{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T16:32:22Z","timestamp":1787157142465,"version":"build-2736575974"},"reference-count":50,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Clin. Med.","JCM"],"abstract":"<jats:p>Background: Hypertensive disorders of pregnancy (HDP), particularly gestational hypertension and preeclampsia, are major causes of maternal and perinatal morbidity. Metabolic disorders such as gestational diabetes mellitus (GDM), type 2 diabetes mellitus (T2DM), obesity, and polycystic ovary syndrome (PCOS) share mechanisms with HDP, including insulin resistance, inflammation, oxidative stress, endothelial dysfunction, and placental maladaptation. Metformin may influence these pathways, but its clinical effect on hypertensive outcomes remains uncertain. Methods: A focused narrative review was conducted using structured, targeted searches of PubMed\/MEDLINE, Scopus, Web of Science, and Google Scholar for literature published primarily from January 2015 through March 2026, supplemented by landmark studies, clinical guidelines, randomized trials, large observational cohorts, systematic reviews, meta-analyses, and mechanistic and placental studies. Evidence was selected for its relevance to the predefined phenotype-based framework and synthesized qualitatively across mechanistic, clinical, and translational domains. Results: Metformin improves insulin sensitivity and may reduce gestational weight gain, metabolic stress, inflammatory signaling, and oxidative stress. Some randomized trials and meta-analyses in GDM, obesity, and PCOS suggest lower rates of pregnancy-induced hypertension or preeclampsia, whereas recent randomized and population-based studies report neutral effects. Findings are limited by heterogeneous populations, late treatment initiation, variable comparators, supplemental insulin use, inconsistent HDP definitions, and insufficient statistical power. Conclusions: Metformin may act as a metabolic and vascular modifier in selected pregnancies, but current evidence does not support its routine use specifically for HDP prevention. Its public health value lies primarily in accessible metabolic treatment and integration into comprehensive antenatal and postpartum risk reduction pathways, rather than replacement of aspirin, blood pressure surveillance, or maternal\u2013fetal monitoring.<\/jats:p>","DOI":"10.3390\/jcm15166423","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T16:12:58Z","timestamp":1787155978000},"page":"6423","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metformin and Hypertensive Disorders of Pregnancy: A Phenotype-Based Focused Narrative Review"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9176-9736","authenticated-orcid":false,"given":"Katarina","family":"Ivanovic","sequence":"first","affiliation":[{"name":"Clinic for Gynecology and Obstetrics, University Clinical Centre of Serbia, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5292-0595","authenticated-orcid":false,"given":"Stefan","family":"Dugalic","sequence":"additional","affiliation":[{"name":"Clinic for Gynecology and Obstetrics, University Clinical Centre of Serbia, 11000 Belgrade, Serbia"},{"name":"Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7926-3916","authenticated-orcid":false,"given":"Miroslava","family":"Gojnic Dugalic","sequence":"additional","affiliation":[{"name":"Clinic for Gynecology and Obstetrics, University Clinical Centre of Serbia, 11000 Belgrade, Serbia"},{"name":"Faculty of Medicine, University of Belgrade, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1822-0314","authenticated-orcid":false,"given":"Milos","family":"Milincic","sequence":"additional","affiliation":[{"name":"Clinic for Gynecology and Obstetrics, University Clinical Centre of Serbia, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/ijgo.12802","article-title":"The International Federation of Gynecology and Obstetrics (FIGO) initiative on pre-eclampsia: A pragmatic guide for first-trimester screening and prevention","volume":"145","author":"Poon","year":"2019","journal-title":"Int. J. Gynecol. Obstet."},{"key":"ref_2","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.preghy.2021.09.008","article-title":"The 2021 International Society for the Study of Hypertension in Pregnancy classification, diagnosis and management recommendations for international practice","volume":"27","author":"Magee","year":"2022","journal-title":"Pregnancy Hypertens."},{"key":"ref_3","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1161\/res.0000000000000315","article-title":"Preeclampsia: Pathophysiology, challenges, and perspectives","volume":"124","author":"Rana","year":"2019","journal-title":"Circ. Res."},{"key":"ref_4","doi-asserted-by":"publisher","first-page":"101127","DOI":"10.1016\/j.preghy.2024.101127","article-title":"Hypertensive disorders of pregnancy and long-term maternal cardiovascular risk: Bridging epidemiological knowledge into personalized postpartum care and follow-up","volume":"36","author":"Staff","year":"2024","journal-title":"Pregnancy Hypertens."