European Journal of Epidemiology

, Volume 33, Issue 10, pp 965–976 | Cite as

Advanced parental age as risk factor for childhood acute lymphoblastic leukemia: results from studies of the Childhood Leukemia International Consortium

  • Eleni Th. PetridouEmail author
  • Marios K. Georgakis
  • Friederike Erdmann
  • Xiaomei Ma
  • Julia E. Heck
  • Anssi Auvinen
  • Beth A. Mueller
  • Logan G. Spector
  • Eve Roman
  • Catherine Metayer
  • Corrado Magnani
  • Maria S. Pombo-de-Oliveira
  • Sameera Ezzat
  • Michael E. Scheurer
  • Ana Maria Mora
  • John D. Dockerty
  • Johnni Hansen
  • Alice Y. Kang
  • Rong Wang
  • David R. Doody
  • Eleanor Kane
  • Waffa M. Rashed
  • Nick Dessypris
  • Joachim Schüz
  • Claire Infante-Rivard
  • Alkistis Skalkidou


Advanced parental age has been associated with adverse health effects in the offspring including childhood (0–14 years) acute lymphoblastic leukemia (ALL), as reported in our meta-analysis of published studies. We aimed to further explore the association using primary data from 16 studies participating in the Childhood Leukemia International Consortium. Data were contributed by 11 case–control (CC) studies (7919 cases and 12,942 controls recruited via interviews) and five nested case–control (NCC) studies (8801 cases and 29,690 controls identified through record linkage of population-based health registries) with variable enrollment periods (1968–2015). Five-year paternal and maternal age increments were introduced in two meta-analyses by study design using adjusted odds ratios (OR) derived from each study. Increased paternal age was associated with greater ALL risk in the offspring (ORCC 1.05, 95% CI 1.00–1.11; ORNCC 1.04, 95% CI 1.01–1.07). A similar positive association with advanced maternal age was observed only in the NCC results (ORCC 0.99, 95% CI 0.91–1.07, heterogeneity I2 = 58%, p = 0.002; ORNCC 1.05, 95% CI 1.01–1.08). The positive association between parental age and risk of ALL was most marked among children aged 1–5 years and remained unchanged following mutual adjustment for the collinear effect of the paternal and maternal age variables; analyses of the relatively small numbers of discordant paternal-maternal age pairs were not fully enlightening. Our results strengthen the evidence that advanced parental age is associated with increased childhood ALL risk; collinearity of maternal with paternal age complicates causal interpretation. Employing datasets with cytogenetic information may further elucidate involvement of each parental component and clarify underlying mechanisms.


Maternal age Paternal age Acute lymphoblastic leukemia Childhood Risk factors Case–control 



The CLIC studies thank the families for their consent and participation, the study staff, interviewers and pediatric oncologists for their support as well as Dr Constantinos Mihas and Dr Antonis Analytis for their contributions to statistical analyses. Acknowledgements by study site are shown in the Supplementary materials.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

10654_2018_402_MOESM1_ESM.docx (1 mb)
Supplementary material 1 (DOCX 1039 kb)


