Abstracts

INTRODUCTION

Leukemia makes up about one third of all malignancies in the 0-14 year old age group. The most common subtype, acute lymphoblastic leukemia (ALL), represents about 80.0% of these cases. ⁵⁷57 . Petridou E, Trichopoulos D. Leukemias. In: Adami H-O, Hunter DJ, Trichopoulos D, editors. Textbook of cancer epidemiology. New York: Oxford University Press; 2002. p. 556-72. The incidence rate of ALL was estimated as 35.2 per million children aged under 15 in Brazil, and children under five are the most affected. ⁶⁰60 . Reis RS, Camargo B, Santos MO, Oliveira JM, Silva FA, Pombo-de-Oliveira MS. Childhood leukemia incidence in Brazil according to different geographical regions. Pediatr Blood Cancer. 2011;56(1):58-64. DOI:10.1002/pbc.22736
https://doi.org/10.1002/pbc.22736...

Potential risk factors for childhood leukemia (CL) are conflicting. Exposure to ionizing radiation, commonly accepted as a cause of leukemia, does not explain all cases of leukemia in children. ⁵5 . Belson M, Kingsley B, Holmes A. Risk factors for acute leukemia in children: a review. Environ Health Perspect. 2007;115(1):138-45. DOI:10.1289/ehp.9023
https://doi.org/10.1289/ehp.9023... The etiology of CL has a multifactorial character. Leukemic cells that carry genetic alterations arise mainly before birth. Translocation between chromosomes 12 and 21 causes fusion of the TEL and AML1 gene; producing aberrant proteins that inhibit gene activity and change the capacity for self-renewal and differentiation of hematopoietic stem cells; this change represents the most common structural genetic abnormality in children with leukemia. ⁴⁵45 . Mori H, Colman SM, Xiao Z, Ford AM, Healy LE, Donaldson C, et al. Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc Natl Acad Sci . 2002;99(12):8242-7. DOI:10.1073/pnas.112218799
https://doi.org/10.1073/pnas.112218799... ^{, 74}74 . Shurtleff SA, Buijs A, Behm FG, Rubnitz JE, Raimondi SC, Hancock ML, et al. TEL/AML1 fusion resulting from a cryptic t(12;21) is the most common genetic lesion in pediatric ALL and defines a subgroup of patients with an excellent prognosis. Leukemia . 1995;9(12):1985-9. About 1.0% of healthy newborns have this translocation and one leukemic clone generated in the uterus, however, they do not develop disease. ⁴⁵45 . Mori H, Colman SM, Xiao Z, Ford AM, Healy LE, Donaldson C, et al. Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc Natl Acad Sci . 2002;99(12):8242-7. DOI:10.1073/pnas.112218799
https://doi.org/10.1073/pnas.112218799... This fact and the low correlation between identical twin ALL (about 5,0% in infants 2-6 years) suggests that the disease probably begins in uterus, but a postnatal event is required for it to develop; this is known as a “two hit model”. ¹⁶16 . Greaves M. Molecular genetics, natural history and the demise of childhood leukaemia. Eur J Cancer. 1999;35(2):17385. DOI:10.1016/S0959-8049(98)00433-X ^{, 17}17 . Greaves M. Childhood leukaemia. BMJ. 2002;324(7332):283-7. DOI:10.1136/bmj.324.7332.283
https://doi.org/10.1136/bmj.324.7332.283... Studies have tested whether infections may be involved in the etiology of CL. Three main hypothesis can explain the impact infections have on the disease development.

Smith ⁷⁶76 . Smith M. Considerations on a possible viral etiology for B-precursor acute lymphoblastic leukemia of childhood. J Immunother. 1997;20(2):89-100. suggested that infection during pregnancy allows the infectious agent to be transmitted to the fetus and cause genetic instability, which leads to increased risk of developing c-ALL (B-cell precursor of common ALL) up to five years of age. This proposal would explain the peak occurrence of ALL in the 2-5 year old age group.

The hypothesis of “delayed infection”, proposed by Greaves^{17, 19}19 . Greaves MF. Speculations on the cause of childhood acute lymphoblastic leukemia. Leukemia . 1988;2(2):120-5. suggests that the occurrence of common infections early in life may play a protective role against ALL (especially subtype c-ALL). Whereas limited exposure to infection in this period of life increases the risk of disease by enhancing the possibility of abnormal immune response to infection acquired later.

The observation of temporary CL clusters in relatively isolated communities after increased entry of new individuals into these populations has provided support for the formulation of the “population mixing” hypothesis. Kinlen ²⁷27 . Kinlen L. Evidence for an infective cause of childhood leukaemia: comparison of a Scottish new town with nuclear reprocessing sites in Britain. Lancet. 1988;2(8624):1323-7. DOI: 10.1016/S0140-6736(88)90867-7
https://doi.org/10.1016/S0140-6736(88)90... ^{, 28}28 . Kinlen L, Balkwill A. Infective cause of childhood leukaemia and wartime population mixing in Orkney and Shetland, UK. Lancet . 2001;357(9259):858. DOI:10.1016/S0140-6736(00)04208-2
https://doi.org/10.1016/S0140-6736(00)04... suggests that the introduction of a specific infectious agent in a non-immune population could cause an abnormal immune response to infection by this pathogen and cause a transient increase in leukemia cases.

This article reviews studies related to Smith and Greaves’ hypothesis on the role of infections and indirect measures of infection exposure on the risk of childhood leukemia, especially ALL.

METHODS

In order to identify eligible studies published before January 3, 2012, a search was made in three scientific publication databases: Medline, ^aaPubMed: the bibliographic database [Internet]. Bethesda (MD): National Library of Medicine (US). 1960s. Available from: http://www.ncbi.nlm.nih.gov/pubmed Lilacs ^bbLILACS: Literatura Latino-Americana e do Caribe em Ciências da Saúde [Internet]. São Paulo (BR): Bireme/OPS/OMS. 1982. Available from: http://lilacs.bvsalud.org/ and SciELO. ^cc SciELO: Scientific Electronic Library Online [Internet]. São Paulo (BR): Bireme/OPS/FAPESP/CNPq. 1998. Available from: http://www.scielo.org/php/index.php?lang=en Studies with subjects age ≤ 15 years old and specific analysis of cases diagnosed as ALL and/or total leukemia were included in this review. The search considered possible associated factors: maternal or infant exposure to infections or proxy of infections (day care attendance, birth order, breastfeeding, vaccination).

The descriptors used for searching in the Medline database were: infection and childhood leukemia. The preliminary list included 612 publications. We pre-selected articles by reading titles and abstracts and created a second list of 145 potentially eligible studies. The inclusion criteria were met in 47 of those 145 articles. The same descriptors were used to search in the SciELO and Lilacs databases. However, the term infection was replaced by infect$. The use of “$” symbol allows recording of words with the same root. The results included eight and fourteen studies, respectively. None met the inclusion criteria.

We looked for studies in the three databases using the descriptors “childhood leukemia”, with the addition of words: infection or maternal disease, breastfeeding, day care, vaccination and birth order. We found a further 15 studies that met inclusion criteria and had not previously been screened.

RESULTS

This review included 62 studies: 85.5% were case-control, 9.7% cohort and 4.8% ecological studies. The studies were conducted in Europe, North America, Asia, Africa, and Oceania and published between 1973 and 2011.

