BACKGROUND AND PURPOSE:

• Feig et al. (The Lancet Diabetes & Endocrinology) investigated whether adding metformin to a standard regimen of insulin could improve neonatal outcomes in pregnant women with type 2 diabetes

METHODS:

• Prospective, multicenter, randomized, parallel, double-masked, placebo-controlled trial
  • Metformin in Women with Type 2 Diabetes in Pregnancy (MiTy) Trial
• Participants
  • Type 2 diabetes on insulin
  • Singleton pregnancy
  • Between 6w0d and 22w6d  
• Intervention
  • Metformin + insulin
    • Metformin 1000 mg twice daily
  • Placebo + insulin
• Study design
  • Randomized 1:1
  • Stratified by center and pre-pregnancy BMI (<30 kg/m2 or ≥30 kg/m2)
  • Fasting blood glucose levels obtained
    • Before the first meal of the day
    • Before the last meal of the day
    • 2 h after each meal
  • Insulin doses adjusted to hit the following glucose targets
    • Fasting glucose < 5.3 mmol/L (95 mg/dL)
    • 2-h postprandial glucose < 6.7 mmol/L (120 mg/dL)
  • Patients were seen every 1 to 4 weeks based on standard clinical care
• Primary outcome
  • Composite of fetal and neonatal outcomes including ≥1 of the following: Pregnancy loss | Preterm birth (<37 weeks’ gestation) | Birth injury | Moderate or severe RDS | Neonatal hypoglycemia | NICU admission >24 hours
• Secondary outcomes
  • Individual outcomes in the composite as well as other maternal and neonatal adverse outcomes

RESULTS:

• Available with complete information for primary outcome
  • 233 in metformin group | 240 in placebo group

Primary Outcome

• There was no significant difference in the primary composite neonatal outcome between the two groups (P = 0.86)
  • Metformin: 40%
  • Placebo: 40%
  • Relative risk (RR) 1.02 (95% CI, 0.83 to 1.26)

Secondary Outcomes

• Women in metformin group achieved better glycemic control
  • Lower HbA1c at 34 weeks’ gestation (P=0.15)
    • Metformin: 5.90%
    • Placebo: 6.10%
  • Required less insulin (P<0.0001)
    • Metformin: 1.1 units per kg per day
    • Placebo: 1.5 units per kg per day
    • Difference −0.4 (95% CI, −0.5 to −0.2)
• Women in the metformin group gained less weight (P<0.0001)
  • Metformin: 7.2 kg
  • Placebo: 9.0 kg
  • Difference −1.8 (95% CI, –2.7 to −0.9)
• Women in the metformin group had fewer cesarean births (P=0.031)
  • Metformin: 53%
  • Placebo: 63%
  • RR 0.85 (95% CI, 0.73 to 0.99)
• There were no significant differences in hypertensive disorders (P=0.93)
• Compared with those in the placebo group, metformin-exposed infants
  • Weighed less (P=0.002)
    • Metformin: mean birthweight 3156 g
    • Placebo: 3375 g
    • Difference −218 (95% CI, –353 to −82)
  • Fewer were above the 97th centile for birthweight (P = 0.041)
    • Metformin: 9%
    • Placebo: 15%
    • RR 0.58 (95% CI, 0.34 to 0.97)
  • Fewer cases of macrosomia (P = 0.046)
    • Metformin: 12%
    • Placebo: 19%
    • RR 0.65 (95% CI, 0.43 to 0.99)
• More infants in the metformin group were small for gestational age (P=0.026)
  • Metformin: 13%
  • Placebo: 7%
  •  RR 1.96 (95% CI, 1.10 to 3.64)

CONCLUSION:

• There was no significant difference in the primary outcome (composite of serious neonatal outcomes) between pregnant women with type 2 diabetes on insulin who were treated with additional metformin vs placebo
• Metformin for management of type 2 diabetes in pregnancy was associated with favorable maternal and neonatal outcomes such as
  • Improvements in maternal glycemic profile
  • Reduced neonatal adiposity
  • Reduced maternal weight gain
  • Lower insulin dosage required
  • Fewer cesareans
• There were a larger number of small for gestational age infants in the metformin group
• The authors conclude

Understanding the implications of these effects on infants will be important to properly advise patients who are contemplating the use of metformin during pregnancy

Learn More – Primary Sources:

Metformin in women with type 2 diabetes in pregnancy (MiTy): a multicentre, international, randomised, placebo-controlled trial

Related ObG Topics:

Updated ACOG Guidance on Gestational Diabetes

ACOG Guidance on Perinatal Management of Pregestational Diabetes

Metformin in Pregnancy

EUROmediCAT Data: Does Metformin Use in the First Trimester of Pregnancy Increase the Risk for Congenital Anomalies?