Advertisement

Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity

  • Roberto Romero
    Correspondence
    Corresponding authors: Roberto Romero, MD, DMedSci.
    Affiliations
    Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI

    Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI

    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI
    Search for articles by this author
  • Offer Erez
    Correspondence
    Offer Erez, MD.
    Affiliations
    Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI

    Department of Obstetrics and Gynecology, Soroka University Medical Center School of Medicine, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beersheba, Israel
    Search for articles by this author
  • Maik Hüttemann
    Affiliations
    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI
    Search for articles by this author
  • Eli Maymon
    Affiliations
    Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI

    Department of Obstetrics and Gynecology, Soroka University Medical Center School of Medicine, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beersheba, Israel
    Search for articles by this author
  • Bogdan Panaitescu
    Affiliations
    Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI
    Search for articles by this author
  • Agustin Conde-Agudelo
    Affiliations
    Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI
    Search for articles by this author
  • Percy Pacora
    Affiliations
    Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS), Bethesda, MD, and Detroit, MI

    Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI
    Search for articles by this author
  • Bo Hyun Yoon
    Affiliations
    Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Republic of Korea
    Search for articles by this author
  • Lawrence I. Grossman
    Affiliations
    Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI
    Search for articles by this author
      Metformin is everywhere. Originally introduced in clinical practice as an antidiabetic agent, its role as a therapeutic agent is expanding to include treatment of prediabetes mellitus, gestational diabetes mellitus, and polycystic ovarian disease; more recently, experimental studies and observations in randomized clinical trials suggest that metformin could have a place in the treatment or prevention of preeclampsia. This article provides a brief overview of the history of metformin in the treatment of diabetes mellitus and reviews the results of metaanalyses of metformin in gestational diabetes mellitus as well as the treatment of obese, non-diabetic, pregnant women to prevent macrosomia. We highlight the results of a randomized clinical trial in which metformin administration in early pregnancy did not reduce the frequency of large-for-gestational-age infants (the primary endpoint) but did decrease the frequency of preeclampsia (a secondary endpoint). The mechanisms by which metformin may prevent preeclampsia include a reduction in the production of antiangiogenic factors (soluble vascular endothelial growth factor receptor-1 and soluble endoglin) and the improvement of endothelial dysfunction, probably through an effect on the mitochondria. Another potential mechanism whereby metformin may play a role in the prevention of preeclampsia is its ability to modify cellular homeostasis and energy disposition, mediated by rapamycin, a mechanistic target. Metformin has a molecular weight of 129 Daltons and therefore readily crosses the placenta. There is considerable evidence to suggest that this agent is safe during pregnancy. New literature on the role of metformin as a chemotherapeutic adjuvant in the prevention of cancer and in prolonging life and protecting against aging is reviewed briefly. Herein, we discuss the mechanisms of action and potential benefits of metformin.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to American Journal of Obstetrics & Gynecology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Onken B.
        • Driscoll M.
        Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans Healthspan via AMPK, LKB1, and SKN-1.
        PloS One. 2010; 5: e8758
        • Cabreiro F.
        • Au C.
        • Leung K.Y.
        • et al.
        Metformin retards aging in C elegans by altering microbial folate and methionine metabolism.
        Cell. 2013; 153: 228-239
        • Martin-Montalvo A.
        • Mercken E.M.
        • Mitchell S.J.
        • et al.
        Metformin improves healthspan and lifespan in mice.
        Nat Commun. 2013; 4: 2192
        • De Haes W.
        • Frooninckx L.
        • Van Assche R.
        • et al.
        Metformin promotes lifespan through mitohormesis via the peroxiredoxin PRDX-2.
        Proc Natl Acad Sci U S A. 2014; 111: E2501-E2509
      1. Crandall J. Metformin in Longevity Study (MILES). Clinical Trial.gov., 2015. Available at: https://clinicaltrials.gov/ct2/show/NCT02432287.

        • Barzilai N.
        • Crandall J.P.
        • Kritchevsky S.B.
        • Espeland M.A.
        Metformin as a tool to target aging.
        Cell Metab. 2016; 23: 1060-1065
        • Zhang Z.J.
        • Bi Y.
        • Li S.
        • et al.
        Reduced risk of lung cancer with metformin therapy in diabetic patients: a systematic review and meta-analysis.
        Am J Epidemiol. 2014; 180: 11-14
        • Franciosi M.
        • Lucisano G.
        • Lapice E.
        • Strippoli G.F.
        • Pellegrini F.
        • Nicolucci A.
        Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review.
        PloS One. 2013; 8: e71583
        • Wang Z.
        • Lai S.T.
        • Xie L.
        • et al.
        Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: a systematic review and meta-analysis.
        Diabetes Res Clin Pract. 2014; 106: 19-26
        • Wu L.
        • Zhu J.
        • Prokop L.J.
        • Murad M.H.
        Pharmacologic therapy of diabetes and overall cancer risk and mortality: a meta-analysis of 265 studies.
        Scientific Rep. 2015; 5: 10147
        • Victor V.M.
        • Rovira-Llopis S.
        • Banuls C.
        • et al.
        Metformin modulates human leukocyte/endothelial cell interactions and proinflammatory cytokines in polycystic ovary syndrome patients.
        Atherosclerosis. 2015; 242: 167-173
        • Tan X.
        • Li S.
        • Chang Y.
        • et al.
        Effect of metformin treatment during pregnancy on women with PCOS: a systematic review and meta-analysis.
        Clin Invest Med. 2016; 39: E120-E131
        • Feng L.
        • Lin X.F.
        • Wan Z.H.
        • Hu D.
        • Du Y.K.
        Efficacy of metformin on pregnancy complications in women with polycystic ovary syndrome: a meta-analysis.
        Gynecol Endocrinol. 2015; 31: 833-839
        • Brock B.
        • Smidt K.
        • Ovesen P.
        • Schmitz O.
        • Rungby J.
        Is metformin therapy for polycystic ovary syndrome safe during pregnancy?.
        Basic Clin Pharmacol toxicol. 2005; 96: 410-412
        • Crowley M.J.
        • Diamantidis C.J.
        • McDuffie J.R.
        • et al.
        Clinical outcomes of metformin use in populations with chronic kidney disease, congestive heart failure, or chronic liver disease: a systematic review.
        Ann Intern Med. 2017; 166: 191-200
        • Nath N.
        • Khan M.
        • Paintlia M.K.
        • Singh I.
        • Hoda M.N.
        • Giri S.
        Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis.
        J Immunol. 2009; 182: 8005-8014
        • Negrotto L.
        • Farez M.F.
        • Correale J.
        Immunologic effects of metformin and pioglitazone treatment on metabolic syndrome and multiple sclerosis.
        JAMA Neurol. 2016; 73: 520-528
        • Takiyama Y.
        • Harumi T.
        • Watanabe J.
        • et al.
        Tubular injury in a rat model of type 2 diabetes is prevented by metformin: a possible role of HIF-1alpha expression and oxygen metabolism.
        Diabetes. 2011; 60: 981-992
        • Bhat A.
        • Sebastiani G.
        • Bhat M.
        Systematic review: preventive and therapeutic applications of metformin in liver disease.
        World J Hepatol. 2015; 7: 1652-1659
        • Brownfoot F.C.
        • Hastie R.
        • Hannan N.J.
        • et al.
        Metformin as a prevention and treatment for preeclampsia: effects on soluble fms-like tyrosine kinase 1 and soluble endoglin secretion and endothelial dysfunction.
        Am J Obstet Gynecol. 2016; 214: 356.e1-356.e15
        • American College of Obstetricians and Gynecologists
        • Task Force on Hypertension in Pregnancy
        Hypertension in Pregnancy. Report of the American College of Obstetricians and Gynecologists' Task Force on Hypertension in Pregnancy.
        Obstet Gynecol. 2013; 122: 1122-1131
        • Witters L.A.
        The blooming of the French lilac.
        J Clin Invest. 2001; 108: 1105-1107
        • Bailey C.J.
        • Turner R.C.
        Metformin.
        N Engl J Med. 1996; 334: 574-579
        • Bailey C.J.
        • Day C.
        Metformin: its botanical background.
        Pract Diabetes Int. 2004; 21: 115-117
        • Watanabe C.
        Studies in the metabolic changes induced by administration of guanidine bases.
        J Biol Chem. 1918; 33: 253-265
        • Sterne J.
