Advertisement
Canadian Journal of Cardiology

Mechanisms and Clinical Significance of Endothelial Dysfunction in High-Risk Pregnancies

  • Kelsey McLaughlin
    Affiliations
    Department of Medicine, Division of Cardiology, Sinai Health System, University of Toronto, Toronto, Ontario, Canada

    The Centre for Women's and Infant's Health at the Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
    Search for articles by this author
  • Melanie C. Audette
    Affiliations
    The Centre for Women's and Infant's Health at the Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
    Search for articles by this author
  • John D. Parker
    Affiliations
    Department of Medicine, Division of Cardiology, Sinai Health System, University of Toronto, Toronto, Ontario, Canada
    Search for articles by this author
  • John C. Kingdom
    Correspondence
    Corresponding author: Dr John C. Kingdom, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, 600 University Ave 3-904, Toronto, Ontario M5G 1X5, Canada. Tel.: +1-416-586-8764; fax: +1-416-586-8565.
    Affiliations
    The Centre for Women's and Infant's Health at the Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada

    Department of Obstetrics and Gynaecology, Division of Maternal-Fetal Medicine, Sinai Health System, University of Toronto, Toronto, Ontario, Canada
    Search for articles by this author
Published:January 15, 2018DOI:https://doi.org/10.1016/j.cjca.2018.01.006

      Abstract

      The maternal cardiovascular system undergoes critical anatomic and functional adaptations to achieve a successful pregnancy outcome which, if disrupted, can result in complications that significantly affect maternal and fetal health. Complications that involve the maternal cardiovascular system are among the most common disorders of pregnancy, including gestational hypertension, preeclampsia, gestational diabetes, and impaired fetal growth. As a central feature, maternal endothelial dysfunction is hypothesized to play a predominant role in mediating the pathogenesis of these high-risk pregnancies, and as such, might proceed and precipitate the clinical presentation of these pregnancy disorders. Improving or normalizing maternal endothelial function in high-risk pregnancies might be an effective therapeutic strategy to ameliorate maternal and fetal clinical outcomes.

      Résumé

      L’appareil cardiovasculaire maternel subit des adaptations anatomiques et fonctionnelles essentielles à une grossesse menée à terme dans des conditions optimales. Leur perturbation peut entraîner des complications qui auront des répercussions considérables sur la santé de la mère et du fœtus. Les complications touchant l’appareil cardiovasculaire maternel font partie des troubles les plus courants durant la grossesse, tels que l’hypertension gestationnelle, la prééclampsie, le diabète gestationnel et le retard de croissance intra-utérin. En tant qu’entité clinique de premier plan, la dysfonction endothéliale maternelle joue en théorie un rôle prédominant dans la médiation de la pathogenèse des grossesses à haut risque et pourrait ainsi précipiter les manifestations cliniques des troubles gestationnels. L’amélioration ou la normalisation de la fonction endothéliale maternelle en cas de grossesse à haut risque pourrait constituer une stratégie thérapeutique efficace pour obtenir de meilleurs résultats cliniques chez la mère et le fœtus.
      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 Canadian Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Deanfield J.E.
        • Halcox J.P.
        • Rabelink T.J.
        Endothelial function and dysfunction: testing and clinical relevance.
        Circulation. 2007; 115: 1285-1295
        • Ignarro L.J.
        • Buga G.M.
        • Wood K.S.
        • Byrns R.E.
        • Chaudhuri G.
        Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide.
        Proc Natl Acad Sci U S A. 1987; 84: 9265-9269
        • Palmer R.M.
        • Ashton D.S.
        • Moncada S.
        Vascular endothelial cells synthesize nitric oxide from L-arginine.
        Nature. 1988; 333: 664-666
        • Huang P.L.
        • Huang Z.
        • Mashimo H.
        • et al.
        Hypertension in mice lacking the gene for endothelial nitric oxide synthase.
        Nature. 1995; 377: 239-242
        • Yetik-Anacak G.
        • Catravas J.D.
        Nitric oxide and the endothelium: history and impact on cardiovascular disease.
        Vasc Pharmacol. 2006; 45: 268-276
        • Radomski M.W.
        • Palmer R.M.
        • Moncada S.
        Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium.
        Lancet. 1987; 2: 1057-1058
        • Halcox J.P.
