The role of reproductive factors, such as parental age, in the pathogenesis of childhood leukemias is being intensively examined; the results of individual studies are controversial. This meta-analysis aims to quantitatively synthesize the published data on the association between parental age and risk of two major distinct childhood leukemia types in the offspring. Eligible studies were identified and pooled relative risk (RR) estimates were calculated using random-effects models, separately for childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Subgroup analyses were performed by study design, geographical region, adjustment factors; sensitivity analyses and meta-regression analyses were also undertaken. 77 studies (69 case–control and eight cohort) were deemed eligible. Older maternal and paternal age were associated with increased risk for childhood ALL (pooled RR = 1.05, 95 % CI 1.01–1.10; pooled RR = 1.04, 95 % CI 1.00–1.08, per 5 year increments, respectively). The association between maternal age and risk of childhood AML showed a U-shaped pattern, with symmetrically associated increased risk in the oldest (pooled RR = 1.23, 95 % CI 1.06–1.43) and the youngest (pooled RR = 1.23, 95 % CI 1.07–1.40) extremes. Lastly, only younger fathers were at increased risk of having a child with AML (pooled RR = 1.28, 95 % CI 1.04–1.59). In conclusion, maternal and paternal age represents a meaningful risk factor for childhood leukemia, albeit of different effect size by leukemia subtype. Genetic and socio-economic factors may underlie the observed associations. Well-adjusted studies, scheduled by large consortia, are anticipated to satisfactorily address methodological issues, whereas the potential underlying genetic mechanisms should be elucidated by basic research studies.
Childhood leukemia Parental age Meta-analysis Meta-regression Risk factor
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The authors would like to thank Dr. Jie Song, Karolinska Institutet, for the translation of Chinese articles on the field, as well as the corresponding authors of studies who replied to our Letters, as detailed in the Supplemental Results section.
Adami HO, Hunter D, Trichopoulos D. Textbook of cancer epidemiology. Oxford: Oxford University Press; 2008.CrossRefGoogle Scholar
Urayama KY, Buffler PA, Gallagher ER, Ayoob JM, Ma X. A meta-analysis of the association between day-care attendance and childhood acute lymphoblastic leukaemia. Int J Epidemiol. 2010;39:718–32.PubMedPubMedCentralCrossRefGoogle Scholar
Lariou MS, Dikalioti SK, Dessypris N, Baka M, Polychronopoulou S, Athanasiadou-Piperopoulou F, et al. Allergy and risk of acute lymphoblastic leukemia among children: a nationwide case control study in Greece. Cancer Epidemiol. 2013;37:146–51.PubMedCrossRefGoogle Scholar
Klimentopoulou A, Antonopoulos CN, Papadopoulou C, Kanavidis P, Tourvas AD, Polychronopoulou S, et al. Maternal smoking during pregnancy and risk for childhood leukemia: a nationwide case-control study in Greece and meta-analysis. Pediatr Blood Cancer. 2012;58:344–51.PubMedCrossRefGoogle Scholar
Diamantaras AA, Dessypris N, Sergentanis TN, Ntouvelis E, Athanasiadou-Piperopoulou F, Baka M, et al. Nutrition in early life and risk of childhood leukemia: a case-control study in Greece. Cancer Causes Control. 2013;24:117–24.PubMedCrossRefGoogle Scholar
Petridou E, Ntouvelis E, Dessypris N, Terzidis A, Trichopoulos D. Maternal diet and acute lymphoblastic leukemia in young children. Cancer Epidemiol Biomarkers Prev. 2005;14:1935–9.PubMedCrossRefGoogle Scholar
Rudant J, Amigou A, Orsi L, Althaus T, Leverger G, Baruchel A, et al. Fertility treatments, congenital malformations, fetal loss, and childhood acute leukemia: the ESCALE study (SFCE). Pediatr Blood Cancer. 2013;60:301–8.PubMedCrossRefGoogle Scholar
Petridou ET, Sergentanis TN, Panagopoulou P, Moschovi M, Polychronopoulou S, Baka M, et al. In vitro fertilization and risk of childhood leukemia in Greece and Sweden. Pediatr Blood Cancer. 2012;58:930–6.PubMedCrossRefGoogle Scholar
Caughey R, Michels K. Birth weight and childhood leukemia: a meta-analysis and review of the current evidence. Int J Cancer. 2009;124:2658–70.PubMedCrossRefGoogle Scholar
