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BackgroundChildhood cancers are associated with high mortality and morbidity, and some maternal prescription drug use during pregnancy has been implicated in cancer risk. There are few studies on the effects of hypertension, preeclampsia, and the use of antihypertensives in pregnancy on children's cancer risks.ObjectiveThis population-based cohort study analyzed the relationship between hypertension, preeclampsia, and antihypertensives taken during pregnancy and the risks of childhood cancers in the offspring.MethodsData on all children born in Taiwan between 2004 and 2015 (N = 2,294,292) were obtained from the Maternal and Child Health Database. This registry was linked with the National Health Insurance Database and Cancer Registry to get the records of maternal use of diuretics or other antihypertensives in pregnancy and records of children with cancer diagnosed before 13 years. We used Cox proportional hazard modeling to estimate the influence of maternal health conditions and antihypertensive drug exposure on the risks of developing childhood cancers.ResultsOffspring of mothers with hypertension (chronic or gestational) had a higher risk of acute lymphocytic lymphoma [hazard ratio (HR) = 1.87, 95% Confidence Interval (CI) 1.32 - 2.65] and non-Hodgkin's lymphoma (HR = 1.96, 95% CI 1.34 - 2.86). We estimated only a weak increased cancer risk in children whose mothers used diuretics (HR = 1.16, 95% CI 0.77 - 1.74) or used antihypertensives other than diuretics (HR = 1.15, 95% CI 0.86 - 1.54) before birth.ConclusionsIn this cohort study, children whose mothers had chronic and gestational hypertension had an increased risk of developing childhood cancer.

BackgroundAutoimmune diseases have been linked to an increased risk of pregnancy-related complications. A family history of autoimmune diseases may be related to the risk of childhood cancer based on similar histocompatibility antigens. We utilized data from national registries in Denmark to examine associations between maternal autoimmune disease and cancer in their offspring.MethodsWe linked data from several national registries in Denmark to identify childhood cancer cases in children

BackgroundMaternal solvent exposure has been suspected to increase offspring cancer risk. The study aimed to evaluate the associations between maternal residential exposure to solvents from industrial pollution during pregnancy and childhood cancer.MethodsThe present study included 15,744 cancer cases (aged 0-19 years at diagnosis) identified from California Cancer Registry and 283,141 controls randomly selected from California Birth Registry (20:1 frequency-matched by birth year: 1998-2016). We examined industrial releases of tetrachloroethylene and 1,1,1-trichloroethane within 3 km of the birth address, while we used a 5 km buffer for carbon disulfide. We calculated the total exposure from all linked Toxic Release Inventory sites during each index pregnancy and assigned "ever/never" and "high/low exposed/unexposed" exposure, using median values. We performed quadratic decay models to estimate cancer risks associated with maternal solvent exposure in pregnancy.Results1,1,1-Trichloroethane was associated with rhabdomyosarcoma (adjusted Odds Ratio (aOR): 1.96; 95% Confidence Interval (CI): 1.16, 3.32) in the "ever exposed" group. Ever exposure to carbon disulfide was associated with increased risks of medulloblastoma (OR = 1.85, 95% CI 1.01, 3.40) and ependymoma (OR = 1.63, 95% CI 0.97, 2.74).ConclusionsOverall, our findings suggested maternal residential exposure to solvents from industrial sources might be associated with elevated childhood cancer risks.

BackgroundA growing literature has reported associations between traffic-related air pollution and breast cancer, however there are fewer investigations into specific ambient agents and any putative risk of breast cancer development, particularly studies occurring in populations residing in higher pollution areas such as Los Angeles.ObjectivesTo estimate breast cancer risks related to ambient air toxics exposure at residential addresses.MethodsWe examined the relationships between ambient air toxics and breast cancer risk in the Multiethnic Cohort among 48,665 California female participants followed for cancer from 2003 through 2013. We obtained exposure data on chemicals acting as endocrine disruptors or mammary gland carcinogens from the National-Scale Air Toxics Assessment. Cox proportional hazards models were used to estimate breast cancer risk per one interquartile range (IQR) increase in air toxics exposure lagged by 5-years. Stratified analyses were conducted by race, ethnicity, and hormone receptor types.ResultsAmong all women, increased risks of invasive breast cancer were observed with toxicants related to industries [1,1,2,2-tetrachloroethane (hazard ratio [HR] = 4.22, 95% confidence interval [95% CI] 3.18-5.60), ethylene dichloride (HR = 2.81, 95% CI 2.20-3.59), and vinyl chloride (HR = 2.27, 95% CI 1.81, 2.85); these 3 agents were correlated (r2 = 0.45-0.77)]. Agents related to gasoline production or combustion were related to increased breast cancer risk [benzene (HR = 1.32, 95% CI 1.24, 1.41), ethylbenzene (HR = 1.20, 95% CI 1.13-1.28), toluene (HR = 1.29, 95% CI 1.20-1.38), naphthalene (HR = 1.11, 95% CI 1.02-2.22), acrolein (HR = 2.26, 95% CI 1.92, 2.65)]. Higher hazard ratios were observed in African Americans and Whites compared to other racial and ethnic groups (p-heterogeneity

Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire-based and three registry-based case-control studies across 13 countries, we used multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a spectrum of birth defects and leukemia. Our analyses included acute lymphoblastic leukemia (ALL, n = 13 115) and acute myeloid leukemia (AML, n = 2120) cases, along with 46 172 controls. We used the false discovery rate to account for multiple comparisons. In the questionnaire-based studies, the prevalence of birth defects was 5% among cases vs 4% in controls, whereas, in the registry-based studies, the prevalence was 11% among cases vs 7% in controls. In pooled adjusted analyses, there were several notable associations, including (1) digestive system defects and ALL (OR = 2.70, 95% CI: 1.46-4.98); (2) congenital anomalies of the heart and circulatory system and AML (OR = 2.86, 95% CI: 1.81-4.52) and (3) nervous system defects and AML (OR = 4.23, 95% CI: 1.50-11.89). Effect sizes were generally larger in registry-based studies. Overall, our results could point to novel genetic and environmental factors associated with birth defects that could also increase leukemia susceptibility. Additionally, differences between questionnaire- and registry-based studies point to the importance of complementary sources of birth defect phenotype data when exploring these associations.