  1. 1.
    Steliarova-Foucher E, Colombet M, Ries LAG, Moreno F, Dolya A, Bray F, et al. International incidence of childhood cancer, 2001-10: a population-based registry study. Lancet Oncol. 2017;18(6):719–31. Scholar
  2. 2.
    Wiemels J. Perspectives on the causes of childhood leukemia. Chem Biol Interact. 2012;196(3):59–67. Scholar
  3. 3.
    Metayer C, Milne E, Clavel J, Infante-Rivard C, Petridou E, Taylor M, et al. The Childhood Leukemia International Consortium. Cancer Epidemiol. 2013;37(3):336–47. Scholar
  4. 4.
    Macmahon B, Levy MA. Prenatal origin of Childhood Leukemia. Evidence from Twins. N Engl J Med. 1964;270:1082–5. Scholar
  5. 5.
    Taub JW, Ge Y. The prenatal origin of childhood acute lymphoblastic leukemia. Leuk Lymphoma. 2004;45(1):19–25.CrossRefPubMedGoogle Scholar
  6. 6.
    Gruhn B, Taub JW, Ge Y, Beck JF, Zell R, Hafer R, et al. Prenatal origin of childhood acute lymphoblastic leukemia, association with birth weight and hyperdiploidy. Leukemia. 2008;22(9):1692–7. Scholar
  7. 7.
    Milne E, Greenop KR, Metayer C, Schuz J, Petridou E, Pombo-de-Oliveira MS, et al. Fetal growth and childhood acute lymphoblastic leukemia: findings from the childhood leukemia international consortium. Int J Cancer. 2013;133(12):2968–79. Scholar
  8. 8.
    Rudant J, Lightfoot T, Urayama KY, Petridou E, Dockerty JD, Magnani C, et al. Childhood acute lymphoblastic leukemia and indicators of early immune stimulation: a Childhood Leukemia International Consortium study. Am J Epidemiol. 2015;181(8):549–62. Scholar
  9. 9.
    Metayer C, Milne E, Dockerty JD, Clavel J, Pombo-de-Oliveira MS, Wesseling C, et al. Maternal supplementation with folic acid and other vitamins and risk of leukemia in offspring: a Childhood Leukemia International Consortium study. Epidemiology. 2014;25(6):811–22. Scholar
  10. 10.
    Thomopoulos TP, Skalkidou A, Dessypris N, Chrousos G, Karalexi MA, Karavasilis TG, et al. Prelabor cesarean delivery and early-onset acute childhood leukemia risk. Eur J Cancer Prev. 2016;25(2):155–61. Scholar
  11. 11.
    Marcotte EL, Thomopoulos TP, Infante-Rivard C, Clavel J, Petridou ET, Schuz J, et al. Caesarean delivery and risk of childhood leukaemia: a pooled analysis from the Childhood Leukemia International Consortium (CLIC). Lancet Haematol. 2016;3(4):e176–85. Scholar
  12. 12.
    Kimberly L, Case A, Cheung AP, Sierra S, AlAsiri S, Carranza-Mamane B, et al. Advanced reproductive age and fertility: no. 269, November 2011. Int J Gynaecol Obstet. 2012;117(1):95–102.CrossRefPubMedGoogle Scholar
  13. 13.
    Mathews TJ, Hamilton BE. Mean Age of Mothers is on the Rise: United States, 2000–2014. NCHS Data Brief. 2016;232:1–8.Google Scholar
  14. 14.
    Martin JA, Hamilton BE, Osterman MJ, Curtin SC, Matthews TJ. Births: final data for 2013. Natl Vital Stat Rep. 2015;64(1):1–65.PubMedGoogle Scholar
  15. 15.
    Laopaiboon M, Lumbiganon P, Intarut N, Mori R, Ganchimeg T, Vogel JP, et al. Advanced maternal age and pregnancy outcomes: a multicountry assessment. BJOG. 2014;121(Suppl 1):49–56. Scholar
  16. 16.
    Hassold T, Abruzzo M, Adkins K, Griffin D, Merrill M, Millie E et al. Human aneuploidy: incidence, origin, and etiology. Environ Mol Mutagen. 1996;28(3):167–75.<167::AID-EM2>3.0.CO;2-B.CrossRefPubMedGoogle Scholar
  17. 17.
    Ramasamy R, Chiba K, Butler P, Lamb DJ. Male biological clock: a critical analysis of advanced paternal age. Fertil Steril. 2015;103(6):1402–6. Scholar
  18. 18.
    Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Magnusson G, et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature. 2012;488(7412):471–5. Scholar
