1. Metformin versus Insulin for the Treatment of Gestational Diabetes
Janet A. Rowan, M.B., Ch.B., William M. Hague, M.D. N Engl J Med 2008;358:
R2 Jang Jeong Yoon / Prof. Jun Suck
N Engl J Med 2008;358:

2. Background Gestatianl DM : about 5% complication of pregnancies
If maternal hyperglycemia persists, treatment with additional insulin have been shown to improve perinatal outcomes.
- Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 2005;352:
Use insulin : associated with hypoglycemia, weight gain
How about oral agent ?
N Engl J Med 2008;358:

3. Background
Metformin
: improves insulin sensitivity, probably by activating AMP kinase, and is not associated with weight gain or hypoglycemia.
Reported favorable outcomes:
-Coetzee EJ, Jackson WP. Pregnancy in established non-insulin-dependent diabetics. S Afr Med J 1980;58:
Hughes RCE, Rowan JA. Pregnancy in women with Type 2 diabetes: who takes metformin and what is the outcome? Diabet Med 2006;23:
increased rates of perinatal loss and preeclampsia as compared with insulin treatment.
- Hellmuth et al. Oral hypoglycaemic agents in 118 diabetic pregnancies Diabet Med 2000;17:
retrograde cohort study
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4. Purpose
assess the efficacy and safety of metformin versus insulin use for GDM
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5. Method- Design and Subjects
Study Design : randomized, open-label trial comparing metformin with insulin treatment in 10 New Zealand and Australian urban obstetrical hospitals
Study Subjects : 18 and 45 years of age
** Gestational diabetes mellitus : the criteria of the Australasian Diabetes in Pregnancy Society (ADIPS)
- pregnant with a single fetus , 20 ~ 33 weeks of gestation age
- usual criteria for starting insulin treatment, and, after lifestyle modification
more than one capillary blood glucose
> 5.4 mmol /L (97.2 mg /dL ) after an overnight fast
> 6.7 mmol /L (120.6 mg /dL ) after 2-hour postprandial
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6. Method- Design and Subjects
Exclusion criteria
prepregnancy diagnosis of diabetes
a contraindication to metformin
a fetal anomaly
gestational hypertension, preeclampsia
fetal growth restriction, and ruptured membranes.
the capillary glucose levels recommended by the ADIPS
level after an overnight fast < 99mg/dL
2-hour postprandial level < 126 mg /dL
Metformin or Diaformin
500mg  2500mg daily

7. Method-Data collection
Demographic and clinical data
Laboratory findings : liver, kidney function , Hb A1C, glucose
glucose : fast , 2 -hours postprandial (MediSense meter )
At 36 to 37 weeks of gestation, after an overnight fast
At delivery, complications of pregnancy, the indication for delivery, the mode of delivery, and neonatal complications were recorded.
After the umbilical cord had been clamped, cord blood was collected for Serum insulin concentration
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8. Methods -Study Outcomes
primary outcome was a composite of neonatal complications
: maternal hyperglycemia , directly influenced by the passage of metformin
across the placenta
- Neonatal hypoglycemia .
- respiratory distress , need for phototherapy, birth trauma ,
- 5-minute Apgar score < 7 , premature birth (<37 weeks of gestation)
Maternal hypertensive complications
Birth-weight percentiles
Neonatal anthropometric measurements : crown–heel length, abdominal circumference,etc.
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9. Methods -Study Outcomes
Secondary outcome
: maternal and neonatal body composition
maternal glycemic control
maternal hypertensive complications
maternal glucose tolerance at 6 to 8 weeks post partum
acceptability of treatment
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10. Results- Study Subjects

11. Metformin or Diaformin
500mg 2500mg
1-2 weeks
46.3%
stopped metformin before delivery : 27 (7.4%)
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12. The baseline characteristics of the two groups were similar

13. Results- Study Subjects
The median daily dose of metformin : mg
supplemental insulin, the median maximum daily dose of insulin
was 42 units : lower than the maximum daily dose in those assigned to insulin (50 units) (P = 0.002).
Supplemental insulin was started at a median of 20.4 days

14. Results- Study Outcomes
<
ccording
to indication for preterm birth, the frequency of
iatrogenic preterm births was similar in both treatment
groups, but there was a trend toward more
spontaneous preterm births (spontaneous labor or
preterm ruptured membranes) in the metformin
group
There was a statistically significant
but clinically small difference in the mean
gestational age at delivery between the metformin
group (38.3 weeks) and the insulin group (38.5
weeks, P = 0.02).
>

15. > < There was a statistically significant
but clinically small difference in the mean
gestational age at delivery between the metformin
group (38.3 weeks) and the insulin group (38.5
weeks, P = 0.02).
There were no significant differences between
the groups in neonatal anthropometric measures
or measurements of umbilical-cord serum
insulin concentrations.
>
<

17. op

18. Reaults- Metformin Treatment and Supplemental insulin
As compared with metformin alone group, women requiring supplemental insulin had a higher BMI and had higher baseline glucose levels
The rates of the primary outcome did not differ between women treated with metformin alone and those treated with supplemental insulin (29.7% and 34.5%, respectively; P = 0.33).

19. Conclusions
Metformin, alone or with supplemental insulin, is not associated with increased perinatal complications as compared with insulin
an effective and safe treatment option for women with gestational diabetes mellitus who meet the usual criteria for starting insulin, and that metformin is more acceptable to women with gestational diabetes mellitus than is insulin.

20. Metformin stop stopped in 27 women (7.4%) before delivery
- 11 (accordance with the protocol )
 9 obsterical Complication
1 sepsis
1 worsening of LFT
- 7 women (1.9%) because of gastrointestinal side effects
- 5 women chose to stop metformin
- 4 women were advised to stop by other health professionals who were not
involved in the trial.
doses were reduced because of gastrointestinal side effects in 32 women (8.8%); all but 1 of these women were able to maintain a dose of at least 1000 mg per day.

21. Universal versus selective screening by blood test
ADIPS
ACOG
Universal versus selective screening by blood test
Universal unless low GDM incidence or resources
limited
No recommendation. States that "many physicians elect to screen all pregnant patients as a practical matter"
Differences in definition of low risk for GDM
Age < 30 years, obesity, family history of diabetes
Age < 25 years, body mass index < 25 kg/m2. No known diabetes in first-degree relative
Oral glucose tolerance test used
75 g, 2-hour, 2-point blood sampling
100 g, 3-hour, 4-point blood sampling
Criteria for diagnosis of GDM
Plasma glucose level: Fasting, ≥ 5.5 mmol/L (99mg/dL)
and/or 2-hour, ≥ 8.0 mmol/L (144mg/dL)
Plasma glucose level: Fasting, ≥ 5.3 mmol/L; 1-hour, ≥ 10.0 mmol/L 2-hour, ≥ 8.6 mmol/L; 3-hour, ≥ 7.8 mmol/L; (2 or more time points need to elevated)
Insulin therapy commenced after medical–nutrition therapy
and/or 1-hour postprandial, ≥ 8.0 mmol/L (144mg/dL)
and/or 2-hour postprandial, ≥7.0 mmol/L (126mg/dL)
Plasma glucose level: Fasting, ≥ 5.3 mmol/L and/or 1-hour postprandial, ≥ 7.2–7.8 mmol/L and/or 2-hour postprandial, ≥ 6.7 mmol/L

22. : neonates were monitored for hypoglycemia by measuring blood glucose levels within 2 hours after birth and before each feed feeding until consecutive glucose values < 2.6 mmol/L (46.8 mg /dL )