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PURPOSE Infections pose a significant risk during therapy for childhood cancer. However, little is known about the risk of infection in long-term survivors of childhood cancer. METHODS We performed a retrospective observational study of children and adolescents born in Washington State diagnosed with cancer before age 20 years and who survived at least 5 years after diagnosis. Survivors were categorized as having a hematologic or nonhematologic malignancy and were matched to individuals without cancer in the state birth records by birth year and sex with a comparator:survivor ratio of 10:1. The primary outcome was incidence of any infection associated with a hospitalization using diagnostic codes from state hospital discharge records. Incidence was reported as a rate (IR) per 1,000 person-years. Multivariate Poisson regression was used to calculate incidence rate ratios (IRR) for cancer survivors versus comparators. RESULTS On the basis of 382 infection events among 3,152 survivors and 771 events among 31,519 comparators, the IR of all hospitalized infections starting 5 years after cancer diagnosis was 12.6 (95% CI, 11.4 to 13.9) and 2.4 (95% CI, 2.3 to 2.6), respectively, with an IRR 5.1 (95% CI, 4.5 to 5.8). The survivor IR during the 5- to 10-year (18.1, 95% CI, 15.9 to 20.5) and > 10-year postcancer diagnosis (8.3, 95% CI, 7.0 to 9.7) periods remained greater than comparison group IRs for the same time periods (2.3, 95% CI, 2.1 to 2.6 and 2.5, 95% CI, 2.3 to 2.8, respectively). When potentially vaccine-preventable infections were evaluated, survivors had a greater risk of infection relative to comparators (IRR, 13.1; 95% CI, 7.2 to 23.9). CONCLUSION Infectious complications continue to affect survivors of childhood cancer many years after initial diagnosis. Future studies are needed to better understand immune reconstitution to determine specific factors that may mitigate this risk.

There is a well-recognized male excess in childhood cancer incidence; however, it is unclear whether there is etiologic heterogeneity by sex when defined by epidemiologic risk factors. Using a 5-state registry-linkage study (cases n = 16,411; controls n = 69,816), we estimated sex-stratified odds ratios (OR) and 95% confidence intervals (95% CI) between birth and demographic characteristics for 16 pediatric cancers. Evidence of statistical interaction (p-interaction 50% of cases for all cancers, except Wilms tumor (49.6%). Sex interacted with a number of risk factors (all p-interaction

Children with cancer are frequently hospitalized. However, hospitalization and death by disease category are not well defined

Accelerated aging is a hallmark of Down syndrome (DS), with adults experiencing early-onset Alzheimer's disease and premature aging of the skin, hair, and immune and endocrine systems. Accelerated epigenetic aging has been found in the blood and brain tissue of adults with DS but when premature aging in DS begins remains unknown. We investigated whether accelerated aging in DS is already detectable in blood at birth. We assessed the association between age acceleration and DS using five epigenetic clocks in 346 newborns with DS and 567 newborns without DS using Illumina MethylationEPIC DNA methylation array data. We compared two epigenetic aging clocks (DNAmSkinBloodClock and pan-tissue DNAmAge) and three epigenetic gestational age clocks (Haftorn, Knight, and Bohlin) between DS and non-DS newborns using linear regression adjusting for observed age, sex, batch, deconvoluted blood cell proportions, and genetic ancestry. Targeted sequencing of GATA1 was performed in a subset of 184 newborns with DS to identify somatic mutations associated with transient abnormal myelopoiesis. DS was significantly associated with increased DNAmSkinBloodClock (effect estimate=0.2442, p

Increasing evidence suggests that breastfeeding may protect from childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). However, most studies have limited their analyses to any breastfeeding, and only a few data have examined exclusive breastfeeding, or other exposures such as formula milk. We performed pooled analyses and individual participant data metaanalyses of data from 16 studies (N = 17 189 controls; N = 10 782 ALL and N = 1690 AML cases) from the Childhood Leukemia International Consortium (CLIC) to characterize the associations of breastfeeding duration with ALL and AML, as well as exclusive breastfeeding duration and age at introduction to formula with ALL. In unconditional multivariable logistic regression analyses of pooled data, we observed decreased odds of ALL among children breastfed 4 to 6 months (0.88, 95% CI 0.81-0.96) or 7 to 12 months (OR 0.85, 0.79-0.92). We observed a similar inverse association between breastfeeding ≥4 months and AML (0.82, 95% CI 0.71-0.95). Odds of ALL were reduced among children exclusively breastfed 4 to 6 months (OR 0.73, 95% CI 0.63-0.85) or 7 to 12 months (OR 0.70, 95% CI 0.53-0.92). Random effects metaanalyses produced similar estimates, and findings were unchanged in sensitivity analyses adjusted for race/ethnicity or mode of delivery, restricted to children diagnosed ≥1 year of age or diagnosed with B-ALL. Our pooled analyses indicate that longer breastfeeding is associated with decreased odds of ALL and AML. Few risk factors for ALL and AML have been described, therefore our findings highlight the need to promote breastfeeding for leukemia prevention.

