Paediatric acute lymphoblastic leukaemia and caesarean section: A report from the United Kingdom Childhood Cancer Study (UKCCS).

BACKGROUND: Reports have suggested that children born by caesarean initiated before labour onset may be at increased risk of developing acute lymphoblastic leukaemia (ALL). However, with most data being derived from case-control study interviews, information on the underpinning reasons for caesarean section is sparse, and evidence is conflicting. OBJECTIVES: Use clinical records compiled at the time of delivery to investigate the association between childhood ALL and caesarean delivery; examining timing in relation to labour onset, and reasons for the procedure. METHODS: Data are from the UK Childhood Cancer Study, a population-based case-control study conducted in the 1990s, when caesarean section rates were relatively low, in England, Scotland, and Wales. Children with ALL were individually matched to two controls on sex, date of birth, and region of residence. Information on mode of delivery and complications was abstracted from obstetric records. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression models adjusted for matching variables and relevant covariates. RESULTS: Around 75% of the 1034 cases and 1914 controls were born through unassisted vaginal delivery. Caesarean delivery was as frequent in cases and controls (OR 1.07, 95% CI 0.84, 1.36). No association was observed between ALL and caesarean delivery either during or before labour, with adjusted ORs of 1.08 (95% CI 0.78, 1.48) and 1.09 (95% CI 0.78, 1.53), respectively. For B-cell ALL, the ORs were 1.14 (95% CI 0.81, 1.59) for caesarean during labour and 1.21 (95% CI 0.85, 1.72) for prelabour. The underpinning reasons for caesarean delivery differed between cases and controls; with preeclampsia, although very rare, being more common amongst cases born by caesarean (OR 8.91, 95% CI 1.48, 53.42). CONCLUSIONS: Our obstetric record-based study found no significant evidence that caesarean delivery increased the risk of childhood ALL, either overall or when carried out before labour.

Home pesticide exposures and risk of childhood leukemia: Findings from the childhood leukemia international consortium.

Some previous studies have suggested that home pesticide exposure before birth and during a child's early years may increase the risk of childhood leukemia. To further investigate this, we pooled individual level data from 12 case-control studies in the Childhood Leukemia International Consortium. Exposure data were harmonized into compatible formats. Pooled analyses were undertaken using multivariable unconditional logistic regression. The odds ratio (ORs) for acute lymphoblastic leukemia (ALL) associated with any pesticide exposure shortly before conception, during pregnancy and after birth were 1.39 (95% confidence interval [CI]: 1.25, 1.55) (using 2,785 cases and 3,635 controls), 1.43 (95% CI: 1.32, 1.54) (5,055 cases and 7,370 controls) and 1.36 (95% CI: 1.23, 1.51) (4,162 cases and 5,179 controls), respectively. Corresponding ORs for risk of acute myeloid leukemia (AML) were 1.49 (95% CI: 1.02, 2.16) (173 cases and 1,789 controls), 1.55 (95% CI: 1.21, 1.99) (344 cases and 4,666 controls) and 1.08 (95% CI: 0.76, 1.53) (198 cases and 2,655 controls), respectively. There was little difference by type of pesticide used. The relative similarity in ORs between leukemia types, time periods and pesticide types may be explained by similar exposure patterns and effects across the time periods in ALL and AML, participants' exposure to multiple pesticides, or recall bias. Although some recall bias is likely, until a better study design can be found to investigate the associations between home pesticide use and childhood leukemia in an equally large sample, it would appear prudent to limit the use of home pesticides before and during pregnancy, and during childhood.

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.

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.

Parental occupational paint exposure and risk of childhood leukemia in the offspring: findings from the Childhood Leukemia International Consortium.

