Caloric Restriction and Cancer

Part of the Energy Balance and Cancer book series (EBAC, volume 2)


In various animal models, caloric restriction is the most effective and reproducible intervention to extend life span and to reduce risks of aging-related chronic diseases, particularly cancer. Findings from human studies based on ecologic comparisons, the Norwegian famine during World War II, and patients with anorexia nervosa suggest that caloric restriction reduces cancer risk, especially the risk of breast cancer. In contrast, transient and abrupt caloric restriction with malnutrition followed by compensatory overnutrition may counter any protection conferred. Several earlier hypotheses for the biological mechanisms underlying the association between caloric restriction and longer life span and decreased cancer risk such as retarded growth and development, reduced metabolism rate, endocrinological changes, and decreased accumulation of oxidative damage were refuted by laboratory results. More recent findings suggest a hormesis hypothesis proposing that caloric restriction conveys a low-intensity biological stress on organisms, which may elicit an adaptive response of enhanced maintenance and repair. The identification of a new class of caloric restriction mimetic molecules that target the SIR2 family of longevity-promoting enzymes may provide a novel intervention for the prevention and treatment of cancer and other aging-related chronic diseases. Epigenetic mechanisms may also play a role.


Anorexia Nervosa Caloric Restriction Breast Cancer Incidence Dwarf Mouse Extend Life Span 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Adami HO, Hunter D, Trichopoulos D. (2002). Textbook of Cancer Epidemiology New York: Oxford University Press, Inc.Google Scholar
  2. 2.
    Albanes D (1987). Total calories, body weight, and tumor incidence in mice. Cancer Res, 47:1987–1992.PubMedGoogle Scholar
  3. 3.
    Araki T, Sasaki Y, Milbrandt J (2004). Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science, 305:1010–1013.CrossRefPubMedGoogle Scholar
  4. 4.
    Armeni T, Pieri C, Marra M et al. (1998). Studies on the life prolonging effects of food restriction: glutathione levels and glyoxylase enzymes in rat liver. Mech Ageing Dev, 101:101–110.CrossRefPubMedGoogle Scholar
  5. 5.
    Armstrong B, Doll R (1975). Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. Int J Cancer, 15:617–631.CrossRefPubMedGoogle Scholar
  6. 6.
    Bartke A, Wright JC, Mattison JA, et al. (2001). Extending the lifespan of long-lived mice. Nature, 414:412.CrossRefPubMedGoogle Scholar
  7. 7.
    Bhat KP, Pezzuto JM (2002). Cancer chemopreventive activity of resveratrol. Ann N Y Acad Sci, 957:210–229.CrossRefPubMedGoogle Scholar
  8. 8.
    Boutwell RK, Brush MK, Rusch HP (1949). The stimulatory effect of dietary fat on carcinogenesis. Cancer Res, 741–746.Google Scholar
  9. 9.
    Brunet A, Sweeney LB, Sturgill JF, et al. (2004). Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science, 303:2011–2015.CrossRefPubMedGoogle Scholar
  10. 10.
    Cabelof DC, Yanamadala S, Raffoul JJ, et al. (2003). Caloric restriction promotes genomic stability by induction of base excision repair and reversal of its age-related decline. DNA Repair (Amst), 2:295–307.CrossRefGoogle Scholar
  11. 11.
    Carling D (2004). The AMP-activated protein kinase cascade – a unifying system for energy control. Trends Biochem Sci, 29:18–24.CrossRefPubMedGoogle Scholar
  12. 12.
    Cassidy A., Hanley B, Lamuela-Raventos RM (2000). Isoflavones, lignans and stilbenes – Origins, metabolism and potential importance to human health. J Sci Food Agric, 80: 1044–1062.CrossRefGoogle Scholar
  13. 13.
    Cohen HY, Miller C, Bitterman KJ, et al. (2004a). Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science, 305:390–392.CrossRefPubMedGoogle Scholar
  14. 14.
    Cohen HY, Lavu S, Bitterman KJ, et al. (2004b). Acetylation of the C terminus of Ku70 by CBP and PCAF controls Bax mediated apoptosis. Mol Cell, 13:627–638.CrossRefPubMedGoogle Scholar
  15. 15.