We compared the relative occurrence of selected pregnancy outcomes and postpartum rehospitalizations among women with and without epilepsy and their infants. Using linked vital-hospital discharge records of women with deliveries in Washington State 1987-2014, comparisons were made overall, by epilepsy type, and by time periods related to antiepileptic drug (AED) marketing changes.This population-based retrospective cohort study identified women with, and without epilepsy per diagnosis codes in the hospital discharge record from among all deliveries during 1987-2014 to examine maternal and infant outcomes, rehospitalization and mortality2 years postpartum. Relative risks (RRs) and 95 % confidence intervals (CI) overall, and by epilepsy type were calculated using Poisson regression. We assessed the validity of epilepsy identification based on diagnosis codes by conducting a medical chart review for a sample of women.Women with epilepsy had increased risks of preeclampsia (RR 1.23; 95 % CI 1.08-1.41) and gestational diabetes (RR 1.18; 95 % CI 1.02-1.36). Their infants had increased malformation (RR 1.23; 95 % C: 1.08-1.42) and small for gestational age (SGA, RR 1.39; 95 % CI 1.25-1.54) risks, and were nearly three times as likely to not be breastfed. Affected mothers (RR 5.25; 95 % CI 2.46-11.23) and their infants (RR 1.64, 95 % CI 1.41-1.89) required more ICU admissions during the delivery hospitalizations, and more postpartum rehospitalization, with greatest risk in the first six months. Maternal mortality 2 years after delivery was increased (RR 7.11; 95 % CI 2.47-20.49). Increased risks were observed for all epilepsy subtypes for nearly all outcomes examined. Risks of preterm delivery and low birthweight increased over time (p .05). Suggestive, but not statistically significant temporal decreases in risks of gestational diabetes and malformations and increased risk of preterm labor were noted. We observed high sensitivity of diagnosis codes for identifying pregnant women with epilepsy.These population-based results emphasize the need for frequent postpartum monitoring of women with epilepsy. Increases in risks of low birthweight and preterm delivery over time are of concern. Possible temporal changes in other outcomes warrant further investigation.

Children with Down syndrome (DS) have a 20-fold increased risk of acute lymphoblastic leukemia (ALL) and distinct somatic features, including CRLF2 rearrangement in ∼50% of cases; however, the role of inherited genetic variation in DS-ALL susceptibility is unknown. We report the first genome-wide association study of DS-ALL, comprising a meta-analysis of 4 independent studies, with 542 DS-ALL cases and 1192 DS controls. We identified 4 susceptibility loci at genome-wide significance: rs58923657 near IKZF1 (odds ratio [OR], 2.02; Pmeta = 5.32 × 10-15), rs3731249 in CDKN2A (OR, 3.63; Pmeta = 3.91 × 10-10), rs7090445 in ARID5B (OR, 1.60; Pmeta = 8.44 × 10-9), and rs3781093 in GATA3 (OR, 1.73; Pmeta = 2.89 × 10-8). We performed DS-ALL vs non-DS ALL case-case analyses, comparing risk allele frequencies at these and other established susceptibility loci (BMI1, PIP4K2A, and CEBPE) and found significant association with DS status for CDKN2A (OR, 1.58; Pmeta = 4.1 × 10-4). This association was maintained in separate regression models, both adjusting for and stratifying on CRLF2 overexpression and other molecular subgroups, indicating an increased penetrance of CDKN2A risk alleles in children with DS. Finally, we investigated functional significance of the IKZF1 risk locus, and demonstrated mapping to a B-cell super-enhancer, and risk allele association with decreased enhancer activity and differential protein binding. IKZF1 knockdown resulted in significantly higher proliferation in DS than non-DS lymphoblastoid cell lines. Our findings demonstrate a higher penetrance of the CDKN2A risk locus in DS and serve as a basis for further biological insights into DS-ALL etiology.

Background Pregnant women with congenital or acquired spinal cord injury face challenges due to compromised neurologic function and mobility, factors that may also affect fetal/infant health. Few studies have examined pregnancy course and longer-term outcomes in this population. Objective To assess pregnancy outcomes among women with spinal cord injury, paralysis, or spina bifida using population-based data. Design Retrospective cohort study. Setting Washington state linked birth-hospital discharge records. Participants All women (N = 529) with spinal cord injury, paralysis, or spina bifida with singleton live birth deliveries 1987-2012, and a comparison group of women without disabilities (N = 5282). Methods Diagnosis codes were screened to identify cases and a 10:1 random sample of comparison women. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated overall and separately for each condition using multivariable regression. Subsequent hospitalizations or death were identified via linkage to hospital discharge/death records for 2 years after delivery. Main outcome measurements Pregnancy course (weight gain, gestational diabetes, preeclampsia, infection, venous thromboembolism), delivery/labor characteristics, infant characteristics (birthweight/size, gestational age), and longer-term outcomes (occurrence/reasons for maternal/infant rehospitalization, mortality). Results Women with these spinal conditions had increased adjusted risks of prenatal urinary tract infection/pyelonephritis (RR 26.43, 95% CI 13.97-49.99), venous thromboembolism (RR 9.16, 95% CI 2.17-38.60), preterm rupture of membranes (RR 2.15, 95% CI 1.18-3.90), and cesarean delivery (RR 1.88, 95% CI 1.70-2.09). They had longer hospitalizations and increased rehospitalization (RR 1.54, 95% CI 1.28-1.87), including for postpartum depression (RR 8.15, 4.29-15.48) or injury (RR 13.05, 95% CI 6.60-25.81). Their infants were more often small for gestational age (RR 1.65, 95% CI 1.33-2.06), but had no increased risk of rehospitalization or death. Conclusions We observed no increased long-term morbidity among infants of women with these conditions. Possible increased maternal morbidities during the first postpartum years indicate areas for intervention. Level of evidence III.

Purpose The aim of the study was to evaluate the association of antidepressant continuation in pregnancy with infant birth weight among women using antidepressants before pregnancy. Methods This retrospective cohort study used electronic health data linked with state birth records. We identified singleton live births (2001-2014) to enrolled women with 1 or more antidepressant prescriptions filled 6 months or less before pregnancy, including "continuers" (≥1 antidepressant fills during pregnancy, n = 1775) and "discontinuers" (no fill during pregnancy, n = 1249). We compared birth weight, small or large for gestational age (SGA or LGA), low birth weight (LBW; 4500 g) between the 2 groups, using inverse probability of treatment weighting to account for pre-pregnancy characteristics, including mental health conditions. Results After weighting, infants born to antidepressant continuers weighed 71.9 g less than discontinuers' infants (95% confidence interval [CI], -115.5 to -28.3 g), with a larger difference for female infants (-106.4 g; 95% CI, -164.6 to -48.1) than male infants (-48.5 g; 95% CI, -107.2 to 10.3). For female infants, SGA risk was greater in continuers than discontinuers (relative risk [RR],1.54; 95% CI, 1.02 to 2.32). Low birth weight risk was greater in continuers with 50% or more of days covered (RR, 1.69; 95% CI, 1.11 to 2.58) and exposure in the second trimester (RR, 1.53; 95% CI, 1.02 to 2.29), as compared with discontinuers. Conclusions Depending on infant sex, as well as duration and timing of use, continuation of antidepressant use during pregnancy may be associated with lower infant birth weight, with corresponding increases in LBW and SGA.

