John D. Dockerty

A pooled analysis of magnetic fields and childhood leukaemia

Previous studies have suggested an association between exposure to 50–60 Hz magnetic fields (EMF) and childhood leukaemia. We conducted a pooled analysis based on individual records from nine studies, including the most recent ones. Studies with 24/48-hour magnetic field measurements or calculated magnetic fields were included. We specified which data analyses we planned to do and how to do them before we commenced the work. The use of individual records allowed us to use the same exposure definitions, and the large numbers of subjects enabled more precise estimation of risks at high exposure levels. For the 3203 children with leukaemia and 10 338 control children with estimated residential magnetic field exposures levels < 0.4 μT, we observed risk estimates near the no effect level, while for the 44 children with leukaemia and 62 control children with estimated residential magnetic field exposures ≥ 0.4 μT the estimated summary relative risk was 2.00 (1.27–3.13), P value = 0.002). Adjustment for potential confounding variables did not appreciably change the results. For North American subjects whose residences were in the highest wire code category, the estimated summary relative risk was 1.24 (0.82–1.87). Thus, we found no evidence in the combined data for the existence of the so-called wire-code paradox. In summary, the 99.2% of children residing in homes with exposure levels < 0.4 μT had estimates compatible with no increased risk, while the 0.8% of children with exposures ≥ 0.4 μT had a relative risk estimate of approximately 2, which is unlikely to be due to random variability. The explanation for the elevated risk is unknown, but selection bias may have accounted for some of the increase.

Infections, vaccinations, and the risk of childhood leukaemia.

SummaryA nationwide case-control study was conducted in New Zealand, to test hypotheses about the role of infections in the aetiology of childhood leukaemia. Children aged 0–14 years with leukaemia were matched on age and sex to controls selected from birth records. Case ascertainment was virtually complete and 121 (92%) of 131 eligible case families took part. The participation rate among the 303 first-choice eligible controls was 69%. Home interviews and serological tests were conducted. Adjusted relative risks were estimated by logistic regression. There was an increased risk of leukaemia in relation to reported influenza infection of the child during the first year of life (adjusted odds ratio 6.8, 95% confidence interval 1.8–25.7). This could be a chance finding due to multiple comparisons, and it should be tested elsewhere. Some key variables relevant to Greaves’ hypothesis were not associated with B-cell precursor acute lymphoblastic leukaemia (numbers of infections and vaccinations, firstborn status, attendance at preschool groups), although a small effect could not be ruled out with a study of this size. Leukaemia risk was higher among children in poorer social circumstances, and this was true for all eligible children as well as for the participants.

Economic effects of childhood cancer on families.

Objective:  To assess the financial impact of childhood cancer on families.

Impact of childhood cancer on the mental health of parents

BACKGROUND When a child is diagnosed with cancer, the family experiences great stress and disruption to daily life. As part of a national study in New Zealand, we evaluated the mental health of mothers and fathers of children with cancer, making comparisons to parents of children from the general population. PROCEDURE This was a cross-sectional study. All children diagnosed with cancer at ages 0-14 years in New Zealand during a defined period were ascertained from the national cancer registry and other databases. The population-based comparison children were selected using national birth records. Parents from both groups completed self-administered questionnaires containing the General Health Questionnaire (GHQ-12) and other measures. The analyses included 218 mothers and 179 fathers of children with cancer, and 266 mothers and 224 fathers of children in the comparison group. Multivariate regression was used to adjust for demographic and socioeconomic characteristics, life events, and social support. RESULTS Mothers and fathers of children with cancer had poorer GHQ-12 and mood rating scores than those of controls. The adjusted difference in the mean total GHQ-12 score (comparing mothers of children with cancer to mothers of controls) was 2.2 (95% confidence interval 1.3-3.2). The 12 items of the GHQ were each scored 0-3, and the total score was the sum, so 2 points is a small difference. For fathers the difference was 1.5 (95% confidence interval 0.6-2.4). Some subgroups of cancer group parents had poorer emotional health scores than others, including those with poor social support and no paid employment and also those who were bereaved. CONCLUSIONS We found statistically significant but small differences between the mental health of parents of children with cancer and controls. The small differences suggest that as a group the parents of children with cancer are relatively resilient.