        • Narayanan S.
        • Cramer-Joyce L.
        • Mincemoyer R.
        • Quyyumi A.A.
        Characterization of endothelium-derived hyperpolarizing factor in the human forearm microcirculation.
        Am J Physiol Heart Circ Physiol. 2001; 280: H2470-H2477
        • Rudic R.D.
        • Brinster D.
        • Cheng Y.
        • et al.
        COX-2-derived prostacyclin modulates vascular remodeling.
        Circ Res. 2005; 96: 1240-1247
        • Haynes W.G.
        • Webb D.J.
        Contribution of endogenous generation of endothelin-1 to basal vascular tone.
        Lancet. 1994; 344: 852-854
        • Nakao K.
        • Kuwahara K.
        • Nishikimi T.
        • et al.
        Endothelium-derived C-type natriuretic peptide contributes to blood pressure regulation by maintaining endothelial integrity.
        Hypertension. 2017; 69: 286-296
        • Moyes A.J.
        • Khambata R.S.
        • Villar I.
        • et al.
        Endothelial C-type natriuretic peptide maintains vascular homeostasis.
        J Clin Invest. 2014; 124: 4039-4051
        • Raman C.S.
        • Li H.
        • Martasek P.
        • et al.
        Crystal structure of constitutive endothelial nitric oxide synthase: a paradigm for pterin function involving a novel metal center.
        Cell. 1998; 95: 939-950
        • Vaziri N.D.
        • Ni Z.
        • Oveisi F.
        Upregulation of renal and vascular nitric oxide synthase in young spontaneously hypertensive rats.
        Hypertension. 1998; 31: 1248-1254
        • Hink U.
        • Li H.
        • Mollnau H.
        • et al.
        Mechanisms underlying endothelial dysfunction in diabetes mellitus.
        Circ Res. 2001; 88: E14-E22
        • Pernow J.
        • Bohm F.
        • Johansson B.L.
        • Hedin U.
        • Ryden L.
        Enhanced vasoconstrictor response to endothelin-B-receptor stimulation in patients with atherosclerosis.
        J Cardiovasc Pharmacol. 2000; 36: S418-S420
        • Kalafat E.
        • Thilaganathan B.
        Cardiovascular origins of preeclampsia.
        Curr Opin Obstetr Gynecol. 2017; 29: 383-389
        • Valensise H.
        • Novelli G.P.
        • Vasapollo B.
        • et al.
        Maternal diastolic dysfunction and left ventricular geometry in gestational hypertension.
        Hypertension. 2001; 37: 1209-1215
        • Gonzalez-Quintero V.H.
        • Smarkusky L.P.
        • Jimenez J.J.
        • et al.
        Elevated plasma endothelial microparticles: preeclampsia versus gestational hypertension.
        Am J Obstet Gynecol. 2004; 191: 1418-1424
        • Spasojevic M.
        • Smith S.A.
        • Morris J.M.
        • Gallery E.D.
        Peripheral arterial pulse wave analysis in women with pre-eclampsia and gestational hypertension.
        BJOG. 2005; 112: 1475-1478
        • Davis K.R.
        • Ponnampalam J.
        • Hayman R.
        • et al.
        Microvascular vasodilator response to acetylcholine is increased in women with pre-eclampsia.
        BJOG. 2001; 108: 610-614
        • Takase B.
        • Goto T.
        • Hamabe A.
        • et al.
        Flow-mediated dilation in brachial artery in the second half of pregnancy and prediction of pre-eclampsia.
        J Hum Hypertens. 2003; 17: 697-704
        • Yoshida A.
        • Nakao S.
        • Kobayashi M.
        • Kobayashi H.
        Flow-mediated vasodilation and plasma fibronectin levels in preeclampsia.
        Hypertension. 2000; 36: 400-404
        • Chambers J.C.
        • Fusi L.
        • Malik I.S.
        • et al.
        Association of maternal endothelial dysfunction with preeclampsia.
        JAMA. 2001; 285: 1607-1612
        • Weissgerber T.L.
        • Milic N.M.
        • Milin-Lazovic J.S.
        • Garovic V.D.
        Impaired flow-mediated dilation before, during, and after preeclampsia: a systematic review and meta-analysis.
        Hypertension. 2016; 67: 415-423
        • Yinon Y.
        • Kingdom J.C.