  19. 19.
    Wong WS, Solomon BD, Bodian DL, Kothiyal P, Eley G, Huddleston KC, et al. New observations on maternal age effect on germline de novo mutations. Nat Commun. 2016;7:10486. Scholar
  20. 20.
    Adkins RM, Thomas F, Tylavsky FA, Krushkal J. Parental ages and levels of DNA methylation in the newborn are correlated. BMC Med Genet. 2011;12:47. Scholar
  21. 21.
    Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48(2):126–33. Scholar
  22. 22.
    Sergentanis TN, Thomopoulos TP, Gialamas SP, Karalexi MA, Biniaris-Georgallis SI, Kontogeorgi E, et al. Risk for childhood leukemia associated with maternal and paternal age. Eur J Epidemiol. 2015;30(12):1229–61. Scholar
  23. 23.
    Contreras ZA, Hansen J, Ritz B, Olsen J, Yu F, Heck JE. Parental age and childhood cancer risk: a Danish population-based registry study. Cancer Epidemiol. 2017;49:202–15. Scholar
  24. 24.
    Urhoj SK, Raaschou-Nielsen O, Hansen AV, Mortensen LH, Andersen PK, Nybo Andersen AM. Advanced paternal age and childhood cancer in offspring: a nationwide register-based cohort study. Int J Cancer. 2017;140(11):2461–72. Scholar
  25. 25.
    Wang R, Metayer C, Morimoto L, Wiemels JL, DeWan AT, Kang A, et al. Parental age and risk of pediatric cancer in the offspring: a population-based record-linkage study in California. Am J Epidemiol. 2017. Scholar
  26. 26.
    Marcotte EL, Druley TE, Johnson KJ, Richardson M, von Behren J, Mueller BA, et al. Parental age and risk of infant leukaemia: a pooled analysis. Paediatr Perinat Epidemiol. 2017. Scholar
  27. 27.
    Schuz J. Non-response bias as a likely cause of the association between young maternal age at the time of delivery and the risk of cancer in the offspring. Paediatr Perinat Epidemiol. 2003;17(1):106–12.CrossRefPubMedGoogle Scholar
  28. 28.
    Mateos MK, Barbaric D, Byatt SA, Sutton R, Marshall GM. Down syndrome and leukemia: insights into leukemogenesis and translational targets. Transl Pediatr. 2015;4(2):76–92. Scholar
  29. 29.
    Orsini N, Li R, Wolk A, Khudyakov P, Spiegelman D. Meta-analysis for linear and nonlinear dose-response relations: examples, an evaluation of approximations, and software. Am J Epidemiol. 2012;175(1):66–73. Scholar
  30. 30.
    VanderWeele TJ, Ding P. Sensitivity analysis in observational research: introducing the E-value. Ann Intern Med. 2017;167(4):268–74. Scholar
  31. 31.
    Maule MM, Vizzini L, Merletti F, Magnani C, Pastore G, Richiardi L. Parental age and risk of acute lymphocytic leukaemia and embryonal tumours in the Piedmont Region, Italy. Int J Epidemiol. 2007;36(3):691–2. Scholar
  32. 32.
    Buka SL, Goldstein JM, Seidman LJ, Tsuang MT. Maternal recall of pregnancy history: accuracy and bias in schizophrenia research. Schizophr Bull. 2000;26(2):335–50.CrossRefPubMedGoogle Scholar
  33. 33.
    Karalexi MA, Dessypris N, Thomopoulos TP, Ntouvelis E, Kantzanou M, Diamantaras AA, et al. Parental alcohol consumption and risk of leukemia in the offspring: a systematic review and meta-analysis. Eur J Cancer Prev. 2017;26(5):433–41. Scholar
  34. 34.
    Contreras ZA, Ritz B, Virk J, Cockburn M, Heck JE. Maternal pre-pregnancy and gestational diabetes, obesity, gestational weight gain, and risk of cancer in young children: a population-based study in California. Cancer Causes Control. 2016;27(10):1273–85. Scholar
  35. 35.
    Amitay EL, Keinan-Boker L. Breastfeeding and childhood leukemia incidence: a meta-analysis and systematic review. JAMA Pediatr. 2015;169(6):e151025. Scholar
  36. 36.
    Pieters R, Schrappe M, De Lorenzo P, Hann I, De Rossi G, Felice M, et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet. 2007;370(9583):240–50. Scholar