Direct assessment of exposure to infection in the mothers and children

Maternal infection

The association between maternal infection during pregnancy and CL was evaluated in 16 studies, and statistically significant increased risks of leukemia were detected in 11 ²2 . Austin DF, Karp S, Dworsky R, Henderson BE. Excess leukemia in cohorts of children born following influenza epidemics. Am J Epidemiol. 1975;101(1):77-83. ^{, 8}8 . Buckley JD, Buckley CM, Ruccione K, Sather HN, Waskerwitz MJ, Woods WG, et al. Epidemiological characteristics of childhood acute lymphocytic leukemia: analysis by immunophenotype. The Childrens Cancer Group. Leukemia . 1994;8(5):856-64. ^{, 21}21 . Hakulinen T, Hovi L, Karkinen-Jääskeläinen M, Penttinen K, Saxén L. Association between influenza during pregnancy and childhood leukaemia. Br Med J . 1973;4(5887):265-7. ^{, 33}33 . Kwan ML, Metayer C, Crouse V, Buffler PA. Maternal illness and drug/medication use during the period surrounding pregnancy and risk of childhood leukemia among offspring. Am J Epidemiol . 2007;165(1):27-35. DOI:10.1093/aje/kwj336
https://doi.org/10.1093/aje/kwj336... ^{, 35}35 . Lehtinen M, Koskela P, Ogmundsdottir HM, Bloigu A, Dillner J, Gudnadottir M, et al. Maternal herpesvirus infections and risk of acute lymphoblastic leukemia in the offspring. Am J Epidemiol . 2003;158(3):207-13. DOI:10.1093/aje/kwg137
https://doi.org/10.1093/aje/kwg137... ^{, 36}36 . Lehtinen M, Ogmundsdottir HM, Bloigu A, Hakulinen T, Hemminki E, Gudnadottir M, et al. Associations between three types of maternal bacterial infection and risk of leukemia in the offspring. Am J Epidemiol . 2005;162(7):662-7. DOI:10.1093/aje/kwi261 ^{, 43}43 . McKinney PA, Cartwright RA, Saiu JM, Mann JR, Stiller CA, Draper GJ, et al. The Inter-Regional Epidemiological Study of Childhood Cancer (IRESCC): a case control study of aetiological factors in leukaemia and lymphoma. Arch Dis Child . 1987;62(3):279-87. ^{, 47}47 . 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
https://doi.org/10.1002/mpo.10084... ^{, 77}77 . Tedeschi R, Bloigu A, Ogmundsdottir HM, Marus A, Dillner J, Depaoli P, et al. Activation of maternal Epstein-Barr virus infection and risk of acute leukemia in the offspring. Am J Epidemiol. 2007;165(2):134-7. DOI:10.1093/aje/kwj332
https://doi.org/10.1093/aje/kwj332... ^{, 78}78 . Till M, Rapson N, Smith PG. Family studies in acute leukaemia in childhood: a possible association with autoimmune disease. Br J Cancer. 1979;40(1):62-71. ^{, 83}83 . Vianna NJ, Polan AK. Childhood lymphatic leukemia: prenatal seasonality and possible association with congenital varicella. Am J Epidemiol. 1976;103(3):321-32. ( Table 1 ). Associated infections were: influenza, pneumonia, chickenpox, herpes zoster, lower genital tract infection, skin disease, sexually transmitted diseases, Epstein-Barr virus (EBV), and Helicobacter pylori . Laboratory tests were performed for antibodies in maternal serum during pregnancy in three studies. ³⁵35 . Lehtinen M, Koskela P, Ogmundsdottir HM, Bloigu A, Dillner J, Gudnadottir M, et al. Maternal herpesvirus infections and risk of acute lymphoblastic leukemia in the offspring. Am J Epidemiol . 2003;158(3):207-13. DOI:10.1093/aje/kwg137
https://doi.org/10.1093/aje/kwg137... ^{, 36}36 . Lehtinen M, Ogmundsdottir HM, Bloigu A, Hakulinen T, Hemminki E, Gudnadottir M, et al. Associations between three types of maternal bacterial infection and risk of leukemia in the offspring. Am J Epidemiol . 2005;162(7):662-7. DOI:10.1093/aje/kwi261 ^{, 77}77 . Tedeschi R, Bloigu A, Ogmundsdottir HM, Marus A, Dillner J, Depaoli P, et al. Activation of maternal Epstein-Barr virus infection and risk of acute leukemia in the offspring. Am J Epidemiol. 2007;165(2):134-7. DOI:10.1093/aje/kwj332
https://doi.org/10.1093/aje/kwj332... Maternal infection with EBV was associated with a significantly increased risk of ALL in two studies (odds ratio [OR] 2.9, 95% confidence interval [95%CI] 1.5;5.8; OR 1.9, 95%CI 1.2;3.0), ³⁵35 . Lehtinen M, Koskela P, Ogmundsdottir HM, Bloigu A, Dillner J, Gudnadottir M, et al. Maternal herpesvirus infections and risk of acute lymphoblastic leukemia in the offspring. Am J Epidemiol . 2003;158(3):207-13. DOI:10.1093/aje/kwg137
https://doi.org/10.1093/aje/kwg137... ^{, 77}77 . Tedeschi R, Bloigu A, Ogmundsdottir HM, Marus A, Dillner J, Depaoli P, et al. Activation of maternal Epstein-Barr virus infection and risk of acute leukemia in the offspring. Am J Epidemiol. 2007;165(2):134-7. DOI:10.1093/aje/kwj332
https://doi.org/10.1093/aje/kwj332... and Lehtinen et al ³⁶36 . Lehtinen M, Ogmundsdottir HM, Bloigu A, Hakulinen T, Hemminki E, Gudnadottir M, et al. Associations between three types of maternal bacterial infection and risk of leukemia in the offspring. Am J Epidemiol . 2005;162(7):662-7. DOI:10.1093/aje/kwi261 found a high risk of CL (but not ALL) associated with Helicobacter pylori infection. Naumburg et al ⁴⁷47 . 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
https://doi.org/10.1002/mpo.10084... identified a significantly increased risk of both ALL (OR 1.63, 95%CI 1.04;2.53) and CL (OR 1.78, 95%CI 1.17;2.72) associated with lower genital tract infections. Likewise, Kwan et al ³³33 . Kwan ML, Metayer C, Crouse V, Buffler PA. Maternal illness and drug/medication use during the period surrounding pregnancy and risk of childhood leukemia among offspring. Am J Epidemiol . 2007;165(1):27-35. DOI:10.1093/aje/kwj336
https://doi.org/10.1093/aje/kwj336... showed that the risk of ALL and CL was increased in children whose mothers had influenza/pneumonia and sexually transmitted diseases during the pregnancy. No statistically significant association was found between maternal infection and leukemia in five studies. ¹²12 . Curnen MG, Varma AA, Christine BW, Turgeon LR. Childhood leukemia and maternal infectious diseases during pregnancy. J Natl Cancer Inst . 1974;53(4):943-7. ^{, 13}13 . Dockerty JD, Skegg DC, Elwood JM, Herbison GP, Becroft DM, Lewis ME. Infections, vaccinations, and the risk of childhood leukaemia. Br J Cancer. 1999;80(9):1483-9. DOI:10.1038/sj.bjc.6690548
https://doi.org/10.1038/sj.bjc.6690548... ^{, 24}24 . Infante-Rivard C, Fortier I, Olson E. Markers of infection, breast-feeding and childhood acute lymphoblastic leukaemia. Br J Cancer. 2000;83(11):1559-64. DOI:10.1054/bjoc.2000.1495
https://doi.org/10.1054/bjoc.2000.1495... ^{, 44}44 . McKinney PA, Juszczak E, Findlay E, Smith K, Thomson CS. Pre- and perinatal risk factors for childhood leukaemia and other malignancies: a Scottish case control study. Br J Cancer. 1999;80(11):1844-51. DOI:10.1038/sj.bjc.6690609
https://doi.org/10.1038/sj.bjc.6690609... ^{, 59}59 . Randolph VL, Heath CW Jr. Influenza during pregnancy in relation to subsequent childhood leukemia and lymphoma. Am J Epidemiol . 1974;100(5):399-409.

Childhood infection

Table 2 shows twenty-three studies that evaluated the association between childhood infection and leukemia. Among those that analyzed infections in the first two years of life, five reported reduced risk of ALL associated with infection in the skin, ⁴⁴44 . McKinney PA, Juszczak E, Findlay E, Smith K, Thomson CS. Pre- and perinatal risk factors for childhood leukaemia and other malignancies: a Scottish case control study. Br J Cancer. 1999;80(11):1844-51. DOI:10.1038/sj.bjc.6690609
https://doi.org/10.1038/sj.bjc.6690609... ears, ⁴⁸48 . Neglia JP, Linet MS, Shu XO, Severson RK, Potter JD, Mertens AC, et al. Patterns of infection and day care utilization and risk of childhood acute lymphoblastic leukaemia. Br J Cancer. 2000;82(1);234-40. DOI:10.1054/bjoc.1999.0905
https://doi.org/10.1054/bjoc.1999.0905... ^{, 81}81 . Urayama KY, Ma X, Selvin S, Metayer C, Chokkalingam AP, Wiemels JL, et al. Early life exposure to infections and risk of childhood acute lymphoblastic leukemia. Int J Cancer . 2011;128(7):1632-43. DOI:10.1002/ijc.25752
https://doi.org/10.1002/ijc.25752... or gastrointestinal tract, ²⁵25 . Jourdan-Da Silva N, Perel Y, Méchinaud F, Plouvier E, Gandemer V, Lutz P, et al. Infectious diseases in the first year of life, perinatal characteristics and childhood acute leukaemia. Br J Cancer. 2004;90(1):139-45. DOI:10.1038/sj.bjc.6601384
https://doi.org/10.1038/sj.bjc.6601384... and episodes of roseola and/or fever and rash. ¹⁰10 . Chan LC, Lam TH, Li CK, Lau YL, Li CK, Yuen HL, et al. Is the timing of exposure to infection a major determinant of acute lymphoblastic leukaemia in Hong Kong? Paediatr Perinat Epidemiol. 2002;16(2):154-65. DOI:10.1046/j.1365-3016.2002.00406.x
https://doi.org/10.1046/j.1365-3016.2002... Other two studies detected a higher risk of ALL in children with more frequent episodes of upper respiratory tract infection, ⁹9 . Cardwell CR, McKinney PA, Patterson CC, Murray LJ. Infections in early life and childhood leukaemia risk: a UK case-control study of general practitioner records. Br J Cancer . 2008;99(9):1529-33. DOI:10.1038/sj.bjc.6604696
https://doi.org/10.1038/sj.bjc.6604696... ^{, 64}64 . Roman E, Simpson J, Ansell P, Kinsey S, Mitchell CD, Mckinney PA, et al. Childhood acute lymphoblastic leukemia and infections in the first year of life: a report from the United Kingdom Childhood Cancer Study. Am J Epidemiol. 2007;165(5):496-504. DOI:10.1093/aje/kwk039
https://doi.org/10.1093/aje/kwk039... fungal infection ⁶⁴64 . Roman E, Simpson J, Ansell P, Kinsey S, Mitchell CD, Mckinney PA, et al. Childhood acute lymphoblastic leukemia and infections in the first year of life: a report from the United Kingdom Childhood Cancer Study. Am J Epidemiol. 2007;165(5):496-504. DOI:10.1093/aje/kwk039
https://doi.org/10.1093/aje/kwk039... and chickenpox. ⁹9 . Cardwell CR, McKinney PA, Patterson CC, Murray LJ. Infections in early life and childhood leukaemia risk: a UK case-control study of general practitioner records. Br J Cancer . 2008;99(9):1529-33. DOI:10.1038/sj.bjc.6604696
https://doi.org/10.1038/sj.bjc.6604696... A further five studies found reduced risk associated with some diseases and increased risk associated with others. ¹³13 . Dockerty JD, Skegg DC, Elwood JM, Herbison GP, Becroft DM, Lewis ME. Infections, vaccinations, and the risk of childhood leukaemia. Br J Cancer. 1999;80(9):1483-9. DOI:10.1038/sj.bjc.6690548
https://doi.org/10.1038/sj.bjc.6690548... ^{, 52}52 . Perrillat F, Clavel J, Auclerc MF, Baruchel A, Leverger G, Nelken B, et al. Day-care, early common infections and childhood acute leukaemia: a multicentre French case-control study. Br J Cancer . 2002;86(7):1064-9. DOI:10.1038/sj.bjc.6600091 ^{, 66}66 . Rosenbaum PF, Buck GM, Brecher ML. Allergy and infectious disease histories and the risk of childhood acute lymphoblastic leukaemia. Paediatr Perinat Epidemiol. 2005;19(2):152-64. DOI:10.1111/j.1365-3016.2005.00634.x
https://doi.org/10.1111/j.1365-3016.2005... ^{, 67}67 . Rudant J, Orsi L, Menegaux F, Petit A, Baruchel A, Bertrand Y, et al. Childhood acute leukemia, early common infections, and allergy: The ESCALE Study. Am J Epidemiol. 2010;172(9):1015-27. DOI:10.1093/aje/kwq233
https://doi.org/10.1093/aje/kwq233... ^{, 75}75 . Simpson J, Smith A, Ansell P, Roman E. Childhood leukaemia and infectious exposure: a report from the United Kingdom Childhood Cancer Study (UKCCS). Eur J Cance r. 2007;43(16):2396-403. DOI:10.1016/j.ejca.2007.07.027
https://doi.org/10.1016/j.ejca.2007.07.0... The association between common cold, fever, history of infection in the infant and leukemia was not significant in two studies. ⁴⁷47 . 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
https://doi.org/10.1002/mpo.10084... ^{, 82}82 . Van Steensel-Moll HA, Valkenburg HA, Zanen GE. Childhood leukemia and infectious diseases in the first year of life: a register-based case-control study. Am J Epidemiol . 1986;124(4):590-4.