Cancer outcomes are relatively poor in adults who belong to minoritized racial and ethnic groups. Survival and long-term outcomes by race and ethnicity in individuals with childhood cancers are less studied.To evaluate survival and hospitalization among American Indian and Alaska Native, Asian, Black, and Hispanic children compared with non-Hispanic White children with cancer.This cohort study evaluated all individuals born in Washington State who were younger than 20 years (hereafter referred to as children) and had been diagnosed with cancer during 1987 to 2012, with follow-up ranging from 1 to 27 years. The data subset was built in 2019, and statistical analyses were completed in January 2022.Race and ethnicity.Mortality and hospitalization events for all other racial and ethnic groups relative to non-Hispanic White children estimated by Cox proportional hazards regressions for the first 5 years after diagnosis and among cancer survivors 5 or more years after diagnosis.A total of 4222 children (mean [SD] age, 8.4 [6.4] years; 2199 [52.1%] male; 113 American Indian and Alaska Native [2.7%], 311 Asian [7.4%], 196 Black [4.6%], 387 Hispanic [9.2%], and 3215 non-Hispanic White [76.1%]) with cancer diagnosed at younger than 20 years during 1987 to 2012 were included. Mortality was similar across all groups. Compared with non-Hispanic White survivors at less than 5 years after diagnosis, there were no greatly increased hazard ratios (HRs) for hospitalization. Among survivors at 5 or more years after diagnosis, hospitalization HRs were 1.7 (95% CI, 1.0-3.0) for American Indian and Alaska Native survivors and 1.5 (95% CI, 0.9-2.4) for Black survivors. Significantly increased HRs among Hispanic children were observed for infection-related (HR, 1.4; 95% CI, 1.2-1.6), endocrine-related (HR, 1.3; 95% CI, 1.1-1.6), hematologic-related (HR, 1.3; 95% CI, 1.1-1.5), respiratory-related (HR, 1.3; 95% CI, 1.0-1.5), and digestive-related (HR, 1.2; 95% CI, 1.0-1.5) conditions. American Indian and Alaskan Native children had increased HRs for infection-related (HR, 2.3; 95% CI, 1.2-4.5), hematologic-related (HR, 3.0; 95% CI, 1.4-6.5), and digestive-related (HR, 2.6; 95% CI, 1.3-5.4) conditions. Both American Indian and Alaska Native (HR, 3.6; 95% CI, 1.4-9.0) and Black (HR, 2.5; 95% CI, 1.2-5.5) children had increased mental health-related hospitalizations and death.In this cohort study, disproportionately increased long-term risks of hospitalization for physical and mental conditions may have contributed to worse outcomes by race. A key component to bridging the morbidity gap by race is improved understanding of reasons for greater cause-specific hospitalizations in some groups, with development of culturally appropriate intervention strategies.

6537 Background: Emerging evidence suggests mortality among children with cancer differs based on socioeconomic factors. The effects of residential location in relation to these factors are not well-characterized. We examined associations of rurality and neighborhood-level socioeconomic (SE) disadvantage with mortality in pediatric patients with cancer. Methods: We conducted a retrospective cohort study using Washington State (WA) Cancer Registry data (1992-2013) linked to state birth (1974-2013) and death records (1992-2013) to identify all children born in WA diagnosed with cancer < 20 years. We defined rural residence as patient addresses within 2010 census tract level rural-urban commuting area (RUCA) codes of ≥4.0 at diagnosis. Neighborhood-level socioeconomic disadvantage was determined using 2010 census block-group level Area Deprivation Index (ADI) quintiles normalized to WA. Patient addresses within the highest ADI quintile were categorized as having SE disadvantage. children in four mutually exclusive groups was compared using Kaplan-Meier analysis, pairwise log rank testing, and Cox proportional hazard ratios (HR): non-rural with SE disadvantage, rural without SE disadvantage, rural with SE disadvantage, and non-rural without SE disadvantage (). Models were adjusted for sex, race and ethnicity, age at diagnosis, birth year, and cancer type. Results: We identified 4,417 children for analysis. Median length of follow up among survivors was 5.0 years (inter-quartile range: 1.0-11.5). SE disadvantaged and 13% were rural. Pairwise log rank tests showed mortality differences among children living in rural, SE disadvantaged, or rural and SE disadvantaged neighborhoods when compared with children without either factor (individual p-values all < 0.005); no other differences were noted. Relative to children in non-rural areas without SE disadvantage, the mortality HR for those in non-rural areas with SE disadvantage was 1.68 (95% confidence intervals [CI] 1.37-2.07). The HR for children in rural areas without SE disadvantage was 1.59 (95% CI 1.19-2.12). The HR for children in rural areas with SE disadvantage was 1.56 (95% CI 1.20-2.03). In sub-analyses, associations for rurality and SE disadvantage remained significant for leukemia mortality, but CNS and solid tumor mortality was only associated with SE disadvantage (but not rural) status. Acute lymphoblastic leukemia mortality was associated with rural (but not SE disadvantage) status. Conclusions: Children with cancer living in socioeconomically disadvantaged and/or rural neighborhoods at diagnosis had higher mortality relative to those in non-rural areas with lower neighborhood deprivation. Associations varied by disease type. The individual effects of SE disadvantage and rurality suggest that interventions should be designed to target both factors.