    Culpitt SV, Rogers DF, Fenwick PS, et al. (2003). Inhibition by red wine extract, resveratrol, of cytokine release by alveolar macrophages in COPD. Thorax, 58:942–6.CrossRefPubMedGoogle Scholar
  16. 15a.
    Das C, Lucia MS, Hansen KC, et al. (2009). CBP/p300-mediated acetylation of histone H3 on lysine 56. Nature, 459:113–117.Google Scholar
  17. 16.
    De Cabo R, Cabello R, Rios M, et al. (2004). Calorie restriction attenuates age-related alterations in the plasma membrane antioxidant system in rat liver. Exp Gerontol, 39:297–304.CrossRefPubMedGoogle Scholar
  18. 17.
    Dirx MJ, van den Brandt PA, et al. (1999). Diet in adolescence and the risk of breast cancer: results of the Netherlands Cohort Study. Cancer Causes Control, 10:189–99.CrossRefPubMedGoogle Scholar
  19. 18.
    Dirx MJ, Zeegers MP, Dagnelie PC, et al. (2003). Energy restriction and the risk of spontaneous mammary tumors in mice: a meta-analysis. Int J Cancer, 106:766–770.CrossRefPubMedGoogle Scholar
  20. 19.
    Docherty JJ, Fu MM, Stiffler BS, et al. (1999). Resveratrol inhibition of herpes simplex virus replication. Antivir Res, 43:145–155.CrossRefPubMedGoogle Scholar
  21. 20.
    Docherty JJ, Smith JS, Fu MM, et al. (2004). Effect of topically applied resveratrol on cutaneous herpes simplex virus infections in hairless mice. Antivir Res, 61:19–26.CrossRefPubMedGoogle Scholar
  22. 21.
    Elias SG, Peeters PH, Grobbee DE, et al. (2004a). Breast cancer risk after caloric restriction during the 1944–1945 Dutch famine. J Natl Cancer Inst, 96:539–546.CrossRefPubMedGoogle Scholar
  23. 22.
    Elias SG, Onland-Moret NC, Peeters PH, et al. (2004b). Urinary endogenous sex hormone levels in postmenopausal women after caloric restriction in young adulthood. Br J Cancer, 90:115–117.CrossRefPubMedGoogle Scholar
  24. 23.
    Elias SG, Keinan-Boker L, Peeters PH, et al. (2004c). Long term consequences of the 1944–1945 Dutch famine on the insulin-like growth factor axis. Int J Cancer, 108:628–630.CrossRefPubMedGoogle Scholar
  25. 24.
    Elias SG, Peeters PH, Grobbee DE, et al. (2005). The 1944–1945 Dutch famine and subsequent overall cancer incidence. Cancer Epidemiol Biomarkers Prev, 14:1981–1985.CrossRefPubMedGoogle Scholar
  26. 25.
    Feuers RJ, Weindruch R, Hart RW (1993). Caloric restriction, aging, and antioxidant enzymes. Mutat Res, 295:191–200.CrossRefPubMedGoogle Scholar
  27. 26.
    Frye RA (1999). Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem Biophys Res Commun, 260:273–279.CrossRefPubMedGoogle Scholar
  28. 27.
    Frye RA (2000). Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun, 273:793–798.CrossRefPubMedGoogle Scholar
  29. 28.
    Furst A (1987). Hormetic effects in pharmacology: pharmacological inversions as prototypes for hormesis. Health Phys, 52:527–530.CrossRefPubMedGoogle Scholar
  30. 29.
    Guo Z, Heydari A, Richardson A (1998). Nucleotide excision repair of actively transcribed versus nontranscribed DNA in rat hepatocytes: effect of age and dietary restriction. Exp Cell Res, 245:228–238.CrossRefPubMedGoogle Scholar
  31. 30.
    Guo ZM, Yang H, Hamilton ML, et al. (2001). Effects of age and food restriction on oxidative DNA damage and antioxidant enzyme activities in the mouse aorta. Mech Ageing Dev, 2001;122:1771–1786.CrossRefGoogle Scholar
  32. 31.