Exposure to infection at any time prior to diagnosis was examined in six studies. ²⁵25 . Jourdan-Da Silva N, Perel Y, Méchinaud F, Plouvier E, Gandemer V, Lutz P, et al. Infectious diseases in the first year of life, perinatal characteristics and childhood acute leukaemia. Br J Cancer. 2004;90(1):139-45. DOI:10.1038/sj.bjc.6601384
https://doi.org/10.1038/sj.bjc.6601384... ^{, 38}38 . Ma X, Buffler PA, Wiemels JL, Selvin S, Metayer C, Loh M, et al. Ethnic difference in daycare attendance, early infections, and risk of childhood acute lymphoblastic leukemia. Cancer Epidemiol Biomarkers Prev. 2005;14(8):1928-34. DOI:10.1158/1055-9965.EPI-05-0115 ^{, 40}40 . MacArthur AC, McBride ML, Spinelli JJ, Tamaro S, Gallagher RP, Theriault GP. Risk of childhood leukemia associated with vaccination, infection, and medication use in childhood: the Cross-Canada Childhood Leukemia Study. Am J Epidemiol. 2008;167(5):598-606. DOI:10.1093/aje/kwm339 ^{, 43}43 . McKinney PA, Cartwright RA, Saiu JM, Mann JR, Stiller CA, Draper GJ, et al. The Inter-Regional Epidemiological Study of Childhood Cancer (IRESCC): a case control study of aetiological factors in leukaemia and lymphoma. Arch Dis Child . 1987;62(3):279-87. ^{, 68}68 . Schlehofer B, Blettner M, Geletneky K, Haaf HG, Kaatsch P, Michaelis J, et al. Sero-epidemiological analysis of the risk of virus infections for childhood leukaemia. Int J Cancer. 1996;65(5):584-90. DOI:10.1002/(SICI)1097-0215(19960301)65:5<584::AID-IJC5>3.0.CO;2-Zm
https://doi.org/10.1002/(SICI)1097-0215(... ^{, 70}70 . Schüz J, Kaletsch U, Meinert R, Kaatsch P, Michaelis J. Association of childhood leukaemia with factors related to the immune system. Br J Cancer . 1999;80(3-4):585-90. DOI:10.1038/sj.bjc.6690395
https://doi.org/10.1038/sj.bjc.6690395... A protective effect against leukemia in children with herpes labialis, ⁶⁸68 . Schlehofer B, Blettner M, Geletneky K, Haaf HG, Kaatsch P, Michaelis J, et al. Sero-epidemiological analysis of the risk of virus infections for childhood leukaemia. Int J Cancer. 1996;65(5):584-90. DOI:10.1002/(SICI)1097-0215(19960301)65:5<584::AID-IJC5>3.0.CO;2-Zm
https://doi.org/10.1002/(SICI)1097-0215(... chickenpox, ⁷⁰70 . Schüz J, Kaletsch U, Meinert R, Kaatsch P, Michaelis J. Association of childhood leukaemia with factors related to the immune system. Br J Cancer . 1999;80(3-4):585-90. DOI:10.1038/sj.bjc.6690395
https://doi.org/10.1038/sj.bjc.6690395... and ear infection was detected. ³⁸38 . Ma X, Buffler PA, Wiemels JL, Selvin S, Metayer C, Loh M, et al. Ethnic difference in daycare attendance, early infections, and risk of childhood acute lymphoblastic leukemia. Cancer Epidemiol Biomarkers Prev. 2005;14(8):1928-34. DOI:10.1158/1055-9965.EPI-05-0115 Mckinney et al ⁴³43 . McKinney PA, Cartwright RA, Saiu JM, Mann JR, Stiller CA, Draper GJ, et al. The Inter-Regional Epidemiological Study of Childhood Cancer (IRESCC): a case control study of aetiological factors in leukaemia and lymphoma. Arch Dis Child . 1987;62(3):279-87. and Jourdan-Da Silva et al, ²⁵25 . Jourdan-Da Silva N, Perel Y, Méchinaud F, Plouvier E, Gandemer V, Lutz P, et al. Infectious diseases in the first year of life, perinatal characteristics and childhood acute leukaemia. Br J Cancer. 2004;90(1):139-45. DOI:10.1038/sj.bjc.6601384
https://doi.org/10.1038/sj.bjc.6601384... respectively, identified an increased risk of leukemia correlating with total number of illness and rubella episodes. Macarthur et al ⁴⁰40 . MacArthur AC, McBride ML, Spinelli JJ, Tamaro S, Gallagher RP, Theriault GP. Risk of childhood leukemia associated with vaccination, infection, and medication use in childhood: the Cross-Canada Childhood Leukemia Study. Am J Epidemiol. 2008;167(5):598-606. DOI:10.1093/aje/kwm339 found a reduced risk of ALL in children with mumps or measles, but the results were not precise.

The occurrence of infection at leukemia diagnosis or in the year before diagnosis was evaluated in seven studies. ¹⁰10 . Chan LC, Lam TH, Li CK, Lau YL, Li CK, Yuen HL, et al. Is the timing of exposure to infection a major determinant of acute lymphoblastic leukaemia in Hong Kong? Paediatr Perinat Epidemiol. 2002;16(2):154-65. DOI:10.1046/j.1365-3016.2002.00406.x
https://doi.org/10.1046/j.1365-3016.2002... ^{, 29}29 . Kroll ME, Draper GJ, Stiller CA, Murphy MFG. Childhood Leukemia Incidence in Britain, 1974-2000: time trends and possible relation to influenza epidemics. J Natl Cancer Inst. 2006;98(6):417-20. DOI:10.1093/jnci/djj095
https://doi.org/10.1093/jnci/djj095... ^{, 41}41 . Mahjour SB, Ghaffarpasand F, Fattahi MJ, Ghaderi A, Fotouhi Ghiam A, Karimi M. Seroprevalence of human herpes simplex, hepatitis B and epstein-barr viruses in children with acute lymphoblastic leukemia in southern Iran. Pathol Oncol Res. 2010;16(4):579-82. DOI:10.1007/s12253-010-9258-6
https://doi.org/10.1007/s12253-010-9258-... ^{, 56}56 . Petridou E, Dalamaga M, Mentis A, Skalkidou A, Moustaki M, Karpathios T, et al. Evidence on the infectious etiology of childhood leukemia: the role of low herd immunity (Greece). Cancer Causes Control. 2001;12(7):645-52. ^{, 68}68 . Schlehofer B, Blettner M, Geletneky K, Haaf HG, Kaatsch P, Michaelis J, et al. Sero-epidemiological analysis of the risk of virus infections for childhood leukaemia. Int J Cancer. 1996;65(5):584-90. DOI:10.1002/(SICI)1097-0215(19960301)65:5<584::AID-IJC5>3.0.CO;2-Zm
https://doi.org/10.1002/(SICI)1097-0215(... ^{, 70}70 . Schüz J, Kaletsch U, Meinert R, Kaatsch P, Michaelis J. Association of childhood leukaemia with factors related to the immune system. Br J Cancer . 1999;80(3-4):585-90. DOI:10.1038/sj.bjc.6690395
https://doi.org/10.1038/sj.bjc.6690395... ^{, 71}71 . Sehgal S, Mujtaba S, Gupta D, Aggarwal R, Marwaha RK. High incidence of Epstein Barr virus infection in childhood acute lymphocytic leukemia: a preliminary study. Indian J Pathol Microbiol. 2010;53(1):63-7. DOI:10.4103/0377-4929.59186
https://doi.org/10.4103/0377-4929.59186... Among those, four performed laboratory tests to investigate exposure to specific infections. Petridou et al ⁵⁶56 . Petridou E, Dalamaga M, Mentis A, Skalkidou A, Moustaki M, Karpathios T, et al. Evidence on the infectious etiology of childhood leukemia: the role of low herd immunity (Greece). Cancer Causes Control. 2001;12(7):645-52. found a lower risk of ALL associated with EBV, human herpes virus 6 (HHV6), and mycoplasma exposure, and increased risk associated with parainfluenza. Other two studies ⁴¹41 . Mahjour SB, Ghaffarpasand F, Fattahi MJ, Ghaderi A, Fotouhi Ghiam A, Karimi M. Seroprevalence of human herpes simplex, hepatitis B and epstein-barr viruses in children with acute lymphoblastic leukemia in southern Iran. Pathol Oncol Res. 2010;16(4):579-82. DOI:10.1007/s12253-010-9258-6
https://doi.org/10.1007/s12253-010-9258-... ^{, 71}71 . Sehgal S, Mujtaba S, Gupta D, Aggarwal R, Marwaha RK. High incidence of Epstein Barr virus infection in childhood acute lymphocytic leukemia: a preliminary study. Indian J Pathol Microbiol. 2010;53(1):63-7. DOI:10.4103/0377-4929.59186
https://doi.org/10.4103/0377-4929.59186... identified increased risk of ALL in children exposed to the herpes simplex virus 1 and 2, hepatitis B virus, and EBV. Schlehofer et al ⁶⁸68 . Schlehofer B, Blettner M, Geletneky K, Haaf HG, Kaatsch P, Michaelis J, et al. Sero-epidemiological analysis of the risk of virus infections for childhood leukaemia. Int J Cancer. 1996;65(5):584-90. DOI:10.1002/(SICI)1097-0215(19960301)65:5<584::AID-IJC5>3.0.CO;2-Zm
https://doi.org/10.1002/(SICI)1097-0215(... found no significant association between EBV infection, HHV6, parvovirus B19, or the adeno-associated virus and ALL.

