Prescription drug use during pregnancy and risk of childhood cancer - is there an association?

In economically developed countries up to 90% of women are prescribed medications, including vitamins and supplements, during pregnancy. Whilst a number of adverse health outcomes in their offspring have been related to prescription drug use, associations with childhood cancer are less clear and most investigations have been reliant on maternal self-report. With a view to providing new insight we investigated maternal prescription drug use and risk of childhood cancer primary care medical records collected as part of the United Kingdom Childhood Cancer Study, a national population-based case-control study conducted between 1991 and 1996. There was evidence that mothers of children with acute lymphoblastic leukaemia (OR 1.36, 95% CI 1.14-1.63), medulloblastoma (OR 1.79, 95% CI 1.00-3.22) and Wilms tumour (OR 1.79; 95% CI 1.05-3.04) were more likely to have been prescribed iron when compared to mothers of controls. In addition, systemic anti-infectives were positively associated with acute myeloid leukaemia (OR 1.58, 95% CI: 1.05-2.38) and rhabdomyosarcoma (OR 1.80, 95% CI 1.03-3.16), and analgesic use (NO2B) was positively associated with Hodgkin lymphoma (OR 5.02, 95% CI 2.16-11.82) and neuroblastoma (OR 1.99, 95% CI 1.07-3.69). Whilst our findings suggest that maternal use of antibiotics, iron, and nervous system drugs during pregnancy may be associated with some childhood cancer subtypes these associations need to be confirmed elsewhere. Unravelling the mechanisms that may underpin these associations is complex and research is needed to determine whether they are directly related to the drugs themselves, or the illnesses for which they were prescribed.

Survival from childhood acute lymphoblastic leukaemia: the impact of social inequality in the United Kingdom.

BACKGROUND: Survival from childhood acute lymphoblastic leukaemia (ALL) has continued to improve in economically-developed regions of the world, but 20% of patients still die within 5-years of diagnosis. Treatment is prolonged and complex; and as survival rates plateau, factors relating to socio-economic status and/or treatment adherence are increasingly scrutinised as potentially important determinants of outcome. METHODS: Predicated on the frame-work of the United Kingdom (UK) NHS, the relationship between socio-demographic factors and ALL survival is examined here using data from a large follow-up study conducted in the 1990s. One thousand five hundred and fifty nine children (0-14 years) diagnosed in England, Scotland &Wales during the era of the national UKALL XI randomized-controlled trial (RCT) were followed-up for an average of 15.9 years (20,826.3 person-years). Area-based deprivation scores and father's occupational social class at the time of the child's birth were used as markers of socio-economic status. Information on deaths was obtained from the NHS Information Centre for Health and Social Care. All children were included in the analyses, irrespective of RCT enrolment or participation in the founding epidemiological study (www.UKCCS.org).Survival effects were assessed using proportional hazards regressions models. RESULTS: Survival varied with both area-based deprivation at diagnosis (hazard ratio (HR) 1.29; 95% confidence interval (CI) 1.05-1.57) and fathers occupational social class at birth (HR 1.12; 95% CI 0.97-1.29); the divergence beginning 6-9 months after diagnosis, and widening thereafter during home-administered therapy. The findings became more marked when analyses were restricted to those enrolled in UKALL XI (n = 1341). As expected, survival differences were also observed with sex, and age at diagnosis. CONCLUSION: The existence of significant social disparities in ALL survival, which are not due to treatment accessibility, is of major clinical importance. Trends should be monitored and further research into potentially modifiable risk factors conducted.

Hodgkin's lymphoma and infection: findings from a UK case-control study.

Between 1998 and 2003, 214 people with Hodgkin's lymphoma and 214 controls randomly selected from population registers in the north of England (after matching for age and sex) were recruited and their primary care medical records examined for details of clinical diagnoses due to infectious and non-infectious conditions in the preceding 15 years. In the year before diagnosis of Hodgkin's lymphoma, almost all cases (99%) visited their general practitioner (GP) at least once. In comparison with controls, the excess was evident both for visits with an infection (odd's ratio (OR)=2.1; 95% confidence interval (CI) 1.4-3.2) and for visits with non-infectious problems (OR=17.2; 95% CI 6.7-43.9). During the rest of the 15-year period prior to diagnosis, the proportion of people visiting their GP with a non-infectious condition did not differ between cases and controls. In contrast, compared to controls, there was an excess of cases visiting the GP with an infection, a finding that was evident for at least a decade prior to diagnosis and increased linearly with time (P=0.02). This excess was not due to a specific infection(s) and may reflect underlying immune abnormality. Alternatively, infection may cause B-cell proliferation from which a malignant clone may evolve.

