, Volume 72, Issue 6, pp 773–788 | Cite as

Statins and Pregnancy

Between Supposed Risks and Theoretical Benefits
  • Edouard Lecarpentier
  • Olivier Morel
  • Thierry Fournier
  • Elisabeth Elefant
  • Pascale Chavatte-Palmer
  • Vassilis Tsatsaris
Review Article


Cardiovascular diseases are the leading cause of mortality in industrialized countries. Treatment with statins is effective in primary prevention in patients at high cardiovascular risk. Statins are inhibitors of hydroxymethylglutarylcoenzyme A (HMG-CoA) reductase and are classed as lipid-lowering drugs. In 2010, atorvastatin was the biggest-selling drug in the world ($US10.73 billion). Increases in the average age of pregnant women and in the prevalence of morbid obesity have inevitably led to exposure to statins in certain women during the first trimester of pregnancy. The teratogenic risk attendant upon use of statins is unclear because the available data are contradictory, but statins remain contraindicated in pregnant women.

The benefits of statins in prevention of cardiovascular risk may not be solely due to their cholesterol-lowering effects: the so-called pleiotropic effects of vascular protection lead some experts to posit a potential benefit in the management of preeclampsia.

In this review we evaluate the theoretical benefits and supposed risks of statins in pregnant women. After a brief overview of the pharmacodynamic properties of statins, we address the question of the teratogenic risk of statins, and then detail the rationale for the therapeutic potential of statins in preeclampsia.


Simvastatin Atorvastatin Preeclampsia Pravastatin Lovastatin 



No sources of funding were used to conduct this study or prepare this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this review.


  1. 1.
    Popkin BM, Doak CM. The obesity epidemic is a world-wide phenomenon. Nutr Rev 1998; 56 (4 Pt 1): 106–14PubMedCrossRefGoogle Scholar
  2. 2.
    Gutiérrez-Fisac JL, Banegas Banegas JR, Artalejo FR, et al. Increasing prevalence of overweight and obesity among Spanish adults, 1987–1997. Int J Obes Relat Metab Disord, 2000; 24(12): 1677–82PubMedCrossRefGoogle Scholar
  3. 3.
    Mokdad AH, Serdula MK, Dietz WH, et al. The spread of the obesity epidemic in the United States, 1991–1998. JAMA 1999; 282(16): 1519–22PubMedCrossRefGoogle Scholar
  4. 4.
    Centers for Disease Control and Prevention. National Center for Health Statistics. Questionnaires, datasets, and related documentation [online]. Available from URL: http://www.cdc.gov/nchs/nhanes/nhanes_questionnaires.htm [Accessed 2011 Dec 1]
  5. 5.
    The Canadian Health Measures Survey. NCHS data Brief 2011; 56 [online]. Available from URL: http://www.cdc.gov/nchs/data/databriefs/db56.htm [Accessed 2011 Dec 1]
  6. 6.
    Ford ES, Li C, Pearson WS, et al. Trends in hypercholesterolemia, treatment and control among United States adults. Int J Cardiol 2008; 140(2): 226–35PubMedCrossRefGoogle Scholar
  7. 7.
    Henshaw SK. Unintended pregnancy in the United States. Fam Plann Perspect 1998; 30(1): 24–9, 46PubMedCrossRefGoogle Scholar
  8. 8.
    Bar-Oz B, Moretti ME, Mareels G, et al. Reporting bias in retrospective ascertainment of drug-induced embryopathy. Lancet 1999; 354(9191): 1700–1PubMedCrossRefGoogle Scholar
  9. 9.
    Boulot P, Chabbert-Buffet N, d’Ercole C, et al. French multicentric survey of outcome of pregnancy in women with pregestational diabetes. Diabetes Care 2003; 26(11): 2990–3PubMedCrossRefGoogle Scholar
  10. 10.
    Shaw SM, Fildes JE, Yonan N, et al. Pleiotropic effects and cholesterol-lowering therapy. Cardiology 2009; 112(1): 4–12PubMedCrossRefGoogle Scholar
  11. 11.
