{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T00:24:58Z","timestamp":1791419098267,"version":"4.3.3"},"reference-count":162,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,6,25]],"date-time":"2021-06-25T00:00:00Z","timestamp":1624579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010621","name":"Medical University of Lublin","doi-asserted-by":"publisher","award":["333"],"award-info":[{"award-number":["333"]}],"id":[{"id":"10.13039\/501100010621","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>The possibility of prophylaxis of hypertensive disorders of pregnancy (HDPs) such as preeclampsia (PE) and pregnancy-induced hypertension is of interest due to the unpredictable course of these diseases and the risks they carry for both mother and fetus. It has been proven that their development is associated with the presence of the placenta, and the processes that initiate it begin at the time of the abnormal invasion of the trophoblast in early pregnancy. The ideal HDP prophylaxis should alleviate the influence of risk factors and, at the same time, promote physiological trophoblast invasion and maintain the physiologic endothelium function without any harm to both mother and fetus. So far, aspirin is the only effective and recommended pharmacological agent for the prevention of HDPs in high-risk groups. Metformin is a hypoglycemic drug with a proven protective effect on the cardiovascular system. Respecting the anti-inflammatory properties of metformin and its favorable impact on the endothelium, it seems to be an interesting option for HDP prophylaxis. The results of previous studies on such use of metformin are ambiguous, although they indicate that in a certain group of pregnant women, it might be effective in preventing hypertensive complications. The aim of this study is to present the possibility of metformin in the prevention of hypertensive disorders of pregnancy with respect to its impact on the pathogenic elements of development<\/jats:p>","DOI":"10.3390\/jcm10132805","type":"journal-article","created":{"date-parts":[[2021,6,25]],"date-time":"2021-06-25T11:07:40Z","timestamp":1624619260000},"page":"2805","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Prevention of Hypertensive Disorders of Pregnancy\u2014Is There a Place for Metformin?"],"prefix":"10.3390","volume":"10","author":[{"given":"El\u017cbieta","family":"Poniedzia\u0142ek-Czajkowska","sequence":"first","affiliation":[{"name":"Chair and Department of Obstetrics and Perinatology, Medical University of Lublin, 20-059 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2224-6365","authenticated-orcid":false,"given":"Radzis\u0142aw","family":"Mierzy\u0144ski","sequence":"additional","affiliation":[{"name":"Chair and Department of Obstetrics and Perinatology, Medical University of Lublin, 20-059 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5886-2664","authenticated-orcid":false,"given":"Dominik","family":"D\u0142uski","sequence":"additional","affiliation":[{"name":"Chair and Department of Obstetrics and Perinatology, Medical University of Lublin, 20-059 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo\u017cena","family":"Leszczy\u0144ska-Gorzelak","sequence":"additional","affiliation":[{"name":"Chair and Department of Obstetrics and Perinatology, Medical University of Lublin, 20-059 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"ACOG (2019). Practice Bulletin No. 203: Chronic hypertension in pregnancy. Obstet. Gynecol., 133, e26\u2013e50.","DOI":"10.1097\/AOG.0000000000003020"},{"key":"ref_2","unstructured":"ACOG (2019). Practice Bulletin No. 202: Gestational hypertension and Preeclampsia. Obstet. Gynecol., 133, e1\u2013e25."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1053\/j.semperi.2009.02.010","article-title":"The global impact of preeclampsia and eclampsia","volume":"33","author":"Duley","year":"2009","journal-title":"Semin. Perinatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1016\/S0140-6736(06)69380-X","article-title":"Maternal mortality: Who, when, where, and why","volume":"368","author":"Ronsmans","year":"2006","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1016\/S0140-6736(06)68397-9","article-title":"WHO analysis of causes of maternal death: A systematic review","volume":"367","author":"Khan","year":"2006","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"757","DOI":"10.33963\/KP.14904","article-title":"Management of hypertension in pregnancy: Prevention, diagnosis, treatment and long-term prognosis","volume":"77","author":"Prejbisz","year":"2019","journal-title":"Kardiol. Pol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.preghy.2018.05.004","article-title":"International Society for the Study of Hypertension in Pregnancy (ISSHP). The hypertensive disorders of pregnancy: ISSHP classification, diagnosis & management recommendations for international practice","volume":"13","author":"Brown","year":"2018","journal-title":"Pregnancy Hypertens."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/S1701-2163(15)30533-8","article-title":"Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy: Executive summary","volume":"36","author":"Magee","year":"2014","journal-title":"J. Obstet. Gynaecol. Can."},{"key":"ref_9","unstructured":"Tong, S., Kaitu\u2019u-Lino, T.J., Hastie, R., Brownfoot, F., Cluver, C., and Hannan, N. (2020). Pravastatin, proton-pump inhibitors, metformin, micronutrients, and biologics: New horizons for the prevention or treatment of preeclampsia. Am. J. Obstet. Gynecol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"327","DOI":"10.4158\/endp.19.2.a38267720403k242","article-title":"American Association of Clinical Endocrinologists. AACE comprehensive diabetes management algorithm 2013","volume":"19","author":"Garber","year":"2013","journal-title":"Endocr. Pract."