Investigation of the sources of residential power frequency magnetic field exposure in the UK Childhood Cancer Study.

There is an unexplained association between exposure to the magnetic fields arising from the supply and use of electricity, and increase in risk of childhood leukaemia. The UK Childhood Cancer Study (UKCCS) provides a large and unique source of information on residential magnetic field exposure in the UK. The purpose of this supplementary study was to investigate a sample of UKCCS homes in order to identify the particular sources that contribute to elevated time-averaged exposure. In all, 196 homes have been investigated, 102 with exposures estimated on the basis of the original study to be above 0.2 microT, and 21 higher than 0.4 microT, a threshold above which a raised risk has been observed. First, surveys were carried out outside the property boundaries of all 196 study homes, and then, where informed consent had been obtained, assessments were conducted inside the properties of 19 homes. The study found that low-voltage (LV) sources associated with the final electricity supply accounted together for 77% of exposures above 0.2 microT, and 57% of those above 0.4 microT. Most of these exposures were linked to net currents in circuits inside and/or around the home. High-voltage (HV) sources, including the HV overhead power lines that are the focus of public concern, accounted for 23% of the exposures above 0.2 microT, and 43% of those above 0.4 microT. Public health interest has focused on the consideration of precautionary measures that would reduce exposure to power frequency magnetic fields. Our study provides a basis for considering the options for exposure mitigation in the UK. For instance, in elevated-exposure homes where net currents are higher than usual, if it is possible to reduce the net currents, then the exposure could be reduced for a sizeable proportion of these homes. Further investigations would be necessary to determine whether this is feasible.

Childhood acute lymphoblastic leukemia and infections in the first year of life: a report from the United Kingdom Childhood Cancer Study.

The United Kingdom Childhood Cancer Study was designed to examine the relation between childhood cancer and preceding exposure to infectious diseases. The authors analyzed the relation between diagnosis (1991-1996) of acute lymphoblastic leukemia (ALL) at ages 2-5 years and clinically diagnosed infections in infancy. Almost all study children (96% of both cases and controls) were taken to a general practitioner for a non-immunization-associated visit at least once before their first birthday. Children diagnosed with ALL had significantly more clinically diagnosed infectious episodes in infancy than did controls; the average number of episodes was 3.6 (95% confidence interval (CI): 3.3, 3.9) versus 3.1 (95% CI: 2.9, 3.2). This case-control difference was most apparent in the neonatal period (< or =1 month); 18% of controls and 24% of ALL cases were diagnosed with at least one infection (odds ratio = 1.4, 95% CI: 1.1, 1.9; p < 0.05). Cases who had more than one neonatal infectious episode tended to be diagnosed with ALL at a comparatively young age; the mean age at ALL diagnosis was 37.7 months for cases with two or more episodes versus 45.3 months for cases with only one episode or none (p < 0.01). These findings support the hypothesis that a dysregulated immune response to infection in the first few months of life promotes transition to overt ALL later in childhood.

Non-Hodgkin's lymphoma and family history of hematologic malignancy.

Familial aggregation of non-Hodgkin's lymphoma, and the co-occurrence of non-Hodgkin's lymphoma and other hematologic malignancies within families, provide evidence for genetic or common environmental etiologies for these conditions. The authors analyzed the association between non-Hodgkin's lymphoma risk and family history of hematologic malignancy using a case-control study based in the United Kingdom. The study recruited patients diagnosed with lymphoma during 1998-2001. Results indicated an increased risk of non-Hodgkin's lymphoma for persons with a positive family history of any hematologic malignancy (odds ratio = 1.70, 95% confidence interval: 1.08, 2.69) and particularly of any lymphoma (odds ratio = 2.43, 95% confidence interval: 1.14, 5.19). The authors compared the number of hematologic malignancies among relatives reported by the cases and controls with that expected from the national rates of hematologic malignancy registered in the United Kingdom. Through these comparisons, the authors raise questions about the validity of self-reported family history of hematologic malignancy, especially regarding identification of specific types of hematologic malignancies. Given these reservations, they consider how future epidemiologic studies may contribute to further understanding the role of familial susceptibility in non-Hodgkin's lymphoma.