    Seely EW, Solomon CG. Insulin resistance and its potential role in pregnancy-induced hypertension. J Clin Endocrinol Metab 2003; 88(6): 2393–8PubMedCrossRefGoogle Scholar
  12. 12.
    Rodie VA, Freeman DJ, Sattar N, et al. Pre-eclampsia and cardiovascular disease: metabolic syndrome of pregnancy? Atherosclerosis 2004; 175(2): 189–202PubMedCrossRefGoogle Scholar
  13. 13.
    Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352(16): 1685–95PubMedCrossRefGoogle Scholar
  14. 14.
    Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science 2005; 308(5728): 1592–4PubMedCrossRefGoogle Scholar
  15. 15.
    Costantine MM, Tamayo E, Lu F, et al. Using pravastatin to improve the vascular reactivity in a mouse model of soluble fms-like tyrosine kinase-1-induced preeclampsia. Obstet Gynecol 2010; 116(1): 114–20PubMedCrossRefGoogle Scholar
  16. 16.
    Ahmed A, Singh J, Khan Y, et al. A new mouse model to explore therapies for preeclampsia. PLoS ONE 2010; 5(10): e13663PubMedCrossRefGoogle Scholar
  17. 17.
    Kumasawa K, Ikawa M, Kidoya H, et al. Pravastatin induces placental growth factor (PGF) and ameliorates preeclampsia in a mouse model. Proc Natl Acad Sci U S A 2011; 108(4): 1451–5PubMedCrossRefGoogle Scholar
  18. 18.
    Ahmed A. New insights into the etiology of preeclampsia: identification of key elusive factors for the vascular complications. Thromb Res 2011; 127 Suppl. 3: S72–5PubMedCrossRefGoogle Scholar
  19. 19.
    University of Birmingham. Statins to ameliorate early onset pre-eclampsia [ISRCTN identifier 23410175; EudraCT 2009-012968-13; online]. Available from URL: http://www.stamp.bham.ac.uk [Accessed 2012 Mar 1]
  20. 20.
    Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol 2005; 19(1): 117–25PubMedCrossRefGoogle Scholar
  21. 21.
    Vahakangas K, Myllynen P. Drug transporters in the human blood-placental barrier. Br J Pharmacol 2009; 158(3): 665–78PubMedCrossRefGoogle Scholar
  22. 22.
    Ni Z, Mao Q. ATP-binding cassette efflux transporters in human placenta. Curr Pharm Biotechnol 2010; 12(4): 674–85CrossRefGoogle Scholar
  23. 23.
    Holtzman CW, Wiggins BS, Spinler SA. Role of P-glycoprotein in statin drug interactions. Pharmacotherapy 2006; 26(11): 1601–7PubMedCrossRefGoogle Scholar
  24. 24.
    Wang X, Sato R, Brown MS, et al. SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis. Cell 1994; 77(1): 53–62PubMedCrossRefGoogle Scholar
  25. 25.
    Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 2005; 45: 89–118PubMedCrossRefGoogle Scholar
  26. 26.
    Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol 2001; 21(11): 1712–9PubMedCrossRefGoogle Scholar
  27. 27.
    Zhou Q, Liao JK. Statins and cardiovascular diseases: from cholesterol lowering to pleiotropy. Curr Pharm Des 2009; 15(5): 467–78PubMedCrossRefGoogle Scholar
  28. 28.
    Zhou Q, Liao JK. Pleiotropic effects of statins: basic research and clinical perspectives. Circ J 2007; 74(5): 818–26CrossRefGoogle Scholar
  29. 29.
    Ray KK, Cannon CP. The potential relevance of the multiple lipid-independent (pleiotropic) effects of statins in the management of acute coronary syndromes. J Am Coll Cardiol 2005; 46(8): 1425–33PubMedCrossRefGoogle Scholar
  30. 30.
    Guzik TJ, Harrison DG. Vascular NADPH oxidases as drug targets for novel antioxidant strategies. Drug Discov Today 2006; 11(11-12): 524–33PubMedCrossRefGoogle Scholar
  31. 31.
