An examination of the sensitivity of reported trends in childhood leukemia incidence rates to geographic location and diagnostic coding (United States)

Background: There have been conflicting reports of increased incidence of childhood leukemia in the United States with some, but not other, registries reporting increasing rates over the past two decades. Because of the reported discrepancy in childhood leukemia incidence rates an analysis of the SEER database was undertaken. Methods: The latest SEER data (1973–1995) were analyzed for trends in childhood (age 0–14) leukemia incidence rates by histologic group (all leukemia combined, acute lymphocytic leukemia (ALL), acute mylogenous leukemia (AML), and other acute leukemia) for each SEER reporting region. Results: A significant increase in ALL during 1973–1995 was observed in the combined SEER data, but the increase was a function of whether the first 3 years, data from the SEER Detroit reporting region are included. For the years 1973–1975 the Detroit region reported to much lower rates for ALL and much higher rates for other acute leukemias relative to the other SEER regions, resulting in an exaggerated temporal increase in ALL. Conclusion: Excluding both the temporal variability, and coding differences for Detroit in the 1973–1975 time frame, there has been no significant increase in childhood leukemia of any histologic group or age category in the United States from the 1970s to 1990s.     

Genomics of racial and ethnic disparities in childhood acute lymphoblastic leukemia

Although the cure rates of childhood acute lymphoblastic leukemia (ALL) have improved dramatically in the past 40 years, not all children have benefited equally from this impressive progress. Racial and ethnic disparities in the incidence and treatment outcome of childhood ALL persist, with Hispanic children having an elevated risk of developing ALL and one of the lowest survival rates after ALL therapy. A critical barrier to progress is the lack of an understanding of the causes of ALL disparities, particularly racial and ethnic differences in ALL biology. In this review, the authors summarize the current knowledge on population variation in childhood ALL incidence and treatment outcome, discuss the contributing genetic and nongenetic variables, and highlight possible therapeutic interventions to mitigate disparities in ALL. Cancer 2014;120:955–962 . © 2013 American Cancer Society.     

Birth characteristics, maternal reproductive history, hormone use during pregnancy, and risk of childhood acute lymphocytic leukemia by immunophenotype (United States)

Objective: To investigate the associations of birth characteristics and maternal reproductive factors with risk of childhood acute lymphoblastic leukemia (ALL) by immunophenotypic subtypes. Methods: Data collected from a case–control study including 1842 ALL cases (age < 15 years) and 1986 individually matched controls were analyzed. Exposure information was obtained through telephone interviews of parents. Results: Factors associated with risk of ALL from all subgroups combined included high birth weight (OR = 1.4, 95% CI = 1.1–1.8), high birth order (OR = 2.0, 95% CI = 1.3–3.0 for fourth-born child compared to first-born child), young maternal age (<20 compared to 25–29, OR = 1.4, 95% CI = 1.1–1.9), advanced paternal age ( > 39 compared to 25–29, OR = 1.4, 95% CI = 1.0–1.9), induced abortion prior to the index pregnancy (OR = 1.2, 95% CI = 1.0–1.4), and oral contraceptive use during the index pregnancy (OR = 1.5, 95% CI = 1.0–2.2) with children under the age of 2 (OR = 5.1, 95% CI = 1.0–24.7) being the predominantly affected group. Risk of early pre-B-cell ALL increased with advanced paternal age (OR = 1.7, 95% CI = 1.1–2.7) and high birth order (OR = 2.0, 95% CI = 1.1–3.6), while risk of pre-B-cell ALL increased with both younger (OR = 3.4, 95% CI = 1.4–8.4) and advanced maternal age (OR = 2.6, 95% CI = 1.1–5.9). T-cell ALL was associated with high birth weight (OR = 2.4, 95% CI = 1.1–5.5) and history of induced abortion (OR = 2.4, 95% CI = 1.3–4.5). Conclusion: This study suggests that the association of ALL with birth characteristics and maternal reproductive factors varies with the immunophenotype of the ALL. Future studies are needed to better understand the effect of maternal hormone in the development of subtype of childhood ALL.     

