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.

Identification of depression in women during pregnancy and the early postnatal period using the Whooley questions and the Edinburgh Postnatal Depression Scale: protocol for the Born and Bred in Yorkshire: PeriNatal Depression Diagnostic Accuracy (BaBY PaNDA) study.

INTRODUCTION: Perinatal depression is well recognised as a mental health condition but <50% of cases are identified by healthcare professionals in routine clinical practice. The Edinburgh Postnatal Depression Scale (EPDS) is often used to detect symptoms of postnatal depression in maternity and child services. The National Institute for Health and Care Excellence (NICE) recommends 2 'ultra-brief' case-finding questions (the Whooley questions) to aid identification of depression during the perinatal period, but this recommendation was made in the absence of any validation studies in a perinatal population. Limited research exists on the acceptability of these depression case-finding instruments and the cost-effectiveness of routine screening for perinatal depression. METHODS AND ANALYSIS: The diagnostic accuracy of the Whooley questions and the EPDS will be determined against a reference standard (the Client Interview Schedule-Revised) during pregnancy (around 20 weeks) and the early postnatal period (around 3-4 months post partum) in a sample of 379 women. Further outcome measures will assess a range of psychological comorbidities, health-related quality of life and resource utilisation. Women will be followed up 12 months postnatally. The sensitivity, specificity and predictive values of the Whooley questions and the EPDS will be calculated against the reference standard at 20 weeks pregnancy and 3-4 months post partum. Acceptability of the depression case-finding instruments to women and healthcare professionals will involve in-depth qualitative interviews. An existing decision analytic model will be adapted to determine the cost-effectiveness of routine screening for perinatal depression. ETHICS AND DISSEMINATION: This study is considered low risk for participants. Robust protocols will deal with cases where risk of depression, self-harm or suicide is identified. The protocol received favourable ethical opinion from the North East-York Research Ethics Committee (reference: 11/NE/0022). The study findings will be published in peer-reviewed journals and presented at relevant conferences.

Palliative care among heart failure patients in primary care: a comparison to cancer patients using English family practice data.

INTRODUCTION: Patients with heart failure have a significant symptom burden and other palliative care needs often over a longer period than patients with cancer. It is acknowledged that this need may be unmet but by how much has not been quantified in primary care data at the population level. METHODS: This was the first use of Clinical Practice Research Datalink, the world's largest primary care database to explore recognition of the need for palliative care. Heart failure and cancer patients who had died in 2009 aged 18 or over and had at least one year of primary care records were identified. A palliative approach to care among patients with heart failure was compared to that among patients with cancer using entry onto a palliative care register as a marker for a palliative approach to care. RESULTS: Among patients with heart failure, 7% (234/3 122) were entered on the palliative care register compared to 48% (3 669/7 608) of cancer patients. Of heart failure patients on the palliative care register, 29% (69/234) were entered onto the register within a week of their death. CONCLUSIONS: This confirms that the stark inequity in recognition of palliative care needs for people with heart failure in a large primary care dataset. We recommend a move away from prognosis based criteria for palliative care towards a patient centred approach, with assessment of and attention to palliative needs including advance care planning throughout the disease trajectory.

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.

Early life exposure to diagnostic radiation and ultrasound scans and risk of childhood cancer: case-control study.

OBJECTIVE: To examine childhood cancer risks associated with exposure to diagnostic radiation and ultrasound scans in utero and in early infancy (age 0-100 days). DESIGN: Case-control study. SETTING: England and Wales. PARTICIPANTS: 2690 childhood cancer cases and 4858 age, sex, and region matched controls from the United Kingdom Childhood Cancer Study (UKCCS), born 1976-96. MAIN OUTCOME MEASURES: Risk of all childhood cancer, leukaemia, lymphoma, and central nervous system tumours, measured by odds ratios. RESULTS: Logistic regression models conditioned on matching factors, with adjustment for maternal age and child's birth weight, showed no evidence of increased risk of childhood cancer with in utero exposure to ultrasound scans. Some indication existed of a slight increase in risk after in utero exposure to x rays for all cancers (odds ratio 1.l4, 95% confidence interval 0.90 to 1.45) and leukaemia (1.36, 0.91 to 2.02), but this was not statistically significant. Exposure to diagnostic x rays in early infancy (0-100 days) was associated with small, non-significant excess risks for all cancers and leukaemia, as well as increased risk of lymphoma (odds ratio 5.14, 1.27 to 20.78) on the basis of small numbers. CONCLUSIONS: Although the results for lymphoma need to be replicated, all of the findings indicate possible risks of cancer from radiation at doses lower than those associated with commonly used procedures such as computed tomography scans, suggesting the need for cautious use of diagnostic radiation imaging procedures to the abdomen/pelvis of the mother during pregnancy and in children at very young ages.