    Wassmann S, Laufs U, Müller K, et al. Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arterioscler Thromb Vasc Biol 2002; 22(2): 300–5PubMedCrossRefGoogle Scholar
  32. 32.
    Rueckschloss U, Galle J, Holtz J, et al. Induction of NAD(P)H oxidase by oxidized low-density lipoprotein in human endothelial cells: antioxidative potential of hydroxymethylglutaryl coenzyme A reductase inhibitor therapy. Circulation 2001; 104(15): 1767–72PubMedCrossRefGoogle Scholar
  33. 33.
    Wagner AH, Köhler T, Rückschloss U, et al. Improvement of nitric oxide-dependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol 2000; 20(1): 61–9PubMedCrossRefGoogle Scholar
  34. 34.
    Landmesser U, Bahlmann F, Mueller M, et al. Simvastatin versus ezetimibe: pleiotropic and lipid-lowering effects on endothelial function in humans. Circulation 2005; 111(18): 2356–63PubMedCrossRefGoogle Scholar
  35. 35.
    Förstermann U. Janus-faced role of endothelial NO synthase in vascular disease: uncoupling of oxygen reduction from NO synthesis and its pharmacological reversal. Biol Chem 2006; 387(12): 1521–33PubMedCrossRefGoogle Scholar
  36. 36.
    Mason RP, Walter MF, Jacob RF. Effects of HMG-CoA reductase inhibitors on endothelial function: role of microdomains and oxidative stress. Circulation 2004; 109 (21 Suppl. 1): II34–41PubMedGoogle Scholar
  37. 37.
    Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem 1998; 273(37): 24266–71PubMedCrossRefGoogle Scholar
  38. 38.
    Kureishi Y, Luo Z, Shiojima I, et al. The HMG-CoA reductase inhibitor simvastatin activates the protein kinase Akt and promotes angiogenesis in normocholesterolemic animals. Nat Med 2000; 6(9): 1004–10PubMedCrossRefGoogle Scholar
  39. 39.
    Simoncini T, Hafezi-Moghadam A, Brazil DP, et al. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 2000; 407(6803): 538–41PubMedCrossRefGoogle Scholar
  40. 40.
    Plenz GA, Hofnagel O, Robenek H. Differential modulation of caveolin-1 expression in cells of the vasculature by statins. Circulation 2004; 109(2): e7–8; author reply e7-8PubMedCrossRefGoogle Scholar
  41. 41.
    Rikitake Y, Kawashima S, Takeshita S, et al. Antioxidative properties of fluvastatin, an HMG-CoA reductase inhibitor, contribute to prevention of atherosclerosis in cholesterol-fed rabbits. Atherosclerosis 2001; 154(1): 87–96PubMedCrossRefGoogle Scholar
  42. 42.
    Tenhunen R, Marver HS, Schmid R. Microsomal heme oxygenase: characterization of the enzyme. J Biol Chem 1969; 244(23): 6388–94PubMedGoogle Scholar
  43. 43.
    Duckers HJ, Boehm M, True AL, et al. Heme oxygenase-1 protects against vascular constriction and proliferation. Nat Med 2001; 7(6): 693–8PubMedCrossRefGoogle Scholar
  44. 44.
    Muchova L, Wong RJ, Hsu M, et al. Statin treatment increases formation of carbon monoxide and bilirubin in mice: a novel mechanism of in vivo antioxidant protection. Can J Physiol Pharmacol 2007; 85(8): 800–10PubMedCrossRefGoogle Scholar
  45. 45.
    Hinkelmann U, Grosser N, Erdmann K, et al. Simvastatin-dependent up-regulation of heme oxygenase-1 via mRNA stabilization in human endothelial cells. Eur J Pharm Sci 2010; 41(1): 118–24PubMedCrossRefGoogle Scholar
  46. 46.
    Lee TS, Chang CC, Zhu Y, et al. Simvastatin induces heme oxygenase-1: a novel mechanism of vessel protection. Circulation 2004; 110(10): 1296–302PubMedCrossRefGoogle Scholar
  47. 47.