Indirect assessment of exposure to infections in childhood

Daycare attendance

Table 3 presents information on studies that investigated the association between daycare attendance and leukemia. Nine studies identified a statistically significant reduced risk of leukemia related to daycare attendance. ¹⁵15 . Gilham C, Peto J, Simpson J, Roman E, Eden TO, Greaves MF, et al. Day care in infancy and risk of childhood acute lymphoblastic leukaemia: findings from UK case-control study. BMJ. 2005;330(7503):1294. DOI:10.1136/bmj.38428.521042.8F
https://doi.org/10.1136/bmj.38428.521042... ^{, 24}24 . Infante-Rivard C, Fortier I, Olson E. Markers of infection, breast-feeding and childhood acute lymphoblastic leukaemia. Br J Cancer. 2000;83(11):1559-64. DOI:10.1054/bjoc.2000.1495
https://doi.org/10.1054/bjoc.2000.1495...

25 . Jourdan-Da Silva N, Perel Y, Méchinaud F, Plouvier E, Gandemer V, Lutz P, et al. Infectious diseases in the first year of life, perinatal characteristics and childhood acute leukaemia. Br J Cancer. 2004;90(1):139-45. DOI:10.1038/sj.bjc.6601384
https://doi.org/10.1038/sj.bjc.6601384... ^{- 26}26 . Kamper-Jørgensen M, Woodward A, Wohlfahrt J, Benn CS, Simonsen J, Hjalgrim H, et al. Childcare in the first 2 years of life reduces the risk of childhood acute lymphoblastic leukemia. Leukemia . 2008;22(1):189-93. DOI:10.1038/sj.leu.2404884
https://doi.org/10.1038/sj.leu.2404884... ^{, 37}37 . Ma X, Buffler PA, Selvin S, Matthay KK, Wiencke JK, Wiemels JL, et al. Day-care attendance and risk of childhood acute lymphoblastic leukaemia. Br J Cancer. 2002;86(9):1419-24. DOI:10.1038/sj.bjc.6600274 ^{, 38}38 . Ma X, Buffler PA, Wiemels JL, Selvin S, Metayer C, Loh M, et al. Ethnic difference in daycare attendance, early infections, and risk of childhood acute lymphoblastic leukemia. Cancer Epidemiol Biomarkers Prev. 2005;14(8):1928-34. DOI:10.1158/1055-9965.EPI-05-0115 ^{, 52}52 . Perrillat F, Clavel J, Auclerc MF, Baruchel A, Leverger G, Nelken B, et al. Day-care, early common infections and childhood acute leukaemia: a multicentre French case-control study. Br J Cancer . 2002;86(7):1064-9. DOI:10.1038/sj.bjc.6600091 ^{, 54}54 . Petridou E, Kassimos D, Kalmanti M, Kosmidis H, Haidas S, Flytzani V, et al. Age of exposure to infections and risk of childhood leukaemia. BMJ. 1993;307(6907):774. ^{, 81}81 . Urayama KY, Ma X, Selvin S, Metayer C, Chokkalingam AP, Wiemels JL, et al. Early life exposure to infections and risk of childhood acute lymphoblastic leukemia. Int J Cancer . 2011;128(7):1632-43. DOI:10.1002/ijc.25752
https://doi.org/10.1002/ijc.25752... Perrilat et al ⁵²52 . Perrillat F, Clavel J, Auclerc MF, Baruchel A, Leverger G, Nelken B, et al. Day-care, early common infections and childhood acute leukaemia: a multicentre French case-control study. Br J Cancer . 2002;86(7):1064-9. DOI:10.1038/sj.bjc.6600091 and Gilham et al ¹⁵15 . Gilham C, Peto J, Simpson J, Roman E, Eden TO, Greaves MF, et al. Day care in infancy and risk of childhood acute lymphoblastic leukaemia: findings from UK case-control study. BMJ. 2005;330(7503):1294. DOI:10.1136/bmj.38428.521042.8F
https://doi.org/10.1136/bmj.38428.521042... detected a more pronounced protective effect for children having started daycare in early life (OR 0.5, 95%CI 0.3;1.0 for age ≤ 6 months; OR 0.56, 95%CI 0.37;0.83 for age < 3 months) than in those having started daycare at older ages, but the trend for age of starting daycare was not statistically significant. In Jourdan-Da Silva et al, ²⁵25 . Jourdan-Da Silva N, Perel Y, Méchinaud F, Plouvier E, Gandemer V, Lutz P, et al. Infectious diseases in the first year of life, perinatal characteristics and childhood acute leukaemia. Br J Cancer. 2004;90(1):139-45. DOI:10.1038/sj.bjc.6601384
https://doi.org/10.1038/sj.bjc.6601384... a statistically significant association was only observed when daycare started before 3 months old (OR 0.6, 95%CI 0.4;0.8) and the trend was also statistically significant (p trend < 0.05).

In other eight studies no statistically significant association or effects were reported. ¹1 . Abdul Rahman HI, Shah SA, Alias H, Ibrahim HM. A case-control study on the association between environmental factors and the occurrence of acute leukemia among children in Klang Valley, Malaysia. Asian Pac J Cancer Prev. 2008;9(4):649-652. ^{, 10}10 . Chan LC, Lam TH, Li CK, Lau YL, Li CK, Yuen HL, et al. Is the timing of exposure to infection a major determinant of acute lymphoblastic leukaemia in Hong Kong? Paediatr Perinat Epidemiol. 2002;16(2):154-65. DOI:10.1046/j.1365-3016.2002.00406.x
https://doi.org/10.1046/j.1365-3016.2002... ^{, 48}48 . Neglia JP, Linet MS, Shu XO, Severson RK, Potter JD, Mertens AC, et al. Patterns of infection and day care utilization and risk of childhood acute lymphoblastic leukaemia. Br J Cancer. 2000;82(1);234-40. DOI:10.1054/bjoc.1999.0905
https://doi.org/10.1054/bjoc.1999.0905... ^{, 55}55 . Petridou E, Trichopoulos D, Kalapothaki V, Pourtsidis A, Kogevinas M, Kalmanti M, et al. The risk profile of childhood leukaemia in Greece: a nationwide case-control study. Br J Cancer. 1997;76(9):1241-7. ^{, 63}63 . Roman E, Watson A, Bull D, Baker K. Leukaemia risk and social contact in children aged 0-4 years in southern England. J Epidemiol Community Health. 1994;48(6):601-2. ^{, 65}65 . Rosenbaum PF, Buck GM, Brecher ML. Early child-care and preschool experiences and the risk of childhood acute lymphoblastic leukemia. Am J Epidemiol. 2000;152(12):1136-44. DOI:10.1093/aje/152.12.1136
https://doi.org/10.1093/aje/152.12.1136... ^{, 67}67 . Rudant J, Orsi L, Menegaux F, Petit A, Baruchel A, Bertrand Y, et al. Childhood acute leukemia, early common infections, and allergy: The ESCALE Study. Am J Epidemiol. 2010;172(9):1015-27. DOI:10.1093/aje/kwq233
https://doi.org/10.1093/aje/kwq233... ^{, 70}70 . Schüz J, Kaletsch U, Meinert R, Kaatsch P, Michaelis J. Association of childhood leukaemia with factors related to the immune system. Br J Cancer . 1999;80(3-4):585-90. DOI:10.1038/sj.bjc.6690395
https://doi.org/10.1038/sj.bjc.6690395... Neglia et al ⁴⁸48 . Neglia JP, Linet MS, Shu XO, Severson RK, Potter JD, Mertens AC, et al. Patterns of infection and day care utilization and risk of childhood acute lymphoblastic leukaemia. Br J Cancer. 2000;82(1);234-40. DOI:10.1054/bjoc.1999.0905
https://doi.org/10.1054/bjoc.1999.0905... did not find association even when the daycare began before 6 months of age.