        • Odutayo A.
        • et al.
        Vascular dysfunction in women with a history of preeclampsia and intrauterine growth restriction: insights into future vascular risk.
        Circulation. 2010; 122: 1846-1853
        • Savvidou M.D.
        • Hingorani A.D.
        • Tsikas D.
        • et al.
        Endothelial dysfunction and raised plasma concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre-eclampsia.
        Lancet. 2003; 361: 1511-1517
        • Choi J.W.
        • Im M.W.
        • Pai S.H.
        Nitric oxide production increases during normal pregnancy and decreases in preeclampsia.
        Ann Clin Lab Sci. 2002; 32: 257-263
        • Schiessl B.
        • Strasburger C.
        • Bidlingmaier M.
        • et al.
        Plasma and urine concentrations of nitrite/nitrate and cyclic guanosinemonophosphate in intrauterine growth restricted and preeclamptic pregnancies.
        Arch Gynecol Obstetr. 2006; 274: 150-154
        • Begum S.
        • Yamasaki M.
        • Mochizuki M.
        Urinary levels of nitric oxide metabolites in normal pregnancy and preeclampsia.
        J Obstetr Gynaecol Res. 1996; 22: 551-559
        • Aydin S.
        • Benian A.
        • Madazli R.
        • et al.
        Plasma malondialdehyde, superoxide dismutase, sE-selectin, fibronectin, endothelin-1 and nitric oxide levels in women with preeclampsia.
        Eur J Obstetr Gynecol Reprod Biol. 2004; 113: 21-25
        • Reid R.A.
        • Prickett T.C.
        • Pullar B.E.
        • et al.
        C-type natriuretic peptide in complicated pregnancy: increased secretion precedes adverse events.
        J Clin Endocrinol Metab. 2014; 99: 1470-1478
        • Espiner E.A.
        • Prickett T.C.
        • Taylor R.S.
        • Reid R.A.
        • McCowan L.M.
        Effects of pre-eclampsia and fetal growth restriction on C-type natriuretic peptide.
        BJOG. 2015; 122: 1236-1243
        • Nova A.
        • Sibai B.M.
        • Barton J.R.
        • Mercer B.M.
        • Mitchell M.D.
        Maternal plasma level of endothelin is increased in preeclampsia.
        Am J Obstet Gynecol. 1991; 165: 724-727
        • Taylor R.N.
        • Varma M.
        • Teng N.N.
        • Roberts J.M.
        Women with preeclampsia have higher plasma endothelin levels than women with normal pregnancies.
        J Clin Endocrinol Metab. 1990; 71: 1675-1677
        • Schiff E.
        • Ben-Baruch G.
        • Peleg E.
        • et al.
        Immunoreactive circulating endothelin-1 in normal and hypertensive pregnancies.
        Am J Obstet Gynecol. 1992; 166: 624-628
        • Karumanchi S.A.
        Angiogenic factors in preeclampsia: from diagnosis to therapy.
        Hypertension. 2016; 67: 1072-1079
        • Noori M.
        • Donald A.E.
        • Angelakopoulou A.
        • Hingorani A.D.
        • Williams D.J.
        Prospective study of placental angiogenic factors and maternal vascular function before and after preeclampsia and gestational hypertension.
        Circulation. 2010; 122: 478-487
        • Melchiorre K.
        • Sutherland G.R.
        • Watt-Coote I.
        • Liberati M.
        • Thilaganathan B.
        Severe myocardial impairment and chamber dysfunction in preterm preeclampsia.
        Hypertens Pregnancy. 2012; 31: 454-471
        • Valensise H.
        • Vasapollo B.
        • Gagliardi G.
        • Novelli G.P.
        Early and late preeclampsia: two different maternal hemodynamic states in the latent phase of the disease.
        Hypertension. 2008; 52: 873-880
        • Melchiorre K.
        • Sutherland G.
        • Sharma R.
        • Nanni M.
        • Thilaganathan B.
        Mid-gestational maternal cardiovascular profile in preterm and term pre-eclampsia: a prospective study.
        BJOG. 2013; 120: 496-504
        • Melchiorre K.
        • Sutherland G.R.
        • Baltabaeva A.
        • Liberati M.
        • Thilaganathan B.
        Maternal cardiac dysfunction and remodeling in women with preeclampsia at term.