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"International Diabetes Federation Guideline Development Group (2014). Global guideline for type 2 diabetes. Diabetes Res. Clin. Pract., 104, 1\u201352.","DOI":"10.1016\/j.diabres.2012.10.001"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2421","DOI":"10.2147\/DDDT.S141675","article-title":"Metformin: A review of its potential indications","volume":"11","author":"Wang","year":"2017","journal-title":"Drug Des. Devel. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1161\/HYPERTENSIONAHA.107.107607","article-title":"Placental origins of preeclampsia: Challenging the current hypothesis","volume":"51","author":"Huppertz","year":"2008","journal-title":"Hypertension"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1081\/PRG-120021060","article-title":"Subclassification of preeclampsia","volume":"22","author":"Magee","year":"2003","journal-title":"Hypertens. Pregnancy"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1053\/j.semperi.2014.03.005","article-title":"Pathophysiology of ischemic placental disease","volume":"38","author":"Roberts","year":"2014","journal-title":"Semin. Perinatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1095\/biolreprod.102.014977","article-title":"Endovascular trophoblast invasion: Implications for the pathogenesis of intrauterine growth retardation and preeclampsia","volume":"69","author":"Kaufmann","year":"2003","journal-title":"Biol. Reprod."},{"key":"ref_17","first-page":"244","article-title":"Innate immune system and preeclampsia","volume":"5","author":"Torres","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1111\/j.1600-0897.2010.00831.x","article-title":"Immunology of pre-eclampsia","volume":"63","author":"Redman","year":"2010","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.siny.2006.04.001","article-title":"Inflammation and pre-eclampsia","volume":"11","author":"Borzychowski","year":"2006","journal-title":"Semin. Fetal. Neonatal. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.clim.2005.11.001","article-title":"Monocytes of preeclamptic women spontaneously synthesize pro-inflammatory cytokines","volume":"118","author":"Luppi","year":"2006","journal-title":"Clin. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3939","DOI":"10.4049\/jimmunol.1202582","article-title":"Conversion of peripheral blood NK cells to a decidual NK-like phenotype by a cocktail of defined factors","volume":"190","author":"Cerdeira","year":"2013","journal-title":"J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1002\/path.4057","article-title":"Impaired decidual natural killer cell regulation of vascular remodelling in early human pregnancies with high uterine artery resistance","volume":"228","author":"Fraser","year":"2012","journal-title":"J. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1084\/jem.187.2.217","article-title":"Engraftment of bone marrow from severe combined immunodeficient (SCID) mice reverses the reproductive deficits in natural killer cell-deficient tg epsilon 26 mice","volume":"187","author":"Guimond","year":"1998","journal-title":"J. Exp. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/0143-4004(91)90339-H","article-title":"Current topic: Pre-eclampsia and the placenta","volume":"12","author":"Redman","year":"1991","journal-title":"Placenta"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.1097\/01.ASN.0000132474.50966.DA","article-title":"Endothelial dysfunction","volume":"15","author":"Endemann","year":"2004","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1111\/micc.12079","article-title":"Vascular dysfunction in preeclampsia","volume":"21","author":"Brennan","year":"2014","journal-title":"Microcirculation"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1038\/jhh.2015.110","article-title":"Maternal serum uric acid concentration is associated with the expression of tumour necrosis factor-\u03b1 and intercellular adhesion molecule-1 in patients with preeclampsia","volume":"30","author":"Zhao","year":"2016","journal-title":"J. Hum. Hypertens."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.mvr.2007.04.009","article-title":"Molecular mechanisms of preeclampsia","volume":"75","author":"Mutter","year":"2008","journal-title":"Microvasc. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/0092-8674(93)90573-9","article-title":"High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis","volume":"26","author":"Millauer","year":"1993","journal-title":"Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"9709","DOI":"10.1074\/jbc.270.17.9709","article-title":"Vascular endothelial growth factor increases urokinase receptor expression in vascular endothelial cells","volume":"270","author":"Mandriota","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1038\/nm1095-1024","article-title":"Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity","volume":"1","author":"Alon","year":"1995","journal-title":"Nat. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2735","DOI":"10.1080\/14767058.2018.1448774","article-title":"Maternal serum AMP-activated protein kinase levels in mild and severe preeclampsia","volume":"32","author":"Koroglu","year":"2019","journal-title":"J. Matern. Fetal. Neonatal. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1152\/physrev.00011.2008","article-title":"AMPK in health and disease","volume":"89","author":"Steinberg","year":"2009","journal-title":"Physiol. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2921","DOI":"10.1089\/scd.2014.0092","article-title":"AMPK knockdown in placental trophoblast cells results in altered morphology and function","volume":"23","author":"Carey","year":"2014","journal-title":"Stem. Cells Dev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1089\/scd.2016.0252","article-title":"AMPK knockdown in placental labyrinthine progenitor cells results in restriction of critical energy resources and terminal differentiation failure","volume":"26","author":"Waker","year":"2017","journal-title":"Stem. Cells Dev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1111\/micc.12113","article-title":"Placenta growth factor and vascular endothelial growth factor-A have differential, cell-type specific atterns of expression in vascular cells","volume":"21","author":"Xian","year":"2014","journal-title":"Microcirculation"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1356","DOI":"10.1046\/j.1538-7836.2003.00263.x","article-title":"Placental growth factor and its receptor, vascular endothelial growth factor receptor-1: Novel targets for stimulation of ischemic tissue revascularization and inhibition of angiogenic and inflammatory disorders","volume":"1","author":"Autiero","year":"2003","journal-title":"J. Thromb. Haemost."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1006\/mvre.1997.2051","article-title":"Automated evaluation of angiogenic effects mediated by VEGF and PlGF homo- and heterodimers","volume":"55","author":"Kurz","year":"1998","journal-title":"Microvasc. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1096\/fasebj.13.1.9","article-title":"Vascular endothelial growth factor (VEGF) and its receptors","volume":"13","author":"Neufeld","year":"1999","journal-title":"FASEB J."},{"key":"ref_40","doi-asserted-by":"crossref","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_41","doi-asserted-by":"crossref","first-page":"3052","DOI":"10.1093\/ndt\/gfl439","article-title":"Soluble endoglin (sEng) joins the soluble fms-like tyrosine ki- nase (sFlt) receptor as a pre-eclampsia molecule","volume":"21","author":"Luft","year":"2006","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1038\/nm1429","article-title":"Soluble endoglin contributes to the pathogenesis of preeclampsia","volume":"12","author":"Venkatesha","year":"2006","journal-title":"Nat. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.semnephrol.2010.10.004","article-title":"Angiogenic factors and preeclampsia","volume":"31","author":"Maynard","year":"2011","journal-title":"Semin. Nephrol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1038\/nrneph.2014.102","article-title":"Pre-eclampsia part 1: Current understanding of its pathophysiology","volume":"10","author":"Chaiworapongsa","year":"2014","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/j.semnephrol.2004.07.003","article-title":"Angiogenic imbalance in the pathophysiology of preeclampsia: Newer insights","volume":"24","author":"Bdolah","year":"2004","journal-title":"Semin. Nephrol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1056\/NEJMoa031884","article-title":"Circulating angiogenic factors and the risk of preeclampsia","volume":"350","author":"Levine","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1172\/JCI17189","article-title":"Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia","volume":"111","author":"Maynard","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"153","DOI":"10.5830\/CVJA-2012-003","article-title":"The role of angiogenic, anti-angiogenic and vasoactive factors in pre-eclamptic African women: Early- versus late-onset pre-eclampsia","volume":"23","author":"Govender","year":"2012","journal-title":"Cardiovasc. J. Afr."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.niox.2019.11.006","article-title":"Nitric oxide signaling in pregnancy and preeclampsia","volume":"95","author":"Sutton","year":"2020","journal-title":"Nitric. Oxide."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1080\/09513590.2017.1318375","article-title":"Placental growth factor (PlGF) as an angiogenic\/inflammatory switcher: Lesson from early pregnancy losses","volume":"33","author":"Nejabati","year":"2017","journal-title":"Gynecol. Endocrinol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1080\/01443615.2018.1454409","article-title":"Second trimester maternal serum-amniotic fluid nitric oxide and vascular endothelial growth factor levels in relation to uterine artery Doppler indices in pregnancies with normal outcome","volume":"38","author":"Zafer","year":"2018","journal-title":"J. Obstet. Gynaecol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1111\/j.1471-0528.2012.03311.x","article-title":"EBM CONNECT Collaboration. Accuracy of circulating placental growth factor, vascular endothelial growth factor, soluble fms-like tyrosine kinase 1 and soluble endoglin in the prediction of pre-eclampsia: A systematic review and meta-analysis","volume":"119","author":"Kleinrouweler","year":"2012","journal-title":"BJOG"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"178","DOI":"10.2174\/1389557518666181015151350","article-title":"Radicals, oxidative\/nitrosative stress and preeclampsia","volume":"19","author":"Taysi","year":"2019","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1161\/HYPERTENSIONAHA.119.13348","article-title":"Soluble endoglin as a marker for preeclampsia, its severity, and the occurrence of adverse outcomes","volume":"74","year":"2019","journal-title":"Hypertension"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"R1085","DOI":"10.1152\/ajpregu.00794.2005","article-title":"Increased expression of sFlt-1 in in vivo and in vitro models of human placental hypoxia is mediated by HIF-1","volume":"291","author":"Nevo","year":"2006","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1095\/biolreprod.112.102723","article-title":"The role of hypoxia and hypoxia-inducible factor-1alpha in preeclampsia pathogenesis","volume":"87","author":"Tal","year":"2012","journal-title":"Biol. Reprod."