BackgroundSystematically recorded smoking data are not always available in vital statistics records, and even when available it can underestimate true smoking rates.ObjectiveTo develop a prediction model for maternal tobacco smoking in late pregnancy based on birth certificate information using a combination of self- or provider-reported smoking and biomarkers (smoking metabolites) in neonatal blood spots as the alloyed gold standard.MethodsWe designed a case-control study where childhood cancer cases were identified from the California Cancer Registry and controls were from the California birth rolls between 1983 and 2011 who were cancer-free by the age of six. In this analysis, we included 894 control participants and performed high-resolution metabolomics analyses in their neonatal dried blood spots, where we extracted cotinine [mass-to-charge ratio (m/z) = 177.1023] and hydroxycotinine (m/z = 193.0973). Potential predictors of smoking were selected from California birth certificates. Logistic regression with stepwise backward selection was used to build a prediction model. Model performance was evaluated in a training sample, a bootstrapped sample, and an external validation sample.ResultsOut of seven predictor variables entered into the logistic model, five were selected by the stepwise procedure: maternal race/ethnicity, maternal education, child's birth year, parity, and child's birth weight. We calculated an overall discrimination accuracy of 0.72 and an area under the receiver operating characteristic curve (AUC) of 0.81 (95% confidence interval [CI] 0.77, 0.84) in the training set. Similar accuracies were achieved in the internal (AUC 0.81, 95% CI 0.77, 0.84) and external (AUC 0.69, 95% CI 0.64, 0.74) validation sets.ConclusionsThis easy-to-apply model may benefit future birth registry-based studies when there is missing maternal smoking information; however, some smoking status misclassification remains a concern when only variables from the birth certificate are used to predict maternal smoking.

BackgroundNeonatal per- and polyfluoroalkyl substance (PFAS) exposure can disrupt hormonal homeostasis and induce neuro- and immunotoxicity in children. In this exploratory study, we investigated associations between PFAS levels in neonatal dried blood spots and retinoblastoma risk.Materials and methodsThis study included 501 retinoblastoma cases born from 1983 to 2011 and 899 controls frequency-matched by birth year (20:1 matching ratio), born to 755 US-born and 366 Mexico-born mothers in California. Perfluorooctanesulfonic acid (PFOS), perflurooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) feature intensities were identified from neonatal blood spots from California newborn Genetic Disease Screening Program. Using logistic regression, we assessed whether an interquartile range (IQR) increase of PFAS levels or having above-mean levels of PFAS in blood affects retinoblastoma risk overall or its subtypes (i.e., unilateral, bilateral). We assessed children of US-born and Mexico-born mothers, separately.Results and discussionAmong all children, above-mean PFOS levels at birth increased the odds of retinoblastoma overall by 29% (95% Confidence Interval (CI): 1.00, 1.67) and unilateral retinoblastoma by 42% (95% CI: 1.03, 1.97). For children of Mexico-born mothers, we estimated the highest odds of retinoblastoma overall (adjusted odds ratio (aOR): 1.67; 95% CI: 1.06, 2.66) and bilateral retinoblastoma (aOR: 2.06; 95% CI: 1.12, 3.92) with above-mean PFOS levels. Among children of US-born mothers, higher PFOS levels increased the odds of unilateral retinoblastoma by 15% (95% CI: 0.99, 1.35) for each IQR increase and by 71% among children with above-mean PFOS levels (95% CI: 1.04, 2.90). In addition, for children of US-born mothers, PFOA increased the odds of retinoblastoma overall (aOR: 1.41; 95% CI: 1.00, 2.02 for above-mean levels, aOR: 1.06; 95% CI: 0.98, 1.16 per IQR increase). PFNA was not associated with retinoblastoma risk.ConclusionsOur results suggested that PFOS and PFOA might contribute to retinoblastoma risk in children born in California.

BackgroundRetinoblastoma is rare but nevertheless the most common pediatric eye cancer that occurs in children under age 5. High-resolution metabolomics (HRM) is a powerful analytical approach to profile metabolic features and pathways or identify metabolite biomarkers. To date, no studies have used pre-diagnosis blood samples from retinoblastoma cases and compared them to healthy controls to elucidate early perturbations in tumor pathways.ObjectivesHere, we report on metabolic profiles of neonatal blood comparing cases later in childhood diagnosed with retinoblastoma and controls.MethodsWe employed untargeted metabolomics analysis using neonatal dried blood spots for 1327 children (474 retinoblastoma cases and 853 healthy controls) born in California from 1983 to 2011. Cases were selected from the California Cancer Registry and controls, frequency matched to cases by birth year, from California birth rolls. We performed high-resolution metabolomics to extract metabolic features, partial least squares discriminant analysis (PLS-DA) and logistic regression to identify features associated with disease, and Mummichog pathway analysis to characterize enriched biological pathways.ResultsPLS-DA identified 1917 discriminative features associated with retinoblastoma and Mummichog identified 14 retinoblastoma-related enriched pathways including linoleate metabolism, pentose phosphate pathway, pyrimidine metabolism, fructose and mannose metabolism, vitamin A metabolism, as well as fatty acid and lipid metabolism.InterpretationOur findings linked a retinoblastoma diagnosis in early life to newborn blood metabolome perturbations indicating alterations in inflammatory pathways and energy metabolism. Neonatal blood spots may provide a venue for early detection for this or potentially other childhood cancers.

