Maternal medically diagnosed infection and antibiotic prescription during pregnancy and risk of childhood cancer: A population-based cohort study in Taiwan, 2004 to 2015.

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.

Nonchromosomal birth defects and risk of childhood acute leukemia: An assessment in 15 000 leukemia cases and 46 000 controls from the Childhood Cancer and Leukemia International Consortium.

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.

Preeclampsia, antihypertensive medication use in pregnancy and risk of childhood cancer in offspring.

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.

Effects of hypertension and use of antihypertensive drugs in pregnancy on the risks of childhood cancers in Taiwan.

BACKGROUND: Childhood 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. OBJECTIVE: This population-based cohort study analyzed the relationship between hypertension, preeclampsia, and antihypertensives taken during pregnancy and the risks of childhood cancers in the offspring. METHODS: Data 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. RESULTS: Offspring 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. CONCLUSIONS: In this cohort study, children whose mothers had chronic and gestational hypertension had an increased risk of developing childhood cancer.

A prediction model for classifying maternal pregnancy smoking using California state birth certificate information.

BACKGROUND: Systematically recorded smoking data are not always available in vital statistics records, and even when available it can underestimate true smoking rates. OBJECTIVE: To 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. METHODS: We 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. RESULTS: Out 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. CONCLUSIONS: This 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.

Neonatal per- and polyfluoroalkyl substance exposure in relation to retinoblastoma.

BACKGROUND: Neonatal 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 METHODS: This 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 DISCUSSION: Among 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. CONCLUSIONS: Our results suggested that PFOS and PFOA might contribute to retinoblastoma risk in children born in California.

Association between medically diagnosed postnatal infection and childhood cancers: A matched case-control study in Denmark, 1978 to 2016.

Although the association between infection and childhood cancer has been long investigated, there is limited information on rarer cancers. This article aimed to explore the association between postnatal infection and childhood cancers in the Danish population. A matched case-control study was conducted using Danish nationwide registries from 1978 to 2016. Each childhood cancer case was matched 1:25 with controls by birth date within a week and sex. Postnatal infections were identified from the Danish National Patient Registry, which lists diagnoses seen in hospital, specialist or emergency care services. Multivariable conditional logistic regression was used to estimate adjusted odds ratios (adj.OR) and 95% confidence intervals (CI). Specific types of infections and the number of infection episodes were also considered. The study included 4125 childhood cancer cases and 103 526 matched controls with ages ranging from 0 to 19 years. Medically diagnosed postnatal infections were positively associated with many types of childhood cancer including acute lymphoblastic leukemia (adj.OR = 1.42; 95% CI: 1.23-1.63), acute myeloid leukemia (adj.OR = 1.80; 95% CI: 1.28-2.52), non-Hodgkin lymphoma (adj.OR = 1.53; 95% CI: 1.19-1.97) and central nervous system tumors (adj.OR = 1.57; 95% CI: 1.39-1.77). A higher number of infection episodes were also associated with an increased risk of these cancers. Specific infections such as viral, enteric and urinary tract infections were also strongly associated with specific types of cancer. In conclusion, children who later develop cancer appear to have adverse reactions to infections necessitating referral to specialized health care services, perhaps indicating dysregulated immune function.

Metabolite Stability in Archived Neonatal Dried Blood Spots Used for Epidemiologic Research.

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.

Maternal migraine and risk of pediatric cancers.

BACKGROUND: Maternal 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. METHODS: We 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. RESULTS: Maternal 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). CONCLUSIONS: Associations 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.

Maternal anemia and the risk of childhood cancer: A population-based cohort study in Taiwan.

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 widely studied. 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 noncases). Cases were taken from the National Cancer Registry, and noncases were selected from birth 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.

Exposure to nitrosatable drugs during pregnancy and childhood cancer: A matched case-control study in Denmark, 1996-2016.

