European Journal of Epidemiology

, Volume 30, Issue 12, pp 1277–1285 | Cite as

Perinatal risk factors for acute myeloid leukemia

  • Casey Crump
  • Jan Sundquist
  • Weiva Sieh
  • Marilyn A. Winkleby
  • Kristina Sundquist


Infectious etiologies have been hypothesized for acute leukemias because of their high incidence in early childhood, but have seldom been examined for acute myeloid leukemia (AML). We conducted the first large cohort study to examine perinatal factors including season of birth, a proxy for perinatal infectious exposures, and risk of AML in childhood through young adulthood. A national cohort of 3,569,333 persons without Down syndrome who were born in Sweden in 1973–2008 were followed up for AML incidence through 2010 (maximum age 38 years). There were 315 AML cases in 69.7 million person-years of follow-up. We found a sinusoidal pattern in AML risk by season of birth (P < 0.001), with peak risk among persons born in winter. Relative to persons born in summer (June–August), incidence rate ratios for AML were 1.72 (95 % CI 1.25–2.38; P = 0.001) for winter (December–February), 1.37 (95 % CI 0.99–1.90; P = 0.06) for spring (March–May), and 1.27 (95 % CI 0.90–1.80; P = 0.17) for fall (September–November). Other risk factors for AML included high fetal growth, high gestational age at birth, and low maternal education level. These findings did not vary by sex or age at diagnosis. Sex, birth order, parental age, and parental country of birth were not associated with AML. In this large cohort study, birth in winter was associated with increased risk of AML in childhood through young adulthood, possibly related to immunologic effects of early infectious exposures compared with summer birth. These findings warrant further investigation of the role of seasonally varying perinatal exposures in the etiology of AML.