        Hypertension. 2011; 57: 85-93
        • Stewart F.M.
        • Freeman D.J.
        • Ramsay J.E.
        • et al.
        Longitudinal assessment of maternal endothelial function and markers of inflammation and placental function throughout pregnancy in lean and obese mothers.
        J Clin Endocrinol Metab. 2007; 92: 969-975
        • Ramsay J.E.
        • Ferrell W.R.
        • Crawford L.
        • et al.
        Maternal obesity is associated with dysregulation of metabolic, vascular, and inflammatory pathways.
        J Clin Endocrinol Metab. 2002; 87: 4231-4237
        • Quinton A.E.
        • Cook C.M.
        • Peek M.J.
        The relationship between cigarette smoking, endothelial function and intrauterine growth restriction in human pregnancy.
        BJOG. 2008; 115: 780-784
        • Koopmans C.M.
        • Blaauw J.
        • van Pampus M.G.
        • Rakhorst G.
        • Aarnoudse J.G.
        Abnormal endothelium-dependent microvascular dilator reactivity in pregnancies complicated by normotensive intrauterine growth restriction.
        Am J Obstet Gynecol. 2009; 200: 66.e1-66.e6
        • Friedman S.A.
        • de Groot C.J.
        • Taylor R.N.
        • Golditch B.D.
        • Roberts J.M.
        Plasma cellular fibronectin as a measure of endothelial involvement in preeclampsia and intrauterine growth retardation.
        Am J Obstet Gynecol. 1994; 170: 838-841
        • Coata G.
        • Pennacchi L.
        • Bini V.
        • Liotta L.
        • Di Renzo G.C.
        Soluble adhesion molecules: marker of pre-eclampsia and intrauterine growth restriction.
        J Matern Fetal Neonatal Med. 2002; 12: 28-34
        • Erdem A.
        • Erdem M.
        • Himmetoglu O.
        • Yildirim G.
        • Arslan M.
        Maternal and fetal plasma endothelin levels in intrauterine growth restriction: relation to umbilical artery Doppler flow velocimetry.
        J Perinat Med. 2003; 31: 52-59
        • Engler M.M.
        • Engler M.B.
        • Malloy M.J.
        • et al.
        Antioxidant vitamins C and E improve endothelial function in children with hyperlipidemia: Endothelial Assessment of Risk from Lipids in Youth (EARLY) trial.
        Circulation. 2003; 108: 1059-1063
        • Watts K.
        • Beye P.
        • Siafarikas A.
        • et al.
        Exercise training normalizes vascular dysfunction and improves central adiposity in obese adolescents.
        J Am Coll Cardiol. 2004; 43: 1823-1827
        • Baldus S.
        • Rudolph V.
        • Roiss M.
        • et al.
        Heparins increase endothelial nitric oxide bioavailability by liberating vessel-immobilized myeloperoxidase.
        Circulation. 2006; 113: 1871-1878
        • McLaughlin K.
        • Baczyk D.
        • Potts A.
        • et al.
        Low molecular weight heparin improves endothelial function in pregnant women at high risk of preeclampsia.
        Hypertension. 2017; 69: 180-188
        • McLaughlin K.
        • Wright S.P.
        • Kingdom J.C.
        • Parker J.D.
        Clinical validation of non-invasive cardiac output monitoring in healthy pregnant women.
        J Obstetr Gynaecol Can. 2017; 39: 1008-1014
        • Melchiorre K.
        • Sharma R.
        • Khalil A.
        • Thilaganathan B.
        Maternal cardiovascular function in normal pregnancy: evidence of maladaptation to chronic volume overload.
        Hypertension. 2016; 67: 754-762
        • Williams D.J.
        • Vallance P.J.
        • Neild G.H.
        • Spencer J.A.
        • Imms F.J.
        Nitric oxide-mediated vasodilation in human pregnancy.
        Am J Physiol. 1997; 272: H748-H752
        • Dorup I.
        • Skajaa K.
        • Sorensen K.E.
        Normal pregnancy is associated with enhanced endothelium-dependent flow-mediated vasodilation.
        Am J Physiol. 1999; 276: H821-H825
        • Anumba D.O.
        • Robson S.C.
        • Boys R.J.
        • Ford G.A.
        Nitric oxide activity in the peripheral vasculature during normotensive and preeclamptic pregnancy.