    Han ES, Levin N, Bengani N, et al. (1995). Hyperadrenocorticism and food restriction-induced life extension in the rat: evidence for divergent regulation of pituitary proopiomelanocortin RNA and adrenocorticotropic hormone biosynthesis. J Gerontol A Biol Sci Med Sci, 50:B288–294.CrossRefPubMedGoogle Scholar
  33. 32.
    Hekimi S, Guarente L (2003). Genetics and the specificity of the aging process. Science, 299:1351–1354.CrossRefPubMedGoogle Scholar
  34. 33.
    Howitz KT, Bitterman KJ, Cohen HY, et al. (2003). Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature, 425:191–196.CrossRefPubMedGoogle Scholar
  35. 34.
    Hursting SD, Lavigne JA, Berrigan D, et al. (2003). Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans .Annu Rev Med, 54:131–152.CrossRefPubMedGoogle Scholar
  36. 35.
    Hyun DH, Emerson SS, Jo DG, et al. (2006). Calorie restriction up-regulates the plasma membrane redox system in brain cells and suppresses oxidative stress during aging. Proc Natl Acad Sci U S A, 103:19908–19912.CrossRefPubMedGoogle Scholar
  37. 36.
    Ingram DK, Anson RM, de Cabo R, et al. (2004). Development of calorie restriction mimetics as a prolongevity strategy. Ann N Y Acad Sci, 1019:412–423.CrossRefPubMedGoogle Scholar
  38. 37.
    Jang M, Cai L, Udeani GO, Slowing KV et al. (1997). Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science, 275:218–220.CrossRefPubMedGoogle Scholar
  39. 38.
    Jones PA, Baylin SB (2002). The fundamental role of epigenetic events in cancer. Nat Rev Genet, 3:415–428.CrossRefPubMedGoogle Scholar
  40. 39.
    Kaaks R, Lukanova A (2001). Energy balance and cancer: the role of insulin and insulin-like growth factor-I. Proc Nutr Soc, 60:91–106.CrossRefPubMedGoogle Scholar
  41. 40.
    Keys A, Taylor HL, Mickelsen O, et al. (1946). Famine Edema and the Mechanism of Its Formation. Science, 103:669–670.CrossRefGoogle Scholar
  42. 41.
    Kim EJ, Um SJ (2008). SIRT1: roles in aging and cancer. BMB Rep, 41:751–6.CrossRefPubMedGoogle Scholar
  43. 42.
    Kiziltepe U, Turan NN, Han U, et al. (2004). Resveratrol, a red wine polyphenol, protects spinal cord from ischemia-reperfusion injury. J Vasc Surg, 40:138–145.CrossRefPubMedGoogle Scholar
  44. 43.
    Klurfeld DM, Weber MM, Kritchevsky D (1987). Inhibition of chemically-induced mammary and colon tumor promotion by caloric restriction in rats fed increased dietary fat. Cancer Res, 47:2759–2762.PubMedGoogle Scholar
  45. 44.
    Klurfeld DM, Welch CB, Davis MJ, et al. (1989a). Determination of degree of energy restriction necessary to reduce DMBA-induced mammary tumorigenesis in rats during the promotion phase. J Nutr, 119:286–291.PubMedGoogle Scholar
  46. 45.
    Klurfeld DM, Welch CB, Lloyd LM, et al. (1989b). Inhibition of DMBA-induced mammary tumorigenesis in rats fed high fat diets. Int J Cancer, 43:922–925.CrossRefPubMedGoogle Scholar
  47. 46.
    Knekt P, Kumpulainen J, Järvinen R, et al. (2002). Flavonoid intake and risk of chronic diseases. Am J Clin Nutr, 76:560–568.PubMedGoogle Scholar
  48. 47.
    Kodama M, Kodama T (1990). Interrelation between Western type cancers and non-Western type cancers as regards their risk variations in time and space. II. Nutrition and cancer risk. AntiCancer Res, 10:1043–1049.PubMedGoogle Scholar
  49. 48.
