EC Gynaecology

Metformin is the most commonly used medication for the treatment of Type II diabetes mellitus worldwide. Currently, the prescription of this drug in other entities is described, which may lead to repositioning or readaptation of the drug. Internationally, the use of this medication during pregnancy has increased significantly in recent decades, because it is relatively cheap, easy to administer, and is associated with clear benefits as a treatment for hyperglycemia during pregnancy. However, it is known that it has an effect on the monocarbon metabolic pathway similar to that of folic acid antagonist drugs, a micronutrient that is essential to achieve adequate levels of DNA methylation necessary during the morphogenesis process. A bibliographic review was carried out in September 2023, based on chronological and thematic criteria, both for scientific monographs and for articles published in national and international medical journals, in Spanish and English. For this purpose, the Google Scholar search engine was used and the databases were consulted: PubMed, Medline, Bireme (Scielo, Lilacs and Cochrane) with the objective of describing the association between the use of metformin and possible adverse outcomes in the product of pregnancy, detail the off-label use of this drug in other clinical entities and describe the genetic and epigenetic mechanisms that underlie the folic acid antagonism described in this. Regarding possible off label indications, researchers are studying metformin for its potential anti-aging, anti-cancer, and immunomodulation effects. This activity warrants a comprehensive review of the indications, precautions, and potential adverse effects of metformin during pregnancy due to its antifolate effect.

 Keywords: Metformin; Type II Diabetes Mellitus; Gestational Diabetes Mellitus; Polycystic Ovary Syndrome; COVID 19; Epigenetic Mechanisms; Epigenetics

