Are statins teratogenic in humans? Addressing the safety of statins in light of potential benefits during pregnancy

Expert Review of Obstetrics and Gynecology

Volumn 8, Issue 6, 2013, Pages 513-524

  Zarek, Judith ^a,b   Delano, Kaitlyn E ^a,c   Nickel, Cheri ^a   Laskin, Carl A ^b,d   Koren, Gideon ^a,b,c  

^a HOSPITAL FOR SICK CHILDREN   (Canada)

^b UNIVERSITY OF TORONTO   (Canada)

^c UNIVERSITY OF TORONTO   (Canada)

^d MOUNT SINAI HOSPITAL   (Canada)

Author keywords

atorvastatin; cholesterol; fluvastatin; lovastatin; pravastatin; pregnancy; rosuvastatin; simvastatin; statins; teratogenic

Indexed keywords

ATORVASTATIN; CHOLESTEROL; FLUINDOSTATIN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; MEVINOLIN; PRAVASTATIN; ROSUVASTATIN; SIMVASTATIN;

BIRTH DEFECT; DRUG CONTRAINDICATION; DRUG EFFECT; DRUG SAFETY; DRUG USE; ENDOMETRIOSIS; HUMAN; HYPERCHOLESTEROLEMIA; META ANALYSIS; NONHUMAN; OVARY POLYCYSTIC DISEASE; PREECLAMPSIA; PREGNANCY; PREGNANCY OUTCOME; PRENATAL DRUG EXPOSURE; REVIEW; SYSTEMATIC REVIEW; TERATOGEN TESTING; TERATOGENICITY;

EID: 84887312121     PISSN: 17474108     EISSN: 17474116     Source Type: Journal    
DOI: 10.1586/17474108.2013.842684     Document Type: Review

References (86)