        Am J Physiol. 1999; 277: H848-H854
        • Meah V.L.
        • Cockcroft J.R.
        • Backx K.
        • Shave R.
        • Stohr E.J.
        Cardiac output and related haemodynamics during pregnancy: a series of meta-analyses.
        Heart. 2016; 102: 518-526
        • Savvidou M.D.
        • Kametas N.A.
        • Donald A.E.
        • Nicolaides K.H.
        Non-invasive assessment of endothelial function in normal pregnancy.
        Ultrasound Obstet Gynecol. 2000; 15: 502-507
        • Gant N.F.
        • Daley G.L.
        • Chand S.
        • Whalley P.J.
        • MacDonald P.C.
        A study of angiotensin II pressor response throughout primigravid pregnancy.
        J Clin Invest. 1973; 52: 2682-2689
        • Lopes van Balen V.A.
        • van Gansewinkel T.A.
        • de Haas S.
        • et al.
        Physiological adaptation of endothelial function to pregnancy: systematic review and meta-analysis.
        Ultrasound Obstet Gynecol. 2017; 50: 697-708
        • Molnar M.
        • Suto T.
        • Toth T.
        • Hertelendy F.
        Prolonged blockade of nitric oxide synthesis in gravid rats produces sustained hypertension, proteinuria, thrombocytopenia, and intrauterine growth retardation.
        Am J Obstet Gynecol. 1994; 170: 1458-1466
        • Kopp L.
        • Paradiz G.
        • Tucci J.R.
        Urinary excretion of cyclic 3',5'-adenosine monophosphate and cyclic 3',5'-guanosine monophosphate during and after pregnancy.
        J Clin Endocrinol Metab. 1977; 44: 590-594
        • Wolff K.
        • Carlstrom K.
        • Fyhrquist F.
        • et al.
        Plasma endothelin in normal and diabetic pregnancy.
        Diabetes Care. 1997; 20: 653-656
        • Duley L.
        The global impact of pre-eclampsia and eclampsia.
        Semin Perinatol. 2009; 33: 130-137
        • Say L.
        • Chou D.
        • Gemmill A.
        • et al.
        Global causes of maternal death: a WHO systematic analysis.
        Lancet Glob Health. 2014; 2: e323-e333
        • Cirillo P.M.
        • Cohn B.A.
        Pregnancy complications and cardiovascular disease death: 50-year follow-up of the Child Health and Development Studies pregnancy cohort.
        Circulation. 2015; 132: 1234-1242
        • Shen M.
        • Smith G.N.
        • Rodger M.
        • et al.
        Comparison of risk factors and outcomes of gestational hypertension and pre-eclampsia.
        PLoS One. 2017; 12: e0175914
        • Cifkova R.
        Why is the treatment of hypertension in pregnancy still so difficult?.
        Exp Rev Cardiovasc Ther. 2011; 9: 647-649
        • Garcia R.G.
        • Celedon J.
        • Sierra-Laguado J.
        • et al.
        Raised C-reactive protein and impaired flow-mediated vasodilation precede the development of preeclampsia.
        Am J Hypertens. 2007; 20: 98-103
        • Villar J.
        • Carroli G.
        • Wojdyla D.
        • et al.
        Preeclampsia, gestational hypertension and intrauterine growth restriction, related or independent conditions?.
        Am J Obstet Gynecol. 2006; 194: 921-931
        • Melamed N.
        • Ray J.G.
        • Hladunewich M.
        • Cox B.
        • Kingdom J.C.
        Gestational hypertension and preeclampsia: are they the same disease?.
        J Obstetr Gynaecol Can. 2014; 36: 642-647
        • Green D.J.
        • Walsh J.H.
        • Maiorana A.
        • et al.
        Comparison of resistance and conduit vessel nitric oxide-mediated vascular function in vivo: effects of exercise training.
        J Appl Physiol. 2004; 97 ([discussion: 748]): 749-755
        • Magee L.A.
        • Pels A.
        • Helewa M.
        • Rey E.
        • von Dadelszen P.
        Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy: executive summary.
        J Obstetr Gynaecol Can. 2014; 36: 575-576
        • North R.A.
        • McCowan L.M.
        • Dekker G.A.
        • et al.