ObjectiveOnly a few studies have reported on the association between hyperemesis gravidarum and the risk of childhood cancer. We examined possible associations in this population-based study in Denmark.MethodsPediatric cancer cases (n = 6420) were ascertained from the Denmark Cancer Registry among children born between 1977 and 2013. Twenty-five controls were matched to each case by sex and birth date from the Central Person Registry (n = 160500). Mothers with hyperemesis gravidarum were ascertained from the National Patient Register. The risk of childhood cancer was estimated using conditional logistic regression. In a separate analysis, we examined pregnancy prescription of antinauseant medications, ascertained from the National Pharmaceutical Register, to determine associations with childhood cancers.ResultsIn Denmark, hyperemesis gravidarum was associated with an increased risk of childhood cancer [all types combined; Odds Ratio (OR) = 1.43, 95% confidence interval (CI) 1.12, 1.81; n = 73 exposed cases). Hyperemesis gravidarum was also associated with an increased risk of neuroblastoma (OR = 2.52, 95% CI 1.00, 6.36; n = 5 exposed cases), acute lymphoblastic leukemia (OR = 1.63, 95% CI 0.98, 2.72; n = 16 exposed cases), and non-Hodgkin's lymphoma (OR = 2.41, 95% CI 0.95, 6.08; n = 5 exposed cases). We observed no childhood cancer risk increase from antinauseant prescriptions (OR = 1.05, 95% CI 0.84, 1.30; n = 91 exposed cases).ConclusionOur results are suggestive of an association between hyperemesis gravidarum and the overall cancer risk in offspring, particularly for neuroblastoma. Mothers with hyperemesis gravidarum should be closely monitored and receive appropriate treatment during pregnancy.

Epidemiologic studies of low-frequency exposures or outcomes using metabolomics analyses of neonatal dried blood spots (DBS) often require assembly of samples with substantial differences in duration of storage. Independent assessment of stability of metabolites in archived DBS will enable improved design and interpretation of epidemiologic research utilizing DBS. Neonatal DBS routinely collected and stored as part of the California Genetic Disease Screening Program between 1983 and 2011 were used. The study population included 899 children without cancer before age 6 years, born in California. High-resolution metabolomics with liquid-chromatography mass spectrometry was performed, and the relative ion intensities of common metabolites and selected xenobiotic metabolites of nicotine (cotinine and hydroxycotinine) were evaluated. In total, we detected 26,235 mass spectral features across 2 separate chromatography methods (C18 hydrophobic reversed-phase chromatography and hydrophilic-interaction liquid chromatography). For most of the 39 metabolites related to nutrition and health status, we found no statistically significant annual trends across the years of storage. Nicotine metabolites were captured in the DBS with relatively stable intensities. This study supports the usefulness of DBS stored long-term for epidemiologic studies of the metabolome. -Omics-based information gained from DBS may also provide a valuable tool for assessing prenatal environmental exposures in child health research.

While associations between maternal infections during pregnancy and childhood leukemia in offspring have been extensively studied, the evidence for other types of childhood cancers is limited. Additionally, antibiotic exposure during pregnancy could potentially increase the risk of childhood cancers. Our study investigates associations between maternal infections and antibiotic prescriptions during pregnancy and the risk of childhood cancer in Taiwan. We conducted a population-based cohort study using the Taiwan Maternal and Child Health Database (TMCHD), linked with national health and cancer registries. The study included 2 267 186 mother-child pairs, and the median follow-up time was 7.96 years. Cox proportional hazard models were utilized to estimate effects. Maternal infections during pregnancy were associated with a moderate increase in the risk of childhood hepatoblastoma (adjusted hazard ratio [HR] = 1.34; 95% confidence interval [CI]: 0.90-1.98) and a weaker increase in the risk of childhood acute lymphoblastic leukemia (ALL) (adjusted HR = 1.15; 95% CI: 0.99-1.35). Antibiotic prescriptions during pregnancy were also associated with an elevated risk of childhood ALL (adjusted HR = 1.30; 95% CI: 1.04-1.63), particularly with tetracyclines (adjusted HR = 2.15; 95% CI: 1.34-3.45). Several specific antibiotics were also associated with an increased risk of hepatoblastoma and medulloblastoma. Children exposed in utero to antibiotic prescription or both infections and antibiotics during pregnancy were at higher risk of developing ALL. Our findings suggest that there are associations between maternal infections, antibiotic use during pregnancy and the risk of several childhood cancers in addition to ALL and highlight the importance of further research in this area.

Purpose: Preeclampsia is a serious pregnancy complication that presents a significant risk to both the mother and the fetus. Preeclampsia and medications associated with its treatment are potentially linked to increased childhood cancer risk. Therefore, we examined the association between preeclampsia, antihypertensive medications, and childhood cancer in offspring.Methods: Cases (n = 6,420) and controls (n = 160,484) were obtained from Danish national registries. We performed conditional logistic regression analyses to estimate the association between preeclampsia and childhood cancer risk, and examined the effects of antihypertensive medication use in pregnancy in relation to childhood cancer risk in the offspring with adjustment for relevant covariates.Results: We observed an increased risk of acute lymphoblastic leukemia (ALL) among those whose mothers had preeclampsia (OR = 1.36, 95% CI 1.03, 1.79), especially for severe preeclampsia (OR = 2.36, 95% CI 1.37, 4.08). We also estimated an increased cancer risk in children born to mothers who were prescribed diuretics during pregnancy [OR = 2.09, 95% confidence interval (CI) 1.39, 3.14]. Intake of other antihypertensive medications was not associated with childhood cancer (OR = 0.78, 95% CI 0.50, 1.23). Among women who did not take diuretics in pregnancy, preeclampsia was associated with neuroblastoma (OR = 2.22, 95% CI 1.08, 4.55).Conclusion: Our findings suggested an increased risk for certain types of cancer in the offspring of mothers with preeclampsia and an increased risk of cancer with diuretic intake during pregnancy.