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2656","DOI":"10.1172\/JCI26373","article-title":"Endoplasmic reticulum stress: Cell life and death decisions","volume":"115","author":"Xu","year":"2005","journal-title":"J. Clin. Investig."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"S43","DOI":"10.1016\/j.placenta.2008.11.003","article-title":"Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia","volume":"30","author":"Burton","year":"2009","journal-title":"Placenta"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.placenta.2016.04.001","article-title":"Mitochondrial-Endoplasmic reticulum interactions in the trophoblast: Stress and senescence","volume":"52","author":"Burton","year":"2017","journal-title":"Placenta"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.tjog.2014.11.002","article-title":"Expression of markers of endoplasmic reticulum stress-induced apoptosis in the placenta of women with early and late onset severe pre-eclampsia","volume":"54","author":"Fu","year":"2015","journal-title":"Taiwan J. Obstet. Gynecol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1053\/plac.2002.0867","article-title":"Expression and activity of matrix metalloproteinase 2 and 9 in human trophoblasts","volume":"24","author":"Isaka","year":"2003","journal-title":"Placenta"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/bs.pmbts.2017.04.001","article-title":"Matrix metalloproteinases in normal pregnancy and preeclampsia","volume":"148","author":"Chen","year":"2017","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"R27","DOI":"10.1530\/JOE-16-0340","article-title":"Vascular adaptation in pregnancy and endothelial dysfunction in preeclampsia","volume":"232","author":"Boeldt","year":"2017","journal-title":"J. Endocrinol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1111\/j.1471-0528.2011.02925.x","article-title":"Impaired vascular permeability regulation caused by the VEGF\u2081\u2086\u2085b splice variant in preeclampsia","volume":"118","author":"Bills","year":"2011","journal-title":"BJOG"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.jash.2011.11.003","article-title":"Cellular biomarkers of endothelial health: Microparticles, endothelial progenitor cells, and circulating endothelial cells","volume":"6","author":"Burger","year":"2012","journal-title":"J. Am. Soc. Hypertens."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"E33","DOI":"10.1210\/jc.2012-2793","article-title":"Endothelial progenitor cells in mothers of low-birthweight infants: A link between defective placental vascularization and increased cardiovascular risk?","volume":"98","author":"King","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1177\/1933719116648411","article-title":"Notch1 impairs endothelial progenitor cell bioactivity in preeclampsia","volume":"24","author":"Liu","year":"2017","journal-title":"Reprod. Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"5329","DOI":"10.1210\/jc.2005-0532","article-title":"Decrease and senescence of endothelial progenitor cells in patients with preeclampsia","volume":"90","author":"Sugawara","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1111\/j.1447-0756.2007.00555.x","article-title":"Decrease and dysfunction of endothelial progenitor cells in umbilical cord blood with maternal pre-eclampsia","volume":"33","author":"Xia","year":"2007","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1111\/j.1600-0897.2006.00387.x","article-title":"Circulating endothelial progenitor cells during normal pregnancy and pre-eclampsia","volume":"56","author":"Matsubara","year":"2006","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1007\/s00404-014-3522-z","article-title":"Transplantation of endothelial progenitor cells for improving placental perfusion in preeclamptic rats","volume":"291","author":"Zhu","year":"2014","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1164\/rccm.200708-1269OC","article-title":"SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease","volume":"177","author":"Rajendrasozhan","year":"2008","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_73","first-page":"4561083","article-title":"Analysis of SIRT1 expression in plasma and in an in vitro model of preeclampsia","volume":"2020","author":"Nunes","year":"2020","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.placenta.2016.12.018","article-title":"Protective proteins and telomere length in placentas from patients with pre-eclampsia in the last trimester of gestation","volume":"50","author":"Broady","year":"2017","journal-title":"Placenta"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/j.biopha.2017.01.087","article-title":"SIRT1 inhibits releases of HMGB1 and HSP70 from human umbilical vein endothelial cells caused by IL-6 and the serum from a preeclampsia patient and protects the cells from death","volume":"88","author":"Yin","year":"2017","journal-title":"Biomed. Pharmacother."