BACKGROUND: Women with visual impairment may have reduced ability to access standard care resources, however, information on their pregnancy and neonatal outcomes is limited. OBJECTIVE: To assess risk of adverse pregnancy and neonatal outcomes among visually impaired women in Washington State from 1987–2014. METHODS: We conducted a retrospective cohort study using linked Washington State birth/fetal death hospital discharge records to compare outcomes among women with and without visual impairment noted at their delivery hospitalization. Pregnancy conditions and outcomes evaluated included gestational diabetes, pre-eclampsia, labor induction and cesarean delivery. Neonatal outcomes included preterm delivery and birth weight

Objective Both excessive and inadequate gestational weight gain (GWG) are associated with adverse health outcomes for the woman and her child. Antidepressant use in pregnancy could affect GWG, based on evidence in nonpregnant women that some antidepressants may cause weight gain and others weight loss. Previous studies of antidepressant use and GWG were small with limited ability to account for confounding, including by maternal mental health status and severity. We assessed the association of antidepressant continuation in pregnancy with GWG among women using antidepressants before pregnancy. Study design Our retrospective cohort study included singleton livebirths from 2001 to 2014 within Kaiser Permanente Washington, an integrated health care system. Data were obtained from electronic health records and linked Washington State birth records. Among women with ≥1 antidepressant fill within 6 months before pregnancy, women who filled an antidepressant during pregnancy were considered "continuers;" women without a fill were "discontinuers." We calculated mean differences in GWG and relative risks (RR) of inadequate and excessive weight gain based on Institute of Medicine guidelines. Using inverse probability of treatment weighting with generalized estimating equations, we addressed differences in maternal characteristics, including mental health conditions. Results Among the 2,887 births, 1,689 (59%) were to women who continued antidepressants in pregnancy and 1,198 (42%) were to discontinuers. After accounting for confounding, continuers had similar weight gain to those who discontinued (mean difference: 1.3 lbs, 95% confidence interval [CI]: -0.1 to 2.8 lbs) and similar risks of inadequate and excessive GWG (RR: 0.95, 95% CI: 0.80-1.14 and RR: 1.06, 95% CI: 0.98-1.14, respectively). Findings were comparable for specific antidepressants and trimesters of exposure. Conclusion We did not find evidence that continuation of antidepressants in pregnancy led to differences in GWG. Key points · Antidepressant use is associated with weight change in nonpregnant populations.. · Prior evidence on whether antidepressant use in pregnancy affects gestational weight gain is sparse.. · We accounted for confounding by characteristics such as mental health conditions and their severity.. · We found no association between pregnancy antidepressant continuation and gestational weight gain..

Importance Injury is a leading cause of childhood morbidity and mortality worldwide. Serious mental illness (SMI) is a major contributor to the global burden of disease. Objective To compare injury event rates in children from birth to 5 years of age among Taiwanese children with and without parents with SMI, including schizophrenia, bipolar disorder, and major depressive disorder. Design, Setting, and Participants This population-based, retrospective cohort study of an 11-year Taiwanese birth cohort used data from the Taiwan National Health Insurance Research Database (covering 99% of Taiwanese citizens), the Maternal and Child Health Database, and birth and death certificate databases. The study included 1 999 322 singletons with Taiwanese citizenship born from January 1, 2004, to December 31, 2014, and followed up from birth to their fifth birthday, December 31, 2014, or the date of death, yielding a total of 7 741 026 person-years. Data analysis was performed from April 20, 2017, to September 24, 2019. Exposures Physician-diagnosed parental SMI defined using outpatient and inpatient records from 6 years before the child’s birth to 5 years after delivery. Main Outcome and Measures Rates of medically attended injury events, injury hospitalization, and injury death retrieved from outpatient records, inpatient records, and death certificates. Generalized estimating equation for log-linear models estimated injury incidence rate ratios (IRRs) comparing parental SMI-exposed children and unexposed children. Results The study cohort included 1 999 322 singletons (52.1% males without parental SMI and 52.2% males with parental SMI). Incidence rates of child injury-related outcomes were higher among children exposed to parental SMI (294.8 injury events per 1000 person-years) compared with children who were unexposed (256.1 injury events per 1000 person-years). After adjustment for sociodemographic factors, children with parental SMI had higher rates of injury events (IRR, 1.14; 95% CI, 1.13-1.15), injury hospitalization (IRR, 1.49; 95% CI, 1.42-1.57), and injury death (IRR, 1.82; 95% CI, 1.38-2.39) compared with unexposed children. The results were confirmed in sensitivity analyses. Appendicitis, a negative control outcome, was not associated with parental SMI (IRR, 1.10; 95% CI, 0.94-1.28). In addition, children with and without parental SMI had similar patterns of preventive health care. The mean (SD) number of prenatal visits was 8.09 (2.50) for children with parental SMI and 8.17 (2.47) among unaffected children. The mean (SD) number of well-child visits was 5.70 (2.24) for children with parental SMI and 5.80 (2.21) among unaffected children. Conclusions and Relevance In this study, children with parental SMI had increased risk of injury, particularly serious injury. Excess risk may be reduced by providing effective mental health treatment, parenting support, and home safety education to parents with SMI who are raising young children.

BACKGROUND: Linked birth certificate–hospital discharge records are a valuable resource for examining pregnancy outcomes among women with disability conditions. Few studies relying on these data have been able to assess the accuracy of identification of pre-existing disability conditions. We assessed the accuracy of International Classification of Diseases version 9 (ICD9) codes for identifying selected physical, sensory, and intellectual conditions that may result in disability. As ICD9 codes were utilized until recently in most states, this information is useful to inform analyses with these records. METHODS: We reviewed 280 of 311 (90%) medical records of pregnant women with disabilities based on ICD9 codes and 390 of 8,337 (5%) records of pregnant women without disabilities who had deliveries at a large university medical center. We estimated sensitivity, specificity, and positive predictive values (PPV) using the medical record as gold standard. We adjusted for verification bias using inverse probability weighting and imputation. RESULTS: The estimated sensitivity of ICD9 codes to identify women with disabilities with deliveries 2009–2012 was 44%; PPV was 98%, improving over time. Although sensitivity was

We examined serious long-term outcomes among childhood cancer survivors using population-based data. We used 1982–2014 Washington State data to compare hospitalization and/or death (including cause-specific) during up to 27 years follow-up among all 5+ year childhood cancer survivors