BackgroundMaternal migraine has been linked to adverse birth outcomes including low birth weight and preterm birth, as well as congenital anomalies in offspring. It has been speculated that this may be due to the use of medications in pregnancy, but lifestyle, genetic, hormonal, and neurochemical factors could also play a role. There is evidence for varying cancer incidences among adults with migraine. Here, we utilized data from national registries in Denmark to examine associations between maternal diagnoses of migraine and risk for cancer in offspring.MethodsWe linked several national registries in Denmark to identify cases from the Cancer Registry among children less than 20 years (diagnoses 1996–2016) and controls from the Central Population Register, matched to cases by birth year and sex (25:1 matching rate). Migraine diagnoses were identified from the National Patient Register using International Classification of Diseases, versions 8 and 10 codes and migraine-specific acute or prophylactic treatment recorded in the National Pharmaceutical Register. We used logistic regression to estimate the risk of childhood cancers associated with maternal migraine.ResultsMaternal migraine was positively associated with risk for non-Hodgkin lymphoma (odds ratio [OR] = 1.70, 95% confidence interval [CI]: 1.01–2.86), central nervous system tumors ([OR = 1.31, 95% CI: 1.02–1.68], particularly glioma [OR = 1.64, 95% CI: 1.12–2.40]), neuroblastoma (OR = 1.75, 95% CI: 1.00–3.08), and osteosarcoma (OR = 2.60, 95% CI: 1.18–5.76).ConclusionsAssociations with maternal migraine were observed for several childhood cancers, including neuronal tumors. Our findings raise questions about the role of lifestyle factors, sex hormones, genetic, and neurochemical factors in the relationship between migraine and childhood cancers.

Background:    Childhood cancer may be related to maternal health in pregnancy. Maternal anemia is a common condition in pregnancy, especially in low-income countries, but the association between maternal anemia and childhood cancer has not been studied using a nationally representative population. Objective:        To examine the potential relation between maternal anemia during pregnancy and childhood cancers in a population-based cohort study in Taiwan. Methods:         We examined the relationship between maternal anemia and childhood cancer in Taiwan (N= 2160 cancer cases, 2,076,877 non-cases). Cases were taken from the National Cancer Registry, and non-cases were selected from national records. Using national health registries, we obtained maternal anemia diagnoses. We estimated the risks for childhood cancers using Cox proportional hazard analysis. Results:           There was an increased risk of cancers in children born to mothers with nutritional anemia (Hazard Ratio (HR): 1.32, 95% CI 0.99, 1.76). Iron deficiency anemia (HR: 1.30, 95% CI 0.97-1.75) carried an increased risk, while non-nutritional anemias were not associated with childhood cancer risk. Conclusion:     Our results provide additional support for screening for anemia during pregnancy. Adequate nutrition and vitamin supplementation may help to prevent some childhood cancer cases.

Childhood cancer risk is associated with maternal health during pregnancy. Anemia in pregnancy is a common condition, especially in low-income countries, but a possible association between maternal anemia and childhood cancer has not been widely studied.We examined the relation in a population-based study in Denmark (N = 6420 cancer cases, 160,485 controls). Cases were taken from the Danish Cancer Registry, and controls were selected from national records. We obtained maternal anemia diagnoses from the National Patient and Medical Births registries. In a separate analysis within the years available (births 1995-2014), we examined cancer risks among mothers taking prescribed vitamin supplements, using data from the National Prescription Register. We estimated the risks of childhood cancer using conditional logistic regression.The risks of neuroblastoma [odds ratio (OR= 1.83, 95% confidence interval (CI): 1.04, 3.22] and acute lymphoblastic leukemia (OR= 1.46, 95% CI 1.09, 1.97) were increased in children born to mothers with anemia in pregnancy. There was a two-fold increased risk for bone tumors (OR= 2.59, 95% CI: 1.42, 4.72), particularly osteosarcoma (OR= 3.54, 95% CI 1.60, 7.82). With regards to prescribed supplement use, mothers prescribed supplements for B12 and folate deficiency anemia (OR= 4.03, 95% CI 1.91, 8.50) had an increased risk for cancer in offspring.Our results suggest that screening for anemia in pregnancy and vitamin supplementation may be an actionable strategy to prevent some cases of childhood cancer.

BackgroundThe effect of maternal diabetes on childhood cancer has not been widely studied.MethodsWe examined this in two population-based studies in Denmark (N = 6420 cancer cases, 160,484 controls) and Taiwan (N = 2160 cancer cases, 2,076,877 non-cases) using logistic regression and Cox proportional hazard regression adjusted for birth year, child's sex, maternal age and birth order.ResultsGestational diabetes in Denmark [odds ratio (OR) = 0.98, 95% confidence interval (CI): 0.71-1.35] or type II and gestational diabetes in Taiwan (type II: hazard ratio (HR) = 0.81, 95% CI: 0.63-1.05; gestational diabetes: HR = 1.06, 95% CI: 0.92-1.22) were not associated with cancer (all types combined). In Denmark, maternal type I diabetes was associated with the risk of glioma (OR = 2.33, 95% CI: 1.04-5.22), while in Taiwan, the risks of glioma (HR = 1.59, 95% CI: 1.01-2.50) were elevated among children whose mothers had gestational diabetes. There was a twofold increased risk for hepatoblastoma with maternal type II diabetes (HR = 2.02, 95% CI: 1.02-4.00).ConclusionsOur results suggest that maternal diabetes is an important risk factor for certain types of childhood cancers, emphasising the need for effective interventions targeting maternal diabetes to prevent serious health effects in offspring.

Retinoblastoma is a rare tumor of the retina, most commonly found in young children. Due to the rarity of this childhood cancer, few studies have been able to examine prenatal pesticide exposure as a risk factor.To examine the relationship between childhood retinoblastoma and prenatal exposure to pesticides through residential proximity to agricultural pesticide applications.We conducted a population-based case-control study using cases aged 5 and younger identified from the California Cancer Registry, and controls randomly selected from California birth certificates. Frequency matching cases to controls by age resulted in 221 cases of unilateral retinoblastoma and 114 cases of bilateral retinoblastoma, totaling 335 cases and 123,166 controls. Based on addresses from birth certificates we employed Pesticide Use Reports and land use information within a geographic information system approach to individually assess exposures to specific pesticides within 4000 m of the residence reported on birth certificates. The associations between retinoblastoma (all types combined and stratified by laterality) and individual pesticides were expressed as odds ratios estimates obtained from unconditional logistic regression models including a single pesticide, and from a hierarchical logistic regression model including all pesticides.We found that exposures to acephate (OR: 1.70, 95% CI: 1.20, 2.41) and bromacil (OR: 1.87, 95% CI: 1.07, 3.26) were associated with increased risk for unilateral retinoblastoma. In addition to acephate, we found that pymetrozine (OR: 1.45, 95% CI: 1.00, 2.08) and kresoxim-methyl (OR: 1.60, 95% CI: 1.00, 2.56) were associated with retinoblastoma (all types combined).Our findings suggest that certain types of prenatal ambient pesticide exposure from residing near agricultural fields may play a role in the development of childhood retinoblastoma.