1. Foretz M., et al. “Metformin: update on mechanisms of action and repurposing potential”. Nature Reviews Endocrinology 19 (2023): 460-476.
2. Brand KMG., et al. “Metformin in pregnancy and risk of adverse long-term outcomes: a register-based cohort study”. BMJ Open Diabetes Research and Care 10 (2022): e002363.
3. Tarry-Adkins JL., et al. “Neonatal, infant and childhood growth following metformin versus insulin treatment for gestational diabetes: A systematic review and meta-analysis”. PLOS Medicine8 (2019): e1002848.
4. Foretz M., et al. “Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus”. Nature Reviews Endocrinology 15 (2020): 569-589.
5. Triggle CR., et al. “Metformin: Is it a drug for all reasons and diseases?” Metabolism (2022): 133.
6. Food and Drugs Administration Metformin (2023).
7. Taboada N. “Regarding the article “Metformin, a therapeutic reality in the treatment of gestational diabetes mellitus”. Acta Medica Centro2 (2023).
8. Hernández M., et al. “Metformina, a therapeutic reality in the treatment of gestational diabetes mellitus”. Acta Medica Centro22 (2022): 374-377.
9. Durántez A. “Metformin: a new anti-aging strategy”. Feed (2020).
10. Lindsay RS and Loeken MR. “Metformin use in pregnancy: promises and uncertainties”. Diabetology 60 (2017): 1612-1619.
11. Brand KMG., et al. “Metformin in pregnancy and risk of abnormal growth outcomes at birth: a register-based cohort study”. BMJ Open Diabetes Research and Care 10 (2022): e003056.
12. Lin S., et al. “Association of pregnancy outcomes in women with type 2 diabetes treated with metformin versus insulin when becoming pregnant”. BMC Pregnancy and Childbirth1 (2020): 512.
13. Landi SN., et al. “Association of long-term child growth and developmental outcomes with metformin vs insulin treatment for gestational diabetes”. The Journal of the American Medical Association Pediatrics 173 (2020): 160-168.
14. Wensink MJ., et al. “Preconception antidiabetic drugs in men and birth defects in offspring: A nationwide cohort study”. Annals of Internal Medicine5 (2023): 665-673.
15. Speranza N and Tomosiunas G. “Use of off-label medications. Off-label use of medications: a necessary evil?” Pharmacology Bulletin2 (2016).
16. Martin-Montalvo A., et al. “An epigenetic aging analysis of randomized metformin and weight loss interventions in overweight postmenopausal breast cancer survivors”. Clinical Epigenetics 13 (2021): 224.
17. Kulkarni AS., et al. “Benefits of Metformin in attenuating the hallmarks of aging”. Cell Metabolism 32 (2020): 15-30.
18. Kim D., et al. “Metformin reduces histone H3K4me3 at the promoter regions of positive cell cycle regulatory genes in lung cancer cells”. Cancers 3 (2021): 739.
19. Villegas CA., et al. “New evidence of the use of metformin in the treatment of cancer”. Revista Cubana de Endocrinologia3 (2016).
20. Ma T., et al. “Low dose metformin targets the lysosomal AMPK pathway through PEN2”. Nature 603 (2022): 159-165.
21. Broadfield LA., et al. “Metformin-induced reductions in tumor growth involve modulation of the gut microbiome”. Molecular Metabolism 61 (2022): 101498.
22. Fornes R., et al. “Pregnancy, perinatal and childhood outcomes in women with and without polycystic ovary syndrome and metformin during pregnancy: a nationwide population-based study”. Reproductive Biology and Endocrinology 20 (2022): 30-42.
23. Bahri Khomami M., et al. “Increased maternal pregnancy complications in polycystic ovary syndrome appear to be independent of obesity-a systematic review, meta-analysis, and meta-regression”. Obesity Reviews5 (2019): 659-674.
24. Bahri Khomami M., et al. “The role of maternal obesity in infant outcomes in polycystic ovary syndrome-a systematic review, meta-analysis, and meta-regression”. Obesity Reviews6 (2019): 842-858.
25. Bharath LP., et al. “Metformin enhances autophagy and normalizes mitochondrial function to alleviate aging-associated inflammation”. Cell Metabolism 32 (2020): 44-55.
26. Alique M., et al. “Hypoxia-Inducible Factor-1α: The master regulation of endothelial cell senescence in vascular aging”. Cells 9 (2020): 195.
27. Bhansali S., et al. “Metformin promotes mitophagy in mononuclear cells: a potential in vitro model for unraveling metformin's mechanism of action”. Annals of the New York Academy of Sciences 1463 (2020): 23-36.
28. De Marañón AM., et al. “Metformin modulates mitochondrial function and mitophagy in peripheral blood mononuclear cells from type 2 diabetic patients”. Redox Biology 53 (2022): 102342.
29. Xiong W., et al. “Metformin alleviates inflammation through suppressing FASN-dependent palmitoylation of Akt”. Cell Death and Disease 12 (2021): 934.
30. Xian H., et al. “Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation”. Immunity 54 (2021): 1463-1477.
31. Taboada Lugo N. “Role of folic acid, zinc and copper in the primary prevention of congenital defects”. Revista Cubana de Medicina General Integral4 (2018).
32. Taboada Lugo N. “Herrera Martínez M. Epigenetic mechanisms and Notch signaling pathway in the origin of different congenital defects”. Medicen Electron3 (2018).
33. Taboada Lugo N. “Epigenetic factors involved in the origin of congenital defects related to maternal deficiency of folic acid and other micronutrients”. ACT Medical Center3 (2019).
34. Marra PS., et al. “Metformin use history and genome-wide DNA methylation profile: potential molecular mechanism for aging and longevity”. Aging3 (2023).
35. Taboada Lugo N. “Genetic and environmental factors in mothers with offspring affected by folate-sensitive congenital defects in Villa Clara”. Villa Clara University of Medical Sciences. Doctoral Thesis (2022).
36. Dai C., et al. “A novel review of homocysteine and pregnancy complications”. BioMed Research International (2021).
37. Vidmar G., et al. “Folate insufficiency due to MTHFR deficiency is bypassed by 5-Methyltetrahydrofolate”. Journal of Clinical Medicine 9 (2020): 2836-2854.
38. Shi H., et al. “Study on maternal SNPs of MTHFR gene and HCY level related to congenital heart diseases”. Pediatric Cardiology1 (2021): 42-46.
39. Brand KMG., et al. “Metformin in pregnancy and risk of adverse long-term outcomes: a register-based cohort study”. BMJ Open Diabetes Research and Care1 (2022): e002363.