Birth order

The relationship between birth order and leukemia was evaluated in 21 studies ( Table 4 ). Van Steensel-Moll ⁸²82 . Van Steensel-Moll HA, Valkenburg HA, Zanen GE. Childhood leukemia and infectious diseases in the first year of life: a register-based case-control study. Am J Epidemiol . 1986;124(4):590-4. detected increased ALL risk in children with lower birth order (first-born). Four studies found a protective effect associated with higher birth order. ¹⁴14 . Dockerty JD, Draper G, Vincent T, Rowan SD, Bunch KJ. Case-control study of parental age, parity and socioeconomic level in relation to childhood cancers. Int J Epidemiol. 2001;30(6):1428-37. DOI:10.1093/ije/30.6.1428
https://doi.org/10.1093/ije/30.6.1428... ^{, 56}56 . Petridou E, Dalamaga M, Mentis A, Skalkidou A, Moustaki M, Karpathios T, et al. Evidence on the infectious etiology of childhood leukemia: the role of low herd immunity (Greece). Cancer Causes Control. 2001;12(7):645-52. ^{, 67}67 . Rudant J, Orsi L, Menegaux F, Petit A, Baruchel A, Bertrand Y, et al. Childhood acute leukemia, early common infections, and allergy: The ESCALE Study. Am J Epidemiol. 2010;172(9):1015-27. DOI:10.1093/aje/kwq233
https://doi.org/10.1093/aje/kwq233... ^{, 81}81 . Urayama KY, Ma X, Selvin S, Metayer C, Chokkalingam AP, Wiemels JL, et al. Early life exposure to infections and risk of childhood acute lymphoblastic leukemia. Int J Cancer . 2011;128(7):1632-43. DOI:10.1002/ijc.25752
https://doi.org/10.1002/ijc.25752... Of these, Dockerty et al ¹⁴14 . Dockerty JD, Draper G, Vincent T, Rowan SD, Bunch KJ. Case-control study of parental age, parity and socioeconomic level in relation to childhood cancers. Int J Epidemiol. 2001;30(6):1428-37. DOI:10.1093/ije/30.6.1428
https://doi.org/10.1093/ije/30.6.1428... observed ALL risk reduction with increased parity (p trend < 0.001) in a sample of 2,942 cases and the same number of controls in England and Wales.

Infante-Rivard et al ²⁴24 . Infante-Rivard C, Fortier I, Olson E. Markers of infection, breast-feeding and childhood acute lymphoblastic leukaemia. Br J Cancer. 2000;83(11):1559-64. DOI:10.1054/bjoc.2000.1495
https://doi.org/10.1054/bjoc.2000.1495... detected a reduced ALL risk in children aged four and over who had at least one older sibling in the first year of life (OR 0.46, 95%CI 0.22;0.97), but they observed a higher ALL risk in children under four years old who had at least one older sibling at diagnosis (OR 4.54, 95%CI 2.27;9.07).

Three studies found higher ALL risk related to higher birth order. ²⁵25 . Jourdan-Da Silva N, Perel Y, Méchinaud F, Plouvier E, Gandemer V, Lutz P, et al. Infectious diseases in the first year of life, perinatal characteristics and childhood acute leukaemia. Br J Cancer. 2004;90(1):139-45. DOI:10.1038/sj.bjc.6601384
https://doi.org/10.1038/sj.bjc.6601384... ^{, 61}61 . Reynolds P, Von Behren J, Elkin EP. Birth characteristics and leukemia in young children. Am J Epidemiol . 2002;155(7):603-13. DOI:10.1093/aje/155.7.603
https://doi.org/10.1093/aje/155.7.603... ^{, 73}73 . Shu XO, 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(1):15-25. DOI:10.1023/A:1013986809917
https://doi.org/10.1023/A:1013986809917... Shu et al ⁷³73 . Shu XO, 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(1):15-25. DOI:10.1023/A:1013986809917
https://doi.org/10.1023/A:1013986809917... in the United States (1,842 cases of ALL, 1,986 controls) detected positive association (OR 2.0, 95%CI 1.3;3.0; p trend < 0.01). Abdul Rahman et al ¹1 . Abdul Rahman HI, Shah SA, Alias H, Ibrahim HM. A case-control study on the association between environmental factors and the occurrence of acute leukemia among children in Klang Valley, Malaysia. Asian Pac J Cancer Prev. 2008;9(4):649-652. identified reduced risk of acute leukemia related to lower birth order.

However, 11 studies showed no statistically significant association. ¹⁵15 . Gilham C, Peto J, Simpson J, Roman E, Eden TO, Greaves MF, et al. Day care in infancy and risk of childhood acute lymphoblastic leukaemia: findings from UK case-control study. BMJ. 2005;330(7503):1294. DOI:10.1136/bmj.38428.521042.8F
https://doi.org/10.1136/bmj.38428.521042... ^{, 26}26 . Kamper-Jørgensen M, Woodward A, Wohlfahrt J, Benn CS, Simonsen J, Hjalgrim H, et al. Childcare in the first 2 years of life reduces the risk of childhood acute lymphoblastic leukemia. Leukemia . 2008;22(1):189-93. DOI:10.1038/sj.leu.2404884
https://doi.org/10.1038/sj.leu.2404884... ^{, 44}44 . McKinney PA, Juszczak E, Findlay E, Smith K, Thomson CS. Pre- and perinatal risk factors for childhood leukaemia and other malignancies: a Scottish case control study. Br J Cancer. 1999;80(11):1844-51. DOI:10.1038/sj.bjc.6690609
https://doi.org/10.1038/sj.bjc.6690609... ^{, 46}46 . Murray L, McCarron P, Bailie K, Middleton R, Davey Smith G, Dempsey S, et al. Association of early life factors and acute lymphoblastic leukaemia in childhood: historical cohort study. Br J Cancer . 2002;86(3):356-61. DOI: 10.1038/sj.bjc.6600012
https://doi.org/10.1038/sj.bjc.6600012... ^{, 48}48 . Neglia JP, Linet MS, Shu XO, Severson RK, Potter JD, Mertens AC, et al. Patterns of infection and day care utilization and risk of childhood acute lymphoblastic leukaemia. Br J Cancer. 2000;82(1);234-40. DOI:10.1054/bjoc.1999.0905
https://doi.org/10.1054/bjoc.1999.0905... ^{, 50}50 . Okcu MF, Goodman KJ, Carozza SE, Weiss NS, Burau KD, Bleyer WA, et al. Birth weight, ethnicity, and occurrence of cancer in children: a population-based, incident case-control study in the state of Texas, USA. Cancer Causes Control. 2002;13(7):595-602. DOI:10.1023/A:1019555912243
https://doi.org/10.1023/A:1019555912243... ^{, 52}52 . Perrillat F, Clavel J, Auclerc MF, Baruchel A, Leverger G, Nelken B, et al. Day-care, early common infections and childhood acute leukaemia: a multicentre French case-control study. Br J Cancer . 2002;86(7):1064-9. DOI:10.1038/sj.bjc.6600091 ^{, 55}55 . Petridou E, Trichopoulos D, Kalapothaki V, Pourtsidis A, Kogevinas M, Kalmanti M, et al. The risk profile of childhood leukaemia in Greece: a nationwide case-control study. Br J Cancer. 1997;76(9):1241-7. ^{, 63}63 . Roman E, Watson A, Bull D, Baker K. Leukaemia risk and social contact in children aged 0-4 years in southern England. J Epidemiol Community Health. 1994;48(6):601-2. ^{, 70}70 . Schüz J, Kaletsch U, Meinert R, Kaatsch P, Michaelis J. Association of childhood leukaemia with factors related to the immune system. Br J Cancer . 1999;80(3-4):585-90. DOI:10.1038/sj.bjc.6690395
https://doi.org/10.1038/sj.bjc.6690395... ^{, 85}85 . Westergaard T, Andersen PK, Pedersen JB, Olsen JH, Frisch M, Sørensen HT, 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. DOI:10.1093/jnci/89.13.939 Westergaard et al, ⁸⁵85 . Westergaard T, Andersen PK, Pedersen JB, Olsen JH, Frisch M, Sørensen HT, 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. DOI:10.1093/jnci/89.13.939 in a cohort study in Denmark, found a reduced risk of ALL related to higher birth order, but the result was not precise (relative risk [RR] 0.72, 95%CI 0.46;1.13).

Assessment of child immune status

Breastfeeding

Table 5 lists the studies that investigated the association between leukemia and breastfeeding. A protective effect in children with more breastfeeding time was detected in five of those 17 studies. ¹³13 . Dockerty JD, Skegg DC, Elwood JM, Herbison GP, Becroft DM, Lewis ME. Infections, vaccinations, and the risk of childhood leukaemia. Br J Cancer. 1999;80(9):1483-9. DOI:10.1038/sj.bjc.6690548
https://doi.org/10.1038/sj.bjc.6690548... ^{, 24}24 . Infante-Rivard C, Fortier I, Olson E. Markers of infection, breast-feeding and childhood acute lymphoblastic leukaemia. Br J Cancer. 2000;83(11):1559-64. DOI:10.1054/bjoc.2000.1495
https://doi.org/10.1054/bjoc.2000.1495... ^{, 53}53 . Perrillat F, Clavel J, Jaussent I, Baruchel A, Leverger G, Nelken B, et al. Breast-feeding, fetal loss and childhood acute leukaemia. Eur J Pediatr. 2002;161(4):235-7. ^{, 67}67 . Rudant J, Orsi L, Menegaux F, Petit A, Baruchel A, Bertrand Y, et al. Childhood acute leukemia, early common infections, and allergy: The ESCALE Study. Am J Epidemiol. 2010;172(9):1015-27. DOI:10.1093/aje/kwq233
https://doi.org/10.1093/aje/kwq233... ^{, 72}72 . Shu XO, Linet MS, Steinbuch M, Wen WQ, Buckley JD, Neglia JP, et al. Breast-feeding and risk of childhood acute leukemia. J Natl Cancer Inst. 1999;91(20):1765-72. DOI:10.1093/jnci/91.20.1765
https://doi.org/10.1093/jnci/91.20.1765... Shu et al ⁷²72 . Shu XO, Linet MS, Steinbuch M, Wen WQ, Buckley JD, Neglia JP, et al. Breast-feeding and risk of childhood acute leukemia. J Natl Cancer Inst. 1999;91(20):1765-72. DOI:10.1093/jnci/91.20.1765
https://doi.org/10.1093/jnci/91.20.1765... identified a reducing ALL risk with increased breastfeeding time (p trend 0.003). Children who were breastfed for more than six months had a lower risk of ALL (OR 0.72, 95%CI 0.60;0.87) than those who were never breastfed. Two studies found a higher ALL risk in children breastfed for less than six months. ⁶6 . Bener A, Denic S, Galadari S. Longer breast-feeding and protection against childhood leukaemia and lymphomas. Eur J Cancer. 2001;37(2):234-8. DOI:10.1016/S0959-8049(00)00339-7
https://doi.org/10.1016/S0959-8049(00)00... ^{, 7}7 . Bener A, Hoffmann GF, Afify Z, Rasul K, Tewfik I. Does prolonged breastfeeding reduce the risk for childhood leukemia and lymphomas? Minerva Pediatr. 2008;60(2):155-61.