BACKGROUND: Nitrosatable drugs can be synthesized to N-nitroso compounds in human stomach. In a pregnant woman, N-nitroso compounds can be translocated to the fetus through the placenta. Maternal exposure of nitrosatable compounds during pregnancy has been associated with childhood brain tumors and leukemia. However, few studies have investigated an association between nitrosatable drug exposure during pregnancy and childhood cancer. We examined if maternal prescriptions of nitrosatable drugs received during pregnancy are associated with childhood cancer. METHODS: A matched case-control study was conducted using Danish nationwide registry data from 1995 to 2016. Each childhood cancer case was matched with twenty-five controls. Maternal exposure of nitrosatable drugs during pregnancy was identified from the Danish National Prescription Register. A multivariable conditional logistic regression model was used to estimate adjusted odds ratios (adj.OR) with 95% confidence intervals (CI) for each childhood cancer type. RESULTS: Maternal prescriptions of nitrosatable drugs positively associate with central nervous system tumors (adj.OR = 1.25; 95% CI = 1.04-1.51) and neuroblastoma (adj.OR = 1.96; 95% CI = 1.34-2.85) in offspring. We also observed a positive association between perinatal exposure of nitrosatable drugs and acute lymphoblastic leukemia (adj.OR = 1.31; 95% CI = 1.07-1.59), however, it appeared to be due to confounding by indication, i.e., maternal infections. CONCLUSION: Nitrosatable drug use during pregnancy potentially increased risk of central nervous system tumors and neuroblastoma. While a positive association between maternal prescriptions of nitrosatable drugs and acute lymphoblastic leukemia should be interpreted cautiously because of confounding by indication.

BIOMARKERS OF MATERNAL SMOKING AND THE RISK OF RETINOBLASTOMA IN OFFSPRING.

PURPOSE: Previous studies examining the risk of retinoblastoma with maternal smoking were inconclusive, likely due in part to the reliance on self-reported maternal smoking. This study uses biomarkers of tobacco smoking in neonatal dried blood spots to investigate associations between maternal smoking and retinoblastoma in offspring. METHODS: The authors randomly selected 498 retinoblastoma cases and 895 control subjects born between 1983 and 2011 from a population-based case-control study in California. Maternal pregnancy-related smoking was measured using the following three metrics: provider or self-reported smoking during pregnancy, cotinine, and hydroxycotinine in neonatal blood. The authors used multivariable logistic regression to estimate the effects of maternal tobacco smoking on retinoblastoma. RESULTS: Using all metrics (biomarkers or self-report), maternal smoking late in pregnancy or early postpartum was related to retinoblastoma (all types; odds ratio = 1.44, 95% confidence interval: 1.00-2.09). Relying on cotinine or hydroxycotinine to ascertain smoking, maternal smoking was related to unilateral retinoblastoma (odds ratio = 1.66, 95% confidence interval: 1.08-2.57). CONCLUSION: The results indicate that maternal smoking during pregnancy may be a risk factor for retinoblastoma, particularly among unilateral cases.

Maternal diabetes and childhood cancer risks in offspring: two population-based studies.

BACKGROUND: The effect of maternal diabetes on childhood cancer has not been widely studied. METHODS: We 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. RESULTS: Gestational 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). CONCLUSIONS: Our 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.

Child serum metabolome and traffic-related air pollution exposure in pregnancy.

BACKGROUND: Maternal 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. METHODS: We 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. RESULTS: In 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. CONCLUSION: The 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.

Parental occupation and childhood germ cell tumors: a case-control study in Denmark, 1968-2016.

PURPOSE: To 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). METHODS: This population-based case-control study included childhood GCT cases in Denmark diagnosed 1968-2015 (< 16 years old at diagnosis) and sex and birth year-matched controls. Demographic information and parental employment histories were obtained from Danish registries. Parental occupation was assessed by industry; job-exposure matrices were used to examine specific occupational exposures (i.e., potentially carcinogenic organic solvents and social contact). Conditional multivariable logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CIs). RESULTS: Overall, 178 childhood GCT cases (50 yolk sac tumors; 65 teratomas) and 4,355 controls were included for analysis. Maternal employment in education during pregnancy was associated with offspring GCTs (OR 2.45, 95% CI 1.23-4.90), especially yolk sac tumors (OR 5.27, 95% CI 1.94-14.28). High levels of both maternal and paternal occupational social contact were also associated with offspring yolk sac tumors across all exposure periods (ORs 2.30-4.63). No signals were observed for paternal occupational solvent exposure, while imprecise associations were estimated for maternal exposure (e.g., dichloromethane exposure during pregnancy, OR 1.51, 95% CI 0.77-2.95). CONCLUSION: Our findings suggest that parental occupation is associated with offspring GCTs, with most consistent evidence supporting an association between maternal employment in education or other high social contact jobs and offspring yolk sac tumors.