        Pharmacology and mode of action of the hypoglycaemic guanidine derivatives.
        in: Campbell G.D. Oral hypoglycaemic agents: pharmacology and therapeutics. Academic Press, London, UK1969: 193-245
        • Muller H.
        • Rheinwein H.
        Pharmacology of galegin.
        Arch Expll Path Pharm. 1927; 125: 212-228
        • Simonnet H.
        • Tanret G.
        [Sur les propietes hypoglycemiantes du sulfate de galegine.].
        Bull Soc Chim Biol Paris. 1927; 8
        • Nattrass M.
        • Alberti K.G.
        Biguanides.
        Diabetologia. 1978; 14: 71-74
        • Paulesco N.
        [Recherches sur le role du pancreas dans l’assimilation nutritive.].
        Arch Int Physiol. 1921; 17: 85-109
        • Banting F.G.
        • Best C.H.
        • Collip J.B.
        • Campbell W.R.
        • Fletcher A.A.
        Pancreatic extracts in the treatment of diabetes mellitus.
        Can Med Assoc J. 1922; 12: 141-146
        • Sterne J.
        [Treatment of diabetes mellitus with N,N-dimethylguanylguanidine (LA. 6023, glucophage)].
        Therapie. 1959; 14: 625-630
        • Bernier G.M.
        • Miller M.
        • Springate C.S.
        Lactic acidosis and phenformin hydrochloride.
        JAMA. 1963; 184: 43-46
        • Ewy G.A.
        • Pabico R.C.
        • Maher J.F.
        • Mintz D.H.
        Lactate acidosis associated with phenformin therapy and localized tissue hypoxia: report of a case treated by hemodialysis.
        Ann Intern Med. 1963; 59: 878-883
        • Tranquada R.E.
        • Bernstein S.
        • Martin H.E.
        Irreversible lactic acidosis associated with phenformine therapy: report of three cases.
        JAMA. 1963; 184: 37-42
        • Davidson M.B.
        • Bozarth W.R.
        • Challoner D.R.
        • Goodner C.J.
        Phenformin, hypoglycemia and lactic acidosis: report of attempted suicide.
        N Engl J Med. 1966; 275: 886-888
        • Proctor D.W.
        • Stowers J.M.
        Fatal lactic acidosis after an overdose of phenformin.
        Br Med J. 1967; 4: 216
        • Shirriffs G.G.
        • Bewsher P.D.
        Hypothermia, abdominal pain, and lactic acidosis in phenformin-treated diabetic.
        Br Med J. 1970; 3: 506
        • Nathan D.M.
        • Buse J.B.
        • Davidson M.B.
        • et al.
        Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes.
        Diabetes Care. 2009; 32: 193-203
        • Inzucchi S.E.
        • Bergenstal R.M.
        • Buse J.B.
        • et al.
        Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes.
        Diabetes Care. 2015; 38: 140-149
        • American Diabetes Association
        4. Prevention or delay of type 2 diabetes.
        Diabetes Care. 2016; 39: S36-S38
        • Diabetes Prevention Program Research Group
        Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study.
        Lancet Diabetes Endocrinol. 2015; 3: 866-875
        • Knowler W.C.
        • Barrett-Connor E.
        • Fowler S.E.
        • et al.
        Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.
        N Engl J Med. 2002; 346: 393-403
        • Natali A.
        • Ferrannini E.
        Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review.
        Diabetologia. 2006; 49: 434-441
        • Foretz M.
        • Guigas B.
        • Bertrand L.
        • Pollak M.
        • Viollet B.
        Metformin: from mechanisms of action to therapies.
        Cell Metab. 2014; 20: 953-966
        • Viollet B.
        • Guigas B.
        • Sanz Garcia N.
        • Leclerc J.
        • Foretz M.
        • Andreelli F.
        Cellular and molecular mechanisms of metformin: an overview.
        Clin Sci. 2012; 122: 253-270
        • Coetzee E.J.
        • Jackson W.P.
        Metformin in management of pregnant insulin-independent diabetics.
        Diabetologia. 1979; 16: 241-245
        • Coetzee E.J.
        • Jackson W.P.
        Diabetes newly diagnosed during pregnancy: a 4-year study at Groote Schuur Hospital.
        S Afr Med J. 1979; 56: 467-475
        • Jackson W.P.
        • Coetzee E.J.
        Side-effects of metformin.
        S Afr Med J. 1979; 56: 1113-1114
        • Coetzee E.J.
        • Jackson W.P.
        Pregnancy in established non-insulin-dependent diabetics: a five-and-a-half year study at Groote Schuur Hospital.
        S Afr Med J. 1980; 58: 795-802
        • Elliott B.D.
        • Langer O.
        • Schuessling F.
        Human placental glucose uptake and transport are not altered by the oral antihyperglycemic agent metformin.
        Am J Obstet Gynecol. 1997; 176: 527-530
        • Simmons D.
        • Walters B.N.
        • Rowan J.A.
        • McIntyre H.D.
        Metformin therapy and diabetes in pregnancy.
        Med J Aust. 2004; 180: 462-464
        • Vanky E.
        • Salvesen K.A.
        • Heimstad R.
        • Fougner K.J.
        • Romundstad P.
        • Carlsen S.M.
        Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women: results of a randomized study.
        Hum Reprod. 2004; 19: 1734-1740
        • Coustan D.R.
        Pharmacological management of gestational diabetes: an overview.
        Diabetes Care. 2007; 30: S206-S208
        • Ecker J.L.
        • Greene M.F.
        Gestational diabetes: setting limits, exploring treatments.
        N Engl J Med. 2008; 358: 2061-2063
        • Rowan J.A.
        • Hague W.M.
        • Gao W.
        • Battin M.R.
        • Moore M.P.
        Metformin versus insulin for the treatment of gestational diabetes.
        N Engl J Med. 2008; 358: 2003-2015
        • Paglia M.J.
        • Coustan D.R.
        The use of oral antidiabetic medications in gestational diabetes mellitus.
        Curr Diabetes Rep. 2009; 9: 287-290
        • Glueck C.J.
        • Goldenberg N.
        • Streicher P.
        • Wang P.
        The contentious nature of gestational diabetes: diet, insulin, glyburide and metformin.
        Expert Opin Pharmacother. 2002; 3: 1557-1568
        • Glueck C.J.
        • Wang P.
        • Kobayashi S.
        • Phillips H.
        • Sieve-Smith L.
        Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome.
        Fertil Steril. 2002; 77: 520-525
        • Glueck C.J.
        • Goldenberg N.
        • Streicher P.
        • Wang P.
        Metformin and gestational diabetes.
        Current Diabetes Rep. 2003; 3: 303-312
        • Homko C.J.
        • Reece E.A.
        Insulins and oral hypoglycemic agents in pregnancy.
        J Matern Fetal Neonatal Med. 2006; 19: 679-686
        • Metzger B.E.
        Diet and medical therapy in the optimal management of gestational diabetes mellitus.
        Nestle Nutr Workshop Ser Clin Perform programme. 2006; 11 (discussion 65-9): 155-165
        • Eyal S.
        • Easterling T.R.
        • Carr D.
        • et al.
        Pharmacokinetics of metformin during pregnancy.
        Drug Metabo Dispos. 2010; 38: 833-840
        • Ballas J.
        • Moore T.R.
        • Ramos G.A.
        Management of diabetes in pregnancy.
        Current Diabetes Rep. 2012; 12: 33-42
        • Langer O.
        Oral hypoglycemic agents: do the ends justify the means? Matern Health.
        Neonatol Perinatol. 2015; 1: 19
        • Ma R.C.
        • Schmidt M.I.
        • Tam W.H.
        • McIntyre H.D.
        • Catalano P.M.
        Clinical management of pregnancy in the obese mother: before conception, during pregnancy, and post partum.
        Lancet Diabetes Endocrinol. 2016; 4: 1037-1049
        • Magon N.
        • Seshiah V.
        Gestational diabetes mellitus: non-insulin management.
        Indian J Endocrinol Metab. 2011; 15: 284-293
        • Kampmann U.
        • Madsen L.R.
        • Skajaa G.O.
        • Iversen D.S.
        • Moeller N.
        • Ovesen P.
        Gestational diabetes: a clinical update.
        World J Diabetes. 2015; 6: 1065-1072
        • DeFronzo R.A.