  37. 37.
    Ross JA, Linabery AM, Blommer CN, Langer EK, Spector LG, Hilden JM, et al. Genetic variants modify susceptibility to leukemia in infants: a Children’s Oncology Group report. Pediatr Blood Cancer. 2013;60(1):31–4. Scholar
  38. 38.
    Janecka M, Mill J, Basson MA, Goriely A, Spiers H, Reichenberg A, et al. Advanced paternal age effects in neurodevelopmental disorders-review of potential underlying mechanisms. Transl Psychiatry. 2017;7(1):e1019. Scholar
  39. 39.
    Merikangas AK, Calkins ME, Bilker WB, Moore TM, Gur RC, Gur RE. Parental age and offspring psychopathology in the Philadelphia Neurodevelopmental Cohort. J Am Acad Child Adolesc Psychiatry. 2017;56(5):391–400. Scholar
  40. 40.
    McGrath JJ, Petersen L, Agerbo E, Mors O, Mortensen PB, Pedersen CB. A comprehensive assessment of parental age and psychiatric disorders. JAMA Psychiatry. 2014;71(3):301–9. Scholar
  41. 41.
    Frans E, MacCabe JH, Reichenberg A. Advancing paternal age and psychiatric disorders. World Psychiatry. 2015;14(1):91–3. Scholar
  42. 42.
    Goriely A, Wilkie AO. Paternal age effect mutations and selfish spermatogonial selection: causes and consequences for human disease. Am J Hum Genet. 2012;90(2):175–200. Scholar
  43. 43.
    Mills MB, Hudgins L, Balise RR, Abramson DH, Kleinerman RA. Mutation risk associated with paternal and maternal age in a cohort of retinoblastoma survivors. Hum Genet. 2012;131(7):1115–22. Scholar
  44. 44.
    Ferguson-Smith MA, Yates JR. Maternal age specific rates for chromosome aberrations and factors influencing them: report of a collaborative european study on 52 965 amniocenteses. Prenat Diagn. 1984;4 Spec No:5–44.CrossRefPubMedGoogle Scholar
  45. 45.
    Miller RW. Relation between cancer and congenital defects in man. N Engl J Med. 1966;275(2):87–93. Scholar
  46. 46.
    Xavier AC, Taub JW. Acute leukemia in children with down syndrome. Haematologica. 2010;95(7):1043–5. Scholar
  47. 47.
    Agha MM, Williams JI, Marrett L, To T, Zipursky A, Dodds L. Congenital abnormalities and childhood cancer. Cancer. 2005;103(9):1939–48. Scholar
  48. 48.
    Carozza SE, Langlois PH, Miller EA, Canfield M. Are children with birth defects at higher risk of childhood cancers? Am J Epidemiol. 2012;175(12):1217–24. Scholar
  49. 49.
    Faro R, Santolaya-Forgas J, Oyelese Y, Ananth C. 660: is paternal age a contributing factor for cesarean delivery? A population based study. AJOG Am J Obstetr Gynecol. 2011;204(1):S260–1.Google Scholar
  50. 50.
    Herstad L, Klungsoyr K, Skjaerven R, Tanbo T, Forsen L, Abyholm T, et al. Elective cesarean section or not? Maternal age and risk of adverse outcomes at term: a population-based registry study of low-risk primiparous women. BMC Pregnancy Childbirth. 2016;16:230. Scholar
  51. 51.
    Barrington-Trimis JL, Cockburn M, Metayer C, Gauderman WJ, Wiemels J, McKean-Cowdin R. Trends in childhood leukemia incidence over two decades from 1992 to 2013. Int J Cancer. 2017;140(5):1000–8. Scholar
  52. 52.
    Shah A, Coleman MP. Increasing incidence of childhood leukaemia: a controversy re-examined. Br J Cancer. 2007;97(7):1009–12. Scholar
  53. 53.
    Petridou ET, Dimitrova N, Eser S, Kachanov D, Karakilinc H, Varfolomeeva S, et al. Childhood leukemia and lymphoma: time trends and factors affecting survival in five Southern and Eastern European Cancer Registries. Cancer Causes Control. 2013;24(6):1111–8. Scholar
  54. 54.
    Adami HO, Nyren O. Enigmas, priorities and opportunities in cancer epidemiology. Eur J Epidemiol. 2016;31(12):1161–71. Scholar