        Clinical risk prediction for pre-eclampsia in nulliparous women: development of model in international prospective cohort.
        BMJ. 2011; 342: d1875
        • Crispi F.
        • Llurba E.
        • Dominguez C.
        • et al.
        Predictive value of angiogenic factors and uterine artery Doppler for early- versus late-onset pre-eclampsia and intrauterine growth restriction.
        Ultrasound Obstet Gynecol. 2008; 31: 303-309
        • Magnussen E.B.
        • Vatten L.J.
        • Lund-Nilsen T.I.
        • et al.
        Prepregnancy cardiovascular risk factors as predictors of pre-eclampsia: population based cohort study.
        BMJ. 2007; 335: 978
        • Chen X.
        • Scholl T.O.
        Maternal biomarkers of endothelial dysfunction and preterm delivery.
        PLoS One. 2014; 9: e85716
        • McCarthy A.L.
        • Woolfson R.G.
        • Raju S.K.
        • Poston L.
        Abnormal endothelial cell function of resistance arteries from women with preeclampsia.
        Am J Obstet Gynecol. 1993; 168: 1323-1330
        • 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
        • Hofmeyr G.J.
        • Lawrie T.A.
        • Atallah A.N.
        • Duley L.
        • Torloni M.R.
        Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems.
        Cochrane Database Syst Rev. 2014; 6: CD001059
        • Magro-Malosso E.R.
        • Saccone G.
        • Di Tommaso M.
        • Roman A.
        • Berghella V.
        Exercise during pregnancy and risk of gestational hypertensive disorders: a systematic review and meta-analysis.
        Acta Obstetr Gynecol Scand. 2017; 96: 921-931
        • Aune D.
        • Saugstad O.D.
        • Henriksen T.
        • Tonstad S.
        Physical activity and the risk of preeclampsia: a systematic review and meta-analysis.
        Epidemiology. 2014; 25: 331-343
        • Husain S.
        • Andrews N.P.
        • Mulcahy D.
        • Panza J.A.
        • Quyyumi A.A.
        Aspirin improves endothelial dysfunction in atherosclerosis.
        Circulation. 1998; 97: 716-720
        • Rolnik D.L.
        • Wright D.
        • Poon L.C.
        • et al.
        Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia.
        N Engl J Med. 2017; 377: 613-622
        • LeFevre M.L.
        Low-dose aspirin use for the prevention of morbidity and mortality from preeclampsia: U.S. Preventive Services Task Force recommendation statement.
        Ann Intern Med. 2014; 161: 819-826
        • McLaughlin K.
        • Drewlo S.
        • Parker J.D.
        • Kingdom J.C.
        Current theories on the prevention of severe preeclampsia with low-molecular weight heparin.
        Hypertension. 2015; 66: 1098-1103
        • Mello G.
        • Parretti E.
        • Fatini C.
        • et al.
        Low-molecular-weight heparin lowers the recurrence rate of preeclampsia and restores the physiological vascular changes in angiotensin-converting enzyme DD women.
        Hypertension. 2005; 45: 86-91
        • Tasatargil A.
        • Ogutman C.
        • Golbasi I.
        • Karasu E.
        • Dalaklioglu S.
        Comparison of the vasodilatory effect of nadroparin, enoxaparin, dalteparin, and unfractioned heparin in human internal mammary artery.
        J Cardiovasc Pharmacol. 2005; 45: 550-554
        • Thadhani R.
        • Kisner T.
        • Hagmann H.
        • et al.
        Pilot study of extracorporeal removal of soluble fms-like tyrosine kinase 1 in preeclampsia.
        Circulation. 2011; 124: 940-950
        • Thadhani R.
        • Hagmann H.
        • Schaarschmidt W.
        • et al.
        Removal of soluble fms-like tyrosine kinase-1 by dextran sulfate apheresis in preeclampsia.
        J Am Soc Nephrol. 2016; 27: 903-913
        • Brownfoot F.C.
        • Tong S.
        • Hannan N.J.
        • et al.
        Effects of pravastatin on human placenta, endothelium, and women with severe preeclampsia.
        Hypertension. 2015; 66 ([discussion: 445]): 687-697
        • Dong X.
        • Shi D.
        Simvastatin alleviates pathology in a rat model of preeclampsia involving ERK/MAPK pathway.
