BACKGROUND AND PURPOSE:

• Tarry-Adkins et al. (PLoS Medicine, 2019) compared metformin vs insulin for GDM treatment to determine offspring perinatal growth trajectories and offspring body composition

METHODS:

• Systematic review and meta-analysis
• Search parameters
  • PubMed, Ovid Embase, Medline, Web of Science, ClinicalTrials.gov, and Cochrane database
  • Two independent reviewers with third reviewer to resolve conflicts
  • When necessary, there was direct communication with study authors
• Inclusion criteria
  • RCTs
  • Abstracts were not excluded, but none had sufficient data to warrant inclusion
  • Studies included that reported outcomes of GDM pregnancies treated with metformin versus insulin
  • Cohorts: European, American, Asian, Australian, and African women
• GDM diagnosis based on local guidelines
• Exclusion criteria
  • Studies that included pre-existing diabetes or non-diabetic women
  • Trials that compared metformin to non-insulin medications
• Statistical analysis
  • Summary data analyzed using odds ratio (ORs) for dichotomous data or differences in means (for continuous data) with random effects modeling
• Primary outcome measures
  • Parameters of fetal, infant, and childhood growth
    •  Weight | Height | BMI | Body composition

RESULTS:

• 28 studies | Total 3,976 participants

Neonatal growth parameters

• 19 studies (n = 3,723 neonates) reported neonatal growth parameters
• Compared to neonates of insulin-treated mothers, neonates born to metformin-treated mothers had
  • Lower birth weights
    • Mean difference −107.7 g (95% CI, −182.3 to −32.7; p = 0.005)
  • Lower ponderal indices
    • Mean difference −0.13 kg/m3 (95% CI, −0.26 to 0.00; p = 0.04)
  • Metformin-exposed neonates were 107.7 g smaller (on average)  vs those exposed to insulin (95% CI, 32.7 to 182.3;  p = 0.005)
• The odds of the following were lower after maternal treatment with metformin compared to insulin
  • Macrosomia: OR 0.59 (95% CI, 0.46 to 0.77; p < 0.001)
  • Large for gestational age: OR 0.78 (95% CI, 0.62 to 0.99; p = 0.04)
• There was no difference in neonatal height or SGA between groups

Infant growth parameters (18-24 months)

• Two studies (n = 411 infants)
• Unlike neonates, metformin-exposed infants were significantly heavier than those exposed to insulin
  • Mean difference 440 g (95% CI, 50 to 830; p = 0.03)

Mid-childhood growth parameters (5-9 years)

• Three studies (n = 520 children) 
• BMI was higher following metformin treatment compared to insulin treatment
  • Mean difference 0.78 kg/m2 (95% CI, 0.23 to 1.33; p = 0.005)
• There was no difference in absolute weights (p = 0.09)
• Adiposity indices were higher in metformin-exposed children vs insulin-exposed
  • Abdominal (p = 0.02) and visceral (p = 0.03) fat volumes
  • Authors caution that these results were based on limited data (just 1 study)
• Data results robust across various cohorts

CONCLUSION:

• Authors acknowledge study limitations
  • Heterogeneity in metformin dosing
  • Heterogeneity in diagnostic criteria for GDM
  • Scarcity of reporting of childhood outcomes
• Metformin-exposed neonates are significantly smaller (e.g., macrosomia was 40% lower) vs insulin-exposed group
• However, metformin-exposed children grow faster than insulin-exposed children
  • Heavier infants and higher BMI in mid-childhood
• The authors point out that this pattern of low birth weight and greater postnatal ‘catch-up growth’ is associated with adverse long-term cardiometabolic outcomes (e.g., obesity, type 2 diabetes, and cardiovascular disease)

Learn More – Primary Sources:

Neonatal, infant, and childhood growth following metformin versus insulin treatment for gestational diabetes: A systematic review and meta-analysis

Related ObG Topics:

Updated ACOG Guidance on Gestational Diabetes

Metformin in Pregnancy

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

The MiG-TOFU Study: Gestational Diabetes, Metformin and Metabolic Outcomes in Offspring 7 Years Later