        • Goodman A.M.
        Efficacy of metformin in patients with noninsulin-dependent diabetes mellitus. The Multicenter Metformin Study Group.
        N Engl J Med. 1995; 333: 541-549
      2. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group.
        Lancet. 1998; 352: 854-865
        • Ijas H.
        • Vaarasmaki M.
        • Morin-Papunen L.
        • et al.
        Metformin should be considered in the treatment of gestational diabetes: a prospective randomised study.
        BJOG. 2011; 118: 880-885
        • Moore L.E.
        • Briery C.M.
        • Clokey D.
        • et al.
        Metformin and insulin in the management of gestational diabetes mellitus: preliminary results of a comparison.
        J Reprod Med. 2007; 52: 1011-1015
        • Niromanesh S.
        • Alavi A.
        • Sharbaf F.R.
        • 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: 422-429
        • Tertti K.
        • Ekblad U.
        • Koskinen P.
        • Vahlberg T.
        • Ronnemaa T.
        Metformin vs insulin in gestational diabetes: a randomized study characterizing metformin patients needing additional insulin.
        Diabetes Obes Metab. 2013; 15: 246-251
        • Gui J.
        • Liu Q.
        • Feng L.
        Metformin vs insulin in the management of gestational diabetes: a meta-analysis.
        PloS One. 2013; 8: e64585
        • Feng Y.
        • Yang H.
        Metformin: a potentially effective drug for gestational diabetes mellitus: a systematic review and meta-analysis.
        J Matern Fetal Neonatal Med. 2017; 30: 1874-1881
        • Butalia S.
        • Gutierrez L.
        • Lodha A.
        • Aitken E.
        • Zakariasen A.
        • Donovan L.
        Short- and long-term outcomes of metformin compared with insulin alone in pregnancy: a systematic review and meta-analysis.
        Diabetic Med. 2017; 34: 27-36
        • Hickman M.A.
        • McBride R.
        • Boggess K.A.
        • Strauss R.
        Metformin compared with insulin in the treatment of pregnant women with overt diabetes: a randomized controlled trial.
        Am J Perinatol. 2013; 30: 483-490
        • Spaulonci C.P.
        • Bernardes L.S.
        • Trindade T.C.
        • Zugaib M.
        • Francisco R.P.
        Randomized trial of metformin vs insulin in the management of gestational diabetes.
        Am J Obstet Gynecol. 2013; 209: 34.e1-34.e7
        • Ibrahim M.I.
        • Hamdy A.
        • Shafik A.
        • Taha S.
        • Anwar M.
        • Faris M.
        The role of adding metformin in insulin-resistant diabetic pregnant women: a randomized controlled trial.
        Arch Gynecol Obstet. 2014; 289: 959-965
        • Ruholamin S.
        • Eshaghian S.
        • Allame Z.
        Neonatal outcomes in women with gestational diabetes mellitus treated with metformin in compare with insulin: a randomized clinical trial.
        J res med sci. 2014; 19: 970-975
        • Ainuddin J.
        • Karim N.
        • Hasan A.A.
        • Naqvi S.A.
        Metformin versus insulin treatment in gestational diabetes in pregnancy in a developing country: a randomized control trial.
        Diabetes Res Clin Pract. 2015; 107: 290-299
        • Refuerzo J.S.
        • Gowen R.
        • Pedroza C.
        • Hutchinson M.
        • Blackwell S.C.
        • Ramin S.
        A pilot randomized, controlled trial of metformin versus insulin in women with type 2 diabetes mellitus during pregnancy.
        American J Perinatol. 2015; 30: 163-170
        • Rodgers G.M.
        • Taylor R.N.
        • Roberts J.M.
        Preeclampsia is associated with a serum factor cytotoxic to human endothelial cells.
        Am J Obstet Gynecol. 1988; 159: 908-914
        • Roberts J.M.
        • Taylor R.N.
        • Musci T.J.
        • Rodgers G.M.
        • Hubel C.A.
        • McLaughlin M.K.
        Preeclampsia: an endothelial cell disorder.
        Am J Obstet Gynecol. 1989; 161: 1200-1204
        • Myatt L.
        • Webster R.P.
        Vascular biology of preeclampsia.
        J Thromb Haemost. 2009; 7: 375-384
        • Myatt L.
        • Kossenjans W.
        • Sahay R.
        • Eis A.
        • Brockman D.
        Oxidative stress causes vascular dysfunction in the placenta.
        J Matern Fetal Med. 2000; 9: 79-82
        • Hubel C.A.
        • Kozlov A.V.
        • Kagan V.E.
        • et al.
        Decreased transferrin and increased transferrin saturation in sera of women with preeclampsia: implications for oxidative stress.
        Am J Obstet Gynecol. 1996; 175: 692-700
        • Many A.
        • Hubel C.A.
        • Roberts J.M.
        Hyperuricemia and xanthine oxidase in preeclampsia, revisited.
        Am J Obstet Gynecol. 1996; 174: 288-291
        • Burton G.J.
        • Jauniaux E.
        Placental oxidative stress: from miscarriage to preeclampsia.
        J Soc Gynecol Investig. 2004; 11: 342-352
        • Burton G.J.
        • Yung H.W.
        • Cindrova-Davies T.
        • Charnock-Jones D.S.
        Placental endoplasmic reticulum stress and oxidative stress in the pathophysiology of unexplained intrauterine growth restriction and early onset preeclampsia.
        Placenta. 2009; 30: S43-S48
        • Myatt L.
        Review: reactive oxygen and nitrogen species and functional adaptation of the placenta.
        Placenta. 2010; 31: S66-S69
        • Burton G.J.
        • Jauniaux E.
        Oxidative stress.
        Best Pract Res Clin Obstet Gynaecol. 2011; 25: 287-299
        • Ilekis J.V.
        • Tsilou E.
        • Fisher S.
        • et al.
        Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
        Am J Obstet Gynecol. 2016; 215: S1-S46
        • Chiswick C.
        • Reynolds R.M.
        • Denison F.
        • et al.
        Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial.
        Lancet Diabetes Endocrinol. 2015; 3: 778-786
        • Syngelaki A.
        • Nicolaides K.H.
        • Balani J.
        • et al.
        Metformin versus placebo in obese pregnant women without diabetes mellitus.
        N Engl J Med. 2016; 374: 434-443
        • Cramer J.A.
        • Spilker B.
        Patient compliance in medical practice and clinical trials.
        Raven Press, New York1991: 387-392
        • Cramer J.A.
        Effect of partial compliance on cardiovascular medication effectiveness.
        Heart. 2002; 88: 203-206
        • Cramer J.
        • Rosenheck R.
        • Kirk G.
        • Krol W.
        • Krystal J.
        • Group VANS
        Medication compliance feedback and monitoring in a clinical trial: predictors and outcomes.
        Value Health. 2003; 6: 566-573
        • Cramer J.A.
        • Roy A.
        • Burrell A.
        • et al.
        Medication compliance and persistence: terminology and definitions.
        Value Health. 2008; 11: 44-47
        • Shingler S.L.
        • Bennett B.M.
        • Cramer J.A.
        • Towse A.
        • Twelves C.
        • Lloyd A.J.
        Treatment preference, adherence and outcomes in patients with cancer: literature review and development of a theoretical model.
        Curr Med Res Opin. 2014; 30: 2329-2341
        • Romero R.
        • Lockwood C.
        • Oyarzun E.
        • Hobbins J.C.
        Toxemia: new concepts in an old disease.
        Semin Perinatol. 1988; 12: 302-323
        • Sibai B.
        • Dekker G.
        • Kupferminc M.
        Pre-eclampsia.
        Lancet. 2005; 365: 785-799
        • Young B.C.
        • Levine R.J.
        • Karumanchi S.A.
        Pathogenesis of preeclampsia.
        Ann Rev Pathol. 2010; 5: 173-192
        • Brosens I.
        • Pijnenborg R.
        • Vercruysse L.
        • Romero R.
        The “Great Obstetrical Syndromes” are associated with disorders of deep placentation.
        Am J Obstet Gynecol. 2011; 204: 193-201
        • Maynard S.E.
        • Karumanchi S.A.
        Angiogenic factors and preeclampsia.
        Semin Nephrol. 2011; 31: 33-46
        • Redman C.W.
        Preeclampsia: a multi-stress disorder.