        Reprod Sci. 2017; 24: 1053-1061
        • 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
        • Lashen H.
        • Fear K.
        • Sturdee D.W.
        Obesity is associated with increased risk of first trimester and recurrent miscarriage: matched case-control study.
        Hum Reprod. 2004; 19: 1644-1646
        • Weiss J.L.
        • Malone F.D.
        • Emig D.
        • et al.
        Obesity, obstetric complications and cesarean delivery rate–a population-based screening study.
        Am J Obstet Gynecol. 2004; 190: 1091-1097
        • Berger H.
        • Gagnon R.
        • Sermer M.
        • et al.
        Diabetes in pregnancy.
        J Obstetr Gynaecol Can. 2016; 38: 667-679.e1
        • Feig D.S.
        • Hwee J.
        • Shah B.R.
        • et al.
        Trends in incidence of diabetes in pregnancy and serious perinatal outcomes: a large, population-based study in Ontario, Canada, 1996-2010.
        Diabetes Care. 2014; 37: 1590-1596
        • Fadl H.E.
        • Ostlund I.K.
        • Magnuson A.F.
        • Hanson U.S.
        Maternal and neonatal outcomes and time trends of gestational diabetes mellitus in Sweden from 1991 to 2003.
        Diabet Med. 2010; 27: 436-441
        • Nerenberg K.A.
        • Johnson J.A.
        • Leung B.
        • et al.
        Risks of gestational diabetes and preeclampsia over the last decade in a cohort of Alberta women.
        J Obstetr Gynaecol Can. 2013; 35: 986-994
        • Rosenstein M.G.
        • Cheng Y.W.
        • Snowden J.M.
        • et al.
        The risk of stillbirth and infant death stratified by gestational age in women with gestational diabetes.
        Am J Obstet Gynecol. 2012; 206: 309.e1-309.e7
        • Sheiner E.
        • Levy A.
        • Menes T.S.
        • et al.
        Maternal obesity as an independent risk factor for caesarean delivery.
        Paediatr Perinat Epidemiol. 2004; 18: 196-201
        • Retnakaran R.
        • Zinman B.
        • Connelly P.W.
        • Sermer M.
        • Hanley A.J.
        Impaired glucose tolerance of pregnancy is a heterogeneous metabolic disorder as defined by the glycemic response to the oral glucose tolerance test.
        Diabetes Care. 2006; 29: 57-62
        • Samuelsson A.M.
        • Matthews P.A.
        • Argenton M.
        • et al.
        Diet-induced obesity in female mice leads to offspring hyperphagia, adiposity, hypertension, and insulin resistance: a novel murine model of developmental programming.
        Hypertension. 2008; 51: 383-392
        • Curhan G.C.
        • Chertow G.M.
        • Willett W.C.
        • et al.
        Birth weight and adult hypertension and obesity in women.
        Circulation. 1996; 94: 1310-1315
        • Williams S.B.
        • Cusco J.A.
        • Roddy M.A.
        • Johnstone M.T.
        • Creager M.A.
        Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus.
        J Am Coll Cardiol. 1996; 27: 567-574
        • Johnstone M.T.
        • Creager S.J.
        • Scales K.M.
        • et al.
        Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus.
        Circulation. 1993; 88: 2510-2516
        • Savvidou M.D.
        • Geerts L.
        • Nicolaides K.H.
        Impaired vascular reactivity in pregnant women with insulin-dependent diabetes mellitus.
        Am J Obstet Gynecol. 2002; 186: 84-88
        • Guimaraes M.F.
        • Brandao A.H.
        • Rezende C.A.
        • et al.
        Assessment of endothelial function in pregnant women with preeclampsia and gestational diabetes mellitus by flow-mediated dilation of brachial artery.
        Arch Gynecol Obstetr. 2014; 290: 441-447
        • Swiderski S.
        • Celewicz Z.
        • Miazgowski T.
        • Ogonowski J.
        Maternal endothelin-1 and cyclic guanosine monophosphate concentrations in pregnancies complicated by pregravid and gestational diabetes mellitus.
        Gynecol Obstetr Invest. 2010; 69: 46-50
        • Telejko B.
        • Zonenberg A.
        • Kuzmicki M.
        • et al.
        Circulating asymmetric dimethylarginine, endothelin-1 and cell adhesion molecules in women with gestational diabetes.