1. Kostis WJ, Cheng JQ, Dobrzynski JM, Cabrera J, Kostis JB. Meta-analysis of statin effects in women versus men. J. Am. Coll. Cardiol. 59(6), 572-582 (2012).
2. Gutierrez J, Ramirez G, Rundek T, Sacco RL. Statin therapy in the prevention of recurrent cardiovascular events: a sex-based meta-analysis. Arch. Intern. Med. 172(12), 909-919 (2012).
3. Athyros VG, Kakafika AI, Papageorgiou AA et al. Effects of statin treatment in men and women with stable coronary heart disease: a subgroup analysis of the GREACE Study. Curr. Med. Res. Opin. 24(6), 1593-1599 (2008).
4. Pedersen TR, Kjekshus J, Berg K et al. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) 1994. Atheroscler. Suppl. 5(3), 81-87 (2004).
5. Downs JR, Clearfield M, Weis S et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 279(20), 1615-1622 (1998).
6. Cooper WO, Hickson GB, Ray WA. Prescriptions for contraindicated category X drugs in pregnancy among women enrolled in TennCare. Paediatr. Perinat. Epidemiol. 18(2), 106-111 (2004).
7. Webster DA, Khunti K, Wilmot EG, Thakrar B, Davies MJ, Anwar A. Exposure to teratogenic drugs and concomitant contraception in women of child-bearing age with type 2 diabetes: A population based cohort study. Poster session presented at the 46th meeting of the European Association for the Study of Diabetes. Stockholm, Sweden. 20-24 September 2010.
8. Christenson LK, Devoto L. Cholesterol transport and steroidogenesis by the corpus luteum. Reprod. Biol. Endocrinol. 1, 90 (2003).
9. Baardman ME, Erwich JJ, Berger RM et al. The origin of fetal sterols in second-trimester amniotic fluid: endogenous synthesis or maternal-fetal transport? Am. J. Obstet. Gynecol. 207(3), 202 e19-e25 (2012).
10. Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 15(23), 3059-3087 (2001).
11. Villavicencio EH, Walterhouse DO, Iannaccone PM. The sonic hedgehog-patched-gli pathway in human development and disease. Am. J. Hum. Genet. 67(5), 1047-1054 (2000).
12. Baardman ME, Kerstjens-Frederikse WS, Berger RM, Bakker MK, Hofstra RM, Plosch T. The role of maternal-fetal cholesterol transport in early fetal life: current insights. Biol. Reprod. 88(1), 24 (2013).
13. Wadsack C, Hammer A, Levak-Frank S et al. Selective cholesteryl ester uptake from high density lipoprotein by human first trimester and term villous trophoblast cells. Placenta 24(2-3), 131-143 (2003).
14. Yoshida S, Wada Y. Transfer of maternal cholesterol to embryo and fetus in pregnant mice. J. Lipid. Res. 46(10), 2168-2174 (2005).
15. Aye IL, Waddell BJ, Mark PJ, Keelan JA. Placental ABCA1 and ABCG1 transporters efflux cholesterol and protect trophoblasts from oxysterol induced toxicity. Biochim. Biophys. Acta 1801(9), 1013-1024 (2010).
16. Porter FD. Smith-Lemli-Opitz syndrome: pathogenesis, diagnosis and management. Eur. J. Hum. Genet. 16(5), 535-541 (2008).
17. Tint GS, Irons M, Elias ER et al. Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N. Engl. J. Med. 330(2), 107-113 (1994).
18. Lindegaard ML, Wassif CA, Vaisman B et al. Characterization of placental cholesterol transport: ABCA1 is a potential target for in utero therapy of Smith- Lemli-Opitz syndrome. Hum. Mol. Genet. 17(23), 3806-3813 (2008).
19. Ekhator CN, Ebomoyi MI. Blood glucose and serum lipid profiles during pregnancy. Afr. J. Diabet. Med. 20(1), 16 (2012).
20. Edison RJ, Berg K, Remaley A et al. Adverse birth outcome among mothers with low serum cholesterol. Pediatrics 120(4), 723-733 (2007).
21. Minsker DH, MacDonald JS, Robertson RT, Bokelman DL. Mevalonate supplementation in pregnant rats suppresses the teratogenicity of mevinolinic acid, an inhibitor of 3-hydroxy-3-methylglutarylcoenzyme a reductase. Teratology 28(3), 449-456 (1983).