Advanced parental age has been associated with adverse health effects in the offspring including childhood (0-14years) acute lymphoblastic leukemia (ALL), as reported in our meta-analysis of published studies. We aimed to further explore the association using primary data from 16 studies participating in the Childhood Leukemia International Consortium. Data were contributed by 11 case-control (CC) studies (7919 cases and 12,942 controls recruited via interviews) and five nested case-control (NCC) studies (8801 cases and 29,690 controls identified through record linkage of population-based health registries) with variable enrollment periods (1968-2015). Five-year paternal and maternal age increments were introduced in two meta-analyses by study design using adjusted odds ratios (OR) derived from each study. Increased paternal age was associated with greater ALL risk in the offspring (ORCC 1.05, 95% CI 1.00-1.11; ORNCC 1.04, 95% CI 1.01-1.07). A similar positive association with advanced maternal age was observed only in the NCC results (ORCC 0.99, 95% CI 0.91-1.07, heterogeneity I2 = 58%, p = 0.002; ORNCC 1.05, 95% CI 1.01-1.08). The positive association between parental age and risk of ALL was most marked among children aged 1-5years and remained unchanged following mutual adjustment for the collinear effect of the paternal and maternal age variables; analyses of the relatively small numbers of discordant paternal-maternal age pairs were not fully enlightening. Our results strengthen the evidence that advanced parental age is associated with increased childhood ALL risk; collinearity of maternal with paternal age complicates causal interpretation. Employing datasets with cytogenetic information may further elucidate involvement of each parental component and clarify underlying mechanisms.

Background: Down syndrome (DS) is associated with an up to 30-fold increased risk of B-cell acute lymphoblastic leukemia (ALL), and DS-ALL patients have worse overall survival and increased long-term treatment-related health conditions compared with non-DS ALL patients. In a recent genome-wide association study of DS-ALL, established ALL genetic risk loci were associated with DS-ALL, with several single nucleotide polymorphisms (SNPs) conferring a larger effect on ALL risk in the context of DS than in euploidy. We performed an epigenome-wide association study (EWAS) to elucidate whether epigenetic differences at birth are associated with risk of subsequent DS-ALL. Methods: The DS-ALL Discovery Study included 147 DS-ALL cases and 198 DS controls from the International Study of Down Syndrome Acute Leukemia, with newborn dried bloodspots (DBS) obtained from California (n=326) and Washington state (n=19) biobanks. The DS-ALL Replication Study included 24 DS-ALL cases and 24 DS controls with newborn DBS from the Michigan Neonatal Biobank. DNA was isolated from DBS, bisulfite converted, and assayed using Illumina Infinium MethylationEPIC Beadchip genome-wide DNA methylation arrays. Raw data were processed using "minfi" and "noob" packages in R. Reference-based deconvolution of blood cell proportions was performed using the Identifying Optimal DNA methylation Libraries (IDOL) algorithm, using DNA methylation data from cord blood reference samples, to estimate proportions of B cells, T cells (CD4+ and CD8+), monocytes, granulocytes, natural killer cells, and nucleated red blood cells. We compared each cell type proportion between DS-ALL cases and DS controls using linear regression adjusting for sex, plate, and principal components (PCs) to account for genetic ancestry. To identify single CpG probes associated with DS-ALL risk, we performed a multiethnic EWAS of DS-ALL in each study using linear regression adjusting for sex, plate, and PCs related to: 1) cell-type proportions and 2) genetic ancestry. Differentially methylated regions (DMRs) were identified using DMRcate and comb-p methods. In the Discovery Study, genome-wide SNP array data were available for 131 cases and 130 controls, and data from targeted sequencing of somatic mutations in exons 2/3 of GATA1 were available for 184/198 DS controls. Results: Deconvolution of blood cell proportions in the DS-ALL Discovery Study showed significantly higher B cell proportions in newborns with DS who later developed ALL (mean=0.0128, sd=0.0151) compared with DS controls (mean=0.00826, sd=0.0115) (P=6.4x10 -4, coefficient=0.0052). A significantly higher B cell proportion at birth was also found in DS-ALL cases in the independent Replication Study (cases mean=0.048, sd=0.024; controls mean=0.039, sd=0.028; P=0.03, coefficient=0.015). In the Discovery Study, the B cell difference remained significant (P=5.8x10 -3) with a similar effect size (coefficient=0.0045) after removal of GATA1 mutation-positive DS controls (n=30). We also investigated whether DS-ALL risk SNPs at ARID5B, IKZF1, GATA3, and CDKN2A may confound the association, but the increased B cell proportions in DS-ALL remained significant and effect estimates slightly increased in SNP genotype-adjusted models (coefficient range:0.0055-0.0059). In the EWAS of DS-ALL, 9 CpGs reached epigenome-wide significance (P Conclusions: Increased B cell proportions in newborns with DS may be a risk factor for development of DS-ALL in childhood. This finding, based on DNA methylation data, requires confirmation using conventional cell count measures, and should be explored as a novel biomarker for ALL risk in the non-DS population. Single CpGs and DMRs associated with DS-ALL risk in our Discovery Study require further investigation, including in additional ALL case-control studies in DS and non-DS populations. Disclosures Ma: Celgene/Bristol Myers Squibb: Consultancy, Research Funding.

Background Existing data on associations between maternal and early childhood exposures and juvenile idiopathic arthritis (JIA) risk is scant and inconsistent with previous studies showing potential role for prematurity, number of siblings and infections. We explored JIA and International League of Associations for Rheumatology (ILAR) JIA categories in relation to selected infant (birthweight, size-for-gestational-age, gestational age), and maternal (parity, delivery type, prior fetal loss) characteristics that may be markers for exposures related to two pathways (hygiene hypothesis, microchimerism) potentially associated with autoimmune disorder occurrence. Methods A case–control analysis with 1,234 JIA cases and 5,993 birth year-matched controls was conducted. Exposure information was obtained from WA state birth certificates. Multivariable logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for associations with maternal and early life exposures for JIA and JIA categories. Results Greater maternal parity was associated with a decreased OR for JIA (most marked for persistent oligoarticular JIA, OR 0.32, 95% CI 0.15; 0.71, p for trend = 0.0001). Prior fetal loss (except for oligoarticular JIA) was associated with an increased OR for JIA. Prematurity was associated with increased risk of enthesitis related arthritis (OR 1.9, 95% CI: 1.3–2.9) and rheumatoid factor positive polyarticular JIA (OR 2.2, 95% CI: 1.0–4.8). Conclusions We observed associations of selected maternal factors with JIA, some of which varied across JIA categories. The findings of decreased ORs for JIA in relation to greater maternal parity may be consistent with the hygiene and microchimerism hypotheses. Future studies with biomarkers relevant to these hypotheses will help elucidate any associations.