Repression of cancer protective genes by 17beta-estradiol: ligand-dependent interaction between human Nrf2 and estrogen receptor alpha.

Repression of cancer-protective phase II enzymes may help explain why estrogen exposure leads to the development of cancer. In an earlier report we described the ability of 17beta-estradiol (E(2)) to repress phase II enzyme activity in vivo. Phase II enzymes are coordinately regulated via the presence of the antioxidant response element (ARE) in their promoter. We wanted to determine if estrogen receptors (ER) repress ARE-dependent gene expression through a mechanism that requires interaction with Nrf2, the transcription factor that regulates ARE-mediated gene transcription. E(2)-bound ERalpha, but not ERbeta, represses ARE-regulated gene expression in the presence of exogenously expressed Nrf2 as well as when the transactivation domain of Nrf2 was fused to a heterologous DNA-binding domain. Deletion of the activation function-2 (AF-2) and the ligand-binding domain of ERalpha result in a constitutive repression of Nrf2-mediated transcription. Finally, E(2)-bound ERalpha co-immunoprecipitates with Nrf2. Repression of Nrf2-mediated transcription by E(2)-bound ERalpha expands our knowledge of E(2)-regulated genes and provides a potential drug-screening target for the development of selective estrogen receptor modulators with a lower risk of causing cancer.

Relationships between perinatal and maternal characteristics and hepatoblastoma: a report from the UKCCS.

Within the context of a national population-based case-control study--the United Kingdom Childhood Cancer Study (UKCCS)--we aimed to explore relationships between perinatal and maternal factors and childhood hepatic tumours, for participants with data available from medical records. 26/28 children with hepatic tumours (22/24 hepatoblastomas, 4/4 hepatocellular carcinomas (HCC)) and 4753 age- and sex-matched controls were included. Polyhydramnios was associated with 0.9% of control pregnancies and 13.6% of case pregnancies (Odds Ratio (OR)=28.64, 95% Confidence Interval (CI)=6.94-118.21, P<0.0001); eclampsia or severe pre-eclampsia complicated the pregnancies of 16.7% of mothers whose children developed hepatoblastoma compared with 0.5% of control pregnancies (OR=52.50, 95% CI=10.75-257.05, P<0.0001). Three children with hepatoblastoma weighed <1500 g at birth, two of whom weighed <1000 g (OR for birthweight <1500 g=69.00, 95% CI=11.98-397.17, P<0.0001). Of children with hepatoblastoma, 50% (11/22) had records of congenital anomalies, as did two of their mothers. Three mothers of children with hepatoblastoma had diagnoses of cancer--two of papillary carcinoma of the thyroid and one of acute lymphoblastic leukaemia (ALL). Paediatricians and others should be alert to the possibility of familial or genetic syndromes in children with hepatoblastomas. Potential links between maternal pre-eclampsia, low birthweight and subsequent malignancy merit further investigation. Hepatoblastoma is an extremely rare childhood tumour, but understanding the mechanism(s) underlying severe pre-eclampsia and eclampsia may also shed light on factors that contribute to the development of hepatoblastoma.

Perinatal and reproductive factors: a report on haematological malignancies from the UKCCS.

