NEJM 2008:358:1991-2002
HAPO Diagnostic GDM Guidelines
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1 step testing
2 hour 75 gram GTT
Only 1 abnormal value required
Fasting 92 mg/dl (5.1 mmol/L)
1 Hour 180 mg/dl (10 mmol/L)
2 Hour 153 mg/dl (8.5 mmol/L)
Guidelines based on outcomes ie macrosomia,
cord C peptide, preeclampsia etc
Diabetes Care 2010; 33:676-682
Maternal Glucose vs Primary
Outcomes
Copyright 2009 ADA. Published online at http://care.diabetesjournals.org/cgi/content/full/dc09-1848/DC1.
Maternal 1 hr Glucose vs Primary
Outcomes
Copyright 2009 ADA. Published online at http://care.diabetesjournals.org/cgi/content/full/dc09-1848/DC1.
Maternal 2 hr Glucose vs Primary
Outcomes
Copyright 2009 ADA. Published online at http://care.diabetesjournals.org/cgi/content/full/dc09-1848/DC1.
All HAPO Outcomes- normal vs 1
abnormal glucose
Copyright 2009 ADA. Published online at http://care.diabetesjournals.org/cgi/content/full/dc09-1848/DC1.
Treatment of Mild GDM
Landon et al 2009; 361:1339-48
• Study group 958 women in 24th to 31st week
gestation.
• Inclusion criteria- Fasting glucose <95 and 1
abnormal value on 3 hour OGTT (1 hr >180, or 2
hr >155 or 3 hr >140
• Randomization- 485 to treatment group and 473
to control group (blinded)
• Treatment group targets: fasting <95, 2 hr <120
mg/dl
Results
Landon et al NEJM 2009; 361; 1339-1448
p<0.001, <0.001, 0.003, 0.02, 0.02, 0.01 respectively below
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Outcome variable Treatment Control
Birth wt
3302 gms 3408 gms
Birth wt > (4000 g)
5.9 %
14.3 %
Fat mass gms
427
464
Cesarean delivery
26.9 %
33.8 %
Shoulder dystocia
1.5 %
4.0 %
Preeclampsia/G HTN 8.6 %
13.6 %
A Comparison of Glyburide and
Insulin in Women with GDM
Langer, et al. NEJM 2000;343:1134-1138
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404 women with GDM
Recruited 11-33 weeks gestation
Singleton pregnancies
Dietary therapy for all subjects
201 Glyburide (2.5-20mg/day; mean
9mg/day)
• 203 Insulin, TID dosing
• Blood Glucose Goals:
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Testing 7x/day
Mean 90-105
Fasting 60-90
Preprandial 80-95
A Comparison of Glyburide and Insulin
in Women with GDM
Langer, et al. NEJM 2000;343:1134-1138
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82% on Glyburide reached BG goals
88% on Insulin reached BG goals
4% on Glyburide required Insulin
No difference in preeclampsia and c-section
rates
• Maternal Hypoglycemia (<40mg/dL)
– 4 vs 41 (2% vs 20%) in Glyburide treatment vs Insulin
• 12 random patients
– Simultaneous maternal and cord blood levels of
Glyburide measured
– Maternal concentrations 50-150 ng/ml
– Cord concentrations were undetectable
50% increase in
Neonatal hypoglycemia
and hyperbilirubinemia
though not significant
Langer, et al. NEJM 2000;343:1134-1138
Predicting which patients might
have better control on Glyburide
• Fasting  110 associated with higher
failure
– Conway et al. J Matern Fetal Neonatal Med
2004;15:51-55
• Failure more likely if diagnosed earlier in
pregnancy, older age, multiparous, higher
mean fasting glucose
– Kahn et al. Obstet Gynecol 2006;107:14303-1309
• GLT  200 predicted failure
– Rochon et al. AJOG 2006;195:1090-1094
Metformin vs Insulin for the Treatment of
Gestational Diabetes
Rowan et al. NEJM 2008;358:2003-2015.
• 751 women with GDM at 20-33 weeks randomly
assigned to open treatment with Metformin (and
insulin if needed) or to insulin
• Primary outcome was a composite of
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Neonatal hypoglycemia
Respiratory distress
Need for phototherapy
Birth trauma
5 min Apgar < 7
Prematurity
Metformin vs Insulin for the Treatment of
Gestational Diabetes
Rowan et al. NEJM 2008;358:2003-2015.
• Secondary outcomes
– Neonatal anthropometric measurements
– Maternal glycemic control
– Maternal hypertensive complications
– Postpartum glucose tolerance
– Acceptability of treatment
Enrollment of Subjects
Rowan JA et al. N Engl J Med 2008;358:2003-2015
Metformin vs Insulin for the Treatment of
Gestational Diabetes
Rowan et al. NEJM 2008;358:2003-2015.
Metformin vs Insulin for the Treatment of
Gestational Diabetes
Rowan et al. NEJM 2008;358:2003-2015.
Metformin vs Insulin for the Treatment of
Gestational Diabetes
Rowan et al. NEJM 2008;358:2003-2015.
Metformin vs Insulin for the Treatment of
Gestational Diabetes
Rowan et al. NEJM 2008;358:2003-2015.