Few studies have compared the incidence of infections occurring ≥2 years after hematopoietic cell transplant (HCT) with other cancer patients and the general population. In this study, ≥2-year HCT survivors who were Washington residents treated from 1992 through 2009 (n = 1792; median age, 46 years; 52% allogeneic; 90% hematologic malignancies) were matched to individuals from the state cancer registry (n = 5455, non-HCT) and driver’s license files (n = 16 340; Department of Licensing [DOL]). Based on hospital and death registry codes, incidence rate ratios (IRRs; 95% confidence interval [CI]) of infections by organism type and organ system were estimated using Poisson regression. With 7-year median follow-up, the incidence rate (per 1000 person-years) of all infections was 65.4 for HCT survivors vs 39.6 for the non-HCT group (IRR, 1.6; 95% CI, 1.3-1.9) and 7.2 for DOL (IRR, 10.0; 95% CI, 8.3-12.1). Bacterial and fungal infections were each 70% more common in HCT vs non-HCT cancer survivors (IRR, 1.7; P < .01), whereas the risk for viral infection was lower (IRR, 1.4; P = .07). Among potentially vaccine-preventable organisms, the IRR was 3.0 (95% CI, 2.1-4.3) vs the non-HCT group. Although the incidences of all infections decreased with time, the relative risk in almost all categories remained significantly increased in ≥5-year HCT survivors vs other groups. Risk factors for late infection included history of relapse and for some infections, history of chronic graft-versus-host disease. Providers caring for HCT survivors should maintain vigilance for infections and ensure adherence to antimicrobial prophylaxis and vaccination guidelines.

Background: High birthweight may predispose children to acute lymphoid leukemia, whereas low birthweight is associated with childhood morbidity and mortality. Low and high birthweight have been inconsistently associated with mortality in children with leukemia. Material and methods: In a cohort of childhood and adolescent leukemia (0–19 years) patients from registries in Denmark, Norway, Sweden, and Washington State in the United States (1967–2015), five-year all-cause mortality was assessed by birthweight and other measures of fetal growth using the cumulative incidence function and Cox regression with adjustment for sex, diagnosis year, country, the presence of Down’s syndrome or other malformations, and type of leukemia. Results: Among 7148 children and adolescents with leukemia (55% male), 4.6% were low (1–2 years old; 1.0 (95% CI: 0.6, 1.5) for 3–8 years old; 1.0 (95% CI: 0.6, 1.8) for 9–13 years old; and 1.2 (95% CI: 0.7, 2.1) for 14–19 years old, and were similar for size for gestational age and Ponderal index. In analyses restricted to children born full term (37–41 weeks of gestation), results were only slightly attenuated but risk was markedly increased for infants aged ≤1 year (HR for low birthweight = 3.2, 95% CI: 1.2, 8.8). Conclusion: This cohort study does not suggest that low birthweight or SGA is associated with increased five-year all-cause mortality risk among children with any type of childhood leukemia or acute lymphoblastic leukemia, specifically, beyond infancy.

Evidence for an association of foetal growth with acute myeloid leukaemia (AML) is inconclusive. AML is a rare childhood cancer, relatively more frequent in girls, with distinct features in infancy. In the context of the Childhood Leukemia International Consortium (CLIC), we examined the hypothesis that the association may vary by age, sex and disease subtype using data from 22 studies and a total of 3564 AML cases.Pooled estimates by age, sex and overall for harmonised foetal growth markers in association with AML were calculated using the International Fetal and Newborn Growth Consortium for the 21st Century Project for 17 studies contributing individual-level data; meta-analyses were, thereafter, conducted with estimates provided ad hoc by five more studies because of administrative constraints. Subanalyses by AML subtype were also performed.A nearly 50% increased risk was observed among large-for-gestational-age infant boys (odds ratio [OR]: 1.49, 95% confidence interval [CI]: 1.03-2.14), reduced to 34% in boys aged2 years (OR: 1.34, 95% CI: 1.05-1.71) and 25% in boys aged 0-14 years (OR: 1.25, 95% CI: 1.06-1.46). The association of large for gestational age became stronger in boys with M0/M1subtype (OR: 1.80, 95% CI: 1.15-2.83). Large birth length for gestational age was also positively associated with AML (OR: 1.38, 95% CI: 1.00-1.92) in boys. By contrast, there were null associations in girls, as well as with respect to associations of decelerated foetal growth markers.Accelerated foetal growth was associated with AML, especially in infant boys and those with minimally differentiated leukaemia. Further cytogenetic research would shed light into the underlying mechanisms.