Ten studies found no association between breastfeeding and CL. ¹⁰10 . Chan LC, Lam TH, Li CK, Lau YL, Li CK, Yuen HL, et al. Is the timing of exposure to infection a major determinant of acute lymphoblastic leukaemia in Hong Kong? Paediatr Perinat Epidemiol. 2002;16(2):154-65. DOI:10.1046/j.1365-3016.2002.00406.x
https://doi.org/10.1046/j.1365-3016.2002... ^{, 25}25 . Jourdan-Da Silva N, Perel Y, Méchinaud F, Plouvier E, Gandemer V, Lutz P, et al. Infectious diseases in the first year of life, perinatal characteristics and childhood acute leukaemia. Br J Cancer. 2004;90(1):139-45. DOI:10.1038/sj.bjc.6601384
https://doi.org/10.1038/sj.bjc.6601384... ^{, 32}32 . Kwan ML, Buffler PA, Wiemels JL, Metayer C, Selvin S, Ducore JM, et al. Breastfeeding patterns and risk of childhood acute lymphoblastic leukaemia. Br J Cancer . 2005;93(3):379-84. DOI:10.1038/sj.bjc.6602706
https://doi.org/10.1038/sj.bjc.6602706... ^{, 34}34 . Lancashire RJ, Sorahan T; OSCC. Breastfeeding and childhood cancer risks: OSCC data. Br J Cancer . 2003;88(7):1035-7. DOI:10.1038/sj.bjc.6600881
https://doi.org/10.1038/sj.bjc.6600881... ^{, 40}40 . MacArthur AC, McBride ML, Spinelli JJ, Tamaro S, Gallagher RP, Theriault GP. Risk of childhood leukemia associated with vaccination, infection, and medication use in childhood: the Cross-Canada Childhood Leukemia Study. Am J Epidemiol. 2008;167(5):598-606. DOI:10.1093/aje/kwm339 ^{, 46}46 . Murray L, McCarron P, Bailie K, Middleton R, Davey Smith G, Dempsey S, et al. Association of early life factors and acute lymphoblastic leukaemia in childhood: historical cohort study. Br J Cancer . 2002;86(3):356-61. DOI: 10.1038/sj.bjc.6600012
https://doi.org/10.1038/sj.bjc.6600012... ^{, 55}55 . Petridou E, Trichopoulos D, Kalapothaki V, Pourtsidis A, Kogevinas M, Kalmanti M, et al. The risk profile of childhood leukaemia in Greece: a nationwide case-control study. Br J Cancer. 1997;76(9):1241-7. ^{, 70}70 . Schüz J, Kaletsch U, Meinert R, Kaatsch P, Michaelis J. Association of childhood leukaemia with factors related to the immune system. Br J Cancer . 1999;80(3-4):585-90. DOI:10.1038/sj.bjc.6690395
https://doi.org/10.1038/sj.bjc.6690395... ^{, 79}79 . UK Childhood Cancer Study Investigators. Breastfeeding and childhood cancer. Br J Cancer. 2001;85(11):1685-94. DOI:10.1054/bjoc.2001.2110
https://doi.org/10.1054/bjoc.2001.2110... ^{, 84}84 . Waly MI, Ali A, Al-Saadoon M, Al-Mukhaini YK, Wali YA. Breastfeeding is not associated with risk of developing childhood leukemia in the Sultanate of Oman. Asian Pac J Cancer Prev . 2011;12(8):2087-91. In a large study (1,342 CL cases) conducted in the United Kingdom, no association was seen with breastfeeding duration (p trend 0.90). ³⁴34 . Lancashire RJ, Sorahan T; OSCC. Breastfeeding and childhood cancer risks: OSCC data. Br J Cancer . 2003;88(7):1035-7. DOI:10.1038/sj.bjc.6600881
https://doi.org/10.1038/sj.bjc.6600881...

Vaccination

Eleven studies explored associations between vaccination and leukemia (data not shown). ³3 . Auvinen A, Hakulinen T, Groves F. Haemophilus influenzae type B vaccination and risk of childhood leukaemia in a vaccine trial in Finland. Br J Cancer. 2000;83(7):956-8. DOI:10.1054/bjoc.2000.1382
https://doi.org/10.1054/bjoc.2000.1382... ^{, 8}8 . Buckley JD, Buckley CM, Ruccione K, Sather HN, Waskerwitz MJ, Woods WG, et al. Epidemiological characteristics of childhood acute lymphocytic leukemia: analysis by immunophenotype. The Childrens Cancer Group. Leukemia . 1994;8(5):856-64. ^{, 13}13 . Dockerty JD, Skegg DC, Elwood JM, Herbison GP, Becroft DM, Lewis ME. Infections, vaccinations, and the risk of childhood leukaemia. Br J Cancer. 1999;80(9):1483-9. DOI:10.1038/sj.bjc.6690548
https://doi.org/10.1038/sj.bjc.6690548... ^{, 20}20 . Groves FD, Gridley G, Wacholder S, Shu XO, Robison LL, Neglia JP, et al. Infant vaccinations and risk of childhood acute lymphoblastic leukaemia in the USA. Br J Cancer . 1999;81(1):175-8. DOI: 10.1038/sj.bjc.6690668
https://doi.org/10.1038/sj.bjc.6690668... ^{, 39}39 . Ma X, Does MB, Metayer C, Russo C, Wong A, Buffler PA. Vaccination history and risk of childhood leukaemia. Int J Epidemiol. 2005;34(5):1100-9. DOI:10.1093/ije/dyi113
https://doi.org/10.1093/ije/dyi113... ^{, 40}40 . MacArthur AC, McBride ML, Spinelli JJ, Tamaro S, Gallagher RP, Theriault GP. Risk of childhood leukemia associated with vaccination, infection, and medication use in childhood: the Cross-Canada Childhood Leukemia Study. Am J Epidemiol. 2008;167(5):598-606. DOI:10.1093/aje/kwm339 ^{, 42}42 . Mallol-Mesnard F, Menegaux A, Auvrignon A, Auclerc MF, Bertrand Y, Nelken B, et al. Vaccination and the risk of childhood acute leukaemia: the ESCALE study (SFCE). Int J Epidemiol. 2007;36(1):110-6. DOI:10.1093/ije/dyl270
https://doi.org/10.1093/ije/dyl270... ^{, 43}43 . McKinney PA, Cartwright RA, Saiu JM, Mann JR, Stiller CA, Draper GJ, et al. The Inter-Regional Epidemiological Study of Childhood Cancer (IRESCC): a case control study of aetiological factors in leukaemia and lymphoma. Arch Dis Child . 1987;62(3):279-87. ^{, 49}49 . Nishi M, Miyake H. A case-control study of non-T cell acute lymphoblastic leukaemia of children in Hokkaido, Japan. J Epidemiol Community Health. 1989;43(4):352-5. ^{, 55}55 . Petridou E, Trichopoulos D, Kalapothaki V, Pourtsidis A, Kogevinas M, Kalmanti M, et al. The risk profile of childhood leukaemia in Greece: a nationwide case-control study. Br J Cancer. 1997;76(9):1241-7. ^{, 70}70 . Schüz J, Kaletsch U, Meinert R, Kaatsch P, Michaelis J. Association of childhood leukaemia with factors related to the immune system. Br J Cancer . 1999;80(3-4):585-90. DOI:10.1038/sj.bjc.6690395
https://doi.org/10.1038/sj.bjc.6690395... Five of these identified a reduced risk in children who were vaccinated (any vaccine) ¹³13 . Dockerty JD, Skegg DC, Elwood JM, Herbison GP, Becroft DM, Lewis ME. Infections, vaccinations, and the risk of childhood leukaemia. Br J Cancer. 1999;80(9):1483-9. DOI:10.1038/sj.bjc.6690548
https://doi.org/10.1038/sj.bjc.6690548... ^{, 43}43 . McKinney PA, Cartwright RA, Saiu JM, Mann JR, Stiller CA, Draper GJ, et al. The Inter-Regional Epidemiological Study of Childhood Cancer (IRESCC): a case control study of aetiological factors in leukaemia and lymphoma. Arch Dis Child . 1987;62(3):279-87. or who had been immunized with BCG ⁴⁹49 . Nishi M, Miyake H. A case-control study of non-T cell acute lymphoblastic leukaemia of children in Hokkaido, Japan. J Epidemiol Community Health. 1989;43(4):352-5. and Hib ( Haemophilus influenzae type B) ²⁰20 . Groves FD, Gridley G, Wacholder S, Shu XO, Robison LL, Neglia JP, et al. Infant vaccinations and risk of childhood acute lymphoblastic leukaemia in the USA. Br J Cancer . 1999;81(1):175-8. DOI: 10.1038/sj.bjc.6690668
https://doi.org/10.1038/sj.bjc.6690668... ^{, 39}39 . Ma X, Does MB, Metayer C, Russo C, Wong A, Buffler PA. Vaccination history and risk of childhood leukaemia. Int J Epidemiol. 2005;34(5):1100-9. DOI:10.1093/ije/dyi113
https://doi.org/10.1093/ije/dyi113... vaccine. Ma et al ³⁹39 . Ma X, Does MB, Metayer C, Russo C, Wong A, Buffler PA. Vaccination history and risk of childhood leukaemia. Int J Epidemiol. 2005;34(5):1100-9. DOI:10.1093/ije/dyi113
https://doi.org/10.1093/ije/dyi113... detected a lower risk of ALL (OR 0.81, 95%CI 0.66;0.98) and CL (OR 0.81, 95%CI 0.68;0.96) associated with the Hib vaccine. Furthermore, Schuz et al ⁷⁰70 . Schüz J, Kaletsch U, Meinert R, Kaatsch P, Michaelis J. Association of childhood leukaemia with factors related to the immune system. Br J Cancer . 1999;80(3-4):585-90. DOI:10.1038/sj.bjc.6690395
https://doi.org/10.1038/sj.bjc.6690395... observed an increased c-ALL risk in children who had received less than four vaccines compared to those who had received six or more.

