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Current Clinical Pharmacology


ISSN (Print): 1574-8847
ISSN (Online): 2212-3938

Review Article

Metformin and Pregnancy Outcomes: Evidence Gaps and Unanswered Questions

Author(s): Claudio D. Gonzalez, Jorge Alvariñas, Maria F.G. Bagnes and Guillermo Di Girolamo*

Volume 14 , Issue 1 , 2019

Page: [54 - 60] Pages: 7

DOI: 10.2174/1574884714666181224151116


Background: Metformin is sometimes used as an alternative to insulin in gestational diabetes mellitus (GDM). It is also used to achieve ovulation in polycystic ovary syndrome (PCOS). Pre-natal exposure to metformin results from its continuation after a successful ovulation in women with PCOS, its maintenance in women with pre-gestational diabetes or the installation of metformin in GDM. Little is known about the potential consequences of metformin exposure on pregnancy outcomes and offspring development. The aim of this review is to summarize the metformin effects on pregnancy outcomes and offspring development. Gaps in the available evidence and unanswered questions are also discussed.

Methods: A comprehensive literature search was carried out to identify eligible studies from MEDLINE/PubMed, EMBASE and SCIELO databases through 1995 first semester.

Results: Several factors limit the effect of metformin on embryos. In contrast, placental transport of metformin is effective allowing for a higher fetal exposure; the impact of this finding remains unclear. It seems that the interruption of metformin after a pregnancy diagnosis in women with PCOS is not associated with a higher miscarriage risk and it continuation does not seem to impair the maternal metabolic prognosis or prevent emerging GDM.

Conclusions: It seems to have no sense to prolong the use of metformin after a pregnancy diagnosis in women with PCOS. Patients with GDM may be treated with metformin under on judicious basis, and a careful attachment to clinical guidelines and regulations is recommended. The long-term effects of pre-natal exposure to metformin on the offspring remain uncertain.

Keywords: Metformin, gestational diabetes mellitus, polycystic ovary syndrome, pregnancy outcomes, hypertension, preeclampsia.