PURPOSE: It has been suggested that parental occupational paint exposure around the time of conception or pregnancy increases the risk of childhood leukemia in the offspring. METHODS: We obtained individual level data from 13 case-control studies participating in the Childhood Leukemia International Consortium. Occupational data were harmonized to a compatible format. Meta-analyses of study-specific odds ratios (ORs) were undertaken, as well as pooled analyses of individual data using unconditional logistic regression. RESULTS: Using individual data from fathers of 8,185 cases and 14,210 controls, the pooled OR for paternal exposure around conception and risk of acute lymphoblastic leukemia (ALL) was 0.93 [95% confidence interval (CI) 0.76, 1.14]. Analysis of data from 8,156 ALL case mothers and 14,568 control mothers produced a pooled OR of 0.81 (95% CI 0.39, 1.68) for exposure during pregnancy. For acute myeloid leukemia (AML), the pooled ORs for paternal and maternal exposure were 0.96 (95% CI 0.65, 1.41) and 1.31 (95% CI 0.38, 4.47), respectively, based on data from 1,231 case and 11,392 control fathers and 1,329 case and 12,141 control mothers. Heterogeneity among the individual studies ranged from low to modest. CONCLUSIONS: Null findings for paternal exposure for both ALL and AML are consistent with previous reports. Despite the large sample size, results for maternal exposure to paints in pregnancy were based on small numbers of exposed. Overall, we found no evidence that parental occupational exposure to paints increases the risk of leukemia in the offspring, but further data on home exposure are needed.

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. © 2013 UICC.

Maternal infections and medications in pregnancy: how does self-report compare to medical records in childhood cancer case-control studies?

BACKGROUND: Studies examining the potential impact of mothers' health during pregnancy on the health of their offspring often rely on self-reported information gathered several years later. To assess the validity of this approach, we analysed data from a national case-control study of childhood cancer (diagnosed <15 years) that collected health information from both interviews and medical records. METHODS: Mothers' interview reports of infections and medications in pregnancy were compared with primary care records. Taking clinical diagnoses and prescriptions as the reference, sensitivity and specificity of maternal recall along with kappa coefficients of agreement were calculated. Differences in the odd ratios estimated using logistic regression for each information source were assessed using the proportional change in the odds ratio (OR). RESULTS: Mothers of 1624 cases and 2524 controls were interviewed ∼6 years (range 0-18 years) after their child's birth. Most drugs and infections were underreported; in general practitioner records, antibiotic prescriptions were nearly three times higher and infections >40% higher. Decreasing with increasing time since pregnancy, sensitivity was ⩽40% for most infections and all drugs except 'anti-epileptics and barbiturates' (sensitivity 80% among controls). ORs associated with individual drug/disease categories that were based on self-reported data varied from 26% lower to 26% higher than those based on medical records; reporting differences between mothers of cases and controls were not systematically in the same direction. CONCLUSIONS: The findings highlight the scale of under-reporting and poor validity of questionnaire-based studies conducted several years after pregnancy. Future research using prospectively collected data should be encouraged to minimize measurement errors.

Cohort profile: the United Kingdom Childhood Cancer Study (UKCCS) - a UK-wide population-based study examining the health of cancer survivors.

PURPOSE: The United Kingdom Childhood Cancer Study's (UKCCS's) matched cohort was established to examine the longer term morbidity and mortality of individuals previously diagnosed with cancer before 15 years of age, comparing future healthcare patterns in 5-year cancer survivors to baseline activity seen in age- and sex-matched individuals from the general population. PARTICIPANTS: Predicated on a national childhood cancer case-control study conducted in the early 1990s (4430 cases, 9753 controls) in England, Scotland and Wales, the case population comprises 3125 cancer survivors (>5 years), and the control population 7156 age- and sex-matched individuals from the general population who did not have cancer as a child. Participants are now being followed up via linkage to national administrative healthcare databases (deaths, cancers and secondary care hospital activity). FINDINGS TO DATE: Enabling the creation of cohorts with minimal selection bias and loss to follow-up, the original case-control study registered all newly diagnosed cases of childhood cancer and their corresponding controls, regardless of their family's participation. Early findings based on the registered case population found marked survival variations with age and sex across subtypes and differences with deprivation among acute lymphoblastic leukaemia (ALL) survivors. More recently, comparing the health-activity patterns of the case and control populations revealed that survivors of childhood ALL experienced excess outpatient and inpatient activity across their teenage/young adult years. Adding to increased risks of cancer and death and involving most clinical specialties, excesses were not related to routine follow-up monitoring and showed no signs of diminishing over time. FUTURE PLANS: With annual linkage updates, the UKCCS's maturing population-based matched cohorts provide the foundation for tracking the health of individuals through their lifetime. Comparing the experience of childhood cancer survivors to that of unaffected general-population counterparts, this will include examining subsequent morbidity and mortality, secondary care hospital activity and the impact of deprivation on longer term outcomes.