On the other hand, Buckley et al ⁸8 . Buckley JD, Buckley CM, Ruccione K, Sather HN, Waskerwitz MJ, Woods WG, et al. Epidemiological characteristics of childhood acute lymphocytic leukemia: analysis by immunophenotype. The Childrens Cancer Group. Leukemia . 1994;8(5):856-64. found an increased risk of c-ALL (OR 1.7, p < 0.01) in children who received the MMR (measles, mumps and rubella) vaccine. Four studies found no statistically significant association between these variables. ³3 . Auvinen A, Hakulinen T, Groves F. Haemophilus influenzae type B vaccination and risk of childhood leukaemia in a vaccine trial in Finland. Br J Cancer. 2000;83(7):956-8. DOI:10.1054/bjoc.2000.1382
https://doi.org/10.1054/bjoc.2000.1382... ^{, 40}40 . MacArthur AC, McBride ML, Spinelli JJ, Tamaro S, Gallagher RP, Theriault GP. Risk of childhood leukemia associated with vaccination, infection, and medication use in childhood: the Cross-Canada Childhood Leukemia Study. Am J Epidemiol. 2008;167(5):598-606. DOI:10.1093/aje/kwm339 ^{, 42}42 . Mallol-Mesnard F, Menegaux A, Auvrignon A, Auclerc MF, Bertrand Y, Nelken B, et al. Vaccination and the risk of childhood acute leukaemia: the ESCALE study (SFCE). Int J Epidemiol. 2007;36(1):110-6. DOI:10.1093/ije/dyl270
https://doi.org/10.1093/ije/dyl270... ^{, 55}55 . Petridou E, Trichopoulos D, Kalapothaki V, Pourtsidis A, Kogevinas M, Kalmanti M, et al. The risk profile of childhood leukaemia in Greece: a nationwide case-control study. Br J Cancer. 1997;76(9):1241-7.

DISCUSSION

Greaves ¹⁷17 . Greaves M. Childhood leukaemia. BMJ. 2002;324(7332):283-7. DOI:10.1136/bmj.324.7332.283
https://doi.org/10.1136/bmj.324.7332.283... ^{, 19}19 . Greaves MF. Speculations on the cause of childhood acute lymphoblastic leukemia. Leukemia . 1988;2(2):120-5. argues that infections play an important role in the natural history of ALL, and especially c-ALL, considering the two hit model involving two independent genetic mutations. The first event concerns the initial genetic damage which occurs in the uterus during B cell precursor expansion producing a pre-leukemic clone. The second concerns postnatal genetic mutation that can lead to disease development.

According to this review, more than 50.0% of studies investigating maternal exposure to infection observed increasing risk of CL. These results support the hypothesis proposed by Smith. ⁷⁶76 . Smith M. Considerations on a possible viral etiology for B-precursor acute lymphoblastic leukemia of childhood. J Immunother. 1997;20(2):89-100. It is possible that exposure to in utero infection is one of the factors involved in genetic damage in the first “hit” referred to by Greaves. ¹⁷17 . Greaves M. Childhood leukaemia. BMJ. 2002;324(7332):283-7. DOI:10.1136/bmj.324.7332.283
https://doi.org/10.1136/bmj.324.7332.283...

Results of childhood exposure to infections support the hypothesis that infection early in life (especially the first year of life) is associated with reduced risk of ALL. Even so, data are conflicting. Some factors may contribute to the apparent inconsistency between studies. ^ddEdgar K, Morgan A. Does infections cause or prevent childhood leukemia? A review of the scientific evidence. London: Children with Leukemia; 2008 [cited 2013 Oct 31]. Available from: http://www.childrenwithcancer.org.uk/infection-and-leukaemia First, infections may only be involved in the etiology of a specific subtype of ALL (most probably c-ALL). For this reason, recent studies have analyzed all cases of ALL and specifically c-ALL. Another difficulty concerns when the infections occurred. Studies evaluating infection occurrence at any time prior to diagnosis showed more inconsistent results. Future studies should evaluate the infection occurrence in specific periods such as the first year and one year before diagnosis. In this way, data would help assess whether a lack of immune system modulation in early childhood, associated with a delay in infection occurrence, increases the risk of ALL. In relation to the display window, infections detected near the leukemia diagnosis may be due to an increased susceptibility to infections resulting from the effects of leukemia itself. Some protocols exclude data on infections occurring in the three months before diagnosis date to avoid bias.

The instrument used to directly assess exposure to infection is another limitation we found. Most studies used data from mothers via questionnaires for the recall of infection occurrence. This method is subject to misclassification bias, with differential recall between cases and controls. Only three of the studies in this review obtained clinical records to evaluate children’s exposure to infection. ⁹9 . Cardwell CR, McKinney PA, Patterson CC, Murray LJ. Infections in early life and childhood leukaemia risk: a UK case-control study of general practitioner records. Br J Cancer . 2008;99(9):1529-33. DOI:10.1038/sj.bjc.6604696
https://doi.org/10.1038/sj.bjc.6604696... ^{, 64}64 . Roman E, Simpson J, Ansell P, Kinsey S, Mitchell CD, Mckinney PA, et al. Childhood acute lymphoblastic leukemia and infections in the first year of life: a report from the United Kingdom Childhood Cancer Study. Am J Epidemiol. 2007;165(5):496-504. DOI:10.1093/aje/kwk039
https://doi.org/10.1093/aje/kwk039... ^{, 75}75 . Simpson J, Smith A, Ansell P, Roman E. Childhood leukaemia and infectious exposure: a report from the United Kingdom Childhood Cancer Study (UKCCS). Eur J Cance r. 2007;43(16):2396-403. DOI:10.1016/j.ejca.2007.07.027
https://doi.org/10.1016/j.ejca.2007.07.0... Although this latter method is not affected by recall bias, it does present other difficulties. The lack of a clinical records system with extensive population coverage and good quality data hinders the use of this instrument. Furthermore, the number of infections can be underestimated because the occurrence of common infections does not always mean that the mother seeks health service help. Simpson et al ⁷⁵75 . Simpson J, Smith A, Ansell P, Roman E. Childhood leukaemia and infectious exposure: a report from the United Kingdom Childhood Cancer Study (UKCCS). Eur J Cance r. 2007;43(16):2396-403. DOI:10.1016/j.ejca.2007.07.027
https://doi.org/10.1016/j.ejca.2007.07.0... compared results from clinical diagnoses of infection with those based on maternal self-report. They observed that mothers of cases and controls under-reported the frequency of infections in the first year of life. However, the degree of under-reporting appeared greater for mothers of cases than of controls.

Chang et al ¹¹11 . Chang JS, Tsai CR, Tsai YW, Wiemels JL. Medically diagnosed infections and risk of childhood leukaemia: a population-based case-control study. Int J Epidemiol. 2012:41(4):1050-9. DOI:10.1093/ije/dys113
https://doi.org/10.1093/ije/dys113... used records of medically diagnosed infections and they found higher risk of ALL in children who had had acute respiratory infections and any infections before 1 year of age. The authors suggest that children who develop leukemia may have dysregulated immune function since early childhood strongly reacting to infections.

However, they do not refute the “delayed infection hypothesis” supported by several studies using proxy measures and state that their results are not relevant to asymptomatic infections or infections not requiring medical attention.

The difficulty in measuring the occurrence of infectious diseases in childhood leads epidemiologists to use proxy measures of exposure to infection: indirect measures that indicate levels of physical and social contact. These variables are easier to obtain, are less prone to recall bias, and probably include children with asymptomatic infections.

Daycare attendance has been widely used as an indicator of a child’s level of social contact and therefore opportunity of contact with infectious agents. Interaction between children, parents, and staff, and the sharing of toys are factors that may contribute to increased transmission of infectious agents. Exposure to respiratory and gastrointestinal tracts infections are known to be more frequent in this type of environment. ²³23 . Holmes SJ, Morrow AL, Pickering LK. Child-care practices: effects of social change on the epidemiology of infectious diseases and antibiotic resistance. Epidemiol Rev . 1996;18(1):10-28. ^{, 51}51 . Osterholm MT. Infectious disease in child day care: an overview. Pediatrics . 1994;94(6 Pt 2):987-90. In general, the studies in our review show evidence supporting a reduced risk of ALL associated with daycare attendance, providing support to the hypothesis proposed by Greaves. In a meta-analysis, Urayama et al ⁸⁰80 . 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(3):718-32. DOI:10.1093/ije/dyp378
https://doi.org/10.1093/ije/dyp378... found a reduced risk of ALL in two subgroups of children – those who attended day-care before two years of age and those where age at day-care attendance was not specified (any age before diagnosis).