Graphical Abstract
Bailey CJ. Metformin: Historial overview. Diabetologia 2017; 60: 1566-76.
Lindsay RS, Loeken MR. Metformin use in pregnancy: Promises and uncertainties. Diabetologia 2017; 60: 1612-9.
DeSisto CL, Kim SY, Sharma AJ. Prevalence Estimates of Gestational Diabetes Mellitus in the United States, Pregnancy Risk Assessment Monitoring System (PRAMS), 2007-2010. Prev Chronic Dis 2014; 11: E104.
International Diabetes Federation (IDF). Diabetes Atlas7th Edition 2015. (Accessed on Oct 10, 2018)
Lazaridou S, Dinas K, Tziomalos K. Prevalence, pathogenesis and management of prediabetes and type 2 diabetes mellitus in patients with polycystic ovary syndrome. Hormones (Athens) 2017; 16: 373-80.
Barbour LA, Scifres C, Valent AM, et al. A cautionary response to SMFM statement: Pharmacological treatment of gestational diabetes. Am J Obstet Gynecol 2018; 219: 367-72.
Priya G, Kalra S. Metformin in the management of diabetes during pregnancy and lactation. Drugs Context 2018; 7: 1-22.
Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia 2017; 60: 1577-85.
Tanbo T, Mellembakken J, Bjercke S, Ring E, Åbyholm T, Fedorcsak P. Ovulation induction in polycystic ovary syndrome. Acta Obstet Gynecol Scand 2018; 97: 1162-7.
Practice Committee of the American Society for Reproductive Medicine Role of metformin for ovulation induction in infertile patients with Polycystic Ovary Syndrome (PCOS): A guideline. Fertil Steril 2017; 108: 426-41.
Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000; 348: 607-14.
Cao J, Meng S, Chang E, et al. Low concentrations of metformin suppress glucose production in hepatocytes through AMP-activated Protein Kinase (AMPK). J Biol Chem 2014; 289: 20435-46.
Fullerton MD, Galic S, Marcinko K, et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med 2013; 19: 1649-54.
Gough NR. Placing the nuclear pore in the metformin mechanism of actionSci Signal 2017. 10(460): eaam6836.
Gonzalez CD, Lee MS, Marchetti P, et al. The emerging role of autophagy in the pathophysiology of diabetes mellitus. Autophagy 2011; 7: 2-11.
Luciano-Mateo F, Hernandez-Aguilera A, Cabre N, et al. Nutrients in energy and one-carbon metabolism: learning from metformin users. Nutrients 2017; 9: 1-19.
Nanovskaya TN, Nekhayeva IA, Patrikeeva SL, Hankins GD, Ahmed MS. Transfer of metformin across the dually perfused human placental lobule. Am J Obstet Gynecol 2006; 195: 1081-5.
Lee N, Hebert MF, Wagner DJ, et al. Organic cation transporter 3 facilitates fetal exposure to metformin during pregnancy. Mol Pharmacol 2018; 94: 1125-31.
Holland O, Dekker Nitert M, Gallo LA, Vejzovic M, Fisher JJ, Perkins AV. Placental mitochondrial function and structure in gestational disorders. Placenta 2017; 54: 2-9.
Romero R, Erez O, Hüttemann M, et al. Metformin, the aspirin of the 21st century: Its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity. Am J Obstet Gynecol 2017; 217: 282-302.
Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000; 348: 607-14.
Salvesen KA, Vanky E, Carlsen SM. Metformin treatment in pregnant women with polycystic ovary syndrome is reduced complication rate mediated by changes in the uteroplacental circulation? Ultrasound Obstet Gynecol 2007; 29: 433-7.
Jamal A, Milani F, Al-Yasin A. Evaluation of the effect of metformin and aspirin on utero placental circulation of pregnant women with PCOS. Iran J Reprod Med 2012; 10: 265-70.
Stridsklev S, Salvesen Ø, Salvesen KÅ, Carlsen SM, Vanky E. Uterine artery doppler in pregnancy: Women with PCOS compared to healthy controls. Int J Endocrinol 2018; 2018: 2604064.
Cassina M, Donà M, Di Gianantonio E, Litta P, Clementi M. First-trimester exposure to metformin and risk of birth defects: A systematic review and meta-analysis. Hum Reprod Update 2014; 20: 656-69.
Vanky E, Stridsklev S, Heimstad R, et al. Metformin versus placebo from first trimester to delivery in polycystic ovary syndrome: A randomized, controlled multicenter study. J Clin Endocrinol Metab 2010; 95: E448-55.
Hjorth-Hansen A, Salvesen Ø, Engen Hanem LG, et al. Fetal Growth and birth anthropometrics in metformin-exposed offspring born to mothers with PCOS. J Clin Endocrinol Metab 2018; 103: 740-7.
Hanem LGE, Stridsklev S, Júlíusson PB, et al. Metformin use in PCOS pregnancies increases the risk of offspring overweight at 4 years of age: Follow-up of two RCTs. J Clin Endocrinol Metab 2018; 103: 1612-21.
Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: From mechanisms of action to therapies. Cell Metab 2014; 20: 953-66.
Sinclair KD, Lea RG, Rees WD, Young LE. The developmental origins of health and disease: Current theories and epigenetic mechanisms. Soc Reprod Fertil Suppl 2007; 64: 425-43.
Glueck CJ, Goldenberg N, Pranikoff J, Loftspring M, Sieve L, Wang P. 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 2004; 19: 1323-30.
Feng L, Lin XF, Wan ZH, Hu D, Du YK. Efficacy of metformin on pregnancy complications in women with polycystic ovary syndrome: A meta-analysis. Gynecol Endocrinol 2015; 31: 833-9.
Scherneck S, Schlinke N, Beck E, Grupe K, Weber-Schoendorfer C, Schaefer C. Pregnancy outcome after first-trimester exposure to metformin: A prospective cohort study. Reprod Toxicol 2018; 81: 79-83.
Underdal MO, Stridsklev S, Oppen IH, Høgetveit K, Andersen MS, Vanky E. Does metformin treatment during pregnancy modify the future metabolic profile in women with PCOS? J Clin Endocrinol Metab 2018; 103: 2408-13.
Valdez E, Sepulveda-Martinez A, Candia P, et al. Metformin as a prophylactic treatment of gestational diabetes in pregnant patients with pregestational insulin resistance: A randomized study. J Obstet Gynaecol Res 2018; 44: 81-6.
Rowan JA, Hague WM, Gao W, Battin MR, Moore MP. MiG Trial investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008; 358: 2003-15.
Rowan JA, Rush EC, Plank LD, et al. Metformin in gestational diabetes: The offspring follow-up (MiG TOFU): Body composition and metabolic outcomes at 7-9 years of age. BMJ Open Diabetes Res Care 2018; 6: e000456.
Ijas H, Vaarasmaki M, Saarela T, Keravuo R, Raudaskoski T. A follow-up of a randomised study of metformin and insulin in gestational diabetes mellitus: Growth and development of the children at the age of 18 months. BJOG 2015; 122: 994-1000.
Niromanesh S, Alavi A, Sharbaf FR, Amjadi N, Moosavi S, Akbari S. Metformin compared with insulin in the management of gestational diabetes mellitus: A randomized clinical trial. Diabetes Res Clin Pract 2012; 98: 422-9.
Mesdaghinia E, Samimi M, Homaei Z, Saberi F, Moosavi SGA, Yaribakht M. Comparison of newborn outcomes in women with gestational diabetes mellitus treated with metformin or insulin: A randomised blinded trial. Int J Prev Med 2013; 4: 327-33.
Ainuddin J, Karim N, Hasan AA, Naqvi SA. Metformin versus insulin treatment in gestational diabetes in pregnancy in a developing country: A randomized control trial. Diabetes Res Clin Pract 2015; 107: 290-9.
Su DF, Wang XY. Metformin vs insulin in the management of gestational diabetes: A systematic review and meta-analysis. Diabetes Res Clin Pract 2014; 104: 353-7.
Sam S, Ehrmann DA. Metformin therapy for the reproductive and metabolic consequences of polycystic ovary syndrome. Diabetologia 2017; 60: 1656-61.
Davies MJ, D’Alessio DA, Fradkin J, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2018; 41: 2669-701.

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