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"189","DOI":"10.3109\/10641955.2013.784788","article-title":"Clinical characterization and outcomes of preeclampsia with normal angiogenic profile","volume":"32","author":"Rana","year":"2013","journal-title":"Hypertens. Pregnancy"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1056\/NEJMoa1414838","article-title":"Predictive value of the sFlt-1:PlGF ratio in women with suspected Preeclampsia","volume":"374","author":"Zeisler","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1002\/uog.13275","article-title":"First-trimester uterine artery Doppler and adverse pregnancy outcome: A meta-analysis involving 55,974 women","volume":"43","author":"Velauthar","year":"2014","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"297397","DOI":"10.1155\/2014\/297397","article-title":"Early prediction of preeclampsia","volume":"2014","author":"Poon","year":"2014","journal-title":"Obstet. Gynecol. Int."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1002\/uog.19019","article-title":"ASPRE trial: Incidence of preterm pre-eclampsia in patients fulfilling ACOG and NICE criteria according to risk by FMF algorithm","volume":"51","author":"Poon","year":"2018","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1056\/NEJMoa0707193","article-title":"MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes","volume":"358","author":"Rowan","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"81","DOI":"10.2165\/11534750-000000000-00000","article-title":"Clinical pharmacokinetics of metformin","volume":"50","author":"Graham","year":"2011","journal-title":"Clin. Pharmacokinet."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1016\/j.cmet.2014.09.018","article-title":"Metformin: From mechanisms of action to therapies","volume":"20","author":"Foretz","year":"2014","journal-title":"Cell Metab."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.cmet.2015.01.003","article-title":"Metformin action: Concentrations matter","volume":"21","author":"He","year":"2015","journal-title":"Cell Metab."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1074\/jbc.275.1.223","article-title":"Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I","volume":"275","author":"Nogueira","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.4161\/cc.8.10.8406","article-title":"Genome-wide inhibitory impact of the AMPK activator metformin on [kinesins, tubulins, histones, auroras and polo-like kinases] M-phase cell cycle genes in human breast cancer cells","volume":"8","author":"Menendez","year":"2009","journal-title":"Cell Cycle"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1172\/JCI13505","article-title":"Role of AMP-activated protein kinase in mechanism of metformin action","volume":"108","author":"Zhou","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1642","DOI":"10.1126\/science.1120781","article-title":"The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin","volume":"310","author":"Shaw","year":"2005","journal-title":"Science"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"43940","DOI":"10.1074\/jbc.M404421200","article-title":"Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species","volume":"279","author":"Zou","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"2355","DOI":"10.1172\/JCI40671","article-title":"Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1\/AMPK pathway via a decrease in hepatic energy state","volume":"120","author":"Foretz","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1038\/nature13270","article-title":"Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase","volume":"510","author":"Madiraju","year":"2014","journal-title":"Nature"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"457","DOI":"10.2217\/fon.09.174","article-title":"AMPK as a metabolic tumor suppressor: Control of metabolism and cell growth","volume":"6","author":"Luo","year":"2010","journal-title":"Future Oncol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1097\/CCO.0b013e32834d8155","article-title":"Metformin and cancer therapy","volume":"24","author":"Bost","year":"2012","journal-title":"Curr. Opin. Oncol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"10804108012","DOI":"10.1158\/0008-5472.CAN-07-2310","article-title":"Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells","volume":"67","author":"Dowling","year":"2007","journal-title":"Cancer Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"4366","DOI":"10.1158\/0008-5472.CAN-10-1769","article-title":"Metformin, independent of AMPK, induces mTOR inhibition and cell-cycle arrest through REDD1","volume":"71","author":"Regazzetti","year":"2011","journal-title":"Cancer Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.diabet.2015.02.003","article-title":"Antidiabetic agents: Potential anti-inflammatory activity beyond glucose control","volume":"41","author":"Scheen","year":"2015","journal-title":"Diabetes Metab."},{"key":"ref_97","first-page":"CD002966","article-title":"Metformin monotherapy for type 2 diabetes mellitus","volume":"3","author":"Saenz","year":"2005","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.metabol.2003.07.020","article-title":"Effect of metformin treatment on multiple cardiovascular disease risk factors in patients with type 2 diabetes mellitus","volume":"53","author":"Abbasi","year":"2004","journal-title":"Metabolism"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.2337\/dc05-2146","article-title":"Metformin improves endothelial vascular reactivity in first-degree relatives of type 2 diabetic patients with metabolic syndrome and normal glucose tolerance","volume":"29","author":"Bahia","year":"2006","journal-title":"Diabetes Care"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.1056\/NEJMra1216063","article-title":"Mechanisms of acute coronary syndromes and their implications for therapy","volume":"368","author":"Libby","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1111\/j.1476-5381.2011.01230.x","article-title":"Metformin restores endothelial function in aorta of diabetic rats","volume":"163","author":"Sena","year":"2011","journal-title":"Br. J. Pharmacol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1007\/s00380-008-1137-7","article-title":"Metformin inhibits nuclear factor kappaB activation and decreases serum high-sensitivity C-reactive protein level in experimental atherogenesis of rabbits","volume":"24","author":"Li","year":"2009","journal-title":"Heart Vessels."