The Childhood Leukemia International Consortium

BACKGROUND Acute leukemia is the most common cancer in children under 15 years of age; 80% are acute lymphoblastic leukemia (ALL) and 17% are acute myeloid leukemia (AML). Childhood leukemia shows further diversity based on cytogenetic and molecular characteristics, which may relate to distinct etiologies. Case-control studies conducted worldwide, particularly of ALL, have collected a wealth of data on potential risk factors and in some studies, biospecimens. There is growing evidence for the role of infectious/immunologic factors, fetal growth, and several environmental factors in the etiology of childhood ALL. The risk of childhood leukemia, like other complex diseases, is likely to be influenced both by independent and interactive effects of genes and environmental exposures. While some studies have analyzed the role of genetic variants, few have been sufficiently powered to investigate gene-environment interactions. OBJECTIVES The Childhood Leukemia International Consortium (CLIC) was established in 2007 to promote investigations of rarer exposures, gene-environment interactions and subtype-specific associations through the pooling of data from independent studies. METHODS By September 2012, CLIC included 22 studies (recruitment period: 1962-present) from 12 countries, totaling approximately 31000 cases and 50000 controls. Of these, 19 case-control studies have collected detailed epidemiologic data, and DNA samples have been collected from children and child-parent trios in 15 and 13 of these studies, respectively. Two registry-based studies and one study comprising hospital records routinely obtained at birth and/or diagnosis have limited interview data or biospecimens. CONCLUSIONS CLIC provides a unique opportunity to fill gaps in knowledge about the role of environmental and genetic risk factors, critical windows of exposure, the effects of gene-environment interactions and associations among specific leukemia subtypes in different ethnic groups.

Parental Occupational Pesticide Exposure and the Risk of Childhood Leukemia in the Offspring: Findings From the Childhood Leukemia International Consortium

Maternal occupational pesticide exposure during pregnancy and/or paternal occupational pesticide exposure around conception have been suggested to increase risk of leukemia in the offspring. With a view to providing insight in this area we pooled individual level data from 13 case‐control studies participating in the Childhood Leukemia International Consortium (CLIC). Occupational data were harmonized to a compatible format. Pooled individual analyses were undertaken using unconditional logistic regression. Using exposure data from mothers of 8,236 cases, and 14,850 controls, and from fathers of 8,169 cases and 14,201 controls the odds ratio (OR) for maternal exposure during pregnancy and the risk of acute lymphoblastic leukemia (ALL) was 1.01 [95% confidence interval (CI) 0.78, 1.30] and for paternal exposure around conception 1.20 (95% 1.06, 1.38). For acute myeloid leukemia (AML), the OR for maternal exposure during pregnancy was 1.94 (CI 1.19, 3.18) and for paternal exposure around conception 0.91 (CI 0.66, 1.24.) based on data from 1,329 case and 12,141 control mothers, and 1,231 case and 11,383 control fathers. Our finding of a significantly increased risk of AML in the offspring with maternal exposure to pesticides during pregnancy is consistent with previous reports. We also found a slight increase in risk of ALL with paternal exposure around conception which appeared to be more evident in children diagnosed at the age of 5 years or more and those with T cell ALL which raises interesting questions on possible mechanisms.

Childhood leukaemias in New Zealand: time trends and ethnic differences

Registrations from the New Zealand Cancer Registry were used to examine time trends in the incidence of leukaemias among children aged 0-14. There was a statistically significant increase in the incidence of leukaemia among children aged 0-4 during 1953-57 to 1988-90. In this age group, the recorded incidence rate increased from 4.89 per 100,000 person-years in 1953-57 to 7.92 in 1988-90. During 1973-77 to 1988-90 (and probably in earlier years), the increase was due to an increase in acute lymphoblastic leukaemia (ALL). The trends were unlikely to be due to changes in diagnosis or case ascertainment. The childhood leukaemia trends might be related to trends in family size, maternal age, socioeconomic level or exposure to infections. However, there are uncertainties about the importance of these factors or about their trends. The incidence of acute non-lymphoblastic leukaemia (ANLL) decreased between 1968-72 and 1988-90. The time trends highlight the likely importance of environmental factors in the aetiology of childhood leukaemias in New Zealand. The risk of ALL was lower in the Maori than in the non-Maori population (relative risk Maori/non-Maori 0.74). The risk of ANLL was higher among Maori (relative risk 1.84).