22. Lankas GR, Cukierski MA, Wise LD. The role of maternal toxicity in lovastatininduced developmental toxicity. Birth Defects Res. B Dev. Reprod. Toxicol. 71(3), 111-123 (2004).
23. Wise LD, Cukierski MA, Lankas GR, Skiles GL. The predominant role of maternal toxicity in lovastatin-induced developmental toxicity. Teratology 61, 444 (2000).
24. Lescol, Product Information. Novartis Pharmaceuticals Corp., East Hanover, NJ, USA (2012).
25. Zocor, Product Information. Merck & Co. Inc., Whitehouse Station, NJ, USA (2012).
26. Wise LD, Prahalada S, Robertson RT, Bokelman DL, Akutsu S, Fujii T. Simvastatin (mk-0733): oral teratogenicity study in rabbits. Oyo Yakuri. 39, 159-167 (1990).
27. Dostal LA, Schardein JL, Anderson JA. Developmental toxicity of the HMG-CoA reductase inhibitor, atorvastatin, in rats and rabbits. Teratology 50(6), 387-394 (1994).
28. CRESTOR oral tablets, rosuvastatin calcium oral tablets, Product Information. AstraZeneca Pharmaceuticals LP., Wilmington, DE, USA (2012).
29. Tanase H, Hirose K. Reproduction study of pravastatin sodium administered prior to and in the early stages of pregnancy in rats. Jpn Pharmacol. Ther. 1537-1544 (1987).
30. Tanase H, Hirose K. Reproduction study of pravastatin sodium administered prior to and in the early stages of pregnancy in rats. Jpn Pharmacol. Ther. 1545-1556 (1987).
31. 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. 131(3), 287-298 (2004).
32. Gibb H, Scialli AR. Statin drugs and congenital anomalies. Am. J. Med. Genet. A. 135(2), 230-231, author reply 232-234 (2005).
33. Bar-Oz B, Moretti ME, Mareels G, Van Tittelboom T, Koren G. Reporting bias in retrospective ascertainment of drug-induced embryopathy. Lancet 354(9191), 1700-1701 (1999).
34. Ghidini A, Sicherer S, Willner J. Congenital abnormalities (VATER) in baby born to mother using lovastatin. Lancet 339(8806), 1416-1417 (1992).
35. Yaris F, Yaris E, Kadioglu M, Ulku C, Kesim M, Kalyoncu NI. Normal pregnancy outcome following inadvertent exposure to rosiglitazone, gliclazide, and atorvastatin in a diabetic and hypertensive woman. Reprod. Toxicol. 18(4), 619-621 (2004).
36. Teelucksingh S, El-Youssef J, Sohan K, Ramsewak S. Prolonged inadvertent pravastatin use in pregnancy. Reprod. Toxicol. 18(2), 299-300 (2004).
37. Vagt A, Kastendieck C. Probable congenital anomaly after exposure to atorvastatin in early pregnancy. From the Bremen register of drug-related diseases. Tagliche Praxis. 41, 409-412 (2000).
38. Seguin J, Samuels P. Fluvastatin exposure during pregnancy. Obstet. Gynecol. 93(5 Pt 2), 847 (1999).
39. Petersen EE, Mitchell AA, Carey JC, Werler MM, Louik C, Rasmussen SA. Maternal exposure to statins and risk for birth defects: a case-series approach. Am. J. Med. Genet. A. 146A(20), 2701-2705 (2008).
40. Pollack PS, Shields KE, Burnett DM, Osborne MJ, Cunningham ML, Stepanavage ME. Pregnancy outcomes after maternal exposure to simvastatin and lovastatin. Birth Defects Res. A Clin. Mol. Teratol. 73(11), 888-896 (2005).
41. Thorogood M, Seed M, De Mott K. Management of fertility in women with familial hypercholesterolaemia: summary of NICE guidance. BJOG 116(4), 478-479 (2009).
42. Kusters DM, Homsma SJ, Hutten BA et al. Dilemmas in treatment of women with familial hypercholesterolaemia during pregnancy. Neth. J. Med. 68(1), 299-303 (2010).
43. Brugts JJ, Yetgin T, Hoeks SE et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ 338, b2376 (2009).
44. Ofori B, Rey E, Berard A. Risk of congenital anomalies in pregnant users of statin drugs. Br. J. Clin. Pharmacol. 64(4), 496-509 (2007).
45. Taguchi N, Rubin ET, Hosokawa A et al. Prenatal exposure to HMG-CoA reductase inhibitors: effects on fetal and neonatal outcomes. Reprod. Toxicol. 26(2), 175-177 (2008).
46. McGrogan A, Snowball J, de Vries CS. Statins and pregnancy outcomes: a cohort study in the GPRD. Pharmacoepidemiol. Drug Saf. 18(Suppl. 18), S75-S76 (2009).