},{"key":"ref_5","doi-asserted-by":"publisher","first-page":"103395","DOI":"10.1016\/j.eclinm.2025.103395","article-title":"The effect of maternal pre-pregnancy body mass index on hypertensive disorders of pregnancy (HDP): A systematic review and dose-response meta-analysis of cohort studies involving 50 million pregnancies","volume":"86","author":"Xiong","year":"2025","journal-title":"eClinicalMedicine"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5591","DOI":"10.1038\/s41467-024-49749-1","article-title":"Increased maternal pregnancy complications in polycystic ovary syndrome appear to be independent of obesity\u2014A systematic review, meta-analysis, and meta-regression","volume":"15","author":"Joham","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_7","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1002\/uog.19084","article-title":"Metformin for prevention of hypertensive disorders of pregnancy in women with gestational diabetes or obesity: Systematic review and meta-analysis of randomized trials","volume":"52","author":"Kalafat","year":"2018","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_8","doi-asserted-by":"publisher","first-page":"9240","DOI":"10.1038\/s41598-021-88650-5","article-title":"Impact of metformin treatment during pregnancy on maternal outcomes: A systematic review and meta-analysis","volume":"11","author":"Ozanne","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_9","doi-asserted-by":"publisher","unstructured":"Gordon, H., Salim, N., Tong, S., Walker, S., De Silva, M., Cluver, C., Mehdipour, P., Hiscock, R., Sutherland, L.D., and Doust, A. (2024). Metformin use and preeclampsia risk in women with diabetes: A two-country cohort analysis. BMC Med., 22.","DOI":"10.1186\/s12916-024-03628-0"},{"key":"ref_10","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1001\/jama.2024.23410","article-title":"Oral glucose-lowering agents vs insulin for gestational diabetes: A randomized clinical trial","volume":"333","author":"Rademaker","year":"2025","journal-title":"JAMA"},{"key":"ref_11","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s41073-019-0064-8","article-title":"SANRA\u2014A scale for the quality assessment of narrative review articles","volume":"4","author":"Baethge","year":"2019","journal-title":"Res. Integr. Peer Rev."},{"key":"ref_12","doi-asserted-by":"publisher","first-page":"356.e1","DOI":"10.1016\/j.ajog.2015.12.019","article-title":"Metformin as a prevention and treatment for preeclampsia: Effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction","volume":"214","author":"Brownfoot","year":"2016","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_13","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.placenta.2021.02.021","article-title":"Metformin and biomarkers of placental disease: A systematic review","volume":"105","author":"Anness","year":"2021","journal-title":"Placenta"},{"key":"ref_14","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.preghy.2021.12.003","article-title":"Clinical interpretation and implementation of the sFlt-1\/PlGF ratio in the prediction, diagnosis and management of preeclampsia","volume":"27","author":"Verlohren","year":"2022","journal-title":"Pregnancy Hypertens."},{"key":"ref_15","doi-asserted-by":"publisher","unstructured":"Nashif, S.K., Mahr, R.M., Jena, S., Jo, S., Nelson, A.B., Sadowski, D., Crawford, P., Puchalska, P., Alejandro, E., and Gearhart, M.D. (2023). Metformin impairs trophoblast metabolism and differentiation in a dose-dependent manner. Front. Cell Dev. Biol., 11.","DOI":"10.3389\/fcell.2023.1167097"},{"key":"ref_16","doi-asserted-by":"publisher","first-page":"2491454","DOI":"10.1080\/14767058.2025.2491454","article-title":"Maternal and cord serum levels of sFlt-1 and PlGF in pregnancies complicated by gestational diabetes mellitus: A prospective cohort study","volume":"38","author":"Kirtis","year":"2025","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_17","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1097\/01.ftd.0000184161.52573.0e","article-title":"Population pharmacokinetics of metformin in late pregnancy","volume":"28","author":"Charles","year":"2006","journal-title":"Ther. Drug Monit."},{"key":"ref_18","doi-asserted-by":"publisher","unstructured":"Tarry-Adkins, J.L., Robinson, I.G., Reynolds, R.M., Aye, I.L.M.H., Charnock-Jones, D.S., Jenkins, B., Koulmann, A., Ozanne, S.E., and Aiken, C.E. (2022). Impact of metformin treatment on human placental energy production and oxidative stress. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.935403"},{"key":"ref_19","doi-asserted-by":"publisher","unstructured":"Tarry-Adkins, J.L., Aiken, C.E., and 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.","DOI":"10.1371\/journal.pmed.1002848"},{"key":"ref_20","doi-asserted-by":"publisher","first-page":"e002363","DOI":"10.1136\/bmjdrc-2021-002363","article-title":"Metformin in pregnancy and risk of adverse long-term outcomes: A register-based cohort study","volume":"10","author":"Brand","year":"2022","journal-title":"BMJ Open Diabetes Res. Care"},{"key":"ref_21","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.ajog.2024.02.316","article-title":"Intrauterine metformin exposure and childhood neurodevelopmental outcomes: A systematic review and meta-analysis","volume":"231","author":"Gordon","year":"2024","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1001\/jama.2023.19869","article-title":"Early metformin in gestational diabetes: A randomized clinical trial","volume":"330","author":"Dunne","year":"2023","journal-title":"JAMA"},{"key":"ref_23","doi-asserted-by":"publisher","first-page":"2293046","DOI":"10.1080\/14767058.2023.2295809","article-title":"A meta-analysis of metformin and insulin on maternal and neonatal outcomes in patients with gestational diabetes mellitus","volume":"37","author":"Wu","year":"2024","journal-title":"J. Matern. Fetal Neonatal Med."},{"key":"ref_24","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1016\/s2213-8587(20)30310-7","article-title":"Metformin in women with type 2 diabetes in pregnancy (MiTy): A multicentre, international, randomized, placebo-controlled trial","volume":"8","author":"Feig","year":"2020","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2182","DOI":"10.1001\/jama.2023.22949","article-title":"Metformin plus insulin for preexisting diabetes or diabetes diagnosed early in pregnancy: The MOMPOD randomized clinical trial","volume":"330","author":"Boggess","year":"2023","journal-title":"JAMA"},{"key":"ref_26","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1097\/aog.0000000000005720","article-title":"Metformin use and preterm preeclampsia in pregnant individuals with early gestational or type 2 diabetes","volume":"144","author":"Patel","year":"2024","journal-title":"Obstet. Gynecol."},{"key":"ref_27","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.2337\/dc23-2056","article-title":"Perinatal outcomes associated with metformin use during pregnancy in women with pregestational type 2 diabetes mellitus","volume":"47","author":"Yland","year":"2024","journal-title":"Diabetes Care"},{"key":"ref_28","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/s2213-8587(18)30310-3","article-title":"Effect of metformin in addition to dietary and lifestyle advice for pregnant women who are overweight or obese: The GRoW randomized, double-blind, placebo-controlled trial","volume":"7","author":"Dodd","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_29","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1016\/s2213-8587(15)00219-3","article-title":"Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): A randomized, double-blind, placebo-controlled trial","volume":"3","author":"Chiswick","year":"2015","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_30","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1016\/s2213-8587(19)30002-6","article-title":"Use of metformin to treat pregnant women with polycystic ovary syndrome (PregMet2): A randomized, double-blind, placebo-controlled trial","volume":"7","author":"Carlsen","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_31","doi-asserted-by":"publisher","first-page":"4148","DOI":"10.1111\/jog.15044","article-title":"Gestational metformin administration in women with polycystic ovary syndrome: A systematic review and meta-analysis of randomized controlled studies","volume":"47","author":"Cao","year":"2021","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_32","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1111\/dom.16361","article-title":"A narrative review of metformin in pregnancy: Navigating benefit and uncertainty","volume":"27","author":"McEvoy","year":"2025","journal-title":"Diabetes Obes. Metab."},{"key":"ref_33","doi-asserted-by":"publisher","first-page":"e210479","DOI":"10.1530\/ec-21-0540","article-title":"Predictors of metformin monotherapy failure in gestational diabetes mellitus","volume":"11","author":"Silva","year":"2022","journal-title":"Endocr. Connect."},{"key":"ref_34","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1038\/s43856-023-00371-0","article-title":"Precision gestational diabetes treatment: A systematic review and meta-analyses","volume":"3","author":"Benham","year":"2023","journal-title":"Commun. Med."},{"key":"ref_35","doi-asserted-by":"publisher","first-page":"929","DOI":"10.1007\/s13300-024-01541-6","article-title":"Insulin use during gestational and pre-existing diabetes in pregnancy: A systematic review of study design","volume":"15","author":"Castorino","year":"2024","journal-title":"Diabetes Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1007\/s00404-021-06349-4","article-title":"The role of aspirin dose and initiation time in the prevention of preeclampsia and corresponding complications: A meta-analysis of randomized controlled trials","volume":"305","author":"Yip","year":"2022","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_37","doi-asserted-by":"publisher","first-page":"e241638","DOI":"10.1001\/jamanetworkopen.2024.36478","article-title":"Hypertensive disorders and cardiovascular severe maternal morbidity in the United States, 2015\u20132019","volume":"7","author":"Nerenberg","year":"2024","journal-title":"JAMA Netw. Open"},{"key":"ref_38","doi-asserted-by":"publisher","first-page":"e15488","DOI":"10.1111\/dme.70173","article-title":"Metformin safety during pregnancy in women with gestational diabetes mellitus: A systematic review and meta-analysis of maternal, neonatal, and long-term outcomes","volume":"42","author":"Brinkmann","year":"2025","journal-title":"Diabet. Med."