BackgroundAlthough viral hepatitis causes paediatric hepatocellular carcinoma and hepatic and extrahepatic cancers in adults, there are few epidemiologic studies on paediatric-cancer risks from parental viral hepatitis. In a nationwide study in a viral hepatitis endemic region and with confirmation in another population-based sample, we examined associations between parental hepatitis B (HBV) and C (HCV) infections and risks of cancers in offspring.MethodsWe included all children born in Taiwan in 2004-2014 (N = 2 079 037) with 2160 cancer cases ascertained from the Cancer Registry. We estimated risks for paediatric cancers using Cox proportional-hazard regressions. We checked these associations in a nationwide case-control study in Denmark (6422 cases, 160 522 controls).ResultsIn Taiwan, paternal HBV was related to child's hepatoblastoma [hazard ratio (HR) = 1.77, 95% confidence interval (CI) = 1.05, 2.97] when identified at any time in the medical record, and when analyses were limited to hepatitis diagnoses occurring before the child's birth, risks increased (HR = 2.08, 95% CI = 1.13-3.80). Paternal HCV was related to child's non-Hodgkin lymphoma (HR = 2.06, 95% CI = 1.13-3.74). Maternal HCV was weakly related to increased risks of all childhood cancers [all types combined; HR = 1.45, 95% CI = 0.95-2.22]. The population-attributable fraction of hepatoblastoma for maternal, paternal and child HBV was 2.6%, 6.8% and 2.8%, respectively.ConclusionsParental HBV and HCV may be risk factors for hepatic and non-hepatic cancers in children. If associations are causal, then parental screening and treatment with antivirals may prevent some paediatric cancers.

BackgroundHead trauma has been associated with increased brain tumor risk in adults. Instrument assisted delivery can be a cause of head trauma in newborns. The goal of this study was to determine if instrument-assisted deliveries influenced the odds of childhood brain tumors in Denmark.MethodsWe conducted a matched case-control study of childhood (

BackgroundMaternal exposure to traffic-related air pollution during pregnancy has been shown to increase the risk of adverse birth outcomes and childhood disorders. High-resolution metabolomics (HRM) has previously been employed to identify metabolic responses to traffic-related air pollution in adults, including pregnant women. Thus far, no studies have examined metabolic effects of air pollution exposure in utero on neonates.MethodsWe retrieved stored neonatal blood spots for 241 children born in California between 1998 and 2007. These children were randomly selected from all California birth rolls to serve as birth-year matched controls for children with retinoblastoma identified from the California cancer registry for a case control study of childhood cancer. We estimated prenatal traffic-related air pollution exposure (particulate matter less than 2.5 μm (PM2.5)) during the third-trimester using the California Line Source Dispersion Model, version 4 (CALINE4) based on residential addresses recorded at birth. We employed untargeted HRM to obtain metabolic profiles, and metabolites associated with air pollution exposure were identified using partial least squares (PLS) regression and linear regressions. Biological effects were characterized using pathway enrichment analyses adjusting for potential confounders including maternal age, race/ethnicity, and education.ResultsIn total we extracted 4038 and 4957 metabolite features from neonatal blood spots in hydrophilic interaction (HILIC) chromatography (positive ion mode) and C18 reverse phase columns (negative ion mode), respectively. After controlling for confounding factors, partial least square regression (Variable Importance in Projection (VIP) ≥ 2) selected 402 HILIC positive and 182 C18 negative features as statistically significantly associated with increasing third trimester PM2.5 exposure. Using pathway enrichment analysis, we identified metabolites in oxidative stress and inflammation pathways as being altered, primarily involving lipid metabolism.ConclusionThe metabolite features and pathways associated with air pollution exposure in neonates suggest that maternal exposure during late pregnancy contributes to oxidative stress and inflammation in newborn children.

PurposeTo examine associations between parental occupation and childhood germ cell tumors (GCTs) in offspring while distinguishing by common histologic subtype (i.e., yolk sac tumor and teratoma).MethodsThis population-based case-control study included childhood GCT cases in Denmark diagnosed 1968-2015 (

BackgroundPreviously, numerous epidemiologic studies reported an association between autism spectrum disorder (ASD) and exposure to air pollution during pregnancy. However, there have been no metabolomics studies investigating the impact of pregnancy pollution exposure to ASD risk in offspring.ObjectivesTo identify differences in maternal metabolism that may reflect a biological response to exposure to high air pollution in pregnancies of offspring who later did or did not develop ASD.MethodsWe obtained stored mid-pregnancy serum from 214 mothers who lived in California's Central Valley and experienced the highest levels of air pollution during early pregnancy. We estimated each woman's average traffic-related air pollution exposure (carbon monoxide, nitric oxides, and particulate matter

Background:Pesticide exposures have been examined previously as risk factors for childhood brain cancers, but few studies were able to assess risk from specific agents.Objective:To evaluate risks for childhood central nervous system tumors associated with residential proximity to agricultural pesticide applications.Methods:Using the California Cancer Registry, we identified cancer cases less than 6 years of age and frequency matched them by year of birth to 20 cancer-free controls identified from birth certificates. We restricted analyses to mothers living in rural areas and births occurring between 1998 and 2011, resulting in 667 cases of childhood central nervous system tumors and 123,158 controls. Possible carcinogens were selected per the Environmental Protection Agency’s (US. EPA) classifications, and prenatal exposure was assessed according to pesticides reported by the California Department of Pesticide Regulation’s (CDPR) Pesticide Use Reporting (PUR) system as being applied within 4000m of the maternal residence at birth. We computed odds ratios for individual pesticide associations using unconditional logistic and hierarchical regression models.Results:We observed elevated risks in the hierarchical models for diffuse astrocytoma with exposure to bromacil (OR: 2.12, 95% CI: 1.13-3.97), thiophanate-methyl (OR: 1.64, 95% CI: 1.02-2.66), triforine (OR: 2.38, 95% CI: 1.44-3.92), and kresoxim methyl (OR: 2.09, 95% CI: 1.03-4.21); elevated risks for medulloblastoma with exposure to chlorothalonil (OR: 1.78, 95% CI: 1.15-2.76), propiconazole (OR: 1.60, 95% CI: 1.02, 2.53), dimethoate (OR: 1.60, 95% CI: 1.06, 2.43), and linuron (OR: 2.52, 95% CI: 1.25, 5.11); and elevated risk for ependymoma with exposure to thiophanate-methyl (OR: 1.72, 95% CI: 1.10-2.68).Conclusion:Our study suggests that exposure to certain pesticides through residential proximity to agricultural applications during pregnancy may increase the risk of childhood central nervous system tumors.

