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Grand Rounds

Metformin vs. Insulin for GDM: How Do Neonatal and Childhood Growth Rates Compare?

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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

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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

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