Infectious illness in children subsequently diagnosed with acute lymphoblastic leukemia: modeling the trends from birth to diagnosis.

Although there is increasing evidence that immune dysregulation in children who develop acute lymphoblastic leukemia (ALL) is detectable from birth, debate about the role of infectious exposures in infancy continues. With the aim of quantifying children's infectious exposures, investigators have used a number of infection exposure proxies, but there is a lack of consistency in findings, with some markers indicating increased ALL risks and others decreased risks, the disparity being evident both within and between studies. Accordingly, the authors conducted an in-depth analysis of key infection exposure proxies used in the United Kingdom Childhood Cancer Study, a national population-based case-control study conducted over the period 1991-1996, which combined data from medical records, parental interview, and population census. This longitudinal approach revealed the marked deterioration in immune response that emerged around 5 months prior to ALL diagnosis and confirmed that infectious diagnoses in the first year of life were significantly increased (P < 0.05) in children who developed leukemia between 2 and 14 years of age, as well as in those who had birth orders >1, were not breastfed, lived in deprived areas, or were diagnosed with eczema. By contrast, no association between infectious illness and preschool activity was detected, the lower infection levels among controls whose mothers reported attendance contributing to a significantly reduced ALL odds ratio.

Genetic variation in the folate metabolic pathway and risk of childhood leukemia.

Studies of childhood leukemia and the potential etiologic role of genetic variation in folate metabolism have produced conflicting findings and have often been based on small numbers. We investigated the association between polymorphisms in key folate metabolism enzymes (MTHFR 677 C>T, MTHFR 1298 A>C, SHMT1 1420 C>T, MTR 2756 A>G, TS 1494del6, and TS 28bp repeat) in 939 cases of childhood acute lymphoblastic leukemia (ALL) and 89 cases of acute myeloid leukemia (AML) recruited into the United Kingdom Childhood Cancer Study. We also examined the maternal genotypes of 752 of these cases. Data from 824 noncancer controls recruited were used for comparison. No evidence of an association with MTHFR 677 was observed for ALL or AML, either in children or their mothers. However, in children an increased risk of ALL (odds ratio [OR] = 1.88; 95% confidence interval [CI], 1.16-3.07; P = .010) and AML (OR = 2.74; 95% CI, 1.07-7.01; P = .036) was observed with the MTR 2756 GG genotype; the association was most pronounced for cases with the MLL translocation (OR = 4.90; 95% CI, 1.30-18.45; P = .019). These data suggest that genetic variation in methionine synthase could mediate risk of childhood leukemia, either via effects on DNA methylation or via effects on fetal growth and development.

Excess morbidity and mortality among survivors of childhood acute lymphoblastic leukaemia: 25 years of follow-up from the United Kingdom Childhood Cancer Study (UKCCS) population-based matched cohort.

OBJECTIVES: To examine morbidity and mortality among teenagers and young adults (TYAs) previously diagnosed with acute lymphoblastic leukaemia (ALL) in childhood, and compare to the general TYA population. DESIGN: National population-based sex-matched and age-matched case-control study converted into a matched cohort, with follow-up linkage to administrative healthcare databases. SETTING: The study population comprised all children (0-14 years) registered for primary care with the National Health Service (NHS) in England 1992-1996. PARTICIPANTS: 1082 5-year survivors of ALL diagnosed<15 years of age (1992-1996) and 2018 unaffected individuals; followed up to 15 March 2020. MAIN OUTCOME MEASURES: Associations with hospital activity, cancer and mortality were assessed using incidence rate ratios (IRR) and differences. RESULTS: Mortality in the 5-year ALL survivor cohort was 20 times higher than in the comparison cohort (rate ratio 21.3, 95% CI 11.2 to 45.6), and cancer incidence 10 times higher (IRR 9.9 95% CI 4.1 to 29.1). Hospital activity was increased for many clinical specialties, the strongest associations being for endocrinology; outpatient IRR 36.7, 95% CI 17.3 to 93.4 and inpatient 19.7, 95% CI 7.9 to 63.2 for males, and 11.0, 95% CI 6.2 to 21.1 and 6.2 95% CI 3.1 to 13.5, respectively, for females. Notable excesses were also evident for cardiology, neurology, ophthalmology, respiratory medicine and general medicine. Males were also more likely to attend gastroenterology; ear, nose and throat; urology; and dermatology, while females were more likely to be seen in plastic surgery and less likely in midwifery. CONCLUSIONS: Adding to excess risks of death and cancer, survivors of childhood ALL experience excess outpatient and inpatient activity across their TYA years, which is not related to routine follow-up monitoring. Involving most clinical specialties, associations are striking, showing no signs of diminishing over time. Recognising that all survivors are potentially at risk of late treatment-associated effects, our findings underscore the need to take prior ALL diagnosis into account when interpreting seemingly unrelated symptoms later in life.

