Long-term Effects of Metformin on Offspring Health Outcomes

Introduction to Metformin’s Role in Pregnancy

Metformin, a widely prescribed medication for managing type 2 diabetes, polycystic ovary syndrome (PCOS), and gestational diabetes mellitus (GDM), has been a subject of extensive research regarding its safety and efficacy during pregnancy. Its use is primarily favored due to its oral administration route, lower risk of hypoglycemia, and potential benefits concerning gestational weight gain. However, concerns persist regarding the long-term effects of metformin exposure on offspring health outcomes. As the prevalence of diabetes in pregnancy rises, understanding the implications of metformin use is essential for clinicians and patients alike.

Metformin’s Pharmacological Mechanisms and Placental Transfer

Metformin operates primarily by enhancing insulin sensitivity, reducing hepatic glucose production, and promoting glucose uptake in peripheral tissues. It achieves these effects by activating the AMP-activated protein kinase (AMPK) pathway, which is crucial for maintaining cellular energy balance (Mayadunne et al., 2025).

The placental transfer of metformin occurs primarily through organic cation transporters (OCTs), particularly OCT3, which are expressed at the foetal-facing membrane of the placenta. This transport mechanism allows metformin to reach foetal circulation, raising questions about its potential impacts on developing tissues. Notably, studies have indicated that metformin concentrations can be significantly higher in the foetal circulation compared to maternal blood, suggesting that the foetus may be exposed to pharmacologically active levels of the drug throughout gestation (Mayadunne et al., 2025).

Table 1: Mechanisms of Metformin Action and Transfer

Observational Studies on Offspring Growth and Development

Research on the long-term effects of metformin on offspring health has produced mixed results, with several observational studies exploring growth trajectories, metabolic parameters, and developmental outcomes in children exposed to metformin in utero. A study conducted by Martine-Edith et al. (2023) found no significant differences in growth parameters between children exposed to metformin and those exposed to insulin for GDM treatment. Similarly, Brand et al. (2022) reported that children born to mothers treated with metformin had comparable metabolic profiles and developmental outcomes compared to those born to mothers receiving insulin.

However, some studies have indicated a potential link between metformin exposure and increased adiposity in childhood. For instance, a systematic review and meta-analysis conducted by Tarry-Adkins et al. (2019) suggested that metformin-exposed infants may experience accelerated postnatal growth, leading to higher body mass index (BMI) and increased risk of obesity later in life. Notably, the variability in study designs and populations raises concerns about the consistency and generalizability of these findings.

Table 2: Summary of Key Observational Studies

Randomized Controlled Trials: Long-term Health Impacts

The impact of metformin on offspring has also been examined through randomized controlled trials (RCTs). Follow-up studies from the landmark Metformin in Gestational Diabetes (MiG) trial indicated that metformin exposure did not adversely affect overall childhood growth trajectories. In a Finnish cohort, children exposed to metformin showed no significant differences in metabolic parameters when compared to those exposed to insulin. However, subtle differences in body composition and growth patterns were observed, particularly in boys, suggesting that metformin may influence growth dynamics differently based on sex.

Moreover, the GRoW trial, which involved pregnant women with obesity, indicated that while metformin reduced gestational weight gain, it did not result in significant differences in offspring weight or metabolic outcomes at 18 months and 3–5 years of age. This lack of difference suggests that metformin may not adversely affect long-term health, although careful monitoring is still warranted for potential impacts on BMI and metabolic health.

Table 3: Summary of Key RCT Findings

Conclusion: Implications and Future Research Directions

The current body of evidence regarding the long-term effects of metformin on offspring health remains inconclusive. While metformin is considered safe for use during pregnancy, concerns about its potential impact on growth trajectories and metabolic health persist. The existing studies highlight the need for more extensive, well-designed trials that can address the methodological limitations seen in previous research and provide clearer insights into the long-term implications of metformin exposure.

Future research should prioritize large-scale prospective studies with diverse populations and long-term follow-up to better understand the potential risks and benefits associated with metformin use during pregnancy. Additionally, individual patient data meta-analyses could enhance the statistical power and robustness of findings, allowing for a more comprehensive evaluation of metformin’s effects on offspring health.

