Research progress on the long-term health effects of intrauterine exposure to metformin during pregnancy on offspring

doi:10.3969/j.issn.1006-7795.2026.01.014

Abstract

Abstract: Hyperglycemia in pregnancy is a disorder of carbohydrate metabolism that occurs during pregnancy and is associated with a variety of adverse pregnancy outcomes and an increased risk of long-term maternal and infant metabolic syndrome. Pregnant women with hyperglycemia who do not achieve the blood glucose standard despite lifestyle interventions should receive hypoglycemic drug treatment. Metformin, a classic hypoglycemic drug, has received increasing attention in its application during pregnancy. Current studies show that it has a certain effect on controlling maternal blood glucose, yet its impact on the long-term health of offspring is controversial. This review summarizes the effects of metformin exposure in utero during pregnancy on the obesity, blood pressure, lipid metabolism, endocrine system, reproductive health, and nervous system of offspring, as well as the viewpoints of guidelines from various countries on the application of metformin during pregnancy, thereby facilitating clinicians’ comprehensive understanding of the safety and rationality of metformin application during pregnancy.

Key words: hyperglycemia during pregnancy, , metformin, offspring long-term health, neurodevelopment, reproductive function, metabolism

CLC Number:

R714

Geng Mozhao, Zhao Yue, Zou Liying. Research progress on the long-term health effects of intrauterine exposure to metformin during pregnancy on offspring[J]. Journal of Capital Medical University, 2026, 47(1): 108-114.

