Comment: The quality of evidence is downgraded by imprecise results (few events for individual end points).
A systemic review and meta-analysis «...»9 included 7 studies with a total of 14042 children with 7641 children exposed exposed to metformin and followed for up to 14 years of age. Metformin use was not associated with neurodevelopmental delay in infancy (RR 1.09; 95% CI 0.54 to 2.17; 3 studies; n=9668) or at ages 3 to 5 years (RR 0.90; 95% CI 0.56 to 1.45; 2 studies; n=6118). When compared with unexposed peers, metformin use during pregnancy was not associated with altered motor scores (mean difference, 0.30; 95% CI -1.15 to 1.74; 3 studies; n=714) or cognitive scores (mean difference, -0.45; 95% CI -1.45 to 0.55; 4 studies; n=734). Studies that were included were of high quality and deemed to be at low risk of bias.
A systemic review and meta-analysis «...»8 included 10 RCTs. Metformin was associated with a statistically significant reduction in neonatal hypoglycaemia (OR 0.65, 95% CI 0.46 to 0.92) and lower birthweight (MD -68.96 g, 95% CI -108.34 to -29.57). A non-significant trend towards reduced LGA risk was observed.
A meta-analysis «...»10 included 24 trials with a total of 4934 patients. Compared with insulin, metformin showed a reduction in the risks of preeclampsia (RR 0.61, 95% CI 0.48 to 0.78, p < .0001), induction of labor (RR 0.90, 95% CI 0.82 to 0.98, p = .02), caesarean delivery (RR 0.91, 95% CI 0.85 to 0.98, p = .01), macrosomia (RR 0.67, 95% CI 0.53 to 0.83, p = .0004), neonatal intensive care unit (NICU) admission (RR 0.75, 95% CI 0.66 to 0.86, p < .0001), neonatal hypoglycemia (RR 0.55, 95% CI 0.48 to 0.63, p < .00001), and large for gestational age (LGA) (RR 0.80, 95% CI 0.68 to 0.94, p = .007). Conversely, metformin showed no significant difference in shoulder dystocia, premature birth, birth trauma, 5-min Apgar score < 7, small for gestational age, respiratory distress syndrome (RDS), or birth defects. However, it should be noted that there is a distinct difference in disease severity between patients with GDM treated with metformin alone and those requiring insulin supplementation.
A meta-analysis «Tarry-Adkins JL, Aiken CE, Ozanne SE. Neonatal, in...»1 assessed outcomes of GDM-pregnancies randomised to treatment with metformin versus insulin and included 28 trials with 3 976 participants. Neonates born to metformin-treated mothers had lower birth weights (mean difference -107.7 g, 95% CI -182.3 to -32.7; 17 trials, n=2816, I² = 83%, p = 0.005) than neonates of insulin-treated mothers. The odds of macrosomia (OR 0.59, 95% CI 0.46 to 0.77; 12 trials, n=2237, p < 0.001) and large for gestational age (OR 0.78, 95% CI 0.62 to 0.99; 9 trials, n=1990, p = 0.04) were lower with metformin compared to insulin. In contrast to the neonatal phase, metformin-exposed infants (18–24 months) were significantly heavier than those in the insulin-exposed group (mean difference 440 g, 95% CI 50 to 830; 2 studies, n=411, I² = 4%, p = 0.03). In mid-childhood (5–9 years), BMI was significantly higher (mean difference 0.78, 95% CI 0.23 to 1.33; 3 studies, n=520, I² = 7%, p = 0.005) following metformin versus insulin exposure.
Another meta-analysis «Guo L, Ma J, Tang J et al. Comparative Efficacy an...»6 included 41 studies involving a total of 7703 GDM patients. Compared with metformin, insulin had a significant increase in the risk of preeclampsia (RR 0.57; 95% CI 0.45 to 0.72; P < 0.001), NICU admission (RR 0.75; 95% CI 0.64 to 0.87; P < 0.001; 14 studies, n=2402), neonatal hypoglycemia (RR 0.57; 95% CI 0.49 to 0.66; P < 0.001;15 studies, n=2755), and macrosomia (RR 0.68; 95% CI 0.55 to 0.86; P < 0.05; 13 studies, n=2331). To the outcomes of birth weight and gestational age at delivery, insulin had a significant increase when compared with metformin (MD 114.48; 95% CI 37.32 to 191.64; P < 0.01; MD 0.23; 95% CI 0.12 to 0.34; P < 0.001; respectively).
