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Effective treatments are essential to prevent the transmission of poor metabolic health from mother to child. Metformin is an effective glucose lowering drug commonly used to treat gestational diabetes mellitus; however, its wider effects on maternal and fetal health are poorly explored. In this study we used a mouse (C57Bl6\/J) model of diet\u2010induced (high sugar\/high fat) maternal obesity to explore the impact of metformin on maternal and feto\u2010placental health. Metformin (300\u00a0mg\u00a0kg<jats:sup>\u22121<\/jats:sup>\u00a0day<jats:sup>\u22121<\/jats:sup>) was given to obese females via the diet and was shown to achieve clinically relevant concentrations in maternal serum (1669\u00a0\u00b1\u00a0568\u00a0nM in late pregnancy). Obese dams developed glucose intolerance during pregnancy and had reduced uterine artery compliance. Metformin treatment of obese dams improved maternal glucose tolerance, reduced maternal fat mass and restored uterine artery function. Placental efficiency was reduced in obese dams, with increased calcification and reduced labyrinthine area. Consequently, fetuses from obese dams weighed less (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) at the end of gestation. Despite normalisation of maternal parameters, metformin did not correct placental structure or fetal growth restriction. Metformin levels were substantial in the placenta and fetal circulation (109.7\u00a0\u00b1\u00a0125.4\u00a0nmol\u00a0g<jats:sup>\u22121<\/jats:sup> in the placenta and 2063\u00a0\u00b1\u00a02327\u00a0nM in fetal plasma). These findings reveal the distinct effects of metformin administration during pregnancy on mother and fetus and highlight the complex balance of risk <jats:italic>vs<\/jats:italic>. benefits that are weighed in obstetric medical treatments.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Maternal obesity and gestational diabetes mellitus have detrimental short\u2010 and long\u2010term effects for mother and child.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Metformin is commonly used to treat gestational diabetes mellitus in many populations worldwide but the effects on fetus and placenta are unknown.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In a mouse model of diet\u2010induced obesity and glucose intolerance in pregnancy we show reduced uterine artery compliance, placental structural changes and reduced fetal growth.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Metformin treatment improved maternal metabolic health and uterine artery compliance but did not rescue obesity\u2010induced changes in the fetus or placenta. Metformin crossed the placenta into the fetal circulation and entered fetal tissue.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Metformin has beneficial effects on maternal health beyond glycaemic control. However, despite improvements in maternal physiology, metformin did not prevent fetal growth restriction or placental ageing. The high uptake of metformin into the placental and fetal circulation highlights the potential for direct immediate effects of metformin on the fetus with possible long\u2010term consequences postnatally.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp281902","type":"journal-article","created":{"date-parts":[[2021,9,10]],"date-time":"2021-09-10T08:11:36Z","timestamp":1631261496000},"page":"903-919","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Maternal but not fetoplacental health can be improved by metformin in a murine diet\u2010induced model of maternal obesity and glucose intolerance"],"prefix":"10.1113","volume":"600","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7030-4419","authenticated-orcid":false,"given":"Antonia","family":"Hufnagel","sequence":"first","affiliation":[{"name":"Wellcome Trust\u2010MRC Institute of Metabolic Science Level 4, Addenbrooke's Hospital 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