Cohort studies Fetal development Gestational age Leukemia Risk factors Seasons 



Acute lymphoblastic leukemia


Acute myeloid leukemia


Confidence interval


Date of birth


International classification of diseases


Incidence rate ratio


Standard deviation


  1. 1.
    Linabery AM, Ross JA. Trends in childhood cancer incidence in the U.S. (1992–2004). Cancer. 2008;112(2):416–32. doi:10.1002/cncr.23169.PubMedCrossRefGoogle Scholar
  2. 2.
    Eden T. Aetiology of childhood leukaemia. Cancer Treat Rev. 2010;36(4):286–97. doi:10.1016/j.ctrv.2010.02.004.PubMedCrossRefGoogle Scholar
  3. 3.
    Kaatsch P. Epidemiology of childhood cancer. Cancer Treat Rev. 2010;36(4):277–85. doi:10.1016/j.ctrv.2010.02.003.PubMedCrossRefGoogle Scholar
  4. 4.
    Deschler B, Lubbert M. Acute myeloid leukemia: epidemiology and etiology. Cancer. 2006;107(9):2099–107. doi:10.1002/cncr.22233.PubMedCrossRefGoogle Scholar
  5. 5.
    Doll R, Wakeford R. Risk of childhood cancer from fetal irradiation. Br J Radiol. 1997;70:130–9. doi:10.1259/bjr.70.830.9135438.PubMedCrossRefGoogle Scholar
  6. 6.
    Bruwier A, Chantrain CF. Hematological disorders and leukemia in children with down syndrome. Eur J Pediatr. 2012;171(9):1301–7. doi:10.1007/s00431-011-1624-1.PubMedCrossRefGoogle Scholar
  7. 7.
    Cnattingius S, Zack M, Ekbom A, Gunnarskog J, Linet M, Adami HO. Prenatal and neonatal risk factors for childhood myeloid leukemia. Cancer Epidemiol Biomarkers Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. 1995;4(5):441–5.Google Scholar
  8. 8.
    Pui CH. Childhood leukemias. New Engl J Med. 1995;332(24):1618–30. doi:10.1056/NEJM199506153322407.PubMedCrossRefGoogle Scholar
  9. 9.
    McNally RJ, Eden TO. An infectious aetiology for childhood acute leukaemia: a review of the evidence. Br J Haematol. 2004;127(3):243–63. doi:10.1111/j.1365-2141.2004.05166.x.PubMedCrossRefGoogle Scholar
  10. 10.
    Greaves M. Childhood leukaemia. BMJ. 2002;324(7332):283–7.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Basta NO, James PW, Craft AW, McNally RJ. Season of birth and diagnosis for childhood cancer in Northern England, 1968-2005. Paediatr Perinat Epidemiol. 2010;24(3):309–18. doi:10.1111/j.1365-3016.2010.01112.x.PubMedCrossRefGoogle Scholar
  12. 12.
    Feltbower RG, Pearce MS, Dickinson HO, Parker L, McKinney PA. Seasonality of birth for cancer in Northern England, UK. Paediatric Perinatal Epidemiol. 2001;15(4):338–45.CrossRefGoogle Scholar
  13. 13.
    Sorensen HT, Pedersen L, Olsen J, Rothman K. Seasonal variation in month of birth and diagnosis of early childhood acute lymphoblastic leukemia. JAMA J Am Med Assoc. 2001;285(2):168–9.CrossRefGoogle Scholar
  14. 14.
    Yaniv I, Lewy H, Avrahami G, Jeison M, Stark B, Laron Z. Possible link between month of birth and childhood leukemia supports the hypothesis of an infectious etiology. Israel Med Assoc J IMAJ. 2010;12(12):776.PubMedGoogle Scholar
  15. 15.
    Nyari TA, Kajtar P, Bartyik K, Thurzo L, McNally R, Parker L. Seasonal variation of childhood acute lymphoblastic leukaemia is different between girls and boys. Pathol Oncol Res POR. 2008;14(4):423–8. doi:10.1007/s12253-008-9017-0.PubMedCrossRefGoogle Scholar
  16. 16.
    Kajtar P, Fazekasne KM, Mehes K. Month of birth in childhood acute lymphoblastic leukemia. Orv Hetil. 2003;144(38):1869–71.PubMedGoogle Scholar
  17. 17.
    Meltzer AA, Annegers JF, Spitz MR. Month-of-birth and incidence of acute lymphoblastic leukemia in children. Leukemia Lymphoma. 1996;23(1–2):85–92. doi:10.3109/10428199609054805.PubMedCrossRefGoogle Scholar
  18. 18.
    Higgins CD, Dos Santos-Silva I, Stiller CA, Swerdlow AJ. Season of birth and diagnosis of children with leukaemia: an analysis of over 15 000 UK cases occurring from 1953–95. Br J Cancer. 2001;84(3):406–12. doi:10.1054/bjoc.2000.1575.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Marsal K, Persson PH, Larsen T, Lilja H, Selbing A, Sultan B. Intrauterine growth curves based on ultrasonically estimated foetal weights. Acta Paediatr. 1996;85(7):843–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Steliarova-Foucher E, Stiller C, Lacour B, Kaatsch P. International classification of childhood cancer, third edition. Cancer. 2005;103(7):1457–67. doi:10.1002/cncr.20910.PubMedCrossRefGoogle Scholar
  21. 21.
    Crump C, Sundquist K, Sundquist J, Winkleby MA. Gestational age at birth and mortality in young adulthood. JAMA J Am Med Assoc. 2011;306(11):1233–40.CrossRefGoogle Scholar
  22. 22.
    Zou G. A modified poisson regression approach to prospective studies with binary data. Am J Epidemiol. 2004;159(7):702–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Efird JT, Nielsen SS. A method to model season of birth as a surrogate environmental risk factor for disease. Int J Env Res Public Health. 2008;5(1):49–53.CrossRefGoogle Scholar
  24. 24.
    StataCorp. Stata statistical software: release 13. College Station, TX: StataCorp LP; 2013.Google Scholar
  25. 25.
    van Laar M, Kinsey SE, Picton SV, Feltbower RG. First description of seasonality of birth and diagnosis amongst teenagers and young adults with cancer aged 15–24 years in England, 1996–2005. BMC Cancer. 2013;13:365. doi:10.1186/1471-2407-13-365.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Naumburg E, Bellocco R, Cnattingius S, Jonzon A, Ekbom A. Perinatal exposure to infection and risk of childhood leukemia. Med Pediatr Oncol. 2002;38(6):391–7. doi:10.1002/mpo.10084.PubMedCrossRefGoogle Scholar
  27. 27.