    Kristal, BS, Yu, BP (1994). Aging and its modulation by dietary restriction. in: Yu, B. P., (ed.), Modulation of Aging Processes by Dietary Restriction, pp.1–36. CRC Press, Boca Raton, FL,.Google Scholar
  50. 49.
    Kritchevsky D, Weber MM, Klurfeld DM (1984). Dietary fat versus caloric content in initiation and promotion of 7,12-dimethylbenz(a)anthracene-induced mammary tumorigenesis in rats. Cancer Res, 44:3174–3177.PubMedGoogle Scholar
  51. 50.
    Kritchevsky D, Welch CB, Klurfeld DM (1989). Response of mammary tumors to caloric restriction for different time periods during the promotion phase. Nutr Cancer, 12:259–269.CrossRefPubMedGoogle Scholar
  52. 51.
    Kritchevsky D (1997). Caloric restriction and experimental mammary carcinogenesis. Breast Cancer Res Treat, 46:161–7.CrossRefPubMedGoogle Scholar
  53. 52.
    Kubo C, Johnson BC, Gajjar A, et al. (1987). Crucial dietary factors in maximizing life span and longevity in autoimmune-prone mice. J Nutr, 117:1129–1135.PubMedGoogle Scholar
  54. 53.
    Kutuk O, Adli M, Poli G, et al. (2004). Resveratrol protects against 4-HNE induced oxidative stress and apoptosis in Swiss 3T3 fibroblasts. Biofactors, 20:1–10.CrossRefPubMedGoogle Scholar
  55. 54.
    Lane MA, Black A, Handy A, et al. (2001). Caloric restriction in primates. Ann N Y Acad Sci, 928:287–295.CrossRefPubMedGoogle Scholar
  56. 55.
    Langcake P, Pryce RJ (1976). The production of resveratrol by Vitis vinifera and other members of the Vitaceae as a response to infection and injury. Physiol. Plant Pathol, 9:77–86.CrossRefGoogle Scholar
  57. 56.
    Langley E, Pearson M, Faretta M, et al. (2002). Human SIR2 deacetylates p.53 and antagonizes PML/p53-induced cellular senescence. EMBO J, 21:2383–2396.CrossRefPubMedGoogle Scholar
  58. 57.
    Lim SS, Jung SH, Ji J, et al. (2001). Synthesis of flavonoids and their effects on aldose reductase and sorbitol accumulation in streptozotocin-induced diabetic rat tissues. J Pharm Pharmacol, 53(5):653–668.PubMedGoogle Scholar
  59. 58.
    Luo J, Nikolaev AY, Imai S, et al. (2001). Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell, 107:137–148.CrossRefPubMedGoogle Scholar
  60. 59.
    McCay CM, Crowell MF, Maynard LA (1935). The effect of retarded growth upon the length of lifespan and upon the ultimate body size. J Nutr, 10:63–79.Google Scholar
  61. 60.
    McCarty MF (2004). Chronic activation of AMP-activated kinase as a strategy for slowing aging. Med Hypotheses, 63:334–339.CrossRefPubMedGoogle Scholar
  62. 61.
    Masoro EJ (1985). Nutrition and aging – a current assessment. J Nutr, 115:842–8.PubMedGoogle Scholar
  63. 62.
    Masoro EJ (1988). Food restriction in rodents: an evaluation of its role in the study of aging. J Gerontol, 43:B59–64.CrossRefPubMedGoogle Scholar
  64. 63.
    Masoro EJ (1990). Assessment of nutritional components in prolongation of life and health by diet. Proc Soc Exp Biol Med, 193:31–4.PubMedGoogle Scholar
  65. 64.
    Masoro EJ, Shimokawa I, Yu BP (1991). Retardation of the aging processes in rats by food restriction. Ann N Y Acad Sci, 621:337–352.CrossRefPubMedGoogle Scholar
  66. 65.
    Masoro, EJ (2001). Dietary restriction: An experimental approach to the study of the biology of aging. In: Masoro, EJ. and Austad, SN., (eds.), Handbook of the Biology of Aging, 5th edn, pp. 396–420. Academic Press, San Diego, CA.Google Scholar
  67. 66.