Illness patterns prior to diagnosis of lymphoma: analysis of UK medical records.

BACKGROUND: Increased understanding of the relationship between lymphomas and co-morbidities is likely to provide valuable insights into the natural history of these disorders. METHODS: 761 cases with lymphoma (310 diffuse large B-cell [DLBCL]; 226 follicular [FL]; and 225 Hodgkin [HL]) and 761 unaffected age and sex matched controls were recruited and their histories of infection and non-infection diagnoses in primary care records were compared using negative binomial regression. RESULTS: No differences were observed between the infectious illness patterns of DLBCL and FL cases and their matched controls over the 15 years preceding lymphoma diagnosis. A marked excess of infectious illness episodes was recorded for HL cases compared to their controls; evident at least a decade prior to HL diagnosis. For non-infectious consultations an excess of case over control visits emerged 4-6 years before DLBCL and FL diagnosis; no specific co-morbidity associations were found. No case-control differences for non-infectious conditions were apparent for HL. CONCLUSION: There are substantial variations in patterns of illness prior to diagnosis of the three lymphoma subtypes examined. The excess of infectious diagnoses prior to HL may point to underlying immune abnormality, but there was no suggestion of this for DLBCL and FL where a generalized excess of non-infectious conditions was evident.

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.

Reproductive factors, menopausal hormone therapy, and risk of non-Hodgkin, diffuse large B-cell and follicular lymphomas: a UK case-control study.

BACKGROUND: Most non-Hodgkin lymphoma (NHL) subtypes occur more among men than women. Since sex hormones may influence immune function, female hormones may be involved. To investigate the relationship between NHL subtypes and reproductive factors, findings from a UK population-based case-control study (1998-2003) are presented. METHODS: Female cases (n = 389) and controls (n = 394) aged 16-69 reported their reproductive histories. Odds ratios (ORs) and 95% confidence intervals (CI) were computed using unconditional logistic regression. RESULTS: No associations were found for age at menarche, parity, or age at first child. Among postmenopausal women, hormone therapy (HT) users had risks of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) below one compared to non-users (OR = 0.7, 95% CI 0.5,1.2; OR = 0.6, 95% CI 0.4,1.0, respectively). Estimates agree with other reports: meta-analyses gave pooled ORs of 0.8 (95% CI 0.6,0.9) for DLBCL and 1.0 (95% CI 0.8,1.2) for FL. In our study, ORs decreased with years of HT use: less and more than 5 years being 0.9 (95% CI 0.5,1.5) and 0.6 (95% CI 0.3,1.1) for DLBCL (p-trend = 0.22), and 0.8 (95% CI 0.4,1.4) and 0.4 (95% CI 0.2,0.9) for FL (p-trend = 0.06). CONCLUSION: For greater power to investigate the association of hormones with DLBCL, FL, and rarer NHL subtypes, pooling data through the International Lymphoma Epidemiology Consortium (InterLymph) is warranted.

Oral disease in children with Down syndrome: causes and prevention.

While healthcare professionals may be familiar with the social and medical management of Down syndrome, dental issues have traditionally been somewhat neglected and are important causes of morbidity. The aims of this review are two-fold. Firstly, to draw attention to the environmental and host factors associated with periodontal disease and dental caries (tooth decay) in children with Down syndrome. Secondly, to highlight key yet largely modifiable risk factors in the causation and progression of these chronic oral conditions, many of which also apply to other children with learning disabilities. The review focuses on the role of community and school-based healthcare professionals in promoting good oral health using evidence-based preventative strategies, and in encouraging early, regular contact with dental services.

Brain tumor signs and symptoms: analysis of primary health care records from the UKCCS.