Spina bifida has been reported to co-occur with pediatric cancer, but comprehensive evaluations remained elusive. We investigated this co-occurrence in two large, population-based studies in Taiwan (N = 1900 cancer cases, 2,077,137 controls) and Denmark (N = 5508 cases, 137,700 controls). Analyses in Denmark were restricted to the period before prenatal diagnostics became available (2004) and pregnancy terminations of fetuses with birth defects became more common. Using national patient and cancer registries, we linked spina bifida and cancer diagnoses among cases and non-cases. The risk of spina bifida among all cancer cases was increased and similar in Denmark [odds ratio (OR)=8.4, 95% confidence interval (CI) 5.1-13.8] and Taiwan (OR = 8.5, 95% CI 4.0-17.8), particularly for central nervous system (CNS) tumors (Denmark: OR = 16.3, 95% CI 8.1-33.0; Taiwan: OR = 26.6, 95% CI 8.5, 83.1), including benign CNS tumors (Denmark: OR = 41.5, 95% CI 21.2, 81.4). These findings suggest the need for comprehensive investigation of shared risk factors in the link between spina bifida and pediatric cancer.

Sustained and inadequately controlled hypertension can promote the development of age-related macular degeneration (AMD) through multiple biologic pathways. Epidemiologic studies of high blood pressure, antihypertensive therapies, and the risk of AMD thus far have been inconclusive. However, few studies evaluated risks according to the use of different classes of antihypertensive drugs or took combinations of use into account. We performed a prospective cohort study by linking the California Teachers Study (CTS) cohort (N = 88 481) to statewide hospital discharge records up to December 31, 2012. History of high blood pressure, regular use of antihypertensive medications, and comprehensive risk factor information was collected via self-administered questionnaires at baseline in 1995-1996, and information on specific classes of antihypertensive drugs was provided by a subsample of CTS participants who completed a follow-up questionnaire in 2000. We identified 1762 female teachers with AMD during 14.8 years of follow-up on average. Applying Cox proportional hazard regression, we estimated increased risks of AMD among women treated for hypertension at baseline (HR = 1.15, 95% CI: 1.03, 1.30); the magnitude of the association increased with longer duration of antihypertensive treatment. In the subsample with more specific information on type of medication use, we estimated a 45% increased risk of AMD among women receiving diuretics as monotherapy compared to women with medications more potent than diuretics (HR = 1.45, 95% CI 1.10, 1.90). In women treated with a combination of antihypertensive drugs, we observed no increased risk of AMD for any individual class of drugs.

ObjectiveTo examine associations with occupational livestock or other animal dust exposure and offspring cancer risk.MethodsIn this population-based case-control study of Danish children aged

BackgroundA number of epidemiologic studies with a variety of exposure assessment approaches have implicated pesticides as risk factors for childhood cancers. Here we explore the association of pesticide exposure in pregnancy and early childhood with childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) utilizing land use and pesticide use data in a sophisticated GIS tool.MethodsWe identified cancer cases less than 6 years of age from the California Cancer Registry and cancer-free controls from birth certificates. Analyses were restricted to those living in rural areas and born 1998-2011, resulting in 162 cases of childhood leukemia and 9,805 controls. Possible carcinogens were selected from the Environmental Protection Agency's classifications and pesticide use was collected from the California Department of Pesticide Regulation's (CDPR) Pesticide Use Reporting (PUR) system and linked to land-use surveys. Exposures for subjects were assessed using a 4000m buffer around the geocoded residential addresses at birth. Unconditional logistic and hierarchical regression models were used to assess individual pesticide and pesticide class associations.ResultsWe observed elevated risks for ALL with exposure to any carcinogenic pesticide (adjusted Odds Ratio (aOR): 2.83, 95% CI: 1.67-4.82), diuron (Single-pesticide model, adjusted (OR): 2.38, 95% CI: 1.57-3.60), phosmet (OR: 2.10, 95% CI: 1.46-3.02), kresoxim-methyl (OR: 1.77, 95% CI: 1.14-2.75), and propanil (OR: 2.58, 95% CI: 1.44-4.63). Analyses based on chemical classes showed elevated risks for the group of 2,6-dinitroanilines (OR: 2.50, 95% CI: 1.56-3.99), anilides (OR: 2.16, 95% CI: 1.38-3.36), and ureas (OR: 2.18, 95% CI: 1.42-3.34).ConclusionOur findings suggest that in rural areas of California exposure to certain pesticides or pesticide classes during pregnancy due to residential proximity to agricultural applications may increase the risk of childhood ALL and AML. Future studies into the mechanisms of carcinogenicity of these pesticides may be beneficial.