Trends in childhood leukemia incidence over two decades from 1992 to 2013

Incidence rates of childhood leukemia in the United States have steadily increased over the last several decades, but only recently have disparities in the increase in incidence been recognized. In the current analysis, Surveillance, Epidemiology and End Results (SEER) data were used to evaluate recent trends in the incidence of childhood leukemia diagnosed at age 0–19 years from 1992 to 2013, overall and by age, race/ethnicity, gender and histologic subtype. Hispanic White children were more likely than non‐Hispanic White, non‐Hispanic Black or non‐Hispanic Asian children to be diagnosed with acute lymphocytic leukemia (ALL) from 2009 to 2013. From 1992 to 2013, a significant increase in ALL incidence was observed for Hispanic White children [annual percent change (APC)_Hispanic = 1.08, 95% CI: 0.59, 1.58]; no significant increase was observed for non‐Hispanic White, Black or Asian children. ALL incidence increased by about 3% per year from 1992 to 2013 for Hispanic White children diagnosed from 15 to 19 years (APC = 2.67; 95% CI: 0.88, 4.49) and by 2% for those 10–14 years (APC = 2.09; 95% CI: 0.57, 3.63), while no significant increases in incidence were observed in non‐Hispanic White, Black, or Asian children of the same age. Acute myeloid leukemia (AML) incidence increased among non‐Hispanic White children under 1 year at diagnosis, and among Hispanic White children diagnosed at age 1–4. The increase in incidence rates of childhood ALL appears to be driven by rising rates in older Hispanic children (10–14, and 15–19 years). Future studies are needed to evaluate reasons for the increase in ALL among older Hispanic children.     

Childhood leukemia following phototherapy for neonatal hyperbilirubinemia (Denmark)

To test the hypothesis that exposure to high intensity lightning (around 400 nanometers) in neonatal nurseries increases the incidence of childhood leukemia, over 55,120 newborn children treated with phototherapy for hyperbilirubinemia were identified from the Danish Hospital Discharge Register for 1977–89. Linkage of the roster with the national cancer registry through 1991 revealed 87 childhood cancers, whereas 85 were expected from the rates for the general population. The incidence of leukemia in 34 children was not unusual (standardized incidence ratio [SIR]=1.2, 95 percent confidence interval [CI]=0.8–1.7). Subgroup analyses revealed no remarkable patterns for any category of leukemia subtype, gender, or age at diagnosis. We conclude that whole-body exposure to phototherapy (420–470 nm) shortly after birth is not a significant risk factor for childhood leukemia.     

Use of medication during pregnancy and risk of childhood leukemia (Canada)

ObjectiveTo examine risk of childhood acute lymphoblastic leukemia (ALL) associated with maternal use of medications during pregnancy; in particular medications known or suspected to be teratogenic. Methods: Seven hundred and eighty nine children (<15years old) diagnosed with ALL in the province of Québec between 1980 and 2000 were recruited for study. A similar number of population based controls matched to cases (1:1) by sex and age were chosen from family allowance or health insurance files. Information was gathered via telephone interview with the subjects parents. Data were analyzed using conditional logistic regression. Results: Risk of childhood ALL was significantly increased in the offspring of mothers who reported using any medication (adjusted odds ratio (OR_adj)=1.3, 95 CI=1.0–1.6) or any teratogenic medication (OR_adj=1.4, 95 CI=1.1–1.9) during pregnancy. Among specific medication categories, only central nervous system depressants were associated with a significantly increased risk, although elevated odd ratios were found for anti-epileptics, immunosuppressants, oral contraceptives, and illicit drugs. Risk associated with use of teratogenic medications was higher with increased dose and in children diagnosed before two years of age. Conclusion: A modest increase in risk of ALL was found among children of mothers who used medication during pregnancy.     

Evidence on the infectious etiology of childhood leukemia: the role of low herd immunity (Greece)

Objective: Acute lymphoblastic leukemia (ALL) among children may be a rare outcome of a delayed non-specific infection in situations of overall low herd immunity. We evaluated the hypothesis as to whether newly diagnosed ALL cases, compared to their controls, are characterized by lower herd immunity, as reflected in a more seronegative spectrum to several agents, with the exception of a strongly positive response to a single infectious agent, assumed to trigger ALL. Methods: The study included 94 incident cases of ALL, from all pediatric hematology–oncology units of Greece, and 94, matched for age and gender, controls hospitalized with minor non-infectious conditions. The past exposure to common infections was assessed using 10 serological markers. Results: There was little evidence for an association of ALL with the serology of any of the studied infectious agents among the very young children. In contrast, among children aged 5 years or older, leukemia was inversely associated with seropositivity to Epstein–Barr virus, human herpes virus-6, Mycoplasma pneumoniae and parvovirus B19. Conclusions: Among children aged 5 years or older the risk of leukemia may be higher when the low herd immunity for several agents is challenged by late infection from an agent that, as a rule, would attack children at a younger age.     