References

［1］Sacks D B, Arnold M, Bakris G L, et al. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus［J］. Diabetes Care, 2023, 46(10): e151－e199.
［2］Anon. ACOG practice bulletin No. 190: gestational diabetes mellitus［J］. Obstet Gynecol, 2018, 131(2): e49－e64.
［3］中华医学会妇产科学分会产科学组, 中华医学会围产医学分会, 中国妇幼保健协会妊娠合并糖尿病专业委员会. 妊娠期高血糖诊治指南(2022)（第一部分）［J］. 中华妇产科杂志, 2022, 57(1): 3－12.
［4］中华医学会妇产科学分会产科学组, 中华医学会围产医学分会, 中国妇幼保健协会妊娠合并糖尿病专业委员会. 妊娠期高血糖诊治指南(2022)（第二部分)［J］. 中华妇产科杂志, 2022, 57(2): 81－90.
［5］Boggess K A, Valint A, Refuerzo J S, et al. Metformin plus insulin for preexisting diabetes or gestational diabetes in early pregnancy: the MOMPOD randomized clinical trial［J］. JAMA, 2023, 330(22): 2182－2190.
［6］Rademaker D, De Wit L, Duijnhoven R G, et al. Oral glucose-lowering agents vs insulin for gestational diabetes: a randomized clinical trial［J］. JAMA, 2025, 333(6): 470－478.
［7］Yu Y H, Platt R W, Reynier P, et al. Metformin and risk of adverse pregnancy outcomes among pregnant women with gestational diabetes in the United Kingdom: a population-based cohort study［J］. Diabetes Obes Metab, 2025, 27(2): 976－986.
［8］Mcevoy R P, Newman C, Egan A M, et al. A narrative review of metformin in pregnancy: navigating benefit and uncertainty［J］. Diabetes Obes Metab, 2025, 27(Suppl 3): 16－30.
［9］Given J E, Loane M, Garne E, et al. Metformin exposure in first trimester of pregnancy and risk of all or specific congenital anomalies: exploratory case-control study［J］. BMJ, 2018, 361: k2477.
［10］Bailey C J. Metformin: therapeutic profile in the treatment of type 2 diabetes［J］. Diabetes Obes Metab, 2024, 26 Suppl 3: 3－19.
［11］肖建中. 二甲双胍的作用机制新进展［J］. 中华糖尿病杂志, 2024, 16(7): 735－739.
［12］Foretz M, Guigas B, Viollet B. Metformin: update on mechanisms of action and repurposing potential［J］. Nat Rev Endocrinol, 2023, 19(8): 460－476.
［13］Andrzejewski S, Gravel S P, Pollak M, et al. Metformin directly acts on mitochondria to alter cellular bioenergetics［J］. Cancer Metab, 2014, 2: 12.
［14］Dutta S, Shah R B, Singhal S, et al. Metformin: a review of potential mechanism and therapeutic utility beyond diabetes［J］. Drug Des Devel Ther, 2023, 17: 1907－1932.
［15］LaMoia T E, Shulman G I. Cellular and molecular mechanisms of metformin action［J］. Endocr Rev, 2021, 42(1): 77－96.
［16］Turner R C. The U K Prospective Diabetes Study. A review［J］. Diabetes Care, 1998,21（Suppl 3）:C35－C38.
［17］廖玖江, 漆洪波. 二甲双胍在妊娠期的应用及思考［J］. 中华围产医学杂志, 2024, 27(1): 13－18.
［18］Vanky E, Zahlsen K, Spigset O, et al. Placental passage of metformin in women with polycystic ovary syndrome［J］. Fertil Steril, 2005, 83(5): 1575－1578.
［19］Faure M C, Khoueiry R, Quanico J, et al. In utero exposure to metformin reduces the fertility of male offspring in adulthood［J］. Front Endocrinol, 2021, 12: 34745014.
［20］Bolte E, Dean T, Garcia B, et al. Initiation of metformin in early pregnancy results in fetal bioaccumulation, growth restriction, and renal dysmorphology in a primate model［J］. Am J Obstet Gynecol, 2024, 231(3): 352.e1－352.e16.
［21］Ijäs H, Vääräsmäki M, Saarela T, et al. 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［J］. BJOG, 2015, 122(7): 994－1000.
［22］Rowan J A, Rush E C, Obolonkin V, et al. Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition at 2 years of age［J］. Diabetes Care, 2011, 34(10): 2279－2284.
［23］Rowan J A, Rush E C, Plank L D, et al. Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition and metabolic outcomes at 7－9 years of age［J］. BMJ Open Diabetes Res Care, 2018, 6(1): e000456.
［24］Tarry-Adkins J L, Aiken C E. Neonatal, infant, and childhood growth following metformin versus insulin treatment for gestational diabetes: a systematic review and meta-analysis［J］. PLoS Med, 2019, 16(8): e1002848.
［25］Rawat D, Gupta Y, Yadav A K, et al. Cardiometabolic outcomes in offspring of women treated with metformin versus insulin for gestational diabetes: a systematic review and meta-analysis［J］. Diabetes Metab Syndr, 2024, 18(9): 103134.
［26］Brand K M G, Saarelainen L, Sonajalg J, et al. Metformin in pregnancy and risk of adverse long-term outcomes: a register-based cohort study［J］. BMJ Open Diabetes Res Care, 2022, 10(1): e002363.
［27］Dutta D, Sharma M, Nagendra L, et al. 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［J］. Endocr Pract, 2024, 30(9): 854－862.
［28］Panagiotopoulou O, Syngelaki A, Georgiopoulos G, et al. Metformin use in obese mothers is associated with improved cardiovascular profile in the offspring［J］. Am J Obstet Gynecol, 2020, 223(2): 246.e1－246.e10.