    Grosser N, Hemmerle A, Berndt G, et al. The antioxidant defense protein heme oxygenase 1 is a novel target for statins in endothelial cells. Free Radic Biol Med 2004; 37(12): 2064–71PubMedCrossRefGoogle Scholar
  48. 48.
    Ali F, Hamdulay SS, Kinderlerer AR, et al. Statin-mediated cytoprotection of human vascular endothelial cells: a role for Kruppel-like factor 2-dependent induction of heme oxygenase-1. J Thromb Haemost, 2007; 5(12): 2537–46PubMedCrossRefGoogle Scholar
  49. 49.
    Vasa M, Fichtlscherer S, Adler K, et al. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation 2001; 103(24): 2885–90PubMedCrossRefGoogle Scholar
  50. 50.
    Spiel AO, Mayr FB, Leitner JM, et al. Simvastatin and rosuvastatin mobilize Endothelial Progenitor Cells but do not prevent their acute decrease during systemic inflammation. Thromb Res 2008; 123(1): 108–13PubMedCrossRefGoogle Scholar
  51. 51.
    Llevadot J, Murasawa S, Kureishi Y, et al. HMG-CoA reductase inhibitor mobilizes bone marrow-derived endothelial progenitor cells. JClin Invest 2001; 108(3): 399–405Google Scholar
  52. 52.
    Nishimoto-Hazuku A, Hirase T, Ide N, et al. Simvastatin stimulates vascular endothelial growth factor production by hypoxia-inducible factor-1alpha upregulation in endothelial cells. J Cardiovasc Pharmacol 2008; 51(3): 267–73PubMedCrossRefGoogle Scholar
  53. 53.
    Weis M, Heeschen C, Glassford AJ, et al. Statins have biphasic effects on angiogenesis. Circulation 2002; 105(6): 739–45PubMedCrossRefGoogle Scholar
  54. 54.
    Belo L, Caslake M, Santos-Silva A, et al. LDL size, total antioxidant status and oxidised LDL in normal human pregnancy: a longitudinal study. Atherosclerosis 2004; 177(2): 391–9PubMedCrossRefGoogle Scholar
  55. 55.
    Alvarez JJ, Montelongo A, Iglesias A, et al. Longitudinal study on lipoprotein profile, high density lipoprotein subclass, and postheparin lipases during gestation in women. J Lipid Res 1996; 37(2): 299–308PubMedGoogle Scholar
  56. 56.
    Piechota W, Staszewski A. Reference ranges of lipids and apolipoproteins in pregnancy. Eur J Obstet Gynecol Reprod Biol 1992; 45(1): 27–35PubMedCrossRefGoogle Scholar
  57. 57.
    Winkler K, Wetzka B, Hoffmann MM, et al. Low density lipoprotein (LDL) subfractions during pregnancy: accumulation of buoyant LDL with advancing gestation. J Clin Endocrinol Metab 2000; 85(12): 4543–50PubMedCrossRefGoogle Scholar
  58. 58.
    Pavan L, Hermouet A, Tsatsaris V, et al. Lipids from oxidized low-density lipoprotein modulate human tropho-blast invasion: involvement of nuclear liver X receptors. Endocrinology 2004; 145(10): 4583–91PubMedCrossRefGoogle Scholar
  59. 59.
    Haggarty P. Effect of placental function on fatty acid re-quirements during pregnancy. Eur J Clin Nutr 2004; 58(12): 1559–70PubMedCrossRefGoogle Scholar
  60. 60.
    Haggarty P. Placental regulation of fatty acid delivery and its effect on fetal growth: a review. Placenta 2002; 23 Suppl. A: S28–38PubMedCrossRefGoogle Scholar
  61. 61.
    Hornstra G, Al MD, van Houwelingen AC, et al. Essential fatty acids in pregnancy and early human development. Eur J Obstet Gynecol Reprod Biol 1995; 61(1): 57–62PubMedCrossRefGoogle Scholar
  62. 62.