Non-Hodgkin lymphoma and autoimmunity: does gender matter?

Autoimmune disorders are more frequent in women, whereas most non-Hodgkin lymphomas (NHLs) are common in men; yet, sexspecific autoimmune­lymphoma associations are rarely reported. Detailed data on autoimmune disease were abstracted from medical records of 791 cases (including 316 diffuse large B-cell lymphomas (DLBCLs); 228 follicular lymphomas (FLs); 127 marginal zone lymphomas (MZLs); 64 T-cell lymphomas and 38 mantle cell lymphomas) and 872 controls. The combined prevalence of autoimmune disease was higher among women (15.7% controls; 19.7% cases) than men (6.6% controls; 14.5% cases), but the overall association with NHL was stronger for men (odds ratio 2.4, 95% confidence interval: 1.5­3.8) than women (1.3, 0.9­1.9), the disparity persisting when data for the year immediately preceding lymphoma diagnosis were excluded (men 2.0, 1.3­3.3; women 1.2, 0.8­1.8). For both sexes, the strongest individual associations were for DLBCL, MZL and T-cell lymphomas, with no associations evident for FL. Among women, there were strong links between MZL and both Sjögren's syndrome and idiopathic thrombocytopenia, and among men, between DLBCL and both rheumatoid arthritis and Crohn's disease. The expected association between coeliac disease and T-cell lymphoma was seen in both sexes. Our results add to the accumulating knowledge on this topic and suggest that future studies should analyze data for men and women separately.

Rationale for an international consortium to study inherited genetic susceptibility to childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia is the major pediatric cancer in developed countries. To date most association studies of acute lymphoblastic leukemia have been based on the candidate gene approach and have evaluated a restricted number of polymorphisms. Such studies have served to highlight difficulties in conducting statistically and methodologically rigorous investigations into acute lymphoblastic leukemia risk. Recent genome-wide association studies of childhood acute lymphoblastic leukemia have provided robust evidence that common variation at four genetic loci confers a modest increase in risk. The accumulated experience to date and relative lack of success of initial efforts to identify novel acute lymphoblastic leukemia predisposition loci emphasize the need for alternative study designs and methods. The International Childhood Acute Lymphoblastic Leukaemia Genetics Consortium includes 12 research groups in Europe, Asia, the Middle East and the Americas engaged in studying the genetics of acute lymphoblastic leukemia. The initial goal of this consortium is to identify and characterize low-penetrance susceptibility variants for acute lymphoblastic leukemia through association-based analyses. Efforts to develop genome-wide association studies of acute lymphoblastic leukemia, in terms of both sample size and single nucleotide polymorphism coverage, and to increase the number of single nucleotide polymorphisms taken forward to large-scale replication should lead to the identification of additional novel risk variants for acute lymphoblastic leukemia. Ethnic differences in the risk of acute lymphoblastic leukemia are well recognized and thus in assessing the interplay between inherited and non-genetic risk factors, analyses using different population cohorts with different incidence rates are likely to be highly informative. Given that the frequency of many acute lymphoblastic leukemia subgroups is small, identifying differential effects will realistically only be possible through multi-center pooled analyses. Here, we review the rationale for identifying genetic risk variants for acute lymphoblastic leukemia and our proposed strategy for establishing the International Childhood Acute Lymphoblastic Leukaemia Genetics Consortium.