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1161\/01.HYP.0000221429.94591.72","article-title":"Metformin inhibits cytokine-induced nuclear factor kappaB activation via AMP-activated protein kinase activation in vascular endothelial cells","volume":"47","author":"Hattori","year":"2006","journal-title":"Hypertension"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1161\/01.ATV.0000201938.78044.75","article-title":"Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells","volume":"26","author":"Isoda","year":"2006","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"123","DOI":"10.4110\/in.2013.13.4.123","article-title":"Metformin down-regulates TNF-\u03b1 secretion via suppression of scavenger receptors in macrophages","volume":"13","author":"Hyun","year":"2013","journal-title":"Immune Netw."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"3161","DOI":"10.1073\/pnas.1222051110","article-title":"AMPK\u03b12 exerts its anti-inflammatory effects through PARP-1 and Bcl-6","volume":"110","author":"Gongol","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1016\/j.bbrc.2012.07.165","article-title":"Metformin inhibits inflammatory response via AMPK-PTEN pathway in vascular smooth muscle cells","volume":"425","author":"Kim","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"6S95","DOI":"10.1016\/S1262-3636(03)72793-1","article-title":"Metformin inhibition of glycation processes","volume":"29","author":"Beisswenger","year":"2003","journal-title":"Diabetes Metab."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"699","DOI":"10.2174\/156652407783220732","article-title":"Receptor for Advanced Glycation Endproducts (RAGE): A formidable force in the pathogenesis of the cardiovascular complications of diabetes & aging","volume":"7","author":"Yan","year":"2007","journal-title":"Curr. Mol. Med."},{"key":"ref_110","first-page":"68","article-title":"Diabetes alters activation and repression of pro- and anti-inflammatory signaling pathways in the vasculature","volume":"4","author":"Gray","year":"2013","journal-title":"Front. Endocrinol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"6S71","DOI":"10.1016\/S1262-3636(03)72790-6","article-title":"Antiatherogenic properties of metformin: The experimental evidence","volume":"29","author":"Mamputu","year":"2003","journal-title":"Diabetes Metab."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"196","DOI":"10.2174\/1871530315666150316124019","article-title":"Metformin and inflammation: Its potential beyond glucose-lowering effect","volume":"15","author":"Saisho","year":"2015","journal-title":"Endocr. Metab. Immune Disord. Drug Targets"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.metabol.2005.01.029","article-title":"Metformin decreases intracellular production of reactive oxygen species in aortic endothelial cells","volume":"54","author":"Ouslimani","year":"2005","journal-title":"Metabolism"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s12933-016-0344-2","article-title":"Metformin improves the angiogenic potential of human CD34\u207a cells co-incident with downregulating CXCL10 and TIMP1 gene expression and increasing VEGFA under hyperglycemia and hypoxia within a therapeutic window for myocardial infarction","volume":"15","author":"Bakhashab","year":"2016","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1186\/s12933-016-0408-3","article-title":"Metformin improves the angiogenic functions of endothelial progenitor cells via activating AMPK\/eNOS pathway in diabetic mice","volume":"15","author":"Yu","year":"2016","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1111\/bph.12496","article-title":"Metformin modulates hyperglycaemia-induced endothelial senescence and apoptosis through SIRT1","volume":"171","author":"Arunachalam","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1159\/000381643","article-title":"Metformin: An old drug for the treatment of diabetes but a new drug for the protection of the endothelium","volume":"24","author":"Kinaan","year":"2015","journal-title":"Med. Princ. Pract."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1186\/1475-2840-12-175","article-title":"Effects of two weeks of metformin treatment on whole-body glycocalyx barrier properties in db\/db mice","volume":"12","author":"Eskens","year":"2013","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/j.fertnstert.2018.11.032","article-title":"Direct toxicity of insulin on the human placenta and protection by metformin","volume":"111","author":"Vega","year":"2019","journal-title":"Fertil. Steril."