［29］Tosti G, Barberio A, Tartaglione L, et al. Lights and shadows on the use of metformin in pregnancy: from the preconception phase to breastfeeding and beyond［J］. Front Endocrinol, 2023, 14: 1176623.
［30］李兰, 冉兴无. 二甲双胍宫内暴露对子代心血管系统影响的研究进展［J］. 中华医学杂志, 2025, 105(11): 855－860.
［31］Feig D S, Sanchez J J, Murphy K E, et al. Outcomes in children of women with type 2 diabetes exposed to metformin versus placebo during pregnancy (MiTy Kids): a 24-month follow-up of the MiTy randomised controlled trial［J］. Lancet Diabetes Endocrinol, 2023, 11(3): 191－202.
［32］Paschou SA, Shalit A, Gerontiti E, et al. Efficacy and safety of metformin during pregnancy: an update［J］. Endocrine, 2024,83(2):259－269.
［33］Mason T, Alesi S, Fernando M, et al. Metformin in gestational diabetes: physiological actions and clinical applications［J］. Nat Rev Endocrinol, 2025, 21(2): 77－91.
［34］Francisca S, Gloria A F, Marco P B, et al. Metformin exposure during pregnancy and lactation affects offsprings long-term body weight and adipose tissue mass Independent of the maternal metabolic state［J］. Biochim Biophys Acta Mol Basis Dis, 2024, 1870(6): 167258.
［35］Feig D S. Metformin for diabetes in pregnancy: are we closer to defining its role?［J］. JAMA, 2023, 330(22): 2167－2169.
［36］Hanem L G E, Salvesen Ø, Madsen A, et al. Maternal PCOS status and metformin in pregnancy: steroid hormones in 5－10 years old children from the PregMet randomized controlled study［J］. PLoS One, 2021, 16(9): e0257186.
［37］Carlsen S M, Vanky E. Metformin influence on hormone levels at birth, in PCOS mothers and their newborns［J］. Hum Reprod, 2010, 25(3): 786－790.
［38］Forcato S, Montagnini B G, De Góes M L M, et al. Reproductive evaluations in female rat offspring exposed to metformin during intrauterine and intrauterine/lactational periods［J］. Reprod Toxicol, 2019, 87: 1－7.
［39］Forcato S, Novi D R B D S, Costa N O, et al. In utero and lactational exposure to metformin induces reproductive alterations in male rat offspring［J］. Reprod Toxicol, 2017, 74: 48－58.
［40］Tartarin P, Moison D, Guibert E, et al. Metformin exposure affects human and mouse fetal testicular cells［J］. Hum Reprod, 2012, 27(11): 3304－3314.
［41］Tseng C H. The effect of metformin on male reproductive function and prostate: an updated review［J］. World J Mens Health, 2022, 40(1): 11－29.
［42］Rozance P J, Brown L D, Wesolowski S R. Absence of metformin in fetal circulation following maternal administration in late gestation pregnant sheep［J］. Reprod Sci, 2024, 31(6): 1763－1766.
［43］Oner M, Cheng P T, Wang H Y, et al. Metformin alters dendrite development and synaptic plasticity in rat cortical neurons［J］. Biochem Biophys Res Commun, 2024, 710: 149874.
［44］Oner M, Chen M C, Cheng P T, et al. Impact of metformin on neocortical development during pregnancy: Involvement of ERK and p35/CDK5 pathways［J］. Chemosphere, 2024, 358: 142124.
［45］Greger H K, Hanem L G E, Østgård H F, et al. Cognitive function in metformin exposed children, born to mothers with PCOS-follow-up of an RCT［J］. BMC Pediatr, 2020, 20(1): 60.
［46］Wouldes T A, Battin M, Coat S, et al. Neurodevelopmental outcome at 2 years in offspring of women randomised to metformin or insulin treatment for gestational diabetes［J］. Arch Dis Child Fetal Neonatal Ed, 2016, 101(6): F488－F493. ［47］Gordon H G, Atkinson J A, Tong S, et al. Metformin in pregnancy and childhood neurodevelopmental outcomes: a systematic review and meta-analysis［J］. Am J Obstet Gynecol, 2024, 231(3): 308－314, e6.
［48］Dashtkoohi M, Noorafrooz M, Hantoushzadeh S. Concerns regarding the safety of metformin use in pregnancy［J］. Am J Obstet Gynecol, 2025, 232(3): e113.
［49］Anon. Diabetes in pregnancy: management from preconception to the postnatal period［M］. London: National Institute for Health and Care Excellence (NICE), 2020.
［50］Queensland Health. Gestational diabetes mellitus (GDM)［EB/OL］. ［2025-09-01］. https://www.health.qld.gov.au/qcg.
［51］Anon. Management of diabetes in pregnancy: standards of care in diabetes－2025［J］. Diabetes Care, 2025,48(1 Suppl 1):S306－S320.
［52］Venkatesh K K, MacPherson C, Clifton R G, et al. Comparative effectiveness trial of metformin versus insulin for the treatment of gestational diabetes in the USA: clinical trial protocol for the multicentre DECIDE study［J］. BMJ Open, 2024, 14(9): e091176.

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