47. Colvin L, Slack-Smith L, Stanley FJ, Bower C. Linking a pharmaceutical claims database with a birth defects registry to investigate birth defect rates of suspected teratogens. Pharmacoepidemiol. Drug Saf. 19(11), 1137-1150 (2010).
48. Paulus WE, Schloemp S, Stoz F. Statin treatment in hypercholesterolemic mothers during early pregnancy. Geburtshilfe Und Frauenheilkunde. 68, S130 (2008).
49. Winterfeld U, Allignol A, Panchaud A et al. Pregnancy outcome following maternal exposure to statins: a multicentre prospective study. BJOG 120(4), 463-471 (2013).
50. Mudd LM, Holzman CB, Catov JM, Senagore PK, Evans RW. Maternal lipids at mid-pregnancy and the risk of preterm delivery. Acta Obstet. Gynecol. Scand. 91(6), 726-735 (2012).
51. Ziaei S, Jahanian S, Kazemnejad A. Lipid concentration in small for gestational age (SGA) pregnancies and hypertensive disorders. Pregnancy Hypertens. 2(2), 164-167 (2012).
52. Goharkhay N, Tamayo EH, Yin H, Hankins GD, Saade GR, Longo M. Maternal hypercholesterolemia leads to activation of endogenous cholesterol synthesis in the offspring. Am. J. Obstet. Gynecol. 199(3), 273 e1-6 (2008).
53. Napoli C, D'Armiento FP, Mancini FP et al. Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions. J. Clin. Invest. 100(11), 2680-2690 (1997).
54. Napoli C, Glass CK, Witztum JL, Deutsch R, D'Armiento FP, Palinski W. Influence of maternal hypercholesterolaemia during pregnancy on progression of early atherosclerotic lesions in childhood: Fate of Early Lesions in Children (FELIC) study. Lancet 354(9186), 1234-1241 (1999).
55. Napoli C, Witztum JL, Calara F, de Nigris F, Palinski W. Maternal hypercholesterolemia enhances atherogenesis in normocholesterolemic rabbits, which is inhibited by antioxidant or lipid-lowering intervention during pregnancy: an experimental model of atherogenic mechanisms in human fetuses. Circ. Res. 87(10), 946-952 (2000).
56. Palinski W, D'Armiento FP, Witztum JL et al. Maternal hypercholesterolemia and treatment during pregnancy influence the long-term progression of atherosclerosis in offspring of rabbits. Circ. Res. 89(11), 991-996 (2001).
57. De Assis SM, Seguro AC, Helou CM. Effects of maternal hypercholesterolemia on pregnancy and development of offspring. Pediatr. Nephrol. 18(4), 328-334 (2003).
58. Bhasin KK, van Nas A, Martin LJ, Davis RC, Devaskar SU, Lusis AJ. Maternal low-protein diet or hypercholesterolemia reduces circulating essential amino acids and leads to intrauterine growth restriction. Diabetes 58(3), 559-566 (2009).
59. Siu SC, Colman JM, Sorensen S et al. Adverse neonatal and cardiac outcomes are more common in pregnant women with cardiac disease. Circulation 105(18), 2179-2184 (2002).
60. Toleikyte I, Retterstol K, Leren TP, Iversen PO. Pregnancy outcomes in familial hypercholesterolemia: a registry-based study. Circulation 124(15), 1606-1614 (2011).
61. Lennernas H, Fager G. Pharmacodynamics and pharmacokinetics of the HMG-CoA eductase inhibitors. Similarities and differences. Clin. Pharmacokinet. 32(5), 403-425 (1997).
62. Hampton R, Dimster-Denk D, Rine J. The biology of HMG-CoA reductase: the pros of contra-regulation. Trends Biochem. Sci. 21(4), 140-145 (1996).
63. Sokalska A, Wong DH, Cress A et al. Simvastatin induces apoptosis and alters cytoskeleton in endometrial stromal cells. J. Clin. Endocrinol. Metab. 95(7), 3453-3459 (2010).
64. Sokalska A, Cress A, Bruner-Tran KL et al. Simvastatin decreases invasiveness of human endometrial stromal cells. Biol. Reprod. 87(1), 2, 1-6 (2012).
65. Bruner-Tran KL, Osteen KG, Duleba AJ. Simvastatin protects against the development of endometriosis in a nude mouse model. J. Clin. Endocrinol. Metabol. 94(7), 2489-2494 (2009).
