Background: Metformin is an emerging option for treating gestational diabetes (GDM). The evidence for the comparative safety and effectiveness of metformin versus insulin (standard of care) is inconclusive.

Objective: To measure the comparative safety and effectiveness of metformin versus insulin for pharmacological management of GDM.

Methods: We conducted a cohort study using New Zealand healthcare data (2005-2015). We identified pregnant women treated with metformin or insulin for GDM and excluded women with evidence of preexisting diabetes. We assessed birth outcomes using maternity care and hospitalization data. We examined child growth and psychosocial development as measured by parent- and teacher-reported Strengths and Difficulties Questionnaires (SDQ), recorded during pre-school health assessments at age 4. We adjusted for measured covariates using inverse probability of treatment weights and used multiple imputation for missing covariates. For dichotomous outcomes, we estimated risk differences (RD) per 100 and risk ratios (RR) with 95% confidence intervals (CI) and used linear regression for continuous measures.

Results: We identified 7,268 pregnancies treated initially with metformin (n=3,818) or insulin (n=3,450). Treatment initiation varied by ethnicity, socioeconomic status, region and calendar year, though both groups were similar with respect to age, body mass index, and timing of diagnosis and treatment initiation. After adjustment, metformin was associated with a reduced risk of large-for-gestational-age (RD= -3.7, 95% CI -5.5, -1.8), and neonatal hypoglycemia (RD= -5.0, 95% CI -6.9, -3.2), compared to insulin. After adjustment, children of metformin-treated mothers were not more likely to be ≥85th percentile for weight (RR=1.04, 95% CI 0.93 1.16) or weight-for-height (RR=0.92, 95% CI 0.83, 1.02) than children of insulin-treated mothers. Children of metformin-treated mothers were not at significantly increased risk of having a concerning parent-reported SDQ score (RR=1.13, 95% CI 0.88, 1.46) compared to insulin, although the upper confidence limit does not exclude a modest increase in risk.

Conclusions: Metformin appears to be an effective treatment for women with GDM and may reduce the risk of some adverse neonatal outcomes when compared to insulin. Growth assessments of children of metformin-treated mothers were similar to those of children of insulin-treated mothers. These results will help inform future GDM treatment guidelines.