    Masoro EJ (2005). Overview of caloric restriction and ageing. Mech Ageing Dev, 126:913–922.CrossRefPubMedGoogle Scholar
  68. 67.
    McCarter R, Masoro EJ, Yu BP (1985). Does food restriction retard aging by reducing the metabolic rate? Am J Physiol, 248:E488–490.PubMedGoogle Scholar
  69. 68.
    McCarter RJ, McGee JR (1989). Transient reduction of metabolic rate by food restriction. Am J Physiol, 257:E175–9.PubMedGoogle Scholar
  70. 69.
    Mellemkjaer L, Emborg C, Gridley G et al. (2001). Anorexia nervosa and cancer risk. Cancer Causes Control, 12:173–177.CrossRefPubMedGoogle Scholar
  71. 70.
    Michels KB, Ekbom A (2004). Caloric restriction and incidence of breast cancer. JAMA, 291:1226–1230.CrossRefPubMedGoogle Scholar
  72. 71.
    Miura D, Miura Y, Yagasaki K (2003). Hypolipidemic action of dietary resveratrol, a phytoalexin in grapes and red wine, in hepatoma-bearing rats. Life Sci, 73:1393–400.CrossRefPubMedGoogle Scholar
  73. 72.
    Motta MC, Divecha N, Lemieux M, et al. (2004). Mammalian SIRT1 represses forkhead transcription factors. Cell, 116:551–563.CrossRefPubMedGoogle Scholar
  74. 73.
    Nilsen TI, Vatten LJ (2001). Adult height and risk of breast cancer: a possible effect of early nutrition. Br J Cancer, 85:959–961.CrossRefPubMedGoogle Scholar
  75. 74.
    Pariza MW (1987). Dietary fat, calorie restriction, ad libitum feeding, and cancer risk. Nutr Rev, 45:1–7.CrossRefPubMedGoogle Scholar
  76. 75.
    Pruitt K, Zinn RL, Ohm JE, et al. (2006). Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS Genet, 2:e40.CrossRefPubMedGoogle Scholar
  77. 76.
    Ragab AS, Van Fleet J, Jankowski B, et al. (2006). Detection and quantitation of resveratrol in tomato fruit (Lycopersicon esculentum Mill.). J Agric Food Chem, 54:7175–9.CrossRefPubMedGoogle Scholar
  78. 77.
    Robsahm TE, Tretli S (2002). Breast cancer incidence in food- vs non-food producing areas in Norway: possible beneficial effects of World War II. Br J Cancer, 86:362–6.CrossRefPubMedGoogle Scholar
  79. 78.
    Rogina B, Helfand SL (2004). Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc Natl Acad Sci U S A, 101:15998–16003.CrossRefPubMedGoogle Scholar
  80. 79.
    Roth GS, Ingram DK, Lane MA (1999). Calorie restriction in primates: will it work and how will we know? J Am Geriatr Soc, 47:896–903.PubMedGoogle Scholar
  81. 80.
    Sabatino F, Masoro EJ, McMahan CA, et al. (1991). Assessment of the role of the glucocorticoid system in aging processes and in the action of food restriction. J Gerontol, 46:B171–179.CrossRefPubMedGoogle Scholar
  82. 81.
    Sacher G.A (1977). Life table modification and life prolongation. In Finch, C.E. and Hayflick, L. (eds.), Handbook of the biology of aging, Van Nostrand Reinhold, pp. 582–638. New York.Google Scholar
  83. 82.
    Sinclair DA (2005). Toward a unified theory of caloric restriction and longevity regulation. Mech Ageing Dev, 126:987–1002.CrossRefPubMedGoogle Scholar
  84. 83.
    Stervbo U, Vang O, Bonnesen C (2007). A review of the content of the putative chemopreventive phytoalexin resveratrol in red wine. Food Chem, 101:449–457.CrossRefGoogle Scholar
  85. 84.