BackgroundParental occupational exposures are suggested as contributing causes of childhood cancer.MethodsChildren age< = 19, born in Denmark and diagnosed with leukemia, central nervous system (CNS) cancers and likely prenatally initiated cancers [hepatoblastoma, medulloblastoma, Wilms tumor (nephroblastoma), neuroblastoma, retinoblastoma and acute lymphoid leukemia] n = 4268 were identified using Danish registries. We randomly selected twenty-five controls per case matched on birth year and sex. Parents and their employment histories were extracted from nationwide registries. We examined occupational dust exposures perinatally and postnatally in both parents. Odds ratios (ORs) and 95 % confidence intervals (95 % CI) were estimated using conditional logistic regression.ResultsMaternal wood dust exposure from birth to diagnosis was associated with increased risks of leukemia (OR 1.44, 95 % CI 1.08-1.94) and acute myeloid leukemia (OR 2.14, 95 % CI 1.13-4.03); exposure to paper dust was associated with CNS cancer (OR 2.28, 95 % CI 1.22-4.2).. Paternal exposure to wood dust was associated with astrocytoma in both periods (OR 1.43, 95 % CI 1.05-1.96 and 1.42, 1.09-1.86, respectively) and CNS cancer (OR 1.24, 95 % CI 1.00-1.53) in the perinatal period. The increased risk observed for potentially prenatally-initiated cancers in relation to wood was driven by ORs for neuroblastoma (1.54, 95 % CI 1.03-2.29) and hepatoblastoma (2.41, 95 % CI 0.99-5.88). An OR of 2.58 (95 % CI 1.10-6.05) for CNS cancer was associated with both parents working in textile industries postnatally.ConclusionThe study suggests that parental exposure to wood dust may increase risk of specific childhood cancers.

Background:Pesticide exposures have been examined previously as risk factors for childhood brain cancers, but few studies were able to assess risk from specific agents.Objective:To evaluate risks for childhood central nervous system tumors associated with residential proximity to agricultural pesticide applications.Methods:Using the California Cancer Registry, we identified cancer cases less than 6 years of age and frequency matched them by year of birth to 20 cancer-free controls identified from birth certificates. We restricted analyses to mothers living in rural areas and births occurring between 1998 and 2011, resulting in 667 cases of childhood central nervous system tumors and 123,158 controls. Possible carcinogens were selected per the Environmental Protection Agency’s (US. EPA) classifications, and prenatal exposure was assessed according to pesticides reported by the California Department of Pesticide Regulation’s (CDPR) Pesticide Use Reporting (PUR) system as being applied within 4000m of the maternal residence at birth. We computed odds ratios for individual pesticide associations using unconditional logistic and hierarchical regression models.Results:We observed elevated risks in the hierarchical models for diffuse astrocytoma with exposure to bromacil (OR: 2.12, 95% CI: 1.13-3.97), thiophanate-methyl (OR: 1.64, 95% CI: 1.02-2.66), triforine (OR: 2.38, 95% CI: 1.44-3.92), and kresoxim methyl (OR: 2.09, 95% CI: 1.03-4.21); elevated risks for medulloblastoma with exposure to chlorothalonil (OR: 1.78, 95% CI: 1.15-2.76), propiconazole (OR: 1.60, 95% CI: 1.02, 2.53), dimethoate (OR: 1.60, 95% CI: 1.06, 2.43), and linuron (OR: 2.52, 95% CI: 1.25, 5.11); and elevated risk for ependymoma with exposure to thiophanate-methyl (OR: 1.72, 95% CI: 1.10-2.68).Conclusion:Our study suggests that exposure to certain pesticides through residential proximity to agricultural applications during pregnancy may increase the risk of childhood central nervous system tumors.

Gestational risk factors such as birth weight, gestational age and parity have been repeatedly found to be related to pediatric cancers, but few reports have emerged from Asian countries. Here we report on demographic and gestational factors in a Taiwanese cohort. Our study included all children born in Taiwan 2004-2014 for whom there was a birth record (n = 2,079,037), of which 1900 children had been diagnosed with cancer prior to age 12. We conducted multivariable hazard regression to examine associations between demographic and gestational factors with cancer. Greater parity (family with 2+ older children) was related to acute myeloid leukemia [Hazard ratio (HR) = 2.15, 95% confidence interval (CI): 1.31, 3.55), central nervous system tumors (HR = 1.67, CI: 1.13, 2.48) and neuroblastoma (HR = 1.67, CI: 1.07, 2.63). Hepatoblastoma cases had a higher risk of low birth weight (

BackgroundThe etiology of childhood cancer is largely unknown, though some research suggests an infectious origin of hematopoietic, central nervous system (CNS) and bone cancers.MethodsWe examined parental occupational social contact as a proxy for exposure to infectious agents and risk of childhood cancer. This population-based case-control study utilized a linkage of four Danish data-registries, and included 3581 cases (

Objectives Parental exposures and offspring's risk of cancer have been studied with inconsistent results. We investigated parental employment in painting and printing industries and risk of childhood leukemia, central nervous system (CNS) cancers, and prenatal cancers (acute lymphoblastic leukemia, Wilms tumor, medulloblastoma, neuroblastoma, retinoblastoma, and hepatoblastoma). Methods Using Danish registries, children aged ≤19 years diagnosed from 1968-2015 with leukemia (N=1999), CNS cancers (N=1111) or prenatal cancers (N=2704) were linked to parents and their employment history one year before birth to birth for fathers, and one year before birth to one year after for mothers. Twenty randomly selected controls per case were matched by age and sex. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using conditional logistic regression. Results For fathers, we found increased risks for acute myeloid leukemia (AML) consistent in painting (OR 2.26, 95% CI 1.07-4.80) and printing industries (OR 2.43, 95% CI 0.94-6.23) and these industries combined (OR 2.10, 95% CI 1.14-3.87). For mothers, increased risks of CNS cancers were found for painting industries (OR 2.34, 95% CI 1.10-4.95) and painting and printing combined (OR 1.97, 95% CI 1.08-3.64). For fathers working in combined industries, the OR for CNS was increased (OR 1.54, 95% CI 1.02-2.31), most prominently in printing industries (OR 2.09, 95% CI 1.17-3.75). Conclusion We observed increased risks of CNS tumors in offspring after parental employment in painting and printing industries. Children of fathers employed in painting and printing industries had a two-fold increase in AML.