The United Kingdom Childhood Cancer Study was designed to examine the potential aetiological role of a range of perinatal and reproductive factors. Our use of clinical records permitted a more exact characterisation of reproductive events than is possible in investigations that rely on self-reporting; and the increased specificity with which antecedent events were measured produced more precise risk estimates, albeit ones based on progressively smaller numbers. Information on the conduct of this component of the study and results for 1485 children with haematological malignancies and 4864 controls are presented. The 'find' rate for obstetric records was high at 86% for cases, with 81% having information on both matched controls. Associations were seen for severe hyperemesis (Odds Ratio=3.6, 95%Confidence Interval=1.3-10.1, for all leukaemias), polyhydramnios (OR=4.0, 95%CI=1.5-10.3, for acute myeloid leukaemia (AML)), anaemia (haemoglobin <10 g, OR=2.6, 95%CI=1.7-4.1, for AML), and pre-eclampsia (OR=1.7, 95%CI=1.1-2.7, for non-Hodgkin's lymphoma). Babies who developed leukaemia were heavier at birth (>4000 g, OR=1.2, 95%CI=1.0-1.4), as were their older siblings (>4000 g, OR=1.4, 95%1.0-1.9). Mothers' whose children developed common B-cell precursor acute lymphoblastic leukaemia (ALL) were more likely to have had a previous molar pregnancy (OR=5.2, 95%CI=1.9-14.7). Gender-specific analysis revealed that findings often differed markedly for boys and girls; and, in common with other reports, strong associations with Down's syndrome were seen for both ALL and AML.

In vitro and in vivo regulation of antioxidant response element-dependent gene expression by estrogens.

Understanding estrogen's regulation of phase II detoxification enzymes is important in explaining how estrogen exposure increases the risk of developing certain cancers. Phase II enzymes such as glutathione-S-transferases (GST) and quinone reductase protect against developing chemically induced cancers by metabolizing reactive oxygen species. Phase II enzyme expression is regulated by a cis-acting DNA sequence, the antioxidant response element (ARE). It has previously been reported that several antiestrogens, but not 17beta-estradiol, could regulate ARE-mediated gene transcription. Our goal was to determine whether additional estrogenic compounds could regulate ARE-mediated gene expression both in vitro and in vivo. We discovered that physiological concentrations (10 nm) of 17beta-estradiol repressed GST Ya ARE-dependent gene expression in vitro. Treatment with other endogenous and anti-, xeno-, and phytoestrogens showed that estrogen receptor/ARE signaling is ligand, receptor subtype, and cell type specific. Additionally, GST and quinone reductase activities were significantly lowered in a dose-dependent manner after 17beta-estradiol exposure in the uteri of mice. In conclusion, we have shown that 17beta-estradiol, and other estrogens, down-regulate phase II enzyme activities. We propose estrogen-mediated repression of phase II enzyme activities may increase cellular oxidative DNA damage that ultimately can result in the formation of cancer in some estrogen-responsive tissues.

Vitamin K and childhood cancer: a report from the United Kingdom Childhood Cancer Study.

The relationship between neonatal vitamin K received by the intramuscular (i.m.) route and the development of leukaemia or other cancers was investigated as part of a national case-control study of childhood cancer, using data abstracted from obstetric and neonatal records. The analyses included 2530 children diagnosed with cancer before 15 years of age, 1174 of whom had leukaemia and 4487 control children without cancer. Overall, 39% of cases and 42% of controls had records of i.m. vitamin K administration, while 24% of cases and 22% of controls had no record of whether or not they had received vitamin K. Using subjects who received i.m. vitamin K as the baseline group, our analyses found no association between the administration of i.m. vitamin K and either leukaemia or other cancers as a group. We conclude that there is no convincing evidence that neonatal vitamin K administration, irrespective of the route by which it is given, influences the risk of children developing leukaemia or any other cancer.

Vitamin K and childhood cancer: analysis of individual patient data from six case-control studies.

To investigate the hypothesis that neonates who receive intramuscular vitamin K are at an increased risk of developing cancer, particularly leukaemia, a pooled analysis of individual patient data from six case-control studies conducted in Great Britain and Germany has been undertaken. Subjects comprised 2431 case children diagnosed with cancer before 15 years of age and 6338 control children. The retrospective assessment of whether or not an individual baby received vitamin K is not straightforward. In many cases no record was found in stored medical notes and two types of analysis were therefore conducted; in the first it was assumed that where no written record of vitamin K was found it had not been given, and in the second, where no written record of administration was found, information on hospital policy and perinatal morbidity was used to 'impute' whether or not vitamin K had been given. In the first analysis, no association was found between neonatal administration of intramuscular. vitamin K and childhood cancer: odds ratios adjusted for mode of delivery, admission to special care baby unit and low birth weight were 1.09 (95% confidence interval 0.92-1.28) for leukaemia and 1.05 (0.92-1.20) for other cancers. In the second analysis, the adjusted odds ratios increased to 1.21 (1.02-1.44) for leukaemia and 1.10 (0.95-1.26) for other cancers. This shift did not occur in all studies, and when data from the hypothesis generating Bristol study were excluded, the adjusted odds ratios for leukaemia became 1.06 (0.89-1.25) in the first analysis and 1.16 (0.97-1.39) when data on prophylaxis imputed from hospital policy and perinatal morbidity were used. We conclude that whilst the broad nature of the diagnostic groups and the poor quality of some of the vitamin K data mean that small effects cannot be entirely ruled out, our analysis provides no convincing evidence that intramuscular vitamin K is associated with childhood leukaemia.