Hargreave M, Jensen A, Toender A, Andersen KK, Kjaer SK. Fertility treatment and childhood cancer risk: a systematic meta-analysis. Fertil Steril. 2013;100:150–61.PubMedCrossRefGoogle Scholar
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;117:95–102.PubMedCrossRefGoogle Scholar
Sergentanis T, Dessypris N, Kanavidis P, Skalkidis I, Baka M, Polychronopoulou S, et al. Socioeconomic status, area remoteness, and survival from childhood leukemia: results from the Nationwide Registry for Childhood Hematological Malignancies in Greece. Eur J Cancer Prev. 2012.Google Scholar
Petridou ET, Sergentanis TN, Perlepe C, Papathoma P, Tsilimidos G, Kontogeorgi E, et al. Socioeconomic disparities in survival from childhood leukemia in the United States and globally: a meta-analysis. Ann Oncol. 2015;26:589–97.PubMedCrossRefGoogle Scholar
Ou SX, Han D, Severson RK, Chen Z, Neglia JP, Reaman GH, et al. Birth characteristics, maternal reproductive history, hormone use during pregnancy, and risk of childhood acute lymphocytic leukemia by immunophenotype (United States). Cancer Causes Control. 2002;13:15–25.PubMedCrossRefGoogle Scholar
Ma X, Metayer C, Does MB, Buffler PA. Maternal pregnancy loss, birth characteristics, and childhood leukemia (United States). Cancer Causes Control. 2005;16:1075–83.PubMedCrossRefGoogle Scholar
Reynolds P, Von Behren J, Elkin EP. Birth characteristics and leukemia in young children. Am J Epidemiol. 2002;155:603–13.PubMedCrossRefGoogle Scholar
Kaye SA, Robison LL, Smithson WA, Gunderson P, King FL, Neglia JP. Maternal reproductive history and birth characteristics in childhood acute lymphoblastic leukemia. Cancer. 1991;68:1351–5.PubMedCrossRefGoogle Scholar
Stark CR, Mantel N. Maternal-age and birth-order effects in childhood leukemia: age of child and type of leukemia. J Natl Cancer Inst. 1969;42:857–66.PubMedGoogle Scholar
Yan K, Xu X, Liu X, Wang X, Hua S, Wang C. The associations between maternal factors during pregnancy and the risk of childhood acute lymphoblastic leukemia: a meta-analysis. Pediatr Blood Cancer. 2015.Google Scholar
Thomopoulos TP, Sergentanis TN, Karalexi MA, Petridou ET. Methodological remarks regarding the meta-analysis on possible associations of maternal factors during pregnancy with the risk of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 2015.Google Scholar
Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011]. In: The Cochrane Collaboration. 2011 http://handbook.cochrane.org/. Accessed 30 Jan 2014.
Wells GA, Shea B, O’Connell D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses. Department of Epidemiology and Community Medicine, University of Ottawa: Ottawa. 2011. http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm. Accessed 30 Jan 2014.
Walter CA, Walter RB, McCarrey JR. Germline genomes—a biological fountain of youth? Sci Aging Knowledge Environ. 2003; 2003:PE4.Google Scholar
Forster P, Hohoff C, Dunkelmann B, Schurenkamp M, Pfeiffer H, Neuhuber F, et al. Elevated germline mutation rate in teenage fathers. Proc Biol Sci. 2015;282:20142898.PubMedPubMedCentralCrossRefGoogle Scholar
McGrath JJ, Petersen L, Agerbo E, Mors O, Mortensen PB, Pedersen CB. A comprehensive assessment of parental age and psychiatric disorders. JAMA Psychiatry. 2014;71:301–9.PubMedCrossRefGoogle Scholar
Antonopoulos CN, Sergentanis TN, Papadopoulou C, Andrie E, Dessypris N, Panagopoulou P, et al. Maternal smoking during pregnancy and childhood lymphoma: a meta-analysis. Int J Cancer. 2011;129:2694–703.PubMedCrossRefGoogle Scholar
Wellings K, Wadsworth J, Johnson A, Field J, Macdowall W. Teenage fertility and life chances. Rev Reprod. 1999;4:184–90.PubMedCrossRefGoogle Scholar
Maule MM, Merletti F, Pastore G, Magnani C, Richiardi L. Effects of maternal age and cohort of birth on incidence time trends of childhood acute lymphoblastic leukemia. Cancer Epidemiol Biomarkers Prev. 2007;16:347–51.PubMedCrossRefGoogle Scholar
Miller B, Messias E, Miettunen J, Alaraisanen A, Jarvelin MR, Koponen H, et al. Meta-analysis of paternal age and schizophrenia risk in male versus female offspring. Schizophr Bull. 2011;37:1039–47.PubMedPubMedCentralCrossRefGoogle Scholar
Sandin S, Hultman CM, Kolevzon A, Gross R, MacCabe JH, Reichenberg A. Advancing maternal age is associated with increasing risk for autism: a review and meta-analysis. J Am Acad Child Adolesc Psychiatry. 2012;51(477–86):e1.PubMedGoogle Scholar