Birth weight,ethnicity, and occurrence of cancer in children: a population-based,incident case-control study in the State of Texas,USA

Objective: To investigate the relationship between birth weight and risk of early age childhood cancer and whether racial differences in birth weight distribution could explain differences in the incidence of cancer in white, Hispanic, and black children. Methods: We compared birth weights of 268 children younger than five years old and diagnosed with cancer in the State of Texas in 1995 to the birth weights of 2680 randomly selected, age-matched population-based controls. Birth weight, sex, race/ethnicity, maternal age, smoking status, parity, and gestational age information was ascertained from the birth certificates. Logistic regression analyses were performed to evaluate the association between high birth weight (> 4000 g) and occurrence of childhood cancer. Results: Increased odds ratios (OR) were found for total cancer cases (OR 1.4, 95% CI 0.9–2.1), leukemia cases (OR 1.7, 95% CI 0.9–3.0) and acute lymphoblastic leukemia (ALL) cases (OR 2.2, 95% CI 1.2–4.1). Increased ORs in the former two groups were shown to be due to ALL cases. Including the race/ethnicity variable in the regression model did not affect the ORs. Conclusion: Compared to newborns who weighed between 2500 and 4000 g at birth, children who weighed > 4000 g had an increased risk of developing childhood ALL during the first five years of life. Birth weight differences does not explain the sequence of childhood cancer incidence by race/ethnicity.     

Epidemiology of childhood leukemia in Hokkaido,Japan

The population-based epidemiological indices (crude incidence, survival rate, mortality, etc.) of childhood leukemia (0–14 years of age) from 1969 to 1993 in Hokkaido Prefecture, Japan, were calculated, using data obtained from the Registry of Childhood Malignancies in Hokkaido Prefecture. A total of 1,084 cases of leukemia were diagnosed in the 1969–93 period. The annual incidence of all types of leukemia from 1984 to 1993 was about 4 per 100,000 children aged 0–14 years, with the incidence of ANLL decreasing slightly and that of ALL increasing. The ratio of ALL/ANLL could similarly be seen to be increasing in all age groups. Out of a cohort of 100,000 live births, about 65 children developed leukemia by 14 years of age, and in this longitudinal observation the ratio of ALL/ANLL was increasing. The incidence of ALL and ANLL and the ratio of ALL/ANLL in Japanese children are approaching those of Caucasians. Approximately 80% of the ALL cases were of the LI type (FAB classification), and about 65% of these could be immunologically classified as “common” ALL. The 5-year survival rate of T- and B-cell ALL cases was 50% or less, while that of “common” ALL cases was about 80%. © 1996 Wiley-Liss, Inc.     

Integrated genetic and epigenetic analysis revealed heterogeneity of acute lymphoblastic leukemia in Down syndrome

Children with Down syndrome (DS) are at a 20‐fold increased risk for acute lymphoblastic leukemia (ALL). Compared to children with ALL and no DS (non‐DS‐ALL), those with DS and ALL (DS‐ALL) harbor uncommon genetic alterations, suggesting DS‐ALL could have distinct biological features. Recent studies have implicated several genes on chromosome 21 in DS‐ALL, but the precise mechanisms predisposing children with DS to ALL remain unknown. Our integrated genetic/epigenetic analysis revealed that DS‐ALL was highly heterogeneous with many subtypes. Although each subtype had genetic/epigenetic profiles similar to those found in non‐DS‐ALL, the subtype distribution differed significantly between groups. The Philadelphia chromosome‐like subtype, a high‐risk B‐cell lineage variant relatively rare among the entire pediatric ALL population, was the most common form in DS‐ALL. Hypermethylation of RUNX1 on chromosome 21 was also found in DS‐ALL, but not non‐DS‐ALL. RUNX1 is essential for differentiation of blood cells, especially B cells; thus, hypermethylation of the RUNX1 promoter in B‐cell precursors might be associated with increased incidence of B‐cell precursor ALL in DS patients.     