},{"key":"ref_39","doi-asserted-by":"publisher","first-page":"1532","DOI":"10.2337\/dc22-0013","article-title":"Determinants of small for gestational age in women with type 2 diabetes in pregnancy: Who should receive metformin?","volume":"45","author":"Feig","year":"2022","journal-title":"Diabetes Care"},{"key":"ref_40","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1016\/j.eprac.2024.05.017","article-title":"Long-term impact on offspring aged 5\u201311 years of metformin use in pregnancy in mothers with diabetes: A systematic review and meta-analysis","volume":"30","author":"Dutta","year":"2024","journal-title":"Endocr. Pract."},{"key":"ref_41","doi-asserted-by":"publisher","first-page":"e089432","DOI":"10.1136\/bmjopen-2024-088653","article-title":"Intrauterine metformin exposure and adiposity outcomes in children: A systematic review and meta-analysis","volume":"15","author":"Fu","year":"2025","journal-title":"BMJ Open"},{"key":"ref_42","doi-asserted-by":"publisher","unstructured":"Escobar, M.F., Benitez-D\u00edaz, N., Blanco-Londo\u00f1o, I., Cer\u00f3n-Garc\u00e9s, C., Pe\u00f1a-Z\u00e1rate, E.E., Guevara-Calder\u00f3n, L.A., Libreros-Pe\u00f1a, L., and Galindo, J.S. (2024). Synthesis of evidence for managing hypertensive disorders of pregnancy in low- and middle-income countries: A scoping review. BMC Pregnancy Childbirth, 24.","DOI":"10.1186\/s12884-024-06796-2"},{"key":"ref_43","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1038\/s41574-022-00734-y","article-title":"A global view of hypertensive disorders and diabetes mellitus during pregnancy","volume":"18","author":"Jiang","year":"2022","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_44","doi-asserted-by":"publisher","first-page":"e29646","DOI":"10.1097\/md.0000000000029646","article-title":"Risk of future cardiovascular diseases in different years postpartum after hypertensive disorders of pregnancy: A systematic review and meta-analysis","volume":"101","author":"Sukmanee","year":"2022","journal-title":"Medicine"},{"key":"ref_45","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1161\/circulationaha.124.073302","article-title":"Hypertension in Pregnancy and Postpartum: Current Standards and Opportunities to Improve Care","volume":"151","author":"Countouris","year":"2025","journal-title":"Circulation"},{"key":"ref_46","doi-asserted-by":"publisher","first-page":"102695","DOI":"10.1016\/j.cpcardiol.2024.102695","article-title":"Maternal-fetal dyad beyond the phenomenology of pregnancy: From primordial cardiovascular prevention on out, do not miss this boat!","volume":"49","author":"Bucciarelli","year":"2024","journal-title":"Curr. Probl. Cardiol."},{"key":"ref_47","doi-asserted-by":"publisher","unstructured":"Atkinson, J., Simpson, G., Walker, S., Tong, S., Hastie, R., and Lindquist, A. (2023). The long-term risk of cardiovascular disease among women with a history of hypertensive disorders of pregnancy: A systematic review of clinical practice guidelines. BMC Cardiovasc. Disord., 23.","DOI":"10.1186\/s12872-023-03446-x"},{"key":"ref_48","doi-asserted-by":"publisher","first-page":"1516","DOI":"10.1111\/1471-0528.16319","article-title":"A core outcome set for pre-eclampsia research: An international consensus development study","volume":"127","author":"Duffy","year":"2020","journal-title":"BJOG"},{"key":"ref_49","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.1007\/s00125-020-05123-6","article-title":"A core outcome set for studies of gestational diabetes mellitus prevention and treatment","volume":"63","author":"Egan","year":"2020","journal-title":"Diabetologia"},{"key":"ref_50","doi-asserted-by":"publisher","first-page":"1855","DOI":"10.1111\/1471-0528.16825","article-title":"A core outcome set for the treatment of pregnant women with pregestational diabetes: An international consensus study","volume":"128","author":"Kgosidialwa","year":"2021","journal-title":"BJOG"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/16\/6423\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T16:15:09Z","timestamp":1787156109000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/16\/6423"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,19]]},"references-count":50,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["jcm15166423"],"URL":"https:\/\/doi.org\/10.3390\/jcm15166423","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,19]]}}}