        Rev Med Interne. 2011; 32: S41-S44
        • Tranquilli A.L.
        • Landi B.
        • Giannubilo S.R.
        • Sibai B.M.
        Preeclampsia: no longer solely a pregnancy disease.
        Pregnancy Hypertens. 2012; 2: 350-357
        • Staff A.C.
        • Benton S.J.
        • von Dadelszen P.
        • et al.
        Redefining preeclampsia using placenta-derived biomarkers.
        Hypertension. 2013; 61: 932-942
        • Staff A.C.
        • Dechend R.
        • Redman C.W.
        Review: preeclampsia, acute atherosis of the spiral arteries and future cardiovascular disease: two new hypotheses.
        Placenta. 2013; 34: S73-S78
        • Chaiworapongsa T.
        • Chaemsaithong P.
        • Korzeniewski S.J.
        • Yeo L.
        • Romero R.
        Pre-eclampsia part 2: prediction, prevention and management.
        Nat Rev Nephrol. 2014; 10: 531-540
        • Roberts J.M.
        Pathophysiology of ischemic placental disease.
        Semin Perinatol. 2014; 38: 139-145
        • Redman C.W.
        • Staff A.C.
        Preeclampsia, biomarkers, syncytiotrophoblast stress, and placental capacity.
        Am J Obstet Gynecol. 2015; 213: S9.e1-S9.e11
        • Hod T.
        • Cerdeira A.S.
        • Karumanchi S.A.
        Molecular mechanisms of preeclampsia. Cold Spring Harbor Perspect Med.
        . 2015; 5
        • Myatt L.
        • Roberts J.M.
        Preeclampsia: syndrome or disease?.
        Current Hypertens Rep. 2015; 17: 83
        • Fisher S.J.
        Why is placentation abnormal in preeclampsia?.
        Am J Obstet Gynecol. 2015; 213: S115-S122
        • Sircar M.
        • Thadhani R.
        • Karumanchi S.A.
        Pathogenesis of preeclampsia.
        Curr Opin Nephrol Hypertens. 2015; 24: 131-138
        • Korzeniewski S.J.
        • Romero R.
        • Chaiworapongsa T.
        • et al.
        Maternal plasma angiogenic index-1 (placental growth factor/soluble vascular endothelial growth factor receptor-1) is a biomarker for the burden of placental lesions consistent with uteroplacental underperfusion: a longitudinal case-cohort study.
        Am J Obstet Gynecol. 2016; 214: 629.e1-629.e17
        • Chaiworapongsa T.
        • Romero R.
        • Espinoza J.
        • et al.
        Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia: Young Investigator Award.
        Am J Obstet Gynecol. 2004; 190: 1541-1550
        • Chaiworapongsa T.
        • Romero R.
        • Kim Y.M.
        • et al.
        Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia.
        J Matern Fetal Neonatal Med. 2005; 17: 3-18
        • Bujold E.
        • Romero R.
        • Chaiworapongsa T.
        • et al.
        Evidence supporting that the excess of the sVEGFR-1 concentration in maternal plasma in preeclampsia has a uterine origin.
        J Matern Fetal Neonatal Med. 2005; 18: 9-16
        • Park C.W.
        • Park J.S.
        • Shim S.S.
        • Jun J.K.
        • Yoon B.H.
        • Romero R.
        An elevated maternal plasma, but not amniotic fluid, soluble fms-like tyrosine kinase-1 (sFlt-1) at the time of mid-trimester genetic amniocentesis is a risk factor for preeclampsia.
        Am J Obstet Gynecol. 2005; 193: 984-989
        • Espinoza J.
        • Romero R.
        • Nien J.K.
        • et al.
        A role of the anti-angiogenic factor sVEGFR-1 in the ‘mirror syndrome’ (Ballantyne’s syndrome).
        J Matern Fetal Neonatal Med. 2006; 19: 607-613
        • Venkatesha S.
        • Toporsian M.
        • Lam C.
        • et al.
        Soluble endoglin contributes to the pathogenesis of preeclampsia.
        Nat Med. 2006; 12: 642-649
        • Levine R.J.
        • Lam C.
        • Qian C.
        • et al.
        Soluble endoglin and other circulating antiangiogenic factors in preeclampsia.
        N Engl J Med. 2006; 355: 992-1005
        • Espinoza J.
        • Romero R.
        • Nien J.K.
        • et al.
        Identification of patients at risk for early onset and/or severe preeclampsia with the use of uterine artery Doppler velocimetry and placental growth factor.
        Am J Obstet Gynecol. 2007; 196: 326.e1-326.e13
        • Chaiworapongsa T.
        • Espinoza J.
        • Gotsch F.
        • et al.
        The maternal plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated in SGA and the magnitude of the increase relates to Doppler abnormalities in the maternal and fetal circulation.
        J Matern Fetal Neonatal Med. 2008; 21: 25-40
        • Erez O.
        • Romero R.
        • Espinoza J.
        • et al.
        The change in concentrations of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters in risk assessment for the subsequent development of preeclampsia and small-for-gestational age.
        J Matern Fetal Neonatal Med. 2008; 21: 279-287
        • Romero R.
        • Nien J.K.
        • Espinoza J.
        • et al.
        A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate.
        J Matern Fetal Neonatal Med. 2008; 21: 9-23
        • Than N.G.
        • Romero R.
        • Hillermann R.
        • Cozzi V.
        • Nie G.
        • Huppertz B.
        Prediction of preeclampsia: a workshop report.
        Placenta. 2008; 29: S83-S85
        • Toft J.H.
        • Lian I.A.
        • Tarca A.L.
        • et al.
        Whole-genome microarray and targeted analysis of angiogenesis-regulating gene expression (ENG, FLT1, VEGF, PlGF) in placentas from pre-eclamptic and small-for-gestational-age pregnancies.
        J Matern Fetal Neonatal Med. 2008; 21: 267-273
        • Kusanovic J.P.
        • Romero R.
        • Chaiworapongsa T.
        • et al.
        A prospective cohort study of the value of maternal plasma concentrations of angiogenic and anti-angiogenic factors in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia.
        J Matern Fetal Neonatal Med. 2009; 22: 1021-1038
        • Chaiworapongsa T.
        • Romero R.
        • Savasan Z.A.
        • et al.
        Maternal plasma concentrations of angiogenic/anti-angiogenic factors are of prognostic value in patients presenting to the obstetrical triage area with the suspicion of preeclampsia.
        J Matern Fetal Neonatal Med. 2011; 24: 1187-1207
        • Romero R.
        • Chaiworapongsa T.
        • Erez O.
        • et al.
        An imbalance between angiogenic and anti-angiogenic factors precedes fetal death in a subset of patients: results of a longitudinal study.
        J Matern Fetal Neonatal Med. 2010; 23: 1384-1399
        • Vaisbuch E.
        • Whitty J.E.
        • Hassan S.S.
        • et al.
        Circulating angiogenic and antiangiogenic factors in women with eclampsia.
        Am J Obstet Gynecol. 2011; 204: 152.e1-152.e9
        • Soto E.
        • Romero R.
        • Kusanovic J.P.
        • et al.
        Late-onset preeclampsia is associated with an imbalance of angiogenic and anti-angiogenic factors in patients with and without placental lesions consistent with maternal underperfusion.
        J Matern Fetal Neonatal Med. 2012; 25: 498-507
        • Chaiworapongsa T.
        • Romero R.
        • Korzeniewski S.J.
        • et al.
        Maternal plasma concentrations of angiogenic/antiangiogenic factors in the third trimester of pregnancy to identify the patient at risk for stillbirth at or near term and severe late preeclampsia.
        Am J Obstet Gynecol. 2013; 208: 287.e1-287.e15
        • Chaiworapongsa T.
        • Romero R.
        • Korzeniewski S.J.
        • et al.
        Plasma concentrations of angiogenic/anti-angiogenic factors have prognostic value in women presenting with suspected preeclampsia to the obstetrical triage area: a prospective study.
        J Matern Fetal Neonatal Med. 2014; 27: 132-144
        • Adekola H.
        • Romero R.
        • Chaemsaithong P.
        • et al.
        Endocan, a putative endothelial cell marker, is elevated in preeclampsia, decreased in acute pyelonephritis, and unchanged in other obstetrical syndromes.
        J Matern Fetal Neonatal Med. 2015; 28: 1621-1632
        • Faupel-Badger J.M.