Allergic Disorders and the Risk of Childhood Acute Lymphoblastic Leukemia (United States)

Objectives: To test the hypothesis that childhood acute lymphoblastic leukemia (ALL) is associated with allergic disorders. Methods: We compared the histories of selected allergic disorders (asthma, hay fever, food or drug allergies, eczema, and hives) of 1842 cases of ALL with those of 1986 individually matched controls. The histories of the allergic disorders among siblings of cases and controls were also compared. Results: The combined history of any one or more of the five allergic disorders evaluated was associated with a significant reduced risk of ALL (adjusted OR = 0.7, 95% CI 0.6–0.8), as were hhistories of four specific allergic disorders (asthma, hay fever, food or drug allergies, and eczema). The combined history of any one or more of the five allergic disorders among any of the siblings of the study subjects also revealed a significantly inverse association (adjusted OR = 0.9, 95% CI 0.8–1.0). Conclusion: The results from this study, in agreement with most previous studies on adult cancer, suggest that allergic disorders may be associated with a reduced risk of childhood ALL.     

Association of cesarean section with risk of childhood leukemia: A meta-analysis from an observational study

Recent studies suggest that children born via cesarean section (CS) are predisposed to immune-mediated diseases later in life. The association between CS and childhood leukemia was investigated in this meta-analysis of observational studies. Two researchers independently searched PubMed, Web of Science, Embase, and Cochrane Library for literature on the association between CS and childhood leukemia before February 2022. And pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated to determine the link between CS and childhood leukemia. The preliminary search resulted in 1321 articles and 16 articles were finally included after screening. The primary outcome was the risk of leukemia in children born via CS versus those born vaginally. The results revealed that having a CS was associated with an increased risk of childhood leukemia compared to having vaginal section (VS) (OR = 1.07, 95% CI: 1.02–1.13, p = 0.01), especially for acute lymphoblastic leukemia (ALL) (OR = 1.09, 95% CI: 1.03–1.16, p = 0.004). Children delivered via elective CS had a higher risk of ALL (OR = 1.18, 95% CI: 1.07–1.31, p = 0.001), but emergency CS did not. It is worth noting that neither emergency CS nor elective CS were found to be associated with acute myeloid leukemia. Compared to VS, CS increased the risk of leukemia in children, with elective CS significantly increasing ALL risk.     

Parental occupational exposure to magnetic fields and childhood cancer (Sweden)

Objectives: To test the hypothesis that parental occupational exposure to magnetic fields before conception and during pregnancy increases the risk of cancer in the offspring. Methods: The study is designed as a cohort study based on a population of 235,635 children born shortly after two different censuses in Sweden. The children were followed from birth to 14 years and cases of cancer were identified in the Swedish cancer registry. The parents' occupational titles in the censuses were linked to a job-exposure matrix with information about magnetic field levels in different occupations. The cancer incidence among the exposed was compared to that among the unexposed using Cox proportional hazards modeling. Results: There was no association between childhood cancer and maternal occupational magnetic field exposure. Paternal exposure was associated with an increased risk of childhood leukemia, with a relative risk of 2.0 (95% CI 1.1–3.5) for exposures 0.30 T. A decreased risk was found for brain tumors (RR = 0.5; 95% CI 0.3–1.0). Conclusions: The results do not support previous findings of an increased risk of childhood brain tumors associated with paternal occupational exposure to magnetic fields. The finding for childhood leukemia has to be interpreted with caution.     

Breast-feeding and risk of childhood acute leukemia.

BACKGROUND: Breast-feeding is well known to have a protective effect against infection in infants. Although the long-term effects of breast-feeding on childhood cancer have not been studied extensively, a protective effect against childhood Hodgkin's disease and lymphoma has been suggested previously from small investigations. In this study, we tested the hypothesis that breast-feeding decreases the risk of childhood acute leukemia. METHODS: A total of 1744 children with acute lymphoblastic leukemia (ALL) and 1879 matched control subjects, aged 1-14 years, and 456 children with acute myeloid leukemia (AML) and 539 matched control subjects, aged 1-17 years, were included in the analysis. Information regarding breast-feeding was obtained through telephone interviews with mothers. All leukemias combined, histologic type of leukemia (ALL versus AML), immunophenotype of ALL (early pre-B cell, pre-B cell, or T cell), and morphology of AML were assessed separately in the data analysis. RESULTS: Ever having breast-fed was found to be associated with a 21% reduction in risk of childhood acute leukemias (odds ratio [OR] for all types combined = 0.79; 95% confidence interval [CI] = 0.70-0.91). A reduction in risk was seen separately for AML (OR = 0.77; 95% CI = 0.57-1.03) and ALL (OR = 0.80; 95% CI = 0.69-0.93). The inverse associations were stronger with longer duration of breast-feeding for total ALL and AML; for M0, M1, and M2 morphologic subtypes of AML; and for early pre-B-cell ALL. CONCLUSION: In this study, breast-feeding was associated with a reduced risk of childhood acute leukemia. If confirmed in additional epidemiologic studies, our findings suggest that future epidemiologic and experimental efforts should be directed at investigating the anti-infective and/or immune-stimulatory or immune-modulating effects of breast-feeding on leukemogenesis in children.     