    Shekhawat P, Bennett MJ, Sadovsky Y, et al. Human placenta metabolizes fatty acids: implications for fetal fatty acid oxidation disorders and maternal liver diseases. Am J Physiol Endocrinol Metab 2003; 284(6): E1098–105PubMedGoogle Scholar
  63. 63.
    Neuringer M, Connor WE. n-3 fatty acids in the brain and retina: evidence for their essentiality. Nutr Rev 1986; 44(9): 285–94PubMedCrossRefGoogle Scholar
  64. 64.
    Bourre JM, Durand G, Pascal G, et al. Brain cell and tissue recovery in rats made deficient in n-3 fatty acids by alteration of dietary fat. J Nutr 1989; 119(1): 15–22PubMedGoogle Scholar
  65. 65.
    Crawford MA, Doyle W, Drury P, et al. n-6 and n-3 fatty acids during early human development. J Intern Med Suppl. 1989; 731: 159–69PubMedGoogle Scholar
  66. 66.
    Allen KG, Harris MA. The role of n-3 fatty acids in gestation and parturition. Exp Biol Med (Maywood) 2001; 226(6): 498–506Google Scholar
  67. 67.
    Chiang C, Litingtung Y, Lee E, et al. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 1996; 383(6599): 407–13PubMedCrossRefGoogle Scholar
  68. 68.
    Roessler E, et al. Mutations in the human Sonic Hedgehog gene cause holoprosencephaly. Nat Genet 1996; 14(3): 357–60PubMedCrossRefGoogle Scholar
  69. 69.
    Woollett LA. Review: transport of maternal cholesterol to the fetal circulation. Placenta 2011; 32 Suppl. 2: 218–21CrossRefGoogle Scholar
  70. 70.
    Edison RJ, Muenke M. Gestational exposure to lovastatin followed by cardiac malformation misclassified as holoprosencephaly [erratum]. N Engl J Med 2005; 352(26): 2759PubMedCrossRefGoogle Scholar
  71. 71.
    Wadsack C, Tabano S, Maier A, et al. Intrauterine growth restriction is associated with alterations in placental lipoprotein receptors and maternal lipoprotein composition. Am J Physiol Endocrinol Metab 2007; 292(2): E476–84PubMedCrossRefGoogle Scholar
  72. 72.
    Cunniff C, Kratz LE, Moser A, et al. Clinical and biochemical spectrum of patients with RSH/Smith-Lemli-Opitz syndrome and abnormal cholesterol metabolism. Am J Med Genet 1997; 68(3): 263–9PubMedCrossRefGoogle Scholar
  73. 73.
    Tint GS, Salen G, Batta AK, et al. Correlation of severity and outcome with plasma sterol levels in variants of the Smith-Lemli-Opitz syndrome. J Pediatr 1995; 127(1): 82–7PubMedCrossRefGoogle Scholar
  74. 74.
    Correa-Cerro LS, Wassif CA, Kratz L, et al. Development and characterization of a hypomorphic Smith-Lemli-Opitz syndrome mouse model and efficacy of simvastatin therapy. Hum Mol Genet 2006; 15(6): 839–51PubMedCrossRefGoogle Scholar
  75. 75.
    Chan YM, Merkens LS, Connor WE, et al. Effects of dietary cholesterol and simvastatin on cholesterol synthesis in Smith-Lemli-Opitz syndrome. Pediatr Res 2009; 65(6): 681–5PubMedCrossRefGoogle Scholar
  76. 76.
    Civeira F. Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia. Atherosclerosis 2004; 173(1): 55–68PubMedCrossRefGoogle Scholar
  77. 77.
    Toleikyte I, Retterstøl K, Leren TP, et al. Pregnancy outcomes in familial hypercholesterolemia: a registry-based study. Circulation 2011; 124(15): 1606–14PubMedCrossRefGoogle Scholar
  78. 78.
    Kazmin A, Garcia-Bournissen F, Koren G. Risks of statin use during pregnancy: a systematic review. J Obstet Gynaecol Can 2007; 29(11): 906–8PubMedGoogle Scholar
  79. 79.