66. Oktem M, Esinler I, Eroglu D, Haberal N, Bayraktar N, Zeyneloglu HB. High-dose atorvastatin causes regression of endometriotic implants: a rat model. Hum. Reprod. 22(5), 1474-1480 (2007).
67. Rashidi B, Abediasl J, Tehraninejad E, Rahmanpour H, Sills ES. Simvastatin effects on androgens, inflammatory mediators, and endogenous pituitary gonadotropins among patients with PCOS undergoing IVF: results from a prospective, randomized, placebocontrolled clinical trial. J. Investig. Med. 59(6), 912-916 (2011).
68. Sathyapalan T, Smith KA, Coady AM, Kilpatrick ES, Atkin SL. Atorvastatin therapy decreases androstenedione and dehydroepiandrosterone sulphate concentrations in patients with polycystic ovary syndrome: randomized controlled study. Ann. Clin. Biochem. 49(Pt 1), 80-85 (2012).
69. Banaszewska B, Pawelczyk L, Spaczynski RZ, Duleba AJ. Effects of simvastatin and metformin on polycystic ovary syndrome after six months of treatment. J. Clin. Endocrinol. Metab. 96(11), 3493-3501 (2011).
70. Rashidi B, Abediasl J, Tehraninejad E, Rahmanpour H, Sills ES. Simvastatin effects on androgens, inflammatory mediators, and endogenous pituitary gonadotropins among patients with PCOS undergoing IVF: results from a prospective, randomized, placebo-controlled clinical trial. J. Investig. Med. 59(6), 912-916 (2011).
71. Raja-Khan N, Kunselman AR, Hogeman CS, Stetter CM, Demers LM, Legro RS. Effects of atorvastatin on vascular function, inflammation, and androgens in women with polycystic ovary syndrome: a double-blind, randomized, placebo-controlled trial. Fertil. Steril. 95(5), 1849-1852 (2011).
72. American Society For Reproductive Medicine. Patient Factsheet: Recurrent Pregnancy Loss (2008).
73. American College of Obstetricians and Gynecologists. ACOG practice bulletin. Management of recurrent pregnancy loss. Number 24, February 2001. (Replaces Technical Bulletin Number 212, September 1995). Int. J. Gynaecol. Obstet. 78(2), 179-190 (2002).
74. Kwak-Kim J, Park JC, Ahn HK, Kim JW, Gilman-Sachs A. Immunological modes of pregnancy loss. Am. J. Reprod. Immunol. 63(6), 611-623 (2010).
75. Redecha P, van Rooijen N, Torry D, Girardi G. Pravastatin prevents miscarriages in mice: role of tissue factor in placental and fetal injury. Blood 113(17), 4101-4109 (2009).
76. Duley L. The global impact of pre-eclampsia and eclampsia. Semin. Perinatol. 33(3), 130-137 (2009).
77. 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. USA 108(4), 1451-1455 (2011).
78. Singh J, Ahmed A, Girardi G. Role of complement component C1q in the onset of preeclampsia in mice. Hypertension 58(4), 716-724 (2011).
79. Costantine MM, Cleary K. Pravastatin for the prevention of preeclampsia in high-risk pregnant women. Obstet. Gynecol. 121(2 Pt 1), 349-353 (2013).
80. [Anonymous]. Better news on population. Lancet 339, 1600 (1992).
81. van Noord-Zaadstra BM, Looman CW, Alsbach H, Habbema JD, te Velde ER, Karbaat J. Delaying childbearing: effect of age on fecundity and outcome of pregnancy. BMJ 302(6789), 1361-1365 (1991).
82. Hatanaka T. Clinical pharmacokinetics of pravastatin: mechanisms of pharmacokinetic events. Clin. Pharmacokinet. 39(6), 397-412 (2000).
83. Igel M, Sudhop T, von Bergmann K. Metabolism and drug interactions of 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors (statins). Eur. J. Clin. Pharmacol. 57(5), 357-364 (2001).
84. Lennernas H. Clinical pharmacokinetics of atorvastatin. Clin. Pharmacokinet. 42(13), 1141-1160 (2003).
85. Hamelin BA, Turgeon J. Hydrophilicity/ lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol. Sci. 19(1), 26-37 (1998).
86. Vickers S, Duncan CA, Chen IW, Rosegay A, Duggan DE. Metabolic disposition studies on simvastatin, a cholesterol-lowering prodrug. Drug Metab. Dispos. 18(2), 138-145 (1990).