        Acta Diabetol. 2009; 46: 303-308
        • Crowther C.A.
        • Hiller J.E.
        • Moss J.R.
        • et al.
        Effect of treatment of gestational diabetes mellitus on pregnancy outcomes.
        N Engl J Med. 2005; 352: 2477-2486
        • 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
        • Wang C.
        • Wei Y.
        • Zhang X.
        • et al.
        A randomized clinical trial of exercise during pregnancy to prevent gestational diabetes mellitus and improve pregnancy outcome in overweight and obese pregnant women.
        Am J Obstet Gynecol. 2017; 216: 340-351
        • Davies G.A.
        • Wolfe L.A.
        • Mottola M.F.
        • et al.
        Exercise in pregnancy and the postpartum period.
        J Obstetr Gynaecol Can. 2003; 25: 516-529
        • Barakat R.
        • Pelaez M.
        • Montejo R.
        • Luaces M.
        • Zakynthinaki M.
        Exercise during pregnancy improves maternal health perception: a randomized controlled trial.
        Am J Obstet Gynecol. 2011; 204: 402.e1-402.e7
        • Owe K.M.
        • Nystad W.
        • Stigum H.
        • Vangen S.
        • Bo K.
        Exercise during pregnancy and risk of cesarean delivery in nulliparous women: a large population-based cohort study.
        Am J Obstet Gynecol. 2016; 215: 791.e1-791.e13
        • Barakat R.
        • Pelaez M.
        • Cordero Y.
        • et al.
        Exercise during pregnancy protects against hypertension and macrosomia: randomized clinical trial.
        Am J Obstet Gynecol. 2016; 214: 649.e1-649.e8
        • Maiorana A.
        • O'Driscoll G.
        • Cheetham C.
        • et al.
        The effect of combined aerobic and resistance exercise training on vascular function in type 2 diabetes.
        J Am Coll Cardiol. 2001; 38: 860-866
        • Lausman A.
        • Kingdom J.
        Intrauterine growth restriction: screening, diagnosis, and management.
        J Obstetr Gynaecol Can. 2013; 35: 741-748
        • Gilbert W.M.
        • Danielsen B.
        Pregnancy outcomes associated with intrauterine growth restriction.
        Am J Obstet Gynecol. 2003; 188 ([discussion: 1599-601]): 1596-1599
        • Garite T.J.
        • Clark R.
        • Thorp J.A.
        Intrauterine growth restriction increases morbidity and mortality among premature neonates.
        Am J Obstet Gynecol. 2004; 191: 481-487
        • Ness R.B.
        • Sibai B.M.
        Shared and disparate components of the pathophysiologies of fetal growth restriction and preeclampsia.
        Am J Obstet Gynecol. 2006; 195: 40-49
        • Kingdom J.C.
        • Audette M.C.
        • Hobson S.R.
        • Windrim R.C.
        • Morgen E.
        A placenta clinic approach to the diagnosis and management of fetal growth restriction.
        Am J Obstet Gynecol. 2018; 218: S803-S817
        • Bujold E.
        • Roberge S.
        • Lacasse Y.
        • et al.
        Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis.
        Obstetr Gynecol. 2010; 116: 402-414
        • McLaughlin K.
        • Lytvyn Y.
        • Luca M.C.
        • et al.
        Repeated daily dosing with sildenafil provides sustained protection from endothelial dysfunction caused by ischemia and reperfusion: a human in vivo study.
        Am J Physiol Heart Circ Physiol. 2014; 307: H888-H894
        • Wareing M.
        • Myers J.E.
        • O'Hara M.
        • Baker P.N.
        Sildenafil citrate (Viagra) enhances vasodilatation in fetal growth restriction.
        J Clin Endocrinol Metab. 2005; 90: 2550-2555
        • Satterfield M.C.
        • Bazer F.W.
        • Spencer T.E.
        • Wu G.
        Sildenafil citrate treatment enhances amino acid availability in the conceptus and fetal growth in an ovine model of intrauterine growth restriction.
        J Nutr. 2010; 140: 251-258
        • Nerenberg K.
        • Daskalopoulou S.S.
        • Dasgupta K.
        Gestational diabetes and hypertensive disorders of pregnancy as vascular risk signals: an overview and grading of the evidence.
        Can J Cardiol. 2014; 30: 765-773