ESPE Yearbook of Paediatric Endocrinology

Diabetes Care. 2024 Sep 1;47(9):1688-1695. doi: 10.2337/dc23-2056

Brief summary: This observational study analysed U.S. healthcare claims data and applied target trial emulation methods to assess the safety of continuing metformin during pregnancy in women with T2D. By mimicking the design of a randomized controlled trial, it found that continuing metformin was not associated with an increased risk of adverse neonatal outcomes.

Comment: With the rising burden of the T2D epidemic at younger ages, an increasing number of pregnancies in young women with T2D is expected. Previous data from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study reported 260 pregnancies among 141 women (mean age 21.5 ± 3.2 years, BMI 35.6 ± 7.2 kg/m², and diabetes duration 8.1 ± 3.2 years). Pregnancy complications occurred in 65% of women, including pregnancy loss in 25% and preterm birth in 32.6% of cases.¹Among the offspring, 7.8% were classified as small for gestational age, 26.8% as large for gestational age, and 17.9% were macrosomic.

Two randomized trials (MiTy and MOMPOD)^2,3 evaluated the addition of metformin to insulin therapy in pregnant women with pregestational T2D. While metformin modestly improved glycemic control, no difference in composite perinatal outcomes was observed.

The current study assessed the safety of continuing metformin treatment during pregnancy in a real-world setting, including 2,255 pregnant women with T2D, 597 who continued metformin during pregnancy and 1,658 who discontinued treatment. The primary outcome was a composite of adverse neonatal events, including preterm birth, birth injury, neonatal respiratory distress, neonatal hypoglycemia, and neonatal intensive care unit admission.

Continuing metformin in women with T2D who were previously treated with metformin plus insulin was not associated withan increased risk of a composite adverse neonatal outcomes compared with remaining on insulin alone. However, in a subgroup of commercially insured women, a twofold increased risk of SGA was observed - a finding not replicated in the publicly insured cohort. This increased risk of SGA may be due tometformin crossing the placenta, potentially exerting a direct in utero effect on fetal growth. In addition, other possible mechanism, include an effect of metformin on maternal diet, reduced weight gain during pregnancy, cell growth, folate-related pathways, and/or placental function. The discrepancy between subgroups may reflect differences in adherence, as well as clinical and demographic characteristics across cohorts.

Key message: Continuing metformin during pregnancy does not appear to increase the risk of adverse neonatal outcomes and does not necessitate discontinuation. However, a potential association with increased SGA risk warrants close monitoring of fetal growth in women with pregestational diabetes who continue metformin treatment.

References: 1. TODAY Study Group. Pregnancy Outcomes in Young Women With Youth-Onset Type 2 Diabetes Followed in the TODAY Study. Diabetes Care. 2021 Dec 8;45(5):1038–45. doi: 10.2337/dc21-1071. Epub ahead of print. PMID: 34880068; PMCID: PMC9174960.2. Feig DS, Donovan LE, Zinman B, Sanchez JJ, Asztalos E, Ryan EA, Fantus IG, Hutton E, Armson AB, Lipscombe LL, Simmons D, Barrett JFR, Karanicolas PJ, Tobin S, McIntyre HD, Tian SY, Tomlinson G, Murphy KE; MiTy Collaborative Group. Metformin in women with type 2 diabetes in pregnancy (MiTy): a multicentre, international, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2020 Oct;8(10):834-844. doi: 10.1016/S2213-8587(20)30310-7. Erratum in: Lancet Diabetes Endocrinol. 2020 Nov;8(11):e6. doi: 10.1016/S2213-8587(20)30349-1. P3. Boggess KA, Valint A, Refuerzo JS, Zork N, Battarbee AN, Eichelberger K, Ramos GA, Olson G, Durnwald C, Landon MB, Aagaard KM, Wallace K, Scifres C, Rosen T, Mulla W, Valent A, Longo S, Young L, Marquis MA, Thomas S, Britt A, Berry D. Metformin Plus Insulin for Preexisting Diabetes or Gestational Diabetes in Early Pregnancy: The MOMPOD Randomized Clinical Trial. JAMA. 2023 Dec 12;330(22):2182-2190. doi: 10.1001/jama.2023.22949.