Frequently Asked Questions (FAQ)

Is metformin safe to use during pregnancy?

Yes, metformin is generally considered safe for managing diabetes during pregnancy. However, individual assessments are essential to weigh its benefits against potential risks.

What are the potential long-term effects of metformin on children exposed in utero?

Current research suggests that there may be altered growth trajectories and increased adiposity in childhood, though findings are inconsistent.

Are there any significant differences in outcomes between metformin and insulin during pregnancy?

Many studies have shown no significant differences in long-term health outcomes between children exposed to metformin and those exposed to insulin.

What further research is needed regarding metformin use in pregnancy?

Future studies should focus on long-term follow-up of metformin-exposed offspring, including diverse populations and comprehensive health assessments.

How does metformin cross the placenta?

Metformin crosses the placenta mainly through organic cation transporters (OCT3), allowing it to enter foetal circulation and potentially affect the developing fetus.

References

1. Mayadunne, T., Saadati, S., Asmelash, D., Mason, T., Vanky, E., & Teede, H. (2025). Long‐term effects of metformin on offspring health: A review of current evidence and future directions. Diabetes, Obesity and Metabolism, 27(Suppl. 3), 48-63. https://doi.org/10.1111/dom.16418

2. Martine-Edith, G., Johnson, W., Petherick, E. S. (2023). Associations between maternal gestational diabetes metformin or insulin treatment and offspring growth trajectories from birth to 60 months of age: findings from the Born in Bradford (BiB) study. Diabet Med, 40(11), e15204

3. Brand, K. M., Saarelainen, L., Sonajalg, J., et al. (2022). Metformin in pregnancy and risk of adverse long‐term outcomes: a register‐based cohort study. BMJ Open Diabetes Res Care, 10(1), e002363. https://doi.org/10.1136/bmjdrc-2021-002363

4. Tarry‐Adkins, J. L., Aiken, C. E., Ozanne, S. E. (2019). Neonatal, infant, and childhood growth following metformin versus insulin treatment for gestational diabetes: a systematic review and meta‐analysis. PLoS Med, 16(8), e1002848. https://doi.org/10.1371/journal.pmed.1002848

5. Paavilainen, E., Niinikoski, H., Parkkola, R., et al. (2023). Metformin versus insulin for gestational diabetes: adiposity variables and adipocytokines in offspring at age of 9 years. Diabetes Res Clin Pract, 202, 110780. https://doi.org/10.1016/j.diabres.2023.110780

6. Rowan, J. A., Rush, E. C., Plank, L. D. (2023). Metformin in gestational diabetes the offspring follow up (MiGTOFU): associations between maternal characteristics and size and adiposity of boys and girls at nine years. Aust N Z J Obstet Gynaecol, 63(6), 825-828

7. Glueck, C. J., Goldenberg, N., Pranikoff, J., Loftspring, M., Sieve, L., Wang, P. (2004). Height, weight, and motor–social development during the first 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived on and continued metformin through pregnancy. Hum Reprod, 19(6), 1323-1330

8. Xu, Q., Xie, Q. (2025). Long‐term effects of prenatal exposure to metformin on offspring health outcomes: a systematic review and meta-analysis. Diabetes Obes Metab, 27, 48-63. https://doi.org/10.1111/dom.16418

9. Dutta, D., Sharma, M., Nagendra, L., Bhattacharya, S., Mohindra, R., Yajnik, C. S. (2024). Long‐term impact on offspring (5 to 11 years of age) of metformin use in pregnancy in mothers with diabetes: a systematic review and meta‐analysis. Endocr Pract, 30(9), 854-862. https://doi.org/10.1016/j.eprac.2024.05.017

10. Gordon, H. G., Atkinson, J. A., Tong, S., et al. (2024). Metformin in pregnancy and childhood neurodevelopmental outcomes: a systematic review and meta‐analysis. Am J Obstet Gynecol, 231(3), 308-314. https://doi.org/10.1016/j.ajog.2024.02.316