Malignant neoplasms of the brain during childhood: the role of prenatal and neonatal factors (United Kingdom).

OBJECTIVES: To evaluate whether factors in pregnancy and around birth influence the risk of childhood malignant neoplasms of the brain or other parts of the nervous system. METHODS: The distribution of certain characteristics of pregnancy and birth among 83 cases of malignant neoplasms of the brain and other parts of the nervous system (diagnosed between 0 and 14 years of age) and 166 controls (individually matched on date of birth, sex, and hospital of birth) were compared. Odds ratios (OR), 95% confidence intervals (95% CI) and two-sided p-values were calculated using conditional logistic regression for matched sets. RESULTS: Children whose mothers had documented evidence of a clinically diagnosed viral infection during pregnancy had an approximately 11-fold increase in risk of developing a malignant neoplasm of the brain or other part of the nervous system (OR = 10.6, 95% CI = 1.1-503.2). In addition, non-statistically significant increased risks were observed among children who had a non-cephalic presentation (OR = 3.3, 95% CI = 0.8-13.9) or a low 1-minute apgar score (OR = 2.7, 95% CI = 1.0-7.4). No other aspects of the index pregnancy, delivery, or maternal characteristics were associated with an increased risk of childhood brain tumors. CONCLUSIONS: The results reported here provide limited evidence for the role of prenatal and neonatal factors in the etiology of childhood malignant neoplasms of the brain. The finding for maternal viral infection during pregnancy warrants further investigation.

Leukaemia and non-Hodgkin's lymphoma in children and young adults: are prenatal and neonatal factors important determinants of disease?

A medical record-based study of leukaemia and non-Hodgkin's lymphoma diagnosed before the age of 30 years was carried out at three hospitals in the south of England. Findings for 177 cases and 354 age- and sex-matched controls are presented here. For documented viral infection in pregnancy, the odds ratio (OR) was 6.0 [95% confidence interval (CI) 1.2-29.7] for leukaemia and infinity (95% CI 1.24-infinity) for non-Hodgkin's lymphoma. Mothers of leukaemic cases were more likely to be anaemic, the OR for a pregnancy haemoglobin below 10 g being 3.8 (95% CI 1.3-11.1). An association with birthweight was found for acute myeloid leukaemia, the OR for birthweights > 3500 g being 6.2 (95% CI 1.3-29.8). Further, the preceding siblings of those diagnosed with any form of leukaemia were also more likely to weigh > 3500 g at birth (OR 2.2; 95% CI 1.1-4.4). Overall, leukaemic cases appeared to be comparatively robust at birth with respect to other indicators of well-being, the ORs for jaundice, phototherapy, admission to special care nursery and neonatal intensive care all being less than 1.0. Further, no relation between childhood leukaemia and neonatal administration of intramuscular vitamin K was noted (OR 0.6, 95% CI 0.3-1.4; for acute lymphoblastic leukaemia diagnosed between the ages of 1 and 6 years).

A case-control study of cryptorchidism and maternal hormone concentrations in early pregnancy.