},{"key":"ref_120","first-page":"8238727","article-title":"Cross-talk between oxidative stress and inflammation in preeclampsia","volume":"2019","author":"Ferreira","year":"2019","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1111\/aji.12339","article-title":"Glucose and metformin modulate human first trimester trophoblast function: A model and potential therapy for diabetes-associated uteroplacental insufficiency","volume":"73","author":"Han","year":"2015","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_122","doi-asserted-by":"crossref","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 randomised, double-blind, placebo-controlled trial","volume":"3","author":"Chiswick","year":"2015","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1111\/fcp.12501","article-title":"Protective effect of metformin on a rat model of lipopolysaccharide-induced preeclampsia","volume":"33","author":"Hu","year":"2019","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"105693","DOI":"10.1016\/j.intimp.2019.105693","article-title":"Metformin exhibits its therapeutic effect in the treatment of pre-eclampsia via modulating the Met\/H19\/miR-148a-5p\/P28 and Met\/H19\/miR-216-3p\/EBI3 signaling pathways","volume":"74","author":"Shu","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.ejphar.2018.05.038","article-title":"Involvement of mTOR, JNK and PI3K in the negative effect of ethanol and metformin on the human first-trimester extravillous trophoblast HTR-8\/SVneo cell line","volume":"833","author":"Keating","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1111\/apha.12644","article-title":"Metformin is not just an antihyperglycaemic drug but also has protective effects on the vascular endothelium","volume":"219","author":"Triggle","year":"2017","journal-title":"Acta Physiol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/S0301-2115(96)02647-4","article-title":"Increased maternal plasma levels of soluble adhesion molecules (ICAM-1, VCAM-1, E-selectin) in preeclampsia","volume":"71","author":"Austgulen","year":"1997","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1080\/jmf.12.1.19.27","article-title":"Soluble adhesion molecule profile in normal pregnancy and pre-eclampsia","volume":"12","author":"Chaiworapongsa","year":"2002","journal-title":"J. Matern. Fetal. Neonatal. Med."},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Kaitu\u2019u-Lino, T.J., Brownfoot, F.C., Beard, S., Cannon, P., Hastie, R., Nguyen, T.V., Binder, N.K., Tong, S., and Hannan, N.J. (2018). Combining metformin and esomeprazole is additive in reducing sFlt-1 secretion and decreasing endothelial dysfunction-implications for treating preeclampsia. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0188845"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1177\/1933719118773484","article-title":"Angiogenic dysregulation in pregnancy-related hypertension-A role for metformin","volume":"25","author":"Soobryan","year":"2018","journal-title":"Reprod. Sci."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.placenta.2020.04.010","article-title":"Combining metformin and sulfasalazine additively reduces the secretion of antiangiogenic factors from the placenta: Implications for the treatment of preeclampsia","volume":"95","author":"Brownfoot","year":"2020","journal-title":"Placenta"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.tem.2012.05.006","article-title":"EG-VEGF: A key endocrine factor in placental development","volume":"23","author":"Brouillet","year":"2012","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Jena, M.K., Sharma, N.R., Petitt, M., Maulik, D., and Nayak, N.R. (2020). Pathogenesis of preeclampsia and therapeutic approaches targeting the placenta. Biomolecules, 10.","DOI":"10.3390\/biom10060953"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"6547019","DOI":"10.1155\/2019\/6547019","article-title":"Effect of metformin on a preeclampsia-like mouse model induced by high-fat diet","volume":"2019","author":"Wang","year":"2019","journal-title":"Biomed. Res. Int."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1177\/1358863X10367537","article-title":"Number of circulating endothelial progenitor cells as a marker of vascular endothelial function for type 2 diabetes","volume":"15","author":"Liao","year":"2010","journal-title":"Vasc. Med."},{"key":"ref_136","doi-asserted-by":"crossref","unstructured":"Asadian, S., Alibabrdel, M., Daei, N., Cheraghi, H., Maedeh Jafari, S., Noshadirad, E., Jabarpour, M., Siavashi, V., and Nassiri, S.M. (2018). Improved angiogenic activity of endothelial progenitor cell in diabetic patients treated with insulin plus metformin. J. Cell Biochem.","DOI":"10.1002\/jcb.27985"},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"2263","DOI":"10.4155\/fmc-2019-0017","article-title":"Metformin inhibits angiogenesis of endothelial progenitor cells via miR-221-mediated p27 expression and autophagy","volume":"11","author":"Ni","year":"2019","journal-title":"Future Med. Chem."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.3892\/ijmm.2017.2929","article-title":"Metformin inhibits endothelial progenitor cell migration by decreasing matrix metalloproteinases, MMP-2 and MMP-9, via the AMPK\/mTOR\/autophagy pathway","volume":"39","author":"Li","year":"2017","journal-title":"Int. J. Mol. Med."},{"key":"ref_139","first-page":"75","article-title":"The roles of metformin and pravastatin on placental endoplasmic reticulum stress and placental growth factor in human villous-Like trophoblastic BeWo cells","volume":"87","author":"Suzuki","year":"2018","journal-title":"Sapporo Med. J."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/j.diabet.2018.01.008","article-title":"Metformin in women at high risk of gestational diabetes mellitus","volume":"44","author":"Brink","year":"2018","journal-title":"Diabetes Metab."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.diabres.2014.10.001","article-title":"Metformin versus insulin treatment in gestational diabetes in pregnancy in a developing country: A randomized control trial","volume":"107","author":"Ainuddin","year":"2015","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1111\/dom.12017","article-title":"Metformin vs. insulin in gestational diabetes. A randomized study characterizing metformin patients needing additional insulin","volume":"15","author":"Tertti","year":"2013","journal-title":"Diabetes Obes. Metab."