Childhood Acute Lymphoblastic Leukemia and Indicators of Early Immune Stimulation: A Childhood Leukemia International Consortium Study

The associations between childhood acute lymphoblastic leukemia (ALL) and several proxies of early stimulation of the immune system, that is, day-care center attendance, birth order, maternally reported common infections in infancy, and breastfeeding, were investigated by using data from 11 case-control studies participating in the Childhood Leukemia International Consortium (enrollment period: 1980-2010). The sample included 7,399 ALL cases and 11,181 controls aged 2-14 years. The data were collected by questionnaires administered to the parents. Pooled odds ratios and 95% confidence intervals were estimated by unconditional logistic regression adjusted for age, sex, study, maternal education, and maternal age. Day-care center attendance in the first year of life was associated with a reduced risk of ALL (odds ratio = 0.77, 95% confidence interval: 0.71, 0.84), with a marked inverse trend with earlier age at start (P < 0.0001). An inverse association was also observed with breastfeeding duration of 6 months or more (odds ratio = 0.86, 95% confidence interval: 0.79, 0.94). No significant relationship with a history of common infections in infancy was observed even though the odds ratio was less than 1 for more than 3 infections. The findings of this large pooled analysis reinforce the hypothesis that day-care center attendance in infancy and prolonged breastfeeding are associated with a decreased risk of ALL.

Fetal growth and childhood acute lymphoblastic leukemia: findings from the childhood leukemia international consortium.

Positive associations have been reported between the measures of accelerated fetal growth and risk of childhood acute lymphoblastic leukemia (ALL). We investigated this association by pooling individual‐level data from 12 case–control studies participating in the Childhood Leukemia International Consortium. Two measures of fetal growth—weight‐for‐gestational‐age and proportion of optimal birth weight (POBW)—were analysed. Study‐specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression, and combined in fixed effects meta‐analyses. Pooled analyses of all data were also undertaken using multivariable logistic regression. Subgroup analyses were undertaken when possible. Data on weight for gestational age were available for 7,348 cases and 12,489 controls from all 12 studies and POBW data were available for 1,680 cases and 3,139 controls from three studies. The summary ORs from the meta‐analyses were 1.24 (95% CI: 1.13, 1.36) for children who were large for gestational age relative to appropriate for gestational age, and 1.16 (95% CI: 1.09, 1.24) for a one‐standard deviation increase in POBW. The pooled analyses produced similar results. The summary and pooled ORs for small‐for‐gestational‐age children were 0.83 (95% CI: 0.75, 0.92) and 0.86 (95% CI: 0.77, 0.95), respectively. Results were consistent across subgroups defined by sex, ethnicity and immunophenotype, and when the analysis was restricted to children who did not have high birth weight. The evidence that accelerated fetal growth is associated with a modest increased risk of childhood ALL is strong and consistent with known biological mechanisms involving insulin‐like growth factors.

Maternal supplementation with folic acid and other vitamins and risk of leukemia in offspring: a Childhood Leukemia International Consortium study.

Background: Maternal prenatal supplementation with folic acid and other vitamins has been inconsistently associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL). Little is known regarding the association with acute myeloid leukemia (AML), a rarer subtype. Methods: We obtained original data on prenatal use of folic acid and vitamins from 12 case-control studies participating in the Childhood Leukemia International Consortium (enrollment period: 1980–2012), including 6,963 cases of ALL, 585 cases of AML, and 11,635 controls. Logistic regression was used to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for child’s age, sex, ethnicity, parental education, and study center. Results: Maternal supplements taken any time before conception or during pregnancy were associated with a reduced risk of childhood ALL; odds ratios were 0.85 (95% CI = 0.78–0.92) for vitamin use and 0.80 (0.71–0.89) for folic acid use. The reduced risk was more pronounced in children whose parents’ education was below the highest category. The analyses for AML led to somewhat unstable estimates; ORs were 0.92 (0.75–1.14) and 0.68 (0.48–0.96) for prenatal vitamins and folic acid, respectively. There was no strong evidence that risks of either types of leukemia varied by period of supplementation (preconception, pregnancy, or trimester). Conclusions: Our results, based on the largest number of childhood leukemia cases to date, suggest that maternal prenatal use of vitamins and folic acid reduces the risk of both ALL and AML and that the observed association with ALL varied by parental education, a surrogate for lifestyle and sociodemographic characteristics.