        • McElrath T.F.
        • Lauria M.
        • et al.
        Maternal circulating angiogenic factors in twin and singleton pregnancies.
        Am J Obstet Gynecol. 2015; 212: 636.e1-636.e8
        • Szalai G.
        • Romero R.
        • Chaiworapongsa T.
        • et al.
        Full-length human placental sFlt-1-e15a isoform induces distinct maternal phenotypes of preeclampsia in mice.
        PloS One. 2015; 10: e0119547
        • Chaiworapongsa T.
        • Romero R.
        • Whitten A.E.
        • et al.
        The use of angiogenic biomarkers in maternal blood to identify which SGA fetuses will require a preterm delivery and mothers who will develop pre-eclampsia.
        J Matern Fetal Neonatal Med. 2016; 29: 1214-1228
        • Chaiworapongsa T.
        • Chaemsaithong P.
        • Yeo L.
        • Romero R.
        Pre-eclampsia part 1: current understanding of its pathophysiology.
        Nat Rev Nephrol. 2014; 10: 466-480
        • Ogge G.
        • Romero R.
        • Kusanovic J.P.
        • et al.
        Serum and plasma determination of angiogenic and anti-angiogenic factors yield different results: the need for standardization in clinical practice.
        J Matern Fetal Neonatal Med. 2010; 23: 820-827
        • Powers R.W.
        • Jeyabalan A.
        • Clifton R.G.
        • et al.
        Soluble fms-Like tyrosine kinase 1 (sFlt1), endoglin and placental growth factor (PlGF) in preeclampsia among high risk pregnancies.
        PloS One. 2010; 5: e13263
        • Rana S.
        • Powe C.E.
        • Salahuddin S.
        • et al.
        Angiogenic factors and the risk of adverse outcomes in women with suspected preeclampsia.
        Circulation. 2012; 125: 911-919
        • Baltajian K.
        • Bajracharya S.
        • Salahuddin S.
        • et al.
        Sequential plasma angiogenic factors levels in women with suspected preeclampsia.
        Am J Obstet Gynecol. 2016; 215: 89.e1-89.e10
        • Karumanchi S.A.
        Angiogenic factors in preeclampsia: from diagnosis to therapy.
        Hypertension. 2016; 67: 1072-1079
        • Holme A.M.
        • Roland M.C.
        • Henriksen T.
        • Michelsen T.M.
        In vivo uteroplacental release of placental growth factor and soluble Fms-like tyrosine kinase-1 in normal and preeclamptic pregnancies.
        Am J Obstet Gynecol. 2016; 215: 782.e1-782.e9
        • Malshe A.K.
        • Sibai B.M.
        Angiogenic and antiangiogenic markers for prediction and risk classification of preeclampsia.
        Clin Obstet Gynecol. 2017; 60: 134-140
        • Levine R.J.
        • Maynard S.E.
        • Qian C.
        • et al.
        Circulating angiogenic factors and the risk of preeclampsia.
        N Engl J Med. 2004; 350: 672-683
        • Lai J.
        • Garcia-Tizon Larroca S.
        • Peeva G.
        • Poon L.C.
        • Wright D.
        • Nicolaides K.H.
        Competing risks model in screening for preeclampsia by serum placental growth factor and soluble fms-like tyrosine kinase-1 at 30-33 weeks’ gestation.
        Fetal Diagn Ther. 2014; 35: 240-248
        • Tsiakkas A.
        • Saiid Y.
        • Wright A.
        • Wright D.
        • Nicolaides K.H.
        Competing risks model in screening for preeclampsia by maternal factors and biomarkers at 30-34 weeks’ gestation.
        Am J Obstet Gynecol. 2016; 215: 87.e1-87.e17
        • Lam C.
        • Lim K.H.
        • Karumanchi S.A.
        Circulating angiogenic factors in the pathogenesis and prediction of preeclampsia.
        Hypertension. 2005; 46: 1077-1085
        • Gallo D.M.
        • Wright D.
        • Casanova C.
        • Campanero M.
        • Nicolaides K.H.
        Competing risks model in screening for preeclampsia by maternal factors and biomarkers at 19-24 weeks' gestation.
        Am J Obstet Gynecol. 2016; 214: 619.e1-619.e17
        • Moore Simas T.A.
        • Crawford S.L.
        • Solitro M.J.
        • Frost S.C.
        • Meyer B.A.
        • Maynard S.E.
        Angiogenic factors for the prediction of preeclampsia in high-risk women.
        Am J Obstet Gynecol. 2007; 197: 244.e1-244.e8
        • Stepan H.
        • Unversucht A.
        • Wessel N.
        • Faber R.
        Predictive value of maternal angiogenic factors in second trimester pregnancies with abnormal uterine perfusion.
        Hypertension. 2007; 49: 818-824
        • Diab A.E.
        • El-Behery M.M.
        • Ebrahiem M.A.
        • Shehata A.E.
        Angiogenic factors for the prediction of pre-eclampsia in women with abnormal midtrimester uterine artery Doppler velocimetry.
        Int J Gynaecol Obstet. 2008; 102: 146-151
        • Stepan H.
        • Geipel A.
        • Schwarz F.
        • Kramer T.
        • Wessel N.
        • Faber R.
        Circulatory soluble endoglin and its predictive value for preeclampsia in second-trimester pregnancies with abnormal uterine perfusion.
        Am J Obstet Gynecol. 2008; 198: 175.e1-175.e6
        • Garovic V.D.
        The role of angiogenic factors in the prediction and diagnosis of preeclampsia superimposed on chronic hypertension.
        Hypertension. 2012; 59: 555-557
        • Hagmann H.
        • Thadhani R.
        • Benzing T.
        • Karumanchi S.A.
        • Stepan H.
        The promise of angiogenic markers for the early diagnosis and prediction of preeclampsia.
        Clin Chem. 2012; 58: 837-845
        • Holmes V.A.
        • Young I.S.
        • Patterson C.C.
        • et al.
        The role of angiogenic and antiangiogenic factors in the second trimester in the prediction of preeclampsia in pregnant women with type 1 diabetes.
        Diabetes Care. 2013; 36: 3671-3677
        • McElrath T.F.
        • Lim K.H.
        • Pare E.
        • et al.
        Longitudinal evaluation of predictive value for preeclampsia of circulating angiogenic factors through pregnancy.
        Am J Obstet Gynecol. 2012; 207: 407.e1-407.e7
        • Zeisler H.
        • Llurba E.
        • Chantraine F.
        • et al.
        Predictive Value of the sFlt-1:PlGF Ratio in Women with Suspected Preeclampsia.
        N Engl J Med. 2016; 374: 13-22
        • Myers J.E.
        • Kenny L.C.
        • McCowan L.M.
        • et al.
        Angiogenic factors combined with clinical risk factors to predict preterm pre-eclampsia in nulliparous women: a predictive test accuracy study.
        BJOG. 2013; 120: 1215-1223
        • Poston L.
        Prediction and diagnosis of pre-eclampsia; the scientific basis.
        Pregnancy Hypertens. 2013; 3: 57
        • Verlohren S.
        • Stepan H.
        • Dechend R.
        Angiogenic growth factors in the diagnosis and prediction of pre-eclampsia.
        Clin Sci. 2012; 122: 43-52
        • Akolekar R.
        • Zaragoza E.
        • Poon L.C.
        • Pepes S.
        • Nicolaides K.H.
        Maternal serum placental growth factor at 11 + 0 to 13 + 6 weeks of gestation in the prediction of pre-eclampsia.
        Ultrasound Obstet Gynecol. 2008; 32: 732-739
        • Foidart J.M.
        • Munaut C.
        • Chantraine F.
        • Akolekar R.
        • Nicolaides K.H.
        Maternal plasma soluble endoglin at 11-13 weeks’ gestation in pre-eclampsia.
        Ultrasound Obstet Gynecol. 2010; 35: 680-687
        • Crovetto F.
        • Figueras F.
        • Triunfo S.
        • et al.
        Added value of angiogenic factors for the prediction of early and late preeclampsia in the first trimester of pregnancy.
        Fetal Diagn Ther. 2014; 35: 258-266
        • Garcia-Tizon Larroca S.
        • Tayyar A.
        • Poon L.C.
        • Wright D.
        • Nicolaides K.H.