A meta-analysis of 13 randomized controlled trials «Poolsup N, Suksomboon N, Amin M. Efficacy and safe...»2 involving a total of 2 151 patients assessed the efficacy and safety of oral antidiabetic drugs (metformin and glyburide). A significant increase in the risk for preterm births (65 vs 44 events, RR, 1.51; 95% CI, 1.04-2.19, p = 0.03; n=1102) was found with metformin compared to insulin. However, a significant decrease in the risk for gestational hypertension (RR, 0.54; 95% CI, 0.31-0.91, p = 0.02) was found. Postprandial glucose levels also decreased significantly in patients receiving metformin (MD, -2.47 mg/dL; 95% CI, -4.00, -0.94, p = 0.002). There was no significant difference between the two groups for the remaining outcomes (macrosomia, large for gestational age, shoulder dystocia, neonatal hypoglycemia, neonatal mortality, caesarean section, pre-eclampsia, or induction of labour).
Another network meta-analysis «Liang HL, Ma SJ, Xiao YN et al. Comparative effica...»3 included 32 RCTs assessing 6 kinds of treatments (metformin, metformin plus insulin, insulin, glyburide, acarbose, and placebo). Regarding the incidence of macrosomia and large for gestational age (LGA), metformin had lower incidence than glyburide (OR 0.54 and 0.4). In terms of the incidence of admission to the NICU, insulin had higher incidence compared with glyburide (OR 1.84). As for the incidence of neonatal hypoglycemia, metformin had lower incidence than insulin and glyburide (OR 0.63 and 0.39), and insulin was lower than glyburide (OR 0.62). For mean birth weight, metformin plus insulin was lower than insulin (SMD -0.58), glyburide (SMD -0.74), and placebo (SMD -0.66). Besides, metformin was observed to have lower birth weight than glyburide (SMD 0.26). As for weight gain, metformin and metformin plus insulin were lower than insulin (SMD -0.92 to -1.53). Metformin (plus insulin when required) had the lowest incidence of macrosomia, LGA, respiratory distress syndrome, low gestational age at delivery, and low birth weight.
A meta-analysis «Cassina M, Donà M, Di Gianantonio E et al. First-t...»5 assessed the rate of major birth defects in women with first-trimester exposure to metformin; a disease-matched control group which was not exposed to metformin or other oral anti-diabetic agents. The rate of major birth defects in metformin-exposed women with PCOS was not statistically increased compared with the disease-matched control group (OR of major birth defects was 0.86 (95% CI 0.18 to 4.08; 9 tials, P heterogeneity = 0.71).
A multicenter, open-label, parallel arms, clinical trial «Picón-César MJ, Molina-Vega M, Suárez-Arana M et a...»7 randomized 200 women with gestational diabetes who needed pharmacologic treatment to insulin or to metformin. Mean fasting and postprandial glycemia did not differ between groups, but postprandial glycemia was significantly better after lunch or dinner in the metformin-treated-group. Hypoglycemic episodes were significantly more common in the insulin-treated group (55.9% vs 17.7% on metformin; odds ratio, 6.118; 95% CI 3.134 to 11.944; P=.000). Women treated with metformin gained less weight and had less caesarean deliveries. Mean birthweight, macrosomia, and large for gestational age and babies' complications were not different between treatment groups.
A population based exploratory case-control study «Given JE, Loane M, Garne E et al. Metformin exposu...»4 (50 167 babies with congenital anomaly) compared cases of 29 specific subgroups of non-genetic anomalies, and all non-genetic anomalies combined with controls (all other non-genetic anomalies or genetic syndromes). 168 babies affected by congenital anomaly (141 non-genetic and 27 genetic) were exposed to metformin, 3.3 per 1000 births. No evidence was found for a higher proportion of exposure to metformin during the first trimester among babies with all non-genetic anomalies combined compared with genetic controls (adjusted odds ratio 0.84, 95% CI 0.55 to 1.30).