The prevalence of signs and symptoms of childhood leukemia and lymphoma in Fars Province, Southern Iran

Background: Leukemia and lymphomas are still the common childhood cancers in Iran. This study was undertaken to determine the prevalence of signs and symptoms of these malignancies in children of Fars Province, Southern Iran. Methods: A total of 368 cases of children who were less than 15 years old and diagnosed as acute lymphocytic leukemia (ALL, n = 211), acute myeloid leukemia (AML, n = 64), Burkitt lymphoma (BL, n = 40), chronic myeloid leukemia (CML, n = 5), Hodgkin's disease (HD, n = 33) or non-Burkitt-type, non-Hodgkin's lymphoma (NBNHL, n = 15) referring to the hospitals of Shiraz University of Medical Sciences from April 1997 to March 2002 were enrolled. A questionnaire was provided to record the age, median age at the onset of the disease, sex, type of malignancy and the signs and symptoms at the time of presentation. Results: The common sign or symptoms were fever (74%), in ALL, AML, NHL, and BL patients, hepatosplenomegaly (100%) in CML patients, and lymphadenopathy (54%) and fever (54%) in Hodgkin's disease. Conclusion: Knowledge of signs and symptoms and types of presentations of childhood leukemia and lymphoma may help a physician to improve the patient's outcome. This study revealed that attention to uncommon signs and symptoms in history taking and physical examination together with laboratory tests may increase the physicians’ awareness and better diagnosis of pediatric malignancies and would also be beneficial for the patient.     

Pharmacokinetics of high-dose busulphan in relation to age and chronopharmacology

Summary Busulphan levels in plasma were measured in 27 patients during conditioning therapy (1 mg/kg×4 for 4 days) before bone marrow transplantation. The mean minimal concentration found in children aged <5 years (237 ng ml^–1) was lower than that observed in adults or older children (607 and 573 ng ml^–1, respectively). The AUC for the last dose was significantly lower in young children (2,315 h ng ml^–1) than in adults or older children (6,134 and 5,937 h ng ml^–1, respectively). The elimination half-life for the last dose in young children was shorter (2.05 h) than that in either adults (2.59 h) or older children (2.79 h). When the AUC was normalized for body surface area, the difference between young children and the other groups was smaller but remained statistically significant. The total body clearance was significantly higher in young children (7.3 ml min^–1 kg^–1) as compared with both older children and adults (3.02 and 2.7 ml min^–1 kg^–1, respectively). The plasma levels of busulphan showed circadian rhythmicity, especially in young children. The concentration measured during the night in some patients was up to 3-fold that observed during daytime. We conclude that the busulphan dosage for children must be reconsidered and that further studies are urgently needed to develop an optimal therapy.Abbreviations AML acute myeloblastic leukemia - ALL acute lymphatic leukemia - AUL acute undifferentiated leukemia - ABMT autologous bone marrow transplantation - BMT allogeneic bone marrow transplantation This work was supported by grant 2805-B90-01X from the Swedish Cancer Society     

Paternal preconceptional irradiation, population mixing and solid tumorsin the children of radiation workers (England)

Objective: To investigate whether there was an increased incidence of solid tumors among offspring of male radiation workers at the Sellafield nuclear installation in Cumbria, northwest England and whether paternal preconceptional irradiation was associated with the risk of solid tumors. Methods: A cohort study of 266,710 live births in Cumbria, 1950–1991, followed up to age 25 years on the end of 1991. Results: Children of radiation workers had a non-significantly increased risk of solid tumors (RR = 1.5, 95% CI: 0.9–2.4, p = 0.09), determined largely by an increased risk of cancers excluding leukemias, lymphomas, brain, spinal and gender-specific tumors (RR = 1.9, 95% CI: 1.0–3.3, p = 0.05), which was partly explained by differing patterns of parental migration (adjusted RR = 1.7, 95% CI: 0.8–3.2, p = 0.50). Within children of radiation workers there was no evidence of an increased risk with increasing paternal preconception dose of external radiation (hazard ratio per 100 mSv for all solid tumors = 0.6, 95% CI: 0.1–1.8, p = 0.52). Conclusions: Any observed excess of solid tumors in children of radiation workers may be partly explained by population mixing. Fathers' occupational exposure to radiation before conception was not found to be risk factor for solid tumors in their children.     