BackgroundMaternal exposure to traffic-related air pollution during pregnancy has been shown to increase the risk of adverse birth outcomes and neurodevelopmental disorders. By utilizing high-resolution metabolomics (HRM), we investigated perturbations of the maternal serum metabolome in response to traffic-related air pollution to identify biological mechanisms.MethodsWe retrieved stored mid-pregnancy serum samples from 160 mothers who lived in the Central Valley of California known for high air particulate levels. We estimated prenatal traffic-related air pollution exposure (carbon monoxide, nitric oxides, and particulate matter

ObjectivesOnly a small number of studies have reported on the association of parental occupational exposure to benzene and risk of childhood and adolescent leukaemias. We examined associations with acute lymphoblastic leukaemia (ALL) in this population-based study in Denmark.MethodsBenzene was largely banned from Danish workplaces after 1975, thus this case-control study focused on the immediately prior years. Paediatric cancer cases (ResultsWe identified 217 employed case fathers and 169 employed case mothers, of which 22 (10.1%) and 11 (6.5%), respectively, were exposed to benzene (vs 6.7% and 2.9% of control fathers and mothers). Most exposed parents worked as machine or engine mechanics, or in the shoe industry. Maternal occupational exposure to benzene in pregnancy was related to increased risk of ALL in offspring (adjusted OR=2.28, 95% CI 1.17 to 4.41), while paternal preconceptional benzene exposure was not as strongly associated (adjusted OR=1.40, 95% CI 0.88 to 2.22).ConclusionsOur study supports an increased risk for ALL with parental occupational benzene exposure.

ObjectiveTo assess prenatal air toxics exposure and risk for childhood germ cell tumors (GCTs) by histological subtype (yolk sac tumor and teratoma).MethodsIn this case-control study, GCT cases less than 6 years (n = 243) identified from California Cancer Registry records were matched by birth year to cancer-free population controls (n = 147,100), 1984 to 2013. Routinely monitored air toxic exposures were linked to subjects' birth address. Logistic regression estimated GCT risks per interquartile range increase in exposure.ResultsPrenatal exposure to various highly-correlated, traffic-related air toxics during the second trimester increased GCT risk, particularly 1,3-butadiene (odds ratio [OR] = 1.51; 95% confidence interval [CI] = 1.01, 2.26) and meta/para-xylene (OR = 1.56; 95% CI = 1.10, 2.21). Analyses by subtype indicated elevated ORs for yolk sac tumors but not teratomas.ConclusionOur estimated ORs are consistent with positive associations between some prenatal traffic-related air toxics and GCT risk, notably yolk sac tumors.

Studies of environmental exposures and childhood cancers that rely on records often only use maternal address at birth or address at cancer diagnosis to assess exposures in early childhood, possibly leading to exposure misclassification and questionable validity due to residential mobility during early childhood. Our objective was to assess patterns and identify factors that may predict residential mobility in early childhood, and examine the impact of mobility on early childhood exposure assessment for agriculturally applied pesticides and childhood cancers in California. We obtained the addresses at diagnosis of all childhood cancer cases born in 1998-2011 and diagnosed at 0-5 years of age (n = 6478) from the California Cancer Registry (CCR), and their birth addresses from linked birth certificates. Controls were randomly selected from California birth records and frequency matched (20:1) to all cases by year of birth. We obtained residential histories from a public-record database LexisNexis for both case (n = 3877 with age at diagnosis 1-5 years) and control (n = 99,262) families. Logistic regression analyses were conducted to assess the socio-demographic factors in relation to residential mobility in early childhood. We employed a Geographic Information System (GIS)-based system to estimate children's first year of life exposures to agriculturally applied pesticides based on birth vs diagnosis address or residential histories based upon Lexis-Nexis Public Records and assessed agreement between exposure measures using Spearman correlations and kappa statistics. Over 20% of case and control children moved in their first year of life, and 55% of children with cancer moved between birth and diagnosis. Older age at diagnosis, younger maternal age, lower maternal education, not having a Hispanic ethnic background, use of public health insurance, and non-metropolitan residence at birth were predictors of higher residential mobility. There was moderate to strong correlation (Spearman correlation = 0.76-0.83) and good agreement (kappa = 0.75-0.81) between the first year of life exposure estimates for agricultural pesticides applied within 2 km of a residence relying on an address at birth or at diagnosis or LexisNexis addresses; this did not differ by outcome status, but agreement decreased with decreasing buffer size, and increasing distance moved or age at diagnosis. These findings suggest that residential addresses collected at one point in time may represent residential history in early childhood to a reasonable extent; nevertheless, they exposure misclassification in the first year of life remains an issue. Also, the highest proportion of women not captured by LexisNexis were Hispanic women born in Mexico and those living in the lowest SES neighborhoods, i.e. possibly those with the higher environmental exposures, as well as younger women and those with less than high school education. Though LexisNexis only captures a sub-population, its data may be useful for augmenting address information and assessing the extent of exposure misclassification when estimating environmental exposures in large record linkage studies. Future research should investigate how to correct for exposure misclassification introduced by residential mobility that is not being captured by records.

Objectives Recent meta-analyses suggest a physical activity health paradox: high levels of occupational physical activity (OPA) increase cardiovascular disease (CVD) risk, while leisure-time physical activity (LTPA) decreases risk. However, studies of women and cerebrovascular disease are limited. This report examines physical activity effects on stroke and transient ischemic attack (TIA) among working women in the United States. Methods OPA history, health status, and lifestyle were assessed by baseline interviews of 31 270 employed Sister Study participants aged 35-74 years. OPA was assessed at six intensity levels (lowest: "mostly sitting"); the highest three were combined as "high intensity work." Independent OPA and LTPA effects on 6-year cerebrovascular disease incidence were estimated in adjusted Cox proportional hazard models. Results Stroke (N=441) and TIA (N=274) risk increased with more standing and higher intensity work at current and longest held job. Compared with mostly sitting, high intensity work at the current job increased TIA risk by 57% [hazard ratio (HR) 1.57, 95% confidence interval (CI) 1.04-2.38]. High intensity OPA at the longest held job increased risk for stroke by 44% (HR 1.44; 95% CI 1.08-1.93). Among women with CVD, sitting and standing equally, especially at the current job, increased risks up to two-fold (TIA HR 1.98, 95% CI 1.10-3.55) compared with mostly sitting at work. LTPA showed inverse associations. Conclusions Higher intensity levels of OPA increased stroke and TIA risks, while LTPA decreased risks; results corroborate the physical activity health paradox for women and cerebrovascular disease. More standing at work increased cerebrovascular disease risks, especially for women with CVD.