Table 3.
Summary of key clinical trials investigating the effects of metformin administration during pregnancy on mothers and/or their children.
| Study | Sample Size | Study Population Characteristics | Metformin Daily Dosage | Timing of Metformin Administration | Primary Study Outcome(s) |
|---|---|---|---|---|---|
| MIG [109], RCT | N = 751 women (N = 363, metformin group; N = 388, insulin group) |
Singleton pregnant women diagnosed with GDM according to ADIPS criteria | 500 to 2500 mg (plus supplemental insulin, if needed) | Starting 20 to 33 weeks of gestation | Perinatal outcome: a composite of neonatal hypoglycemia, respiratory distress, need for phototherapy, birth trauma, 5-min Apgar score <7, or prematurity (RR 1.00, 95% CI 0.90–1.10, ns) |
| MIG TOFU [136], Post-RCT follow-up | N = 318 children (N = 154, children born to metformin-treated women; N = 164, children born to insulin-treated women) |
Children (aged 2 years), born to mothers randomized in the MiG-trial | Children outcome: body composition measured with anthropometry, bioimpedance, and DXA (larger mid-upper arm circumferences, and larger subscapular and biceps skinfolds in the metformin-exposed group) | ||
| MIG TOFU [110], Post-RCT follow-up | N = 208 children (N = 103, children born to metformin-treated women; N = 105, children born to insulin-treated women) |
Children (aged 7–9 years), born to mothers randomized in the MiG trial | Children outcome: body composition measured with anthropometry, bioimpedance, DXA, and MRI (larger measures of weight, arm and waist circumferences, waist-to-height ratio, BMI, triceps skinfold, fat mass and lean mass, abdominal fat volume in the metformin-exposed group from the Auckland cohort, no differences between groups in the Adelaide cohort) | ||
| ISRCTN10845466 [137], RCT | N = 106 women (N = 53, metformin group; N = 53, placebo group) |
Singleton pregnant women diagnosed with GDM according to Malaysian national criteria | 1000 to 1500 mg (plus supplemental insulin, if needed) | Starting 16 to 30 weeks of gestation | Maternal outcome: change in A1c at 36 weeks of gestation (mean A1c increment +0.20% vs. +0.27%, ns) |
| MiTy [138], RCT | N = 502 women (N = 233, metformin group; N = 240, placebo group) | Singleton pregnant women with pregestational T2D | 2000 mg (as add-on to insulin) | Starting 6 to 22 weeks of gestation | Perinatal outcome: a composite of pregnancy loss, preterm birth, birth injury, moderate/severe respiratory distress, neonatal hypoglycemia, or neonatal intensive care unit admission longer than 24 h (RR 1.02, 95% CI 0.83–1.26, ns) |
| PregMet [83], RCT | N = 257 women (N= 136 metformin group, N = 240 placebo group) | Singleton pregnant women with PCOS | 2000 mg | Starting 5 to 12 weeks of gestation | Maternal outcomes: prevalence of pre-eclampsia (risk difference 3.7%, 95% CI −1.7–9.2, ns), GDM (risk difference 0.8%, 95% CI −8.6–10.2, ns), preterm delivery (risk difference −4.4%, 95% CI, −10.1–1.2, ns), and a composite of these three endpoints (risk difference 1.5%, 95% CI −8.9–11.3, ns) |
| PregMet 2 [84], RCT | N = 487 women (N= 244 metformin group, N = 243 placebo group) | Singleton pregnant women with PCOS | 2000 mg | Starting 6 to 12 weeks of gestation | Maternal outcomes: frequency of late miscarriage and preterm birth (5% vs. 10%, odds ratio 0.5, 95% CI 0.22–1.08, ns), incidence of GDM (25% vs. 24%, odds ratio 1.09, 95% CI 0.69–1.66, ns) |
| PedMet [111], Post-RCT follow-up | N = 141 children (N = 71, children born to metformin-treated women; N = 70, children born to placebo-treated women) |
Children (aged 5–10 years), born to mothers randomized in the PregMet trial | Children outcomes: BMI Z score (difference in means +0.41, 95% CI 0.03–0.78) | ||
| NCT01240785 [139], RCT | N = 221 women (N= 111, metformin group; N = 110, insulin group) | Singleton pregnant women with GDM diagnosed according to Finnish national criteria | 1000 to 2000 mg (plus supplemental insulin, if needed) | Starting 22 to 34 weeks of gestation | Perinatal outcomes: birthweight expressed in grams (difference in means +15, 90% CI −121–89, ns), birthweight > 90 centile (RR 0.9, 95% CI 0.5–1.8, ns) |
| UMIN 000005393 [140], RCT | N = 94 women (N = 47, metformin group; N = 47, insulin group) | Singleton pregnant women with GDM diagnosed according to Carpenter-Coustan criteria | 1700 to 2550 mg | Starting 28 to 34 weeks of gestation | Maternal outcomes: gestational weight gain (mean Kg, 0.53 vs. 2.3), frequency of pre-eclampsia (21.7% vs. 15.2%, ns), preterm birth (10.9% vs. 10.9%, ns), caesarean section (71.7% vs. 65.2%, ns) |
| IRCT201306057841N4 [141], RCT | N = 119 women (N = 59, metformin group; N = 60, insulin group) | Singleton pregnant women with GDM diagnosed according to ADIPS criteria | 500 to 1500 mg (plus supplemental insulin, if needed) |
Starting 25 to 35 weeks of gestation | Perinatal outcomes: caesarean section (74% vs. 70%, ns), neonatal hypoglycemia (ns), Apgar score (ns), birthweight (mean grams, 3176 vs. 3342, ns) |
| EMPOWaR [82], RCT |
N = 449 (N = 226 metformin group, N = 223 placebo group) | Singleton pregnant women with obesity according to WHO criteria and without GDM | 500 to 2500 mg | Starting 12 to 16 weeks of gestation | Perinatal outcome: Z score of birthweight percentile (difference in means −0.029, 95% CI −0·217–0.158, ns) |