Clustering of childhood leukaemia in Hong Kong: association with the childhood peak and common acute lymphoblastic leukaemia and with population mixing.

Incidence data of childhood leukaemia (CL) in Hong Kong (1984-90) have been analysed for evidence of variation between small areas. All cases (n=261) were classified by morphological cell type, with the majority (n=205) being acute lymphoblastic leukaemia (ALL), and haematological review has permitted immunophenotypic classification for 73% of these. The data have been examined for evidence of spatial clustering within small census areas (TPUs) and for association with population mixing, with attention focused on those subgroups (especially the childhood peak of ALL--taken here to be diagnoses in children from 24 months up to the seventh birthday--and common ALL) which, it has been hypothesized, may be caused by unusual patterns of exposure and response to common infections. For the whole of Hong Kong, there was evidence of spatial clustering of ALL at ages 0-4 years (P = 0.09) and in the childhood peak (P<0.05). When these analyses were restricted to TPUs where extreme population mixing may have occurred, overall incidence was elevated and significant evidence of clustering was found for ALL (P<0.007) at these ages and for the common ALL in the childhood peak (P = 0.032). Replication of the analyses for subsets of leukaemia that were not dominated by the childhood peak of ALL found no evidence of clustering. This is the first investigation of an association between population mixing and childhood leukaemia in Asia and the first to include clustering and to consider particular subsets. The results are supportive of the ''infectious'' aetiology hypothesis for subsets of childhood leukaemia, specifically common ALL in the childhood peak.     

Endogenous risk factors for childhood leukemia in relation to the IGF system (Greece)

Objective: Insulin-like growth factor-1 (IGF-1) and its principal binding protein-3 (IGFBP-3) are central in the mediation of the effect of growth hormone, and the IGF system has been reported to play a role in the pathogenesis of childhood leukemia. Methods: To further evaluate the hypothesis connecting the IGF system to this disease, we have examined whether IGF-1 and IGFBP-3 are associated with the two main endogenous risk factors for childhood leukemia, namely gender and birth weight, since boys and heavier newborns are known to be at higher risk. IGF-1 and IGFBP-3 were measured under code in the serum of 118 apparently healthy children aged 0–14years and the values of each of these components were regressed on age, gender and birth weight. Insulin-like growth factor-2 (IGF-2), as a dependent variable, and anemia during the corresponding pregnancy, as a predictor variable, were also evaluated for exploratory purposes. Results: In the total data set, IGF-1 was positively associated with birth weight (p = 0.0001), whereas girls had higher levels of IGFBP-3 (p = 0.01). Conclusions: It appears that the associations of measured components of the IGF system with the examined risk factors for childhood leukemia are largely compatible with those that would have been expected, if this system played a role in the pathogenesis of childhood leukemia.     

The association between birth order and childhood leukemia may be modified by paternal age and birth weight. Pooled results from the International Childhood Cancer Cohort Consortium (I4C)

The “delayed infection hypothesis” states that a paucity of infections in early childhood may lead to higher risks of childhood leukemia (CL), especially acute lymphoblastic leukemia (ALL). Using prospectively collected data from six population-based birth cohorts we studied the association between birth order (a proxy for pathogen exposure) and CL. We explored whether other birth or parental characteristics modify this association. With 2.2 × 10⁶ person-years of follow-up, 185 CL and 136 ALL cases were ascertained. In Cox proportional hazards models, increasing birth order (continuous) was inversely associated with CL and ALL; hazard ratios (HR) = 0.88, 95% confidence interval (CI): (0.77–0.99) and 0.85: (0.73–0.99), respectively. Being later-born was associated with similarly reduced hazards of CL and ALL compared to being first-born; HRs = 0.78: 95% CI: 0.58–1.05 and 0.73: 0.52–1.03, respectively. Successive birth orders were associated with decreased CL and ALL risks (P for trend 0.047 and 0.055, respectively). Multivariable adjustment somewhat attenuated the associations. We found statistically significant and borderline interactions between birth weight (p = 0.024) and paternal age (p = 0.067), respectively, in associations between being later-born and CL, with the lowest risk observed for children born at <3 kg with fathers aged 35+ (HR = 0.18, 95% CI: 0.06–0.50). Our study strengthens the theory that increasing birth order confers protection against CL and ALL risks, but suggests that this association may be modified among subsets of children with different characteristics, notably advanced paternal age and lower birth weight. It is unclear whether these findings can be explained solely by infectious exposures.