Birth order has also been used as a proxy variable for infection since children with older siblings are more likely to be exposed to infection due to contact with their siblings. ^ddEdgar K, Morgan A. Does infections cause or prevent childhood leukemia? A review of the scientific evidence. London: Children with Leukemia; 2008 [cited 2013 Oct 31]. Available from: http://www.childrenwithcancer.org.uk/infection-and-leukaemia Most studies showed no evidence of an association between these variables. Parity is probably influenced by selection bias. Couples with higher socioeconomic status (SES) tend to have fewer children so there may be some confounding effect if SES is assessed differently between groups (cases and controls). Moreover, Edgar & Morgan ^ddEdgar K, Morgan A. Does infections cause or prevent childhood leukemia? A review of the scientific evidence. London: Children with Leukemia; 2008 [cited 2013 Oct 31]. Available from: http://www.childrenwithcancer.org.uk/infection-and-leukaemia report that studies generally do not differentiate between the firstborn and the only child. Then, the association of ALL with a history of abortion and reproductive failures may be a confounding factor.

The association between SES and CL has been discussed in the literature. SES does influence the level of exposure and vulnerability of individuals to certain diseases. However, some studies have shown that increased risk of CL seems to be associated with increased SES. ³⁰30 . Kroll ME, Stiller CA, Murphy MF, Carpenter LM. Childhood leukaemia and socioeconomic status in England and Wales 1976-2005: evidence of higher incidence in relatively affluent communities persists over time. Br J Cancer. 2011;105(11):1783-7. DOI:10.1038/bjc.2011.415
https://doi.org/10.1038/bjc.2011.415... ^{, 62}62 . Ribeiro KB, Buffler PA, Metayer C. Socioeconomic status and childhood acute lymphocytic leukemia incidence in São Paulo, Brazil. Int J Cancer. 2008;123(8):1907-12. DOI:10.1002/ijc.23738
https://doi.org/10.1002/ijc.23738... In Sao Paulo, Southwestern Brazil, Ribeiro et al ⁶²62 . Ribeiro KB, Buffler PA, Metayer C. Socioeconomic status and childhood acute lymphocytic leukemia incidence in São Paulo, Brazil. Int J Cancer. 2008;123(8):1907-12. DOI:10.1002/ijc.23738
https://doi.org/10.1002/ijc.23738... found a lower risk of leukemia in children living in areas with lower SES and in areas where a high percentage of families had more than seven members. However, in the review conducted by Poole et al, ⁵⁸58 . Poole C, Greenland S, Luetters C, Kelsey JL, Mezei G. Socioeconomic status and childhood leukaemia: a review. Int J Epidemiol. 2006;35(2):370-84. DOI:10.1093/ije/dyi248
https://doi.org/10.1093/ije/dyi248... the association direction seems to vary according to study design, place and time; they also highlighted comparison difficulties between studies because of differences in assessing SES. Measures such as family income and parental education presented an inverse association. Evaluation considering professional class revealed increased CL risk associated with higher SES in both ecological and individual approach studies.

Breast milk protects the child against infections and boosts the immune system contributing to its modulation. ²²22 . Hanson LA. Breastfeeding provides passive and likely long-lasting active immunity. Ann Allergy Asthma Immunol. 1998;81(6):523-37. DOI:10.1016/S1081-1206(10)62704-4 It is therefore reasonable to assume that breastfeeding exerts a similar effect to early infection on a child’s immunity inducing a protective effect against leukemia. ^ddEdgar K, Morgan A. Does infections cause or prevent childhood leukemia? A review of the scientific evidence. London: Children with Leukemia; 2008 [cited 2013 Oct 31]. Available from: http://www.childrenwithcancer.org.uk/infection-and-leukaemia Most of the studies in our review did not identify a statistically significant association between ALL and breastfeeding duration. However, in a meta-analysis including 14 studies, Kwan et al ³¹31 . Kwan ML, Buffler PA, Abrams B, Kiley VA. Breastfeeding and the risk of childhood leukemia: a meta-analysis. Public Health Rep. 2004;119(6):521-35. DOI:10.1016/j.phr.2004.09.002
https://doi.org/10.1016/j.phr.2004.09.00... identified a protective effect from breastfeeding on ALL.

While not an actual infection, vaccine acts on the immune system as an infection does. ^ddEdgar K, Morgan A. Does infections cause or prevent childhood leukemia? A review of the scientific evidence. London: Children with Leukemia; 2008 [cited 2013 Oct 31]. Available from: http://www.childrenwithcancer.org.uk/infection-and-leukaemia Results from the reviewed studies have provided some evidence of a protective effect from vaccination on the risk of ALL, especially regarding the Hib vaccine. One major difficulty with this variable is that high vaccination coverage makes it difficult to gauge the effect on CL. ^ddEdgar K, Morgan A. Does infections cause or prevent childhood leukemia? A review of the scientific evidence. London: Children with Leukemia; 2008 [cited 2013 Oct 31]. Available from: http://www.childrenwithcancer.org.uk/infection-and-leukaemia

Although no specific etiological agent has been identified, results of the studies reviewed provide evidence that the lack of exposure to infections during early childhood, and consequent failure in modulation of the immune system, may increase the risk of developing leukemia by the occurrence of an abnormal immune response after exposure to a later infection, as reported by Greaves. ¹⁷17 . Greaves M. Childhood leukaemia. BMJ. 2002;324(7332):283-7. DOI:10.1136/bmj.324.7332.283
https://doi.org/10.1136/bmj.324.7332.283... ^{, 18}18 . Greaves M. Infection, immune responses and the aetiology of childhood leukaemia. Nat Rev Cancer . 2006;6(3):193-203. DOI:10.1038/nrc1816
https://doi.org/10.1038/nrc1816... However, the mechanisms involved in this process are still not completely clear.

Schmiegelow et al ⁶⁹69 . Schmiegelow K, Vestergaard T, Nielsen SM, Hjalgrim H. Etiology of common childhood acute lymphoblastic leukemia: the adrenal hypothesis. Leukemia . 2008;22(12):2137-41. DOI:10.1038/leu.2008.212
https://doi.org/10.1038/leu.2008.212... proposed in 2008 an explanation for the observed association between infections in early childhood and reduced risk of ALL: the adrenal hypothesis. This postulates that children with lower SES, thus subject to getting infections more often, have a lower risk of ALL, because changes in the hypothalamic-pituitary-adrenal axis induced by infection lead to increased cortisol plasma levels similar to those observed during antileukemic therapy, leading to pre-leukemic cell apoptosis. Furthermore, the immune system can adapt to high infectious loads preventing a more reactive inflammatory response induced by Th1 cytokines in that cortisol favors the production of anti-inflammatory Th2 cytokines. Azevedo-Silva et al ⁴4 . Azevedo-Silva F, Camargo B, Pombo-de-Oliveira MS. Implications of infectious diseases and the adrenal hypothesis for the etiology of childhood acute lymphoblastic leukemia. Braz J Med Biol Res. 2010;43(3):226-9. DOI:10.1590/S0100-879X2010007500011
https://doi.org/10.1590/S0100-879X201000... show differences in ALL incidence rates across Brazilian regions. Salvador and Aracaju, cities in the Northeast, had the lowest rates, while Curitiba, Southeast, and Goiania, Midwest, had the highest. Brazilian regions show very distinct social and economic profiles. These authors suggest that the differences in incidence rates could be due to an early exposure to infectious agents in children living in areas with characteristics favoring the continued exposure to such agents. The lower ALL incidence rates in children from those cities (less developed) would then support the adrenal hypothesis.

Besides the lack of immune system modulation, WIEMELS ⁸⁶86 . Wiemels J. Perspectives on the causes of childhood leukemia. Chem Biol Interact. 2012;196(3):59-67. DOI:10.1016/j.cbi.2012.01.007.
https://doi.org/10.1016/j.cbi.2012.01.00... reports another phenomenon that would leads to an increased risk of CL: children with dysregulated immune function at birth are at higher risk for developing leukemia due to constitutively lower expression of IL-10, a cytokine that is critical in preventing an overactive inflammatory response to pathogenic infections. This factor would explain why in some studies ¹¹11 . Chang JS, Tsai CR, Tsai YW, Wiemels JL. Medically diagnosed infections and risk of childhood leukaemia: a population-based case-control study. Int J Epidemiol. 2012:41(4):1050-9. DOI:10.1093/ije/dys113
https://doi.org/10.1093/ije/dys113... children with ALL had significantly more clinically diagnosed infectious episodes in the first year of life compared to controls.

The purpose of this study was to review epidemiological studies related to two hypotheses which propose a role for infections in CL etiology. Considering the “two hit” model by Greaves, ¹⁷17 . Greaves M. Childhood leukaemia. BMJ. 2002;324(7332):283-7. DOI:10.1136/bmj.324.7332.283
https://doi.org/10.1136/bmj.324.7332.283... it is possible that the Smith hypothesis may play a role in the first hit and delayed infection in the second. Overall, this review provides evidence supporting the role of infections in the natural history of CL. This justifies further research even though no specific infectious agent has so far been associated with the disease. With regard to assessing exposure to infection or modulation of the immune system using a proxy, results were more consistent using daycare attendance than birth order, breastfeeding, or vaccination. Future studies should consider carefully evaluating exposure to infection at different stages of childhood. Accurate data on exposure period (in early childhood or near diagnosis), especially in relation to daycare attendance and the occurrence of infection episodes, are essential in eliminating potential bias and improving study accuracy. Furthermore, different subtypes of the disease require specific analysis because infectious agents can have distinct roles in the etiology of each subtype. Specific attention to these points, in addition to the contribution from genetic studies, is essential to help clarify the relationship between infections and CL etiology.

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