    Kenis I, Tartakover-Matalong S, Cherepnin N, et al. Simvastatin has deleterious effects on human first trimester placental explants. Hum Reprod 2005; 20(10): 2866–72PubMedCrossRefGoogle Scholar
  80. 80.
    Tartakover-Matalon S, Cherepnin N, Kuchuk M, et al. Impaired migration of trophoblast cells caused by simvastatin is associated with decreased membrane IGF-I receptor, MMP2 activity and HSP27 expression. Hum Reprod 2007; 22(4): 1161–7PubMedCrossRefGoogle Scholar
  81. 81.
    Forbes K, Hurst LM, Aplin JD, et al. Statins are detrimental to human placental development and function; use of statins during early pregnancy is inadvisable. J Cell Mol Med 2008; 12(6A): 2295–6PubMedCrossRefGoogle Scholar
  82. 82.
    Jasinska M, Owczarek J, Orszulak-Michalak D. Statins: a new insight into their mechanisms of action and consequent pleiotropic effects. Pharmacol Rep 2007; 59(5): 483–99PubMedGoogle Scholar
  83. 83.
    Fournier T, Guibourdenche J, Handschuh K, et al. PPARgamma and human trophoblast differentiation. J Reprod Immunol 2011; 90(1): 41–9PubMedCrossRefGoogle Scholar
  84. 84.
    Tarrade A, Schoonjans K, Guibourdenche J, et al. PPAR gamma/RXR alpha heterodimers are involved in human CG beta synthesis and human trophoblast differentiation. Endocrinology 2001; 142(10): 4504–14PubMedCrossRefGoogle Scholar
  85. 85.
    Tarrade A, Schoonjans K, Pavan L, et al. PPARgamma/ RXRalpha heterodimers control human trophoblast invasion. J Clin Endocrinol Metab 2001; 86(10): 5017–24PubMedCrossRefGoogle Scholar
  86. 86.
    Yano M, Matsumura T, Senokuchi T, et al. Statins activate peroxisome proliferator-activated receptor gamma through extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase-dependent cyclooxygenase-2 expression in macrophages. Circ Res 2007; 100(10): 1442–51PubMedCrossRefGoogle Scholar
  87. 87.
    Desjardins F, Sekkali B, Verreth W, et al. Rosuvastatin increases vascular endothelial PPARgamma expression and corrects blood pressure variability in obese dyslipidaemic mice. Eur Heart J 2008; 29(1): 128–37PubMedCrossRefGoogle Scholar
  88. 88.
    Brewer LM, Sheardown SA, Brown NA. HMG-CoA reductase mRNA in the post-implantation rat embryo studied by in situ hybridization. Teratology 1993; 47(2): 137–46PubMedCrossRefGoogle Scholar
  89. 89.
    Minsker DH, MacDonald JS, Robertson RT, et al. Mevalonate supplementation in pregnant rats suppresses the teratogenicity of mevinolinic acid, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme a reductase. Teratology 1983; 28(3): 449–56PubMedCrossRefGoogle Scholar
  90. 90.
    Tanase TM, Hirose K. Reproduction study of pravastatine sodium administered during the period of fetal organogenesis in rats. Jpn Pharmacol Ther 1987; 15(12): 4983–94Google Scholar
  91. 91.
    Tanase TM, Asai M, Hirose K. Reproduction study of pravastatin sodium administered during the period of fetal organogenesis in rabbits. Jpn Pharmacol Ther 1987; 15: 5005–11Google Scholar
  92. 92.
    Dostal LA, Schardein JL, Anderson JA. Developmental toxicity of the HMG-CoA reductase inhibitor, atorvastatin, in rats and rabbits. Teratology 1994; 50(6): 387–94PubMedCrossRefGoogle Scholar
  93. 93.
    Edison RJ, Muenke M. Central nervous system and limb anomalies in case reports of first-trimester statin exposure. N Engl J Med 2004; 350(15): 1579–82PubMedCrossRefGoogle Scholar
  94. 94.