        Competing risks model in screening for preeclampsia by biophysical and biochemical markers at 30-33 weeks’ gestation.
        Fetal Diagn Ther. 2014; 36: 9-17
        • Moore Simas T.A.
        • Crawford S.L.
        • Bathgate S.
        • et al.
        Angiogenic biomarkers for prediction of early preeclampsia onset in high-risk women.
        J Matern Fetal Neonatal Med. 2014; 27: 1038-1048
        • Crovetto F.
        • Figueras F.
        • Triunfo S.
        • et al.
        First trimester screening for early and late preeclampsia based on maternal characteristics, biophysical parameters, and angiogenic factors.
        Prenatal Diagn. 2015; 35: 183-191
        • Widmer M.
        • Cuesta C.
        • Khan K.S.
        • et al.
        Accuracy of angiogenic biomarkers at 20weeks’ gestation in predicting the risk of pre-eclampsia: a WHO multicentre study.
        Pregnancy Hypertens. 2015; 5: 330-338
        • Di Martino D.
        • Cetin I.
        • Frusca T.
        • et al.
        Italian Advisory Board: sFlt-1/PlGF ratio and preeclampsia, state of the art and developments in diagnostic, therapeutic and clinical management.
        Eur J Obstet Gynecol Reprod Biol. 2016; 206: 70-73
        • Kienast C.
        • Moya W.
        • Rodriguez O.
        • Jijon A.
        • Geipel A.
        Predictive value of angiogenic factors, clinical risk factors and uterine artery Doppler for pre-eclampsia and fetal growth restriction in second and third trimester pregnancies in an Ecuadorian population.
        J Matern Fetal Neonatal Med. 2016; 29: 537-543
        • Khalil A.
        • Maiz N.
        • Garcia-Mandujano R.
        • Penco J.M.
        • Nicolaides K.H.
        Longitudinal changes in maternal serum placental growth factor and soluble fms-like tyrosine kinase-1 in women at increased risk of pre-eclampsia.
        Ultrasound Obstet Gynecol. 2016; 47: 324-331
        • Lai J.
        • Pinas A.
        • Poon L.C.
        • Agathokleous M.
        • Nicolaides K.H.
        Maternal serum placental growth factor, pregnancy-associated plasma protein-a and free beta-human chorionic gonadotrophin at 30-33 weeks in the prediction of pre-eclampsia.
        Fetal Diagn Ther. 2013; 33: 164-172
        • Nucci M.
        • Poon L.C.
        • Demirdjian G.
        • Darbouret B.
        • Nicolaides K.H.
        Maternal serum placental growth factor (PlGF) isoforms 1 and 2 at 11-13 weeks’ gestation in normal and pathological pregnancies.
        Fetal Diagn Ther. 2014; 36: 106-116
        • Maynard S.E.
        • Min J.Y.
        • Merchan J.
        • et al.
        Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia.
        J Clin Invest. 2003; 111: 649-658
        • Weinstein L.
        Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy.
        Am J Obstet Gynecol. 1982; 142: 159-167
        • Romero R.
        • Vizoso J.
        • Emamian M.
        • et al.
        Clinical significance of liver dysfunction in pregnancy-induced hypertension.
        Am J Perinatol. 1988; 5: 146-151
        • Abildgaard U.
        • Heimdal K.
        Pathogenesis of the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP): a review.
        Eur J Obstet Gynecol Reprod Biol. 2013; 166: 117-123
        • Szabo S.
        • Mody M.
        • Romero R.
        • et al.
        Activation of villous trophoblastic p38 and ERK1/2 signaling pathways in preterm preeclampsia and HELLP syndrome.
        Pathol Oncol Res. 2015; 21: 659-668
        • Weel I.C.
        • Baergen R.N.
        • Romao-Veiga M.
        • et al.
        Association between placental lesions, cytokines and angiogenic factors in pregnant women with preeclampsia.
        PloS One. 2016; 11: e0157584
        • Ananth C.V.
        • Peltier M.R.
        • Chavez M.R.
        • Kirby R.S.
        • Getahun D.
        • Vintzileos A.M.
        Recurrence of ischemic placental disease.
        Obstet Gynecol. 2007; 110: 128-133
        • Ananth C.V.
        • Peltier M.R.
        • Kinzler W.L.
        • Smulian J.C.
        • Vintzileos A.M.
        Chronic hypertension and risk of placental abruption: is the association modified by ischemic placental disease?.
        Am J Obstet Gynecol. 2007; 197: 273.e1-273.e7
        • Ananth C.V.
        • Smulian J.C.
        • Vintzileos A.M.
        Ischemic placental disease: maternal versus fetal clinical presentations by gestational age.
        J Matern Fetal Neonatal Med. 2010; 23: 887-893
        • Ananth C.V.
        • Vintzileos A.M.
        Ischemic placental disease: epidemiology and risk factors.
        Eur J Obstet Gynecol Reprod Biol. 2011; 159: 77-82
        • Vince G.S.
        • Starkey P.M.
        • Austgulen R.
        • Kwiatkowski D.
        • Redman C.W.
        Interleukin-6, tumour necrosis factor and soluble tumour necrosis factor receptors in women with pre-eclampsia.
        Br J Obstet Gynaecol. 1995; 102: 20-25
        • Bartha J.L.
        • Romero-Carmona R.
        • Escobar-Llompart M.
        • Comino-Delgado R.
        The relationships between leptin and inflammatory cytokines in women with pre-eclampsia.
        BJOG. 2001; 108: 1272-1276
        • Velzing-Aarts F.V.
        • Muskiet F.A.
        • van der Dijs F.P.
        • Duits A.J.
        High serum interleukin-8 levels in afro-caribbean women with pre-eclampsia: relations with tumor necrosis factor-alpha, duffy negative phenotype and von Willebrand factor.
        Am j reprod immunol. 2002; 48: 319-322
        • Visser W.
        • Beckmann I.
        • Knook M.A.
        • Wallenburg H.C.
        Soluble tumor necrosis factor receptor II and soluble cell adhesion molecule 1 as markers of tumor necrosis factor-alpha release in preeclampsia.
        Acta Obstet Gynecol Scand. 2002; 81: 713-719
        • Tosun M.
        • Celik H.
        • Avci B.
        • Yavuz E.
        • Alper T.
        • Malatyalioglu E.
        Maternal and umbilical serum levels of interleukin-6, interleukin-8, and tumor necrosis factor-alpha in normal pregnancies and in pregnancies complicated by preeclampsia.
        J Matern Fetal Neonatal Med. 2010; 23: 880-886
        • Szarka A.
        • Rigo Jr., J.
        • Lazar L.
        • Beko G.
        • Molvarec A.
        Circulating cytokines, chemokines and adhesion molecules in normal pregnancy and preeclampsia determined by multiplex suspension array.
        BMC Immunol. 2010; 11: 59
        • Torbergsen T.
        • Oian P.
        • Mathiesen E.
        • Borud O.
        Pre-eclampsia: a mitochondrial disease?.
        Acta Obstet Gynecol Scand. 1989; 68: 145-148
        • Masoura S.
        • Makedou K.
        • Theodoridis T.
        • Kourtis A.
        • Zepiridis L.
        • Athanasiadis A.
        The involvement of uric acid in the pathogenesis of preeclampsia.
        Curr Hypertens Rev. 2015; 11: 110-115
        • Shanklin D.R.
        • Sibai B.M.
        Ultrastructural aspects of preeclampsia: II, mitochondrial changes.
        Am J Obstet Gynecol. 1990; 163: 943-953
        • Berkowitz K.
        • Monteagudo A.
        • Marks F.
        • Jackson U.
        • Baxi L.
        Mitochondrial myopathy and preeclampsia associated with pregnancy.
        Am J Obstet Gynecol. 1990; 162: 146-147
        • Shi Z.
        • Long W.
        • Zhao C.
        • Guo X.
        • Shen R.
        • Ding H.
        Comparative proteomics analysis suggests that placental mitochondria are involved in the development of pre-eclampsia.
        PloS One. 2013; 8: e64351
        • Qiu C.
        • Hevner K.
        • Enquobahrie D.A.
        • Williams M.A.
        A case-control study of maternal blood mitochondrial DNA copy number and preeclampsia risk.
        Int J Mol Epidemiol Genet. 2012; 3: 237-244
        • Bonney E.A.
        Preeclampsia: a view through the danger model.