Relationship between HLA-DP supertype and survival in childhood acute lymphoblastic leukaemia: evidence for selective loss of immunological control of residual disease?

We recently reported that two of six HLA-DP supertypes (DP1-4, 6, 8) were associated with susceptibility (DP2) and resistance (DP1) to childhood acute lymphoblastic leukaemia (ALL). To determine whether DP supertypes are associated with childhood ALL prognosis, we compared treatment outcomes in a cohort (n = 798) of DPB1-typed ALL cases in the UK Medical Research Council UKALL XI trial. No differences in clinical characteristics and outcome between DPB1-typed and untyped (n = 1292) cases suggest no selection bias. Event-free survival (EFS) rates in patients with DP1 and DP3 supertypes were significantly worse than in patients with DP2, DP4, DP6 and DP8 [10-year EFS: 55%; 95% confidence interval (CI) = 49-61%; compared with 64% (61-68%), P = 0.006]. Ten-year EFS in DP1/DP3 heterozygous patients [30% (2-58%)] was significantly worse than in patients with DP1, DP3 or neither allele [56% (50-62%); P = 0.02]. Lack of evidence that DP1 or DP3 are associated with known prognostic factors leads us to suggest that these two supertypes exert an independent effect on prognosis. This may involve abrogation of DP1/3-restricted T-cell control of residual disease due to selective effects of chemotherapy. Further studies of HLA supertypes in relation to outcome in recent childhood ALL trials may resolve this question.

Infectious proxies and childhood leukaemia: findings from the United Kingdom Childhood Cancer Study (UKCCS).

The United Kingdom Childhood Cancer Study (UKCCS) was specifically designed to investigate the potential etiological role of infections as one of its objectives and information on a number of markers of infectious exposure from multiple sources was collected (www.ukccs.org). This study found that a mother's recollections of past minor illness episodes in her children were unreliable, producing systematic case-control differences. From birth onwards children diagnosed with ALL between 2-5 years were found to have had more clinically diagnosed infectious illness episodes (not fewer) than unaffected children, with those with two or more neonatal infections being diagnosed with leukaemia around 7 months earlier than those with only one or none. The findings from these analyses and their implications for future research are reviewed and discussed in this paper.

Power frequency magnetic fields and risk of childhood leukaemia: misclassification of exposure from the use of the 'distance from power line' exposure surrogate.

A recent study examining the relationship between distance to nearby power lines and childhood cancer risk re-opened the debate about which exposure metrics are appropriate for power frequency magnetic field investigations. Using data from two large population-based UK and German studies we demonstrate that distance to power lines is a comparatively poor predictor of measured residential magnetic fields. Even at proximities of 50 m or less, the positive predictive value of having a household measurement over 0.2 microT was only 19.4%. Clearly using distance from power lines, without taking account of other variables such as load, results in a poor proxy of residential magnetic field exposure. We conclude that such high levels of exposure misclassification render the findings from studies that rely on distance alone uninterpretable.

Eczema, birth order, and infection.

The association between infections occurring in the first 2 years of life and development of eczema was investigated in 1,782 control children from a national population-based case-control study in the United Kingdom conducted over the period 1991-1996. Dates of eczema and infectious diagnoses were ascertained from contemporaneously collected primary care records. Children diagnosed with eczema before the age of 2 years had more prior clinically diagnosed infections recorded than did children without eczema (rate ratio = 1.26, 95% confidence interval (CI): 1.18, 1.36). The difference in infection rates between children with and without eczema was apparent from birth and throughout the first 2 years of life. As expected, compared with children of second or higher birth order, those firstborn were at increased risk of eczema (p = 0.020); however, the relation between eczema and prior infection was evident only among children of second or higher birth order and not among firstborn children (rate ratio = 1.45, 95% CI: 1.32, 1.59, and rate ratio = 1.08, 95% CI: 0.98, 1.20, respectively). The authors' results are consistent with the notion that the association between birth order and eczema is unlikely to be attributable to variations in early infectious exposure.

Childhood leukaemia and infectious exposure: a report from the United Kingdom Childhood Cancer Study (UKCCS).