    Brown LY, Odent S, David V, et al. Holoprosencephaly due to mutations in ZIC2: alanine tract expansion mutations may be caused by parental somatic recombination. Hum Mol Genet 2001; 10(8): 791–6PubMedCrossRefGoogle Scholar
  95. 95.
    Kim J, Kim P, Hui CC. The VACTERL association: lessons from the Sonic hedgehog pathway. Clin Genet 2001; 59(5): 306–15PubMedCrossRefGoogle Scholar
  96. 96.
    Edison RJ, Muenke M. Mechanistic and epidemiologic considerations in the evaluation of adverse birth outcomes following gestational exposure to statins. Am J Med Genet A 2004; 131(3): 287–98PubMedCrossRefGoogle Scholar
  97. 97.
    Gibb H, Scialli AR. Statin drugs and congenital anomalies. Am J Med Genet A 2005; 135(2): 230–1; author reply 232-4PubMedGoogle Scholar
  98. 98.
    Incardona JP, Gaffield W, Kapur RP, et al. The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction. Development 1998; 125(18): 3553–62PubMedGoogle Scholar
  99. 99.
    Roux C, Horvath C, Dupuis R. Teratogenic action and embryo lethality of AY 9944R: prevention by a hypercholes-terolemia-provoking diet. Teratology 1979; 19(1): 35–8PubMedCrossRefGoogle Scholar
  100. 100.
    Taguchi N, Rubin ET, Hosokawa A, et al. Prenatal exposure to HMG-CoA reductase inhibitors: effects on fetal and neonatal outcomes. Reprod Toxicol 2008; 26(2): 175–7PubMedCrossRefGoogle Scholar
  101. 101.
    Ofori B, Rey E, Berard A. Risk of congenital anomalies in pregnant users of statin drugs. Br J Clin Pharmacol 2007; 64(4): 496–509PubMedCrossRefGoogle Scholar
  102. 102.
    Petersen EE, Mitchell AA, Carey JC, et al. Maternal exposure to statins and risk for birth defects: a case-series approach. Am J Med Genet A 2008; 146A(20): 2701–5PubMedCrossRefGoogle Scholar
  103. 103.
    Pollack PS, Shields KE, Burnett DM, et al. Pregnancy outcomes after maternal exposure to simvastatin and lovastatin. Birth Defects Res A Clin Mol Teratol 2005; 73(11): 888–96PubMedCrossRefGoogle Scholar
  104. 104.
    Honein MA, Paulozzi LJ, Cragan JD, et al. Evaluation of selected characteristics of pregnancy drug registries. Teratology 1999; 60(6): 356–64PubMedCrossRefGoogle Scholar
  105. 105.
    Manson JM, Freyssinges C, Ducrocq MB, et al. Postmarketing surveillance of lovastatin and simvastatin exposure during pregnancy. Reprod Toxicol 1996; 10(6): 439–46PubMedCrossRefGoogle Scholar
  106. 106.
    Kane AD, Herrera EA, Hansell JA, et al. Statin treatment depresses the fetal defence to acute hypoxia via increasing nitric oxide bioavailability. J Physiol 2012 Jan; 590 (Pt 2): 323–34PubMedCrossRefGoogle Scholar
  107. 107.
    Redman CW, Sargent IL. Pre-eclampsia, the placenta and the maternal systemic inflammatory response: a review. Placenta 2003; 24 Suppl. A: S21–7PubMedCrossRefGoogle Scholar
  108. 108.
    Burton GJ, Jauniaux E. Oxidative stress. Best Pract Res Clin Obstet Gynaecol 2010; 25(3): 287–99PubMedCrossRefGoogle Scholar
  109. 109.
    Redman CW, Sargent IL. Placental stress and pre-eclampsia: a revised view. Placenta 2009; 30 Suppl. A: S38–42PubMedCrossRefGoogle Scholar
  110. 110.