        J Reprod Immunol. 2007; 76: 68-74
        • Mando C.
        • De Palma C.
        • Stampalija T.
        • et al.
        Placental mitochondrial content and function in intrauterine growth restriction and preeclampsia.
        Am J Physiol Endocrinol Metab. 2014; 306: E404-E413
        • Zhu X.M.
        • Han T.
        • Sargent I.L.
        • Yin G.W.
        • Yao Y.Q.
        Differential expression profile of microRNAs in human placentas from preeclamptic pregnancies vs normal pregnancies.
        Am J Obstet Gynecol. 2009; 200: 661.e1-661.e7
        • Pineles B.L.
        • Romero R.
        • Montenegro D.
        • et al.
        Distinct subsets of microRNAs are expressed differentially in the human placentas of patients with preeclampsia.
        Am J Obstet Gynecol. 2007; 196: 261.e1-261.e6
        • Lee D.C.
        • Romero R.
        • Kim J.S.
        • et al.
        MiR-210 targets iron-sulfur cluster scaffold homologue in human trophoblast cell lines: siderosis of interstitial trophoblasts as a novel pathology of preterm preeclampsia and small-for-gestational-age pregnancies.
        Am J Pathol. 2011; 179: 590-602
        • Muralimanoharan S.
        • Maloyan A.
        • Mele J.
        • Guo C.
        • Myatt L.G.
        • Myatt L.
        MIR-210 modulates mitochondrial respiration in placenta with preeclampsia.
        Placenta. 2012; 33: 816-823
        • Vishnyakova P.A.
        • Volodina M.A.
        • Tarasova N.V.
        • et al.
        Mitochondrial role in adaptive response to stress conditions in preeclampsia.
        Sci Rep. 2016; 6: 32410
        • Bianco-Miotto T.
        • Blundell C.
        • Buckberry S.
        • et al.
        IFPA meeting 2015 workshop report I: placental mitochondrial function, transport systems and epigenetics.
        Placenta. 2016; 48: S3-S6
        • Owen M.R.
        • Doran E.
        • Halestrap A.P.
        Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain.
        Biochem J. 2000; 348: 607-614
        • Hur K.Y.
        • Lee M.S.
        New mechanisms of metformin action: Focusing on mitochondria and the gut.
        J Diabetes Investig. 2015; 6: 600-609
        • Madiraju A.K.
        • Erion D.M.
        • Rahimi Y.
        • et al.
        Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase.
        Nature. 2014; 510: 542-546
        • Selak M.A.
        • Armour S.M.
        • MacKenzie E.D.
        • et al.
        Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase.
        Cancer Cell. 2005; 7: 77-85
        • Kanasaki K.
        • Palmsten K.
        • Sugimoto H.
        • et al.
        Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia.
        Nature. 2008; 453: 1117-1121
        • Tal R.
        The role of hypoxia and hypoxia-inducible factor-1alpha in preeclampsia pathogenesis.
        Biol Reprod. 2012; 87: 1-8
        • Zhou G.
        • Myers R.
        • Li Y.
        • et al.
        Role of AMP-activated protein kinase in mechanism of metformin action.
        J Clin Invest. 2001; 108: 1167-1174
        • Miller R.A.
        • Chu Q.
        • Xie J.
        • Foretz M.
        • Viollet B.
        • Birnbaum M.J.
        Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP.
        Nature. 2013; 494: 256-260
        • Batandier C.
        • Guigas B.
        • Detaille D.
        • El-Mir M.Y.
        • Fontaine E.
        • Rigoulet M.
        • et al.
        The ROS production induced by a reverse-electron flux at respiratory-chain complex 1 is hampered by metformin.
        J Bioenerg Biomembr. 2006; 38: 33-42
        • Portela L.V.
        • Gnoatto J.
        • Brochier A.W.
        • et al.
        Intracerebroventricular metformin decreases body weight but has pro-oxidant effects and decreases survival.
        Neurochem Res. 2015; 40: 514-523
        • Blagosklonny M.V.
        • Hall M.N.
        Growth and aging: a common molecular mechanism.
        Aging. 2009; 1: 357-362
        • Chantranupong L.
        • Wolfson R.L.
        • Sabatini D.M.
        Nutrient-sensing mechanisms across evolution.
        Cell. 2015; 161: 67-83
        • Meier U.
        • Gressner A.M.
        Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin.
        Clin Chem. 2004; 50: 1511-1525
        • Hopkins M.
        • Blundell J.E.
        Energy balance, body composition, sedentariness and appetite regulation: pathways to obesity.
        Clin Sci. 2016; 130: 1615-1628
        • Hu F.
        • Xu Y.
        • Liu F.
        Hypothalamic roles of mTOR complex I: integration of nutrient and hormone signals to regulate energy homeostasis.
        Am J Physiol Endocrinol Metabol. 2016; 310: E994-E1002
        • Jansson T.
        • Powell T.L.
        Role of placental nutrient sensing in developmental programming.
        Clin Obstet Gynecol. 2013; 56: 591-601
        • Roos S.
        • Powell T.L.
        • Jansson T.
        Placental mTOR links maternal nutrient availability to fetal growth.
        Biochem Soc Trans. 2009; 37: 295-298
        • Rosario F.J.
        • Kanai Y.
        • Powell T.L.
        • Jansson T.
        Mammalian target of rapamycin signalling modulates amino acid uptake by regulating transporter cell surface abundance in primary human trophoblast cells.
        J Physiol. 2013; 591: 609-625
        • Vezina C.
        • Kudelski A.
        • Sehgal S.N.
        Rapamycin (AY-22,989), a new antifungal antibiotic: I, taxonomy of the producing streptomycete and isolation of the active principle.
        J Antibiot. 1975; 28: 721-726
        • Lamming D.W.
        Inhibition of the mechanistic target of rapamycin (mTOR)-rapamycin and beyond.
        Cold Spring Harbor Perspect Med. 2016; 6: a025924
        • Zoncu R.
        • Efeyan A.
        • Sabatini D.M.
        mTOR: from growth signal integration to cancer, diabetes and ageing.
        Nat Rev Mol Cell Biol. 2011; 12: 21-35
        • Hirota Y.
        • Cha J.
        • Yoshie M.
        • Daikoku T.
        • Dey S.K.
        Heightened uterine mammalian target of rapamycin complex 1 (mTORC1) signaling provokes preterm birth in mice.
        Proc Natl Acad Sci U S A. 2011; 108: 18073-18078
        • Shimobayashi M.
        • Hall M.N.
        Making new contacts: the mTOR network in metabolism and signalling crosstalk.
        Nat Rev Mol Cell Biol. 2014; 15: 155-162
        • Kim Y.C.
        • Guan K.L.
        MTOR: a pharmacologic target for autophagy regulation.
        J Clin Invest. 2015; 125: 25-32
        • Deng W.
        • Cha J.
        • Yuan J.
        • et al.
        P53 coordinates decidual sestrin 2/AMPK/mTORC1 signaling to govern parturition timing.
        J Clin Invest. 2016; 126: 2941-2954
        • Kennedy B.K.
        • Lamming D.W.
        The mechanistic target of rapamycin: the grand conducTOR of metabolism and aging.
        Cell Metab. 2016; 23: 990-1003
        • Xie J.
        • Wang X.
        • Proud C.G.
        MTOR inhibitors in cancer therapy.
        F1000Res. 2016; 5: 2078
        • Aylett C.H.
        • Sauer E.
        • Imseng S.
        • et al.
        Architecture of human mTOR complex 1.
        Science. 2016; 351: 48-52
        • Xu S.
        • Cai Y.
        • Wei Y.
        MTOR signaling from cellular senescence to organismal aging.
        Aging Dis. 2014; 5: 263-273
        • Wei Y.
        • Zhang Y.J.
        • Cai Y.
        • Xu M.H.
        The role of mitochondria in mTOR-regulated longevity.
        Biol Rev Camb Philos Soc. 2015; 90: 167-181
        • Lager S.
        • Powell T.L.
        Regulation of nutrient transport across the placenta.
        J Pregnancy. 2012; 2012: 179827
        • Fujita D.
        • Tanabe A.
        • Sekijima T.
        • et al.
        Role of extracellular signal-regulated kinase and AKT cascades in regulating hypoxia-induced angiogenic factors produced by a trophoblast-derived cell line.