OBJECTIVE: To compare the frequency of brain tumor signs and symptoms in children with and without brain tumors. METHODS: This was a UK population-based retrospective analysis of primary care records. Participants were 195 children (1-14 years) newly diagnosed with brain tumors and 285 controls matched by age, gender, and region. Comparisons included total number of prediagnosis consultations, number with >or=1 symptom suggestive of a brain tumor, total number of symptoms, number of different symptoms, and number of visits with specific combinations of symptoms. RESULTS: On average, cases consulted more often than controls between birth and diagnosis/pseudodiagnosis with brain tumor signs and symptoms. Their consultation rate with >or=1 suggestive symptom escalated in the 2 years before diagnosis. Symptom prevalence was higher among cases than controls, a relative difference of 3.29 times as many consultations with >or=1 suggestive symptom (95% confidence interval [CI]: 2.82-3.83) and 7.01 as many with more than 1 (95% CI: 5.38-9.13). In each 6-month period in the 4 years before diagnosis, cases had at least twice as many consultations with >or=1 suggestive symptom (20.81 times as many in the 6 months before diagnosis [95% CI: 14.29-30.30]) and 2-3 times more records of suggestive symptoms (28.35 times more in the 6 months before diagnosis [95% CI: 19.05-42.19]). Symptoms rarely or not observed among control children included head tilt, odd head movements, odd posture, back or neck stiffness, and unsteadiness without obvious cause. CONCLUSION Key to identifying the 1 child among many who merits prompt investigation is recognition of unusual symptoms, or specific symptom patterns.

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.

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.

What determines referral of UK patients with haematological malignancies to palliative care services? An exploratory study using hospital records.

We investigated the frequency and characteristics of patients with haematological malignancies (HMs) who were, or were not, referred for specialist palliative care (SPC). Data were abstracted from hospital records of 108 patients who died - 27 with leukaemia, 11 with myelodysplastic syndromes, 48 with lymphoma and 22 with myeloma. Ninety-three patients (86.1%) were >60 years of age at diagnosis, with 33 (30.6%) being >or=80 years and 31 (28.7%) having existing comorbidities. Thirty-three patients (30.6%) were referred to SPC services. There was little difference by age or HM diagnosis in referred patients. Seventeen of 67 patients (25.4%) dying on a hospital ward received SPC compared with 6/7 (85.7%) dying at home. Time between diagnosis and death influenced the referral - 24/52 patients (46.2%) dying >or=30 days after diagnosis received SPC compared with 8/42 (19.1%) dying within 30 days. In 14 patients, HM diagnosis was confirmed after death. Identification of these 14 patients is likely to be a unique feature of our study, as patients were selected from a regional, population-based register with centralized diagnostic services, enabling the identification of all patients with HM. The interface between curative and palliative treatment in HM is more complex than the National Institute for Clinical Excellence recommendations suggest.

Allergy and risk of childhood leukaemia: results from the UKCCS.

We investigated the relationship between childhood leukaemia and preceding history of allergy. A nationwide case-control study of childhood cancers was conducted in the United Kingdom with population-based sampling of cases (n = 839) and controls (n = 1,337), matched on age, sex and region of residence. Information about clinically diagnosed allergies was obtained from primary care records. More than a third of subjects had at least one allergy diagnosed prior to leukaemia diagnosis (cases) or pseudo-diagnosis (controls). For both total acute lymphoblastic leukaemia (ALL) and common-ALL/precursor B-cell ALL (c-ALL), a history of eczema was associated with a 30% significant reduction in risk: the odds ratios (OR) and 95% confidence intervals (CI) were 0.70 (0.51-0.97) and 0.68 (0.48-0.98), respectively. Similar associations were observed for hayfever (OR = 0.47; 95% CI: 0.26-0.85 and OR = 0.62; 95% CI: 0.33-1.16 for ALL and c-ALL, respectively). No such patterns were seen either for asthma and ALL, or for any allergy and acute myeloid leukaemia. A comparative analysis of primary care records with parents recall of allergy revealed only moderate agreement with contemporaneous clinical diagnoses for both cases and controls--confirming the unreliability of parental report at interview. Our finding of a reciprocal relationship between allergy and ALL in children is compatible with the hypothesis that a dysregulated immune response is a critical determinant of childhood ALL.

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.

Ovulation induction, assisted conception and childhood cancer.

Rapid advances have been made in the treatment of infertility over the last 30 years following the introduction of in vitro fertilisation and intracytoplasmic sperm injection. Whilst effects of assisted reproductive technology (ART) on birth outcomes are well documented little is known about effects on child health after the neonatal period. Childhood cancer is one area warranting further examination. The hypothesis that cancer in children may be initiated during early fetal development means that events leading up to and around conception may be important. Whilst the few large-scale epidemiological studies that have looked at childhood cancer incidence following ART have failed to find any significant increased risk, some case-control studies have reported an increased risk of specific cancers. However, it is important not to over interpret these findings as the reason for the infertility may be the predisposing factor, rather than the procedure itself. Recent recommendations by the UK's National Health Service to offer intra-uterine insemination and one free treatment cycle for infertile couples will result in increasing numbers of children born following ART. More detailed investigations that include larger numbers plus sufficient follow-up periods and information on the underlying causes of the infertility are needed since long term outcomes for these children, in particular the risk of developing cancer, remain largely unknown.