    Stuart JA, Karahalil B, Hogue BA, et al. (2004). Mitochondrial and nuclear DNA base excision repair are affected differently by caloric restriction. FASEB J, 18:595–597.PubMedGoogle Scholar
  86. 85.
    Tannenbaum A (1940). The initiation and growth of tumors. Introduction. Effects of undernutrition. Am J Cancer, 38:335–350.Google Scholar
  87. 86.
    Tannenbaum A (1942). The genesis and growth of tumors. II. Effects of caloric restriction per se. Cancer Res, 2:460–467.Google Scholar
  88. 87.
    Tannenbaum A (1944). The dependence of the genesis of induced skin tumors on the caloric intake during different stage of carcinogenesis. Cancer Res, 4:463–477.Google Scholar
  89. 88.
    Tannenbaum A (1945). The dependence of tumor formation on the composition of the calorie-restricted diet as well as on the degree of restriction. Cancer Res, 5:616–625.Google Scholar
  90. 89.
    Tissenbaum HA, Guarente L (2001). Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature, 410:227–230.CrossRefPubMedGoogle Scholar
  91. 90.
    Tretli S, Gaard M (1996). Lifestyle changes during adolescence and risk of breast cancer: an ecologic study of the effect of World War II in Norway. Cancer Causes Control, 7:507–512.CrossRefPubMedGoogle Scholar
  92. 91.
    Vatten LJ, Kvinnsland S (1990). Body height and risk of breast cancer. A prospective study of 23,831 Norwegian women. Br J Cancer, 61:881–885.CrossRefPubMedGoogle Scholar
  93. 92.
    Vaziri H, Dessain SK, Ng Eaton E, et al. (2001). hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell, 107:149–159.CrossRefPubMedGoogle Scholar
  94. 93.
    Weindruch R, Walford RL, Fligiel S, et al. (1986). The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutr, 116:641–654.PubMedGoogle Scholar
  95. 94.
    Weindruch R, Keenan KP, Carney JM, et al. (2001). Caloric restriction mimetics: metabolic interventions. J Gerontol A Biol Sci Med Sci, 56 Spec No, 1:20–33.CrossRefGoogle Scholar
  96. 95.
    Wood JG, Rogina B, Lavu S, et al. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature, 430:686–689.CrossRefPubMedGoogle Scholar
  97. 96.
    Xia E, Rao G, Van Remmen H, et al. (1995). Activities of antioxidant enzymes in various tissues of male Fischer 344 rats are altered by food restriction. J Nutr, 125:195–201.PubMedGoogle Scholar
  98. 97.
    Yu BP, Masoro EJ, Murata I, et al. (1982). Life span study of SPF Fischer 344 male rats fed ad libitum or restricted diets: longevity, growth, lean body mass and disease. J Gerontol, 37:130–141.CrossRefPubMedGoogle Scholar
  99. 98.
    Yu BP, Masoro EJ, McMahan CA (1985). Nutritional influences on aging of Fischer 344 rats: I. Physical, metabolic, and longevity characteristics. J Gerontol, 40:657–670.CrossRefPubMedGoogle Scholar
  100. 99.
    Yu BP (1996). Aging and oxidative stress: modulation by dietary restriction. Free Radic Biol Med, 21:651–668.CrossRefPubMedGoogle Scholar
  101. 100.
    Zainal TA, Oberley TD, Allison DB, et al. (2000). Caloric restriction of rhesus monkeys lowers oxidative damage in skeletal muscle. FASEB J, 14:1825–1836.CrossRefPubMedGoogle Scholar
  102. 101.
    Zhu Z, Jiang W, McGinley J, et al. (2005). Effects of dietary energy repletion and IGF-1 infusion on the inhibition of mammary carcinogenesis by dietary energy restriction. Mol Carcinog, 42:170–176.CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.i3 Drug Safety, IngenixUnited Health GroupsWalthamUSA
  2. 2.Obstetrics and Gynecology Epidemiology Center, Department of ObstetricsGynecology and Reproductive Biology, Brigham and Women’s Hospital, Harvard Medical SchoolBostonUSA
  3. 3.Department of EpidemiologyHarvard School of Public HealthBostonUSA

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