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.diabres.2012.09.031","article-title":"Metformin compared with insulin in the management of gestational diabetes mellitus: A randomized clinical trial","volume":"98","author":"Niromanesh","year":"2012","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_144","doi-asserted-by":"crossref","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, randomised, placebo-controlled trial","volume":"8","author":"Feig","year":"2020","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"325851","DOI":"10.1155\/2015\/325851","article-title":"Metformin treatment in type 2 diabetes in pregnancy: An active controlled, parallel-group, randomized, open label study in patients with type 2 diabetes in pregnancy","volume":"2015","author":"Ainuddin","year":"2015","journal-title":"J. Diabetes Res."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"290","DOI":"10.20945\/2359-3997000000251","article-title":"Metformin for prevention of cesarean delivery and large-for-gestational-age newborns in non-diabetic obese pregnant women: A randomized clinical trial","volume":"64","author":"Nascimento","year":"2020","journal-title":"Arch. Endocrinol. Metab."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1056\/NEJMoa1509819","article-title":"Metformin versus placebo in obese pregnant women without diabetes mellitus","volume":"374","author":"Syngelaki","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_148","doi-asserted-by":"crossref","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 randomised, double-blind, placebo-controlled trial","volume":"7","author":"Carlsen","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1055\/s-0038-1675214","article-title":"Evaluation of preeclampsia results after use of metformin in gestation: Systematic review and meta-analysis","volume":"40","author":"Nascimento","year":"2018","journal-title":"Rev. Bras. Ginecol. Obstet."},{"key":"ref_150","doi-asserted-by":"crossref","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_151","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/dme.13150","article-title":"Short- and long-term outcomes of metformin compared with insulin alone in pregnancy: A systematic review and meta-analysis","volume":"34","author":"Butalia","year":"2017","journal-title":"Diabet. Med."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"1874","DOI":"10.1080\/14767058.2016.1228061","article-title":"Metformin-A potentially effective drug for gestational diabetes mellitus: A systematic review and meta-analysis","volume":"30","author":"Feng","year":"2017","journal-title":"J. Matern. Fetal. Neonatal. Med."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s00404-014-3566-0","article-title":"Effect comparison of metformin with insulin treatment for gestational diabetes: A meta-analysis based on RCTs","volume":"292","author":"Li","year":"2015","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_154","doi-asserted-by":"crossref","unstructured":"Poolsup, N., Suksomboon, N., and Amin, M. (2014). Efficacy and safety of oral antidiabetic drugs in comparison to insulin in treating gestational diabetes mellitus: A meta-analysis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0109985"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1007\/s11845-016-1414-x","article-title":"Metformin versus insulin in gestational diabetes mellitus: A meta-analysis of randomized clinical trials","volume":"185","author":"Zhu","year":"2016","journal-title":"Ir. J. Med. Sci."},{"key":"ref_156","doi-asserted-by":"crossref","unstructured":"Gui, J., Liu, Q., and Feng, L. (2013). Metformin vs insulin in the management of gestational diabetes: A meta-analysis. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0064585"},{"key":"ref_157","first-page":"CD010564","article-title":"Metformin for women who are overweight or obese during pregnancy for improving maternal and infant outcomes","volume":"7","author":"Dodd","year":"2018","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"833","DOI":"10.3109\/09513590.2015.1041906","article-title":"Efficacy of metformin on pregnancy complications in women with polycystic ovary syndrome: A meta-analysis","volume":"31","author":"Feng","year":"2015","journal-title":"Gynecol. Endocrinol."},{"key":"ref_159","first-page":"797","article-title":"The efficacy of metformin in pregnant women with polycystic ovary syndrome: A meta-analysis of clinical trials","volume":"36","author":"Zheng","year":"2013","journal-title":"J. Endocrinol. Investig."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1210\/jc.2013-3227","article-title":"Midpregnancy Doppler ultrasound of the uterine artery in metformin- versus placebo-treated PCOS women: A randomized trial","volume":"99","author":"Stridsklev","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1111\/j.1471-0528.2012.03493.x","article-title":"Aspirin in the prevention of pre-eclampsia in high-risk women: A randomised placebo-controlled PREDO Trial and a meta-analysis of randomised trials","volume":"120","author":"Villa","year":"2013","journal-title":"BJOG"},{"key":"ref_162","first-page":"CD012327","article-title":"Treatments for women with gestational diabetes mellitus: An overview of Cochrane systematic reviews","volume":"8","author":"Martis","year":"2018","journal-title":"Cochrane Database Syst. 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