    Buhimschi IA, Saade GR, Chwalisz K, et al. The nitric oxide pathway in pre-eclampsia: pathophysiological implications. Hum Reprod Update 1998; 4(1): 25–42PubMedCrossRefGoogle Scholar
  111. 111.
    Yuan HT, Haig D, Ananth Karumanchi S. Angiogenic factors in the pathogenesis of preeclampsia. Curr Top Dev Biol 2005; 71: 297–312PubMedCrossRefGoogle Scholar
  112. 112.
    Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 2004; 350(7): 672–83PubMedCrossRefGoogle Scholar
  113. 113.
    Levine RJ, Thadhani R, Qian C, et al. Urinary placental growth factor and risk of preeclampsia. Jama 2005; 293(1): 77–85PubMedCrossRefGoogle Scholar
  114. 114.
    Levine RJ, Lam C, Qian C, et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med 2006; 355(10): 992–1005PubMedCrossRefGoogle Scholar
  115. 115.
    Maynard SE, Min JY, 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(5): 649–58PubMedGoogle Scholar
  116. 116.
    Cudmore M, Ahmad S, Al-Ani B, et al. Negative regulation of soluble Flt-1 and soluble endoglin release by heme oxygenase-1. Circulation 2007; 115(13): 1789–97PubMedCrossRefGoogle Scholar
  117. 117.
    Raijmakers MT, Peters WH, Steegers EA, et al. Amino thiols, detoxification and oxidative stress in pre-eclampsia and other disorders of pregnancy. Curr Pharm Des 2005; 11(6): 711–34PubMedCrossRefGoogle Scholar
  118. 118.
    Poston L, Briley AL, Seed PT, et al. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebo-controlled trial. Lancet 2006; 367(9517): 1145–54PubMedCrossRefGoogle Scholar
  119. 119.
    Rumbold AR, Crowther CA, Haslam RR, et al. Vitamins C and E and the risks of preeclampsia and perinatal complications. N Engl J Med 2006; 354(17): 1796–806PubMedCrossRefGoogle Scholar
  120. 120.
    Ahmed A, Cudmore MJ. Can the biology of VEGF and haem oxygenases help solve pre-eclampsia? Biochem Soc Trans 2009; 37 (Pt 6): 1237–42PubMedCrossRefGoogle Scholar
  121. 121.
    Barker DJ, Eriksson JG, Forsén T, et al. Fetal origins of adult disease: strength of effects and biological basis. Int J Epidemiol 2002; 31(6): 1235–9PubMedCrossRefGoogle Scholar
  122. 122.
    Nelson DM, Burton GJ. Does a picture of the human placenta predict the future? Placenta 2010; 31(11): 943PubMedCrossRefGoogle Scholar
  123. 123.
    Ray JG, Vermeulen MJ, Schull MJ, et al. Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study. Lancet 2005; 366(9499): 1797–803PubMedCrossRefGoogle Scholar
  124. 124.
    University of Oxford. Can atorvastatin improve vascular function in women with a history of preeclampsia? [Clinical Trials.gov identifier NCT01278459]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://http://www.clinicaltrials.gov [Accessed 2012 Mar 1]

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© Springer International Publishing AG 2012

Authors and Affiliations

  • Edouard Lecarpentier
    • 1
  • Olivier Morel
    • 2
  • Thierry Fournier
    • 3
  • Elisabeth Elefant
    • 4
  • Pascale Chavatte-Palmer
    • 5
    • 6
  • Vassilis Tsatsaris
    • 1
    • 3
    • 6
  1. 1.Maternité Port-Royal, Cochin Hospital, AP-HP, Paris-Descartes UniversityParisFrance
  2. 2.Department of Obstetrics and GynecologyMaternité Régionale Universitaire de Nancy, Nancy I H. Poincaré UniversityNancyFrance
  3. 3.INSERM U767, Paris-Descartes UniversityParisFrance
  4. 4.Centre de Référence sur les Agents Tératogènes, Armand Trousseau HospitalParisFrance
  5. 5.INRA, UMR 1198 Biologie du Développement et ReproductionJouy en JosasFrance
  6. 6.Premup FoundationParisFrance

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