BACKGROUND: Parental age has been associated with several childhood cancers, albeit the evidence is still inconsistent. AIM: To examine the associations of parental age at birth with acute myeloid leukemia (AML) among children aged 0-14 years using individual-level data from the Childhood Leukemia International Consortium (CLIC) and non-CLIC studies. MATERIAL/METHODS: We analyzed data of 3182 incident AML cases and 8377 controls from 17 studies [seven registry-based case-control (RCC) studies and ten questionnaire-based case-control (QCC) studies]. AML risk in association with parental age was calculated using multiple logistic regression, meta-analyses, and pooled-effect estimates. Models were stratified by age at diagnosis (infants

Introduction Low birth weight has been associated with an increased risk of hypertension in children. Less clear is whether high birth weight is also associated with risk. We evaluated overall and age-specific risks of primary hypertension in children and young adults associated with birth weight and birth weight for gestational age. Methods We conducted a population-based case-control study using linked Washington State birth certificate and hospital discharge data from 1987 to 2003. Cases were persons hospitalized with primary hypertension at 8-24 years of age (n = 533). Controls were randomly selected among those born in the same years who were not hospitalized with hypertension (n = 25,966). Results Birth weight was not related to risk of primary hypertension overall, except for a suggestion of an increased risk associated with birth weight ≥4500 g relative to 3500-3999 g (odds ratio (OR) 1.55; 95 % confidence interval (CI) 0.96-2.49). Compared to children born appropriate weight for gestational age, those born small (SGA) (OR 1.32; 95 % CI 1.02-1.71) and large for gestational age (LGA) (OR 1.30; 95 % CI 1.00-1.71) had increased risks of primary hypertension. These overall associations were due to increased risks of hypertension at 15-24 years of age; no associations were observed with risk at 8-14 years of age. Discussion In this study, both SGA and LGA were associated with increased risks of primary hypertension. Our findings suggest a possible nonlinear (U-shaped) association between birth weight for gestational age and primary hypertension risk in children and young adults.

OBJECTIVE. Rheumatoid arthritis (RA) often ameliorates during pregnancy and flares postpartum, but the relationship of pregnancy and childbirth to RA prognosis is unclear. We examined RA severity for association with parity prior to RA onset and asked whether time from birth (latency) and/or the mother’s HLA genotype influenced results. METHODS. A cohort study was conducted of 222 women previously identified in a prospective study of newly diagnosed RA, who returned for follow-up evaluation a median of 8 years later. Stratified analyses using Mantel-Haenszel methods were conducted to evaluate 5 RA severity measures including hand and wrist radiographs, physical exams, and Health Assessment Questionnaires for association with parity. RESULTS. Overall we observed little evidence of altered risk of progression to severe RA in relation to pre-onset parity, adjusting for RA onset age and time to follow-up. Stratifying parous women who had only live births by latency (

PURPOSE: Previous studies observed modestly higher risk of gestational diabetes (GDM) associated with antidepressant use in pregnancy, potentially due to confounding by indication. We assessed the association of antidepressant continuation in pregnancy with GDM, as well as blood glucose levels, after accounting for confounding. METHODS: We conducted a retrospective cohort study of singleton live births from 2001–2014 to women enrolled in Kaiser Permanente Washington, an integrated healthcare delivery system, utilizing electronic health data and linked Washington State birth records. We required that women have ≥1 antidepressant prescription fills ≤6 months before pregnancy. Women with an antidepressant fill during pregnancy were categorized as “continuers” (n=1634); those without a fill were “discontinuers” (n=1211). We calculated relative risks (RRs) for GDM and mean differences in screening blood glucose levels using generalized estimating equations with inverse probability of treatment weighting to account for baseline characteristics, including mental health conditions and indicators of mental health severity. RESULTS: Compared with discontinuers, antidepressant continuers had comparable risk of GDM (RR: 1.10, 95% confidence interval [CI]: 0.84–1.44) and screening blood glucose levels (mean difference: 2.3 mg/dL, 95% CI: −1.5 to 6.1 mg/dL). We observed generally similar results for specific antidepressants, with the potential exceptions of risk of GDM associated with sertraline (RR: 1.30, 95% CI: 0.90–1.88) and venlafaxine (RR: 1.52, 95% CI: 0.87–2.68), but neither association was statistically significant. CONCLUSIONS: Our study suggests that overall, women who continue antidepressants in pregnancy are not at increased risk for GDM or higher blood glucose, although further study may be warranted for sertraline and venlafaxine.

One in 1,000 pregnancies is complicated by malignancies. Prevalence is greater for benign neoplasms. Adverse outcomes among women with malignancies have been reported. Less is known of postpartum outcomes for infants, or outcomes among women with benign neoplasms. We conducted a population-based cohort study using Washington State-linked vital-hospital discharge records. Women with neoplasms (707 malignant; 13,156 benign) with deliveries in 1987–2012 were identified, and a randomly selected comparison cohort. Obstetrical/infant outcomes and rehospitalization

Background Male sex is associated with an increased risk of childhood cancer as is high birthweight. Given that sex determination precedes birthweight we conducted a mediation analysis to estimate the direct effect of sex in association with childhood cancer tumor type with birthweight as the mediator. Methods Cases (n = 12,632) and controls (n = 64,439) (ages 0–14 years) were identified from population-based cancer and birth registries in Minnesota, New York, and Washington states (1970–2014). An inverse odds weighting (IOW) mediation analysis was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) as the measure of association between sex and cancer. Results A significant indirect effect was observed for sex and lymphoid leukemia, mediated by birthweight (indirectOR: 1.03; 95% CI: 1.02–1.04). We observed significant direct effects for male sex and lymphoid leukemia (directOR: 1.16; 95% CI: 1.08–1.25), Hodgkin lymphoma (directOR: 1.48; 95% CI: 1.22–1.81), Burkitt lymphoma (directOR: 5.02; 95% CI: 3.40–7.42), other non-Hodgkin lymphoma (directOR: 1.42; 95% CI: 1.18–1.70), intracranial embryonal tumors (directOR: 1.49; 95% CI: 1.26–1.76), hepatoblastoma (directOR: 1.90; 95% CI: 1.40–2.59), and rhabdomyosarcoma (directOR: 1.47; 95% CI: 1.19–1.81). There were also inverse associations for extracranial GCTs (directOR: 0.41; 95% CI: 0.26–0.63) and thyroid carcinoma (directOR: 0.35; 95% CI: 0.25–0.50). Conclusion Significant direct effects for sex and numerous childhood cancer types suggests sex-specific factors such as differences in gene expression from the autosomes or the X chromosome, rather than birthweight, may underlie sex differences in tumor risk.