Copyright information

© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  • Eleni Th. Petridou
    • 1
    • 2
    Email author
  • Marios K. Georgakis
    • 1
  • Friederike Erdmann
    • 3
    • 4
  • Xiaomei Ma
    • 5
  • Julia E. Heck
    • 6
  • Anssi Auvinen
    • 7
  • Beth A. Mueller
    • 8
    • 9
  • Logan G. Spector
    • 10
  • Eve Roman
    • 11
  • Catherine Metayer
    • 12
  • Corrado Magnani
    • 13
  • Maria S. Pombo-de-Oliveira
    • 14
  • Sameera Ezzat
    • 15
  • Michael E. Scheurer
    • 16
  • Ana Maria Mora
    • 17
  • John D. Dockerty
    • 18
  • Johnni Hansen
    • 19
  • Alice Y. Kang
    • 12
  • Rong Wang
    • 5
  • David R. Doody
    • 8
  • Eleanor Kane
    • 11
  • Waffa M. Rashed
    • 20
    • 21
  • Nick Dessypris
    • 1
  • Joachim Schüz
    • 3
  • Claire Infante-Rivard
    • 22
  • Alkistis Skalkidou
    • 23
  1. 1.Department of Hygiene, Epidemiology and Medical Statistics, Medical SchoolNational and Kapodistrian University of AthensAthensGreece
  2. 2.Clinical Epidemiology Unit, Department of MedicineKarolinska InstituteStockholmSweden
  3. 3.Section of Environment and RadiationInternational Agency for Research on CancerLyonFrance
  4. 4.Unit of Survivorship, Childhood Cancer Survivorship Research GroupDanish Cancer Society Research CenterCopenhagenDenmark
  5. 5.Department of Chronic Disease Epidemiology, Yale School of Public Health, Cancer Prevention and Control, Yale Comprehensive Cancer CenterYale School of MedicineNew HavenUSA
  6. 6.Department of Epidemiology, School of Public HealthUniversity of California, Los AngelesLos AngelesUSA
  7. 7.Faculty of Social SciencesUniversity of TampereTampereFinland
  8. 8.Public Health Sciences DivisionFred Hutchinson Cancer Research CenterSeattleUSA
  9. 9.Department of Epidemiology, School of Public HealthUniversity of WashingtonSeattleUSA
  10. 10.Division of Epidemiology and Clinical Research, Department of PediatricsUniversity of MinnesotaMinneapolisUSA
  11. 11.Epidemiology and Cancer Statistics Group, Department of Health SciencesUniversity of YorkHeslingtonUK
  12. 12.School of Public HealthUniversity of California, BerkeleyBerkeleyUSA
  13. 13.Dipartimento di Medicina Traslazionale, SCDU Epidemiologia del TumoriUniversitá del Piemonte OrientaleNovaraItaly
  14. 14.Pediatric Hematology-Oncology ProgramInstituto Nacional de CancerRio de JaneiroBrazil
  15. 15.Department of Epidemiology and Preventive Medicine, NLI-SSI Collaborative Research Center, National Liver InstituteMenoufia UniversityCairoEgypt
  16. 16.Department of Pediatrics Texas Children’s Cancer CenterBaylor College of MedicineHoustonUSA
  17. 17.Central American Institute for Studies on Toxic Substances (IRET)Universidad NacionalHerediaCosta Rica
  18. 18.Department of Preventative and Social Medicine, Dunedin School of MedicineUniversity of OtagoDunedinNew Zealand
  19. 19.Danish Cancer Society Research CenterCopenhagenDenmark
  20. 20.Research DepartmentChildren’s Cancer Hospital EgyptCairoEgypt
  21. 21.Biomedical Research DepartmentArmed Forces College of MedicineCairoEgypt
  22. 22.Department of Epidemiology, Biostatistics and Occupational Health, Faculty of MedicineMcGill UniversityMontrealCanada
  23. 23.Department of Women’s and Children’s HealthUppsala UniversityUppsalaSweden

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