Residential proximity to pesticide application as a risk factor for childhood central nervous system tumors.

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.

Metabolomics analysis of maternal serum exposed to high air pollution during pregnancy and risk of autism spectrum disorder in offspring.

BACKGROUND: Previously, 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. OBJECTIVES: To 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. METHODS: We 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 <2.5 µm) during the first trimester using the California Line Source Dispersion Model, version 4 (CALINE4). By utilizing liquid chromatography-high resolution mass spectrometry, we identified the metabolic profiles of maternal serum for 116 mothers with offspring who later developed ASD and 98 control mothers. Partial least squares discriminant analysis (PLS-DA) was employed to select metabolic features associated with air pollution exposure or autism risk in offspring. We also conducted extensive pathway enrichment analysis to elucidate potential ASD-related changes in the metabolome of pregnant women. RESULTS: We extracted 4022 and 4945 metabolic features from maternal serum samples in hydrophilic interaction (HILIC) chromatography (positive ion mode) and C18 (negative ion mode) columns, respectively. After controlling for potential confounders, we identified 167 and 222 discriminative features (HILIC and C18, respectively). Pathway enrichment analysis to discriminate metabolic features associated with ASD risk indicated various metabolic pathway perturbations linked to the tricarboxylic acid (TCA) cycle and mitochondrial function, including carnitine shuttle, amino acid metabolism, bile acid metabolism, and vitamin A metabolism. CONCLUSION: Using high resolution metabolomics, we identified several metabolic pathways disturbed in mothers with ASD offspring among women experiencing high exposure to traffic-related air pollution during pregnancy that were associated with mitochondrial dysfunction. These findings provide us with a better understanding of metabolic disturbances involved in the development of ASD under adverse environmental conditions.

Gestational risk factors and childhood cancers: A cohort study in Taiwan.

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 (<2,500 g; HR = 3.01, CI: 1.85, 4.91), very preterm birth (<33 weeks gestation; HR = 13.71, CI: 7.45, 25.23), plural pregnancies (HR = 2.37, CI: 1.10, 5.14) and both small (HR = 2.13, CI: 1.23, 3.67) and large (HR = 1.83, CI: 1.01, 3.32) for gestational age. Germ cell tumors were more common among children born in rural areas (HR = 1.63, CI: 1.02, 2.60). Despite that Taiwan has lower rates of both high and low birthweight compared to other developed nations, we observed several similar associations to those reported in Western Countries. Further research should examine unique exposures in Taiwan that may be contributing to higher incidence of certain cancer types.

Occupational livestock or animal dust exposure and offspring cancer risk in Denmark, 1968-2016.

OBJECTIVE: To examine associations with occupational livestock or other animal dust exposure and offspring cancer risk. METHODS: In this population-based case-control study of Danish children aged < 17 years old, 5078 childhood cancer cases diagnosed 1968-2016 were matched to cancer-free controls by birth year and sex (n = 123,228). Occupational livestock or animal dust exposure was identified using a job-exposure matrix. We employed multivariable conditional logistic regression models to estimate associations with offspring cancer for births 1968-2016 and 1989-2016, with the latter timeframe reflecting a period of presumed higher exposure due to changes in Danish farming practices. Sensitivity analyses considered place of birth (urban areas vs. rural areas and small towns). RESULTS: For births 1968-2016, paternal exposure from offspring birth to cancer diagnosis was associated with central nervous system tumors (adjusted odds ratio [OR] = 1.30, 95% confidence interval [CI] 1.04-1.63) and germ cell tumors (OR = 1.82, 95% CI 1.05-3.27), while maternal pregnancy exposure was associated with astrocytoma (OR = 1.89, 95% CI 1.00-3.57). For births 1989-2016, paternal exposure from offspring birth to cancer diagnosis was negatively associated with acute lymphoid leukemia (OR = 0.58, 95% CI 0.33-1.00). For births in rural areas only, maternal exposure from offspring birth to cancer diagnosis was positively associated with acute myeloid leukemia (OR = 2.16, 95% CI 1.09-4.29). CONCLUSIONS: This study suggests that paternal occupational animal exposure is associated with offspring germ cell tumors, and maternal pregnancy exposure with astrocytomas. Our results are mixed with respect to leukemia subtypes.

Spina bifida and pediatric cancers.

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.