    Crump C, Sundquist J, Sieh W, Winkleby MA, Sundquist K. Season of birth and risk of Hodgkin and non-Hodgkin lymphoma. Int J Cancer. 2014;. doi:10.1002/ijc.28909.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Savitz DA, Andrews KW. Review of epidemiologic evidence on benzene and lymphatic and hematopoietic cancers. Am J Ind Med. 1997;31(3):287–95.PubMedCrossRefGoogle Scholar
  29. 29.
    Pui CH, Ribeiro RC, Hancock ML, et al. Acute myeloid leukemia in children treated with epipodophyllotoxins for acute lymphoblastic leukemia. New Engl J Med. 1991;325(24):1682–7. doi:10.1056/NEJM199112123252402.PubMedCrossRefGoogle Scholar
  30. 30.
    Ben-David Y, Bernstein A. Friend virus-induced erythroleukemia and the multistage nature of cancer. Cell. 1991;66(5):831–4.PubMedCrossRefGoogle Scholar
  31. 31.
    Kerr JR, Barah F, Cunniffe VS, et al. Association of acute parvovirus B19 infection with new onset of acute lymphoblastic and myeloblastic leukaemia. J Clin Pathol. 2003;56(11):873–5.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Caughey RW, Michels KB. Birth weight and childhood leukemia: a meta-analysis and review of the current evidence. Int J Cancer. 2009;124(11):2658–70. doi:10.1002/ijc.24225.PubMedCrossRefGoogle Scholar
  33. 33.
    O’Neill KA, Murphy MF, Bunch KJ, et al. Infant birthweight and risk of childhood cancer: international population-based case control studies of 40 000 cases. Int J Epidemiol. 2015;44(1):153–68. doi:10.1093/ije/dyu265.PubMedCrossRefGoogle Scholar
  34. 34.
    Crump C, Sundquist K, Sieh W, Winkleby MA, Sundquist J. Perinatal and family risk factors for Hodgkin lymphoma in childhood through young adulthood. Am J Epidemiol. 2012;176(12):1147–58. doi:10.1093/aje/kws212.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Crump C, Sundquist K, Sieh W, Winkleby MA, Sundquist J. Perinatal and family risk factors for non-Hodgkin lymphoma in early life: a Swedish national cohort study. J Natl Cancer Inst. 2012;104(12):923–30. doi:10.1093/jnci/djs225.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Hjalgrim LL, Westergaard T, Rostgaard K, et al. Birth weight as a risk factor for childhood leukemia: a meta-analysis of 18 epidemiologic studies. Am J Epidemiol. 2003;158(8):724–35.PubMedCrossRefGoogle Scholar
  37. 37.
    Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat Rev Cancer. 2004;4(7):505–18. doi:10.1038/nrc1387nrc1387.PubMedCrossRefGoogle Scholar
  38. 38.
    Tower RL, Spector LG. The epidemiology of childhood leukemia with a focus on birth weight and diet. Crit Rev Clin Lab Sci. 2007;44(3):203–42. doi:10.1080/10408360601147536.PubMedCrossRefGoogle Scholar
  39. 39.
    McLaughlin CC, Baptiste MS, Schymura MJ, Nasca PC, Zdeb MS. Birth weight, maternal weight and childhood leukaemia. Br J Cancer. 2006;94(11):1738–44. doi:10.1038/sj.bjc.6603173.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Hjalgrim LL, Rostgaard K, Hjalgrim H, et al. Birth weight and risk for childhood leukemia in Denmark, Sweden, Norway, and Iceland. J Natl Cancer Inst. 2004;96(20):1549–56. doi:10.1093/jnci/djh287.PubMedCrossRefGoogle Scholar
  41. 41.
    Johnson KJ, Soler JT, Puumala SE, Ross JA, Spector LG. Parental and infant characteristics and childhood leukemia in Minnesota. BMC Pediatr. 2008;8:7. doi:10.1186/1471-2431-8-7.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Reynolds P, Von Behren J, Elkin EP. Birth characteristics and leukemia in young children. Am J Epidemiol. 2002;155(7):603–13.PubMedCrossRefGoogle Scholar
  43. 43.
    Ma X, Metayer C, Does MB, Buffler PA. Maternal pregnancy loss, birth characteristics, and childhood leukemia (United States). Cancer Causes Control CCC. 2005;16(9):1075–83. doi:10.1007/s10552-005-0356-9.PubMedCrossRefGoogle Scholar
  44. 44.
    Rudant J, Orsi L, Monnereau A, et al. Childhood hodgkin’s lymphoma, non-Hodgkin’s lymphoma and factors related to the immune system: the escale study (SFCE). Int J Cancer. 2010;. doi:10.1002/ijc.25862.Google Scholar
  45. 45.
    Johnson KJ, Carozza SE, Chow EJ, et al. Parental age and risk of childhood cancer: a pooled analysis. Epidemiology. 2009;20(4):475–83. doi:10.1097/EDE.0b013e3181a5a332.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Zack M, Adami HO, Ericson A. Maternal and perinatal risk factors for childhood leukemia. Cancer Res. 1991;51(14):3696–701.PubMedGoogle Scholar
  47. 47.
    Shu XO, Gao YT, Brinton LA, et al. A population-based case-control study of childhood leukemia in Shanghai. Cancer. 1988;62(3):635–44.PubMedCrossRefGoogle Scholar
  48. 48.
    Westergaard T, Andersen PK, Pedersen JB, et al. Birth characteristics, sibling patterns, and acute leukemia risk in childhood: a population-based cohort study. J Natl Cancer Inst. 1997;89(13):939–47.PubMedCrossRefGoogle Scholar
  49. 49.
    Centre for Epidemiology. The swedish medical birth registry–a summary of content and quality. Stockholm: The National Board of Health and Welfare; 2003.Google Scholar
  50. 50.
    Centre for Epidemiology. Cancer incidence in Sweden 2011. Stockholm: The National Board of Health and Welfare; 2011.Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • Casey Crump
    • 1
  • Jan Sundquist
    • 2
  • Weiva Sieh
    • 3
  • Marilyn A. Winkleby
    • 4
  • Kristina Sundquist
    • 2
  1. 1.Department of MedicineStanford UniversityStanfordUSA
  2. 2.Center for Primary Health Care Research, Clinical Research Centre (CRC)Lund UniversityMalmöSweden
  3. 3.Department of Health Research and PolicyStanford UniversityStanfordUSA
  4. 4.Stanford Prevention Research CenterStanford UniversityStanfordUSA

Personalised recommendations