Serum samples taken between 6 and 20 weeks of gestation were obtained from 28 mothers who gave birth to cryptorchid sons (cases) and from 108 control mothers. In comparison with controls the cases had 10% higher geometric mean oestradiol (95% CI -13% to +39%: P=0.42) and 10% lower geometric mean testosterone (95% CI -27% to +10%: P=0.30). Among the samples collected between 6 and 14 weeks of gestation geometric mean concentrations of oestradiol and testosterone were 5% lower (95% CI -32% to +31%: P=0.74) and 25% lower (95% CI -45% to +1%: P=0.06) respectively in cases than in controls. Among the samples collected between 15 and 20 weeks of gestation geometric mean concentrations of oestradiol and testosterone were 29% higher (95% CI -8% to +79%: P=0.14) and 21% higher (95% CI -8% to +60%: P=0.18) respectively in cases than in controls. The results do not support the hypothesis that cryptorchidism may be caused by high concentrations of oestradiol in the maternal blood during the first phase of testicular descent, but suggest that the possible association of cryptorchidism with low maternal testosterone during early gestation should be further investigated.

Health of children born to medical radiographers.

OBJECTIVES: To develop a reliable method for collecting information on reproductive outcome in an occupational setting; and to investigate the health of children born to medical radiographers. METHODS: The study population comprised 6730 members of the College of Radiographers who were, at the time of survey; aged between 30 and 64 years, on the current membership file of the College, and were resident in Britain. RESULTS: The postal method developed proved to be reliable, with around 87% of questionnaires being returned. The observed frequencies of reproductive events were broadly in line with findings from other studies: of the 9208 pregnancies reported, 83% were livebirths, 12% were miscarriages (gestational age < 20 weeks), 1% were stillbirths (gestational age > or = 20 weeks), and 1% were other rarer spontaneous adverse events (ectopic pregnancy, blighted ovum, and hydatidiform mole). There was little difference between men and women in the frequency of adverse reproductive events reported, with the exception that male radiographers reported fewer medical terminations, the proportions being 3.1% and 1.4% for women and men respectively. Among children, the overall risks of major congenital malformation (RR 1.0, 95%CI 0.9-1.2), chromosomal anomaly (RR 1.4, 95%CI 0.8-2.3), and cancer (RR 1.2 95%CI 0.7-2.0) were as expected based on general population rates. Borderline excesses of chromosomal anomalies other than Down's syndrome in the children of female radiographers (RR 3.9, 95%CI 1.3-9.0, based on five observations), and cancer in the children of male radiographers (RR 2.7, 95%CI 0.9-6.5, based on five observations) were noted. The numbers on which these risks are based are small and the findings should be interpreted cautiously. CONCLUSIONS: The postal methods developed for obtaining information about reproductive events and child health proved to be reliable in men, as well as in women. Overall, the findings for medical radiographers are reassuring. Dose-response relations could not, however, be examined as long term dose records of radiographers are not routinely kept in an accessible form.

The prevalence and characteristics of congenital pigmented lesions in newborn babies in Oxford.

Melanocytic naevi (MN) are recognised risk factors for malignant melanoma but the epidemiology of MN is poorly understood. Some MN are present at birth and the study of congenital lesions is an important first step toward understanding the development of MN in early life. In this study, the prevalence and characteristics of congenital pigmented lesions were documented in 1012 White caucasian newborn babies at a maternity hospital in Oxford. Only 12 babies (1.2%) were found to have pigmented skin marks and each of these had only one lesion and no other abnormalities. MN were identified with certainty in only five babies (0.5% of the population; 95% CI, 0.06%-0.93%) thus confirming the relatively low prevalence of this lesion. Four of the MN were noted to be 'small' (less than 15 mm diameter) and all five were less than or equal to 20 mm in diameter. In other respects, the MN displayed a diversity of features. Of the other lesions there were two Mongolian blue spots, one melanocytic pustule, one 'probable' MN and three unusual skin marks where the diagnosis was uncertain but considered unlikely to be MN. During the course of the study, examinations were also carried out incidentally on 39 non-White babies. Twenty-two of these were noted to have Mongolian spots (57%) and three had other pigmented lesions (8%).

Convolution in human rods: an ageing process.

In a morphological survey of 73 human retinae spanning 9 decades, and including 20 retinae which were obtained from eyes enucleated for malignant melanomas, nodular excrescences were noted in the outer segments of rods with an incidence which increased with age. These structures were sectioned in both their vertical and horizontal axes and on electron microscopical examination were seen to result from the localised convolution of affected outer segments. The topographic morphology of such convolutions is described and their modes of formation are discussed.