Data from a national case-control study are used to explore the relationships between childhood leukaemia, infant infection and three markers of infectious exposure - birth order, infant-activity group attendance and area-based deprivation. Amongst controls, clinically diagnosed infection in the first year varied little with birth order and infant-activity group attendance - with 4 in 5 children having at least one infection, and each child averaging around 2.9 (2.8-3.0). Amongst cases of acute lymphoblastic leukaemia (ALL), the levels of infection increased as the indices of infectious exposure increased - for example, odds ratios associated with at least one infection in the first year being 0.9 (95% confidence interval (CI): 0.6-1.4) for birth order one and 1.6 (95% CI: 1.1-2.2) for birth order two or more. By contrast, interview data were misleading, with mothers - particularly case mothers - consistently under-reporting. We conclude that the findings based on clinical data, combined with the markers of infectious exposure, confirm the observation that immune dysregulation among children who develop ALL is detectable from an early age.

Childhood leukaemia and socioeconomic status: fact or artefact? A report from the United Kingdom childhood cancer study (UKCCS).

BACKGROUND: It is widely believed that children of high socioeconomic status (SES) are more likely than those of low SES to develop acute lymphoblastic leukaemia (ALL). Such observations have led to wide-ranging speculations about the potential aetiological role of factors associated with affluence and modernization. METHODS: Children (0-14 years) newly diagnosed with cancer in the UK between 1991 and 1996 were ascertained via a rapid hospital-based case finding system (n = 4430, of which 1578 were ALL). Children without cancer (controls) were randomly selected from primary care population registries for comparative purposes (n = 7763). Area-based deprivation scores were assigned as markers of SES at two time points - birth and diagnosis. An individual-based marker of SES - social class - was assigned using father's occupation as recorded on the child's birth certificate. RESULTS: No differences in area-based measures of deprivation were observed between cases and controls at time of diagnosis, either for all cancers combined [n = 4430, odds ratio (OR) = 1.00 (95% confidence intervals (CI) 0.98-1.01)] or for ALL alone (n = 1578 OR = 0.99, 95%CI 0.96-1.01). Findings were similar at time of birth (all cancers, OR = 0.99 95%CI 0.98-1.01, ALL OR = 0.98, 95%CI 0.96-1.00). In addition, no case-control differences were observed when an individual-based measure of SES - social class - based on father's occupation at time of birth was used. CONCLUSIONS: The comprehensive nature of the data, coupled with complete case-ascertainment and representative population-based controls suggests that SES in the UK is not a determinant of ALL in children. We believe the small effects reported for SES in some past studies may be artefactual.

Molar pregnancy, childhood cancer and genomic imprinting - is there a link?

The United Kingdom Childhood Cancer Study (UKCCS) is a national multi-centre case-control study that was designed to evaluate the potential aetiological role of prenatal events in childhood cancer. The obstetric records of 2692 mothers of children diagnosed with cancer and 4864 mothers of children without cancer were available for analysis. Overall, 1754 (65%) case mothers and 3220 (66%) control mothers had at least one prior pregnancy before the birth of the index child. Of these, 12 (0.68%) of the former and 9 (0.28%) of the latter had a prior molar pregnancy (odds ratio 2.5, 95% confidence interval 1.1 - 6.1). Both childhood cancer and molar pregnancy are rare neoplastic events, and the numbers are small. Nonetheless, whilst the associations were strongest for common precursor B-cell acute lymphoblastic leukaemia (OR 5.2, 95% CI 1.9 - 14.7) and sarcoma (OR 6.2, 95% CI 1.3 - 30.3), the spread across the remaining diagnostic groups suggests that the relationship, if confirmed, may be of a generalized, rather than specific, type. This is the first time that an association between childhood cancer and hydatidiform mole has been reported. The UKCCS's systematic use of clinical records permitted a more precise characterization of reproductive events than is possible in investigations that rely on individuals own accounts, and we are confident that our findings cannot be explained by recall bias or other methodological limitations. Accordingly, we suggest that there may be an aetiologic connection between molar pregnancy and childhood cancer, and speculate here on the various genetic/epigenetic mechanisms that could be involved.