        J Endocrinol. 2010; 206: 131-140
        • Nanovskaya T.N.
        • Nekhayeva I.A.
        • Patrikeeva S.L.
        • Hankins G.D.
        • Ahmed M.S.
        Transfer of metformin across the dually perfused human placental lobule.
        Am J Obstet Gynecol. 2006; 195: 1081-1085
        • Charles B.
        • Davoren P.
        • Hague W.
        • McIntyre D.
        • Norris R.
        • Xiaonian X.
        Metformin crosses the placenta: a modulator for fetal insulin resistance?.
        Br Med J. 2004; 327: 880-881
        • Vanky E.
        • Zahlsen K.
        • Spigset O.
        • Carlsen S.M.
        Placental passage of metformin in women with polycystic ovary syndrome.
        Fertil Steril. 2005; 83: 1575-1578
        • Cassina M.
        • Dona 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: 656-669
        • Gilbert C.
        • Valois M.
        • Koren G.
        Pregnancy outcome after first-trimester exposure to metformin: a meta-analysis.
        Fertil steril. 2006; 86: 658-663
        • Gray S.G.
        • McGuire T.M.
        • Cohen N.
        • Little P.J.
        The emerging role of metformin in gestational diabetes mellitus.
        Diabetes Obes Metab. 2017; 19: 765-772
        • Nestler J.E.
        Metformin for the treatment of the polycystic ovary syndrome.
        N Engl J Med. 2008; 358: 47-54
        • Nicholson W.
        • Baptiste-Roberts K.
        Oral hypoglycaemic agents during pregnancy: the evidence for effectiveness and safety.
        Best Pract Res Clin Obstet Gynaecol. 2011; 25: 51-63
        • Wouldes T.A.
        • Battin M.
        • Coat S.
        • Rush E.C.
        • Hague W.M.
        • Rowan J.A.
        Neurodevelopmental outcome at 2 years in offspring of women randomised to metformin or insulin treatment for gestational diabetes.
        Arch Dis Child Fetal Neonatal Ed. 2016; 101: F488-F493
        • Rowan J.A.
        • Rush E.C.
        • Obolonkin V.
        • Battin M.
        • Wouldes T.
        • Hague W.M.
        Metformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition at 2 years of age.
        Diabetes Care. 2011; 34: 2279-2284
        • Lautatzis M.E.
        • Goulis D.G.
        • Vrontakis M.
        Efficacy and safety of metformin during pregnancy in women with gestational diabetes mellitus or polycystic ovary syndrome: a systematic review.
        Metabolism. 2013; 62: 1522-1534
        • Evans J.M.
        • Donnelly L.A.
        • Emslie-Smith A.M.
        • Alessi D.R.
        • Morris A.D.
        Metformin and reduced risk of cancer in diabetic patients.
        BMJ. 2005; 330: 1304-1305
        • Libby G.
        • Donnelly L.A.
        • Donnan P.T.
        • Alessi D.R.
        • Morris A.D.
        • Evans J.M.
        New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes.
        Diabetes Care. 2009; 32: 1620-1625
        • Gandini S.
        • Puntoni M.
        • Heckman-Stoddard B.M.
        • et al.
        Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders.
        Cancer Prev Res. 2014; 7: 867-885
        • Mohammed A.
        • Janakiram N.B.
        • Brewer M.
        • et al.
        Antidiabetic drug metformin prevents progression of pancreatic cancer by targeting in part cancer stem cells and mTOR signaling.
        Transl Oncol. 2013; 6: 649-659
        • Anisimov V.N.
        • Berstein L.M.
        • Egormin P.A.
        • et al.
        Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice.
        Exp gerontol. 2005; 40: 685-693
        • Anisimov V.N.
        Do metformin a real anticarcinogen? A critical reappraisal of experimental data.
        Ann Transl Med. 2014; 2: 60
        • Afzal M.
        • Kazmi I.
        • Gupta G.
        • Rahman M.
        • Kimothi V.
        • Anwar F.
        Preventive effect of Metformin against N-nitrosodiethylamine-initiated hepatocellular carcinoma in rats.
        Saudi Pharm J. 2012; 20: 365-370
        • Anisimov V.N.
        • Berstein L.M.
        • Popovich I.G.
        • et al.
        If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice.
        Aging. 2011; 3: 148-157
        • Huang X.
        • Wullschleger S.
        • Shpiro N.
        • et al.
        Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice.
        Biochem J. 2008; 412: 211-221
        • Tajima K.
        • Nakamura A.
        • Shirakawa J.
        • et al.
        Metformin prevents liver tumorigenesis induced by high-fat diet in C57Bl/6 mice.
        Am J Physiol Endocrinol Metab. 2013; 305: E987-E998
        • Tomimoto A.
        • Endo H.
        • Sugiyama M.
        • et al.
        Metformin suppresses intestinal polyp growth in ApcMin/+ mice.
        Cancer Sci. 2008; 99: 2136-2141
        • Vazquez-Martin A.
        • Lopez-Bonetc E.
        • Cufi S.
        • et al.
        Repositioning chloroquine and metformin to eliminate cancer stem cell traits in pre-malignant lesions.
        Drug Resist Updat. 2011; 14: 212-223
        • Cufi S.
        • Vazquez-Martin A.
        • Oliveras-Ferraros C.
        • Martin-Castillo B.
        • Joven J.
        • Menendez J.A.
        Metformin against TGFbeta-induced epithelial-to-mesenchymal transition (EMT): from cancer stem cells to aging-associated fibrosis.
        Cell cycle. 2010; 9: 4461-4468
        • Shackelford D.B.
        • Shaw R.J.
        The LKB1-AMPK pathway: metabolism and growth control in tumour suppression.
        Nat Rev Cancer. 2009; 9: 563-575
        • Green A.S.
        • Chapuis N.
        • Maciel T.T.
        • et al.
        The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid leukemia through the repression of mTOR-dependent oncogenic mRNA translation.
        Blood. 2010; 116: 4262-4273
        • Zakikhani M.
        • Dowling R.
        • Fantus I.G.
        • Sonenberg N.
        • Pollak M.
        Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells.
        Cancer Res. 2006; 66: 10269-10273
        • Lettieri Barbato D.
        • Vegliante R.
        • Desideri E.
        • Ciriolo M.R.
        Managing lipid metabolism in proliferating cells: new perspective for metformin usage in cancer therapy.
        Biochimica et biophysica acta. 2014; 1845: 317-324
        • Jiralerspong S.
        • Palla S.L.
        • Giordano S.H.
        • et al.
        Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer.
        J Clin Oncol. 2009; 27: 3297-3302
        • Daugan M.
        • Dufay Wojcicki A.
        • d’Hayer B.
        • Boudy V.
        Metformin: an anti-diabetic drug to fight cancer.
        Pharmacol Res. 2016; 113: 675-685
        • Sosnicki S.
        • Kapral M.
        • Weglarz L.
        Molecular targets of metformin antitumor action.
        Pharmacol Rep. 2016; 68: 918-925
        • Lee S.S.
        • Lee R.Y.
        • Fraser A.G.
        • Kamath R.S.
        • Ahringer J.
        • Ruvkun G.
        A systematic RNAi screen identifies a critical role for mitochondria in C elegans longevity.
        Nature Genet. 2003; 33: 40-48
        • Dillin A.
        • Hsu A.L.
        • Arantes-Oliveira N.
        • et al.
        Rates of behavior and aging specified by mitochondrial function during development.
        Science. 2002; 298: 2398-2401
        • Slack C.
        • Foley A.
        • Partridge L.
        Activation of AMPK by the putative dietary restriction mimetic metformin is insufficient to extend lifespan in Drosophila.
        PloS One. 2012; 7: e47699
        • Lopez-Otin C.
        • Galluzzi L.
        • Freije J.M.
        • Madeo F.
        • Kroemer G.
        Metabolic control of longevity.
        Cell. 2016; 166: 802-821
        • Novelle M.G.
        • Ali A.
        • Dieguez C.
        • Bernier M.
        • de Cabo R.
        Metformin: a hopeful promise in aging research.
        Cold Spring Harbor Perspect Med. 2016; 6: a025932
        • Wu L.
        • Zhou B.
        • Oshiro-Rapley N.
        • et al.
        An ancient, unified mechanism for metformin growth inhibition in C elegans and cancer.
        Cell. 2016; 167: 1705-1718.e13