BACKGROUND: Pregnant women with intellectual disability (ID) may have greater levels of comorbidity and decreased care access, social support, or ability to monitor their status and communicate needs, but few studies have examined their pregnancy course and outcome, and little is known about their longer-term maternal and infant health. OBJECTIVE: We compared pre-pregnancy characteristics, pregnancy outcomes, and rehospitalization

Background/Purpose: Cigarette smoking increases the risk of seropositive adult Rheumatoid arthritis. Juveinile idiopathic arthritis (JIA) is a heterogenous group of 7 mutually exclusive categories of chronic childhood inflammatory arthritides. Objectives: To determine the association between JIA and its categories with maternal prenatal smoking. Methods: This case-control study used ICD-9 codes from hospital records to identify 1196 JIA cases born in Washington State and diagnosed at a tertiary pediatric center during 1997—2010. Controls (n = 5618) were randomly selected from birth records of children without JIA, frequency matched on birth year. Prenatal smoking exposure was assessed from subjects' birth certificates. Chart review categorized JIA into ILAR categories. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression adjusted for maternal age and marital status. Results: We did not observe an increased risk of JIA in relation to maternal prenatal smoking. Prenatal smoking was reported less often among mothers of JIA cases (11%), than among control mothers (17%, OR 0.71, 95% CI: 0.58—0.87), a relationship somewhat more marked for oligoarticular/ extended oligoarticular JIA. Although the inverse relationship persisted after adjustment for maternal education or health insurance status, we cannot rule out the possibility that this effect may have been at least partially due to residual confounding by socio-economic status. Conclusion: We did not observe an increased risk of JIA with maternal prenatal smoking.

Background High birthweight is an established risk factor for childhood leukaemia. Its association with other childhood cancers is less clear, with studies hampered by low case numbers. Methods We used two large independent datasets to explore risk associations between birthweight and all subtypes of childhood cancer. Data for 16 554 cases and 53 716 controls were obtained by linkage of birth to cancer registration records across five US states, and 23 772 cases and 33 206 controls were obtained from the UK National Registry of Childhood Tumours. US, but not UK, data were adjusted for gestational age, birth order, plurality, and maternal age and race/ethnicity. Results Risk associations were found between birthweight and several childhood cancers, with strikingly similar results between datasets. Total cancer risk increased linearly with each 0.5 kg increase in birthweight in both the US [odds ratio 1.06 (95% confidence interval 1.04, 1.08)] and UK [1.06 (1.05, 1.08)] datasets. Risk was strongest for leukaemia [USA: 1.10 (1.06, 1.13), UK: 1.07 (1.04, 1.10)], tumours of the central nervous system [USA: 1.05 (1.01, 1.08), UK: 1.07 (1.04, 1.10)], renal tumours [USA: 1.17 (1.10, 1.24), UK: 1.12 (1.06, 1.19)] and soft tissue sarcomas [USA: 1.12 (1.05, 1.20), UK: 1.07 (1.00, 1.13)]. In contrast, increasing birthweight decreased the risk of hepatic tumours [USA: 0.77 (0.69, 0.85), UK: 0.79 (0.71, 0.89) per 0.5 kg increase]. Associations were also observed between high birthweight and risk of neuroblastoma, lymphomas, germ cell tumours and malignant melanomas. For some cancer subtypes, risk associations with birthweight were non-linear. We observed no association between birthweight and risk of retinoblastoma or bone tumours. Conclusions Approximately half of all childhood cancers exhibit associations with birthweight. The apparent independence from other factors indicates the importance of intrauterine growth regulation in the aetiology of these diseases.

Background Increased risk of adverse birth outcomes is well described in women with systemic lupus erythematosus (SLE), but risk of maternal or infant infection in the peripartum period has not been well studied. We conducted a population-based cohort study of infection risk in women with and without SLE and their infants. Methods Linked birth-hospital discharge data identified 1297 deliveries to women with SLE and a 4:1 comparison cohort of deliveries to women without SLE in Washington State, 1987-2013. Maternal and infant infections during the first 30 days after delivery were identified. Relative risks (RR) and 95% confidence intervals (CI) were estimated. Results Women with SLE were 1.7 times more likely (95% CI 1.4, 2.0) to have an infection during the birth hospitalisation and more likely to receive antibiotics during labour (RR 1.3, 95% CI 1.1, 1.5), though there was no increased risk of chorioamnionitis in women with SLE. Infants of women with SLE had an increased risk for an infection during the birth hospitalisation (RR 2.2, 95% CI 1.3, 3.5), although the size of the difference was smaller when adjusted for gestational age (RR 1.4, 95% CI 0.9, 2.1). Risks of neonatal infection, sepsis, receipt of antibiotics, and admission to neonatal intensive care were also increased, and were also attenuated after adjustment for gestational age. Conclusions Women with SLE have an increased risk of peripartum infections and antibiotic exposure. Their neonates have a greater likelihood of infection, much of which is attributable to preterm birth.

Objective To evaluate pregnancy and neonatal outcomes among deaf women using population-based vital records data in Washington State from 1987 to 2012. Methods We performed a retrospective cohort study using the Washington State birth and fetal death records linked to state hospital discharge records to identify women with diagnosis codes for deafness indicated at their delivery hospitalization and compared them with randomly selected women without these codes. Pregnancy conditions and outcomes evaluated included gestational diabetes, preeclampsia, placental abruption, labor induction, and cesarean delivery. Neonatal outcomes evaluated included preterm gestational age (less than 28, 28 to less than 37 weeks) at delivery and low birth weight. We also assessed length of maternal and neonatal delivery hospitalization. We performed Poisson regression to estimate relative risks (RRs) and 95% CIs for each outcome, adjusting for birth year, maternal age, and parity. Results Most adverse pregnancy and neonatal outcomes were similar for deaf and comparison women. Among women who underwent vaginal delivery, deaf women were more than twofold (RR 2.15, 95% CI 1.43-3.22) more likely to have a delivery hospitalization of 4 or more days (6.0% compared with 2.8%). We found a modestly increased risk of cesarean delivery (RR 1.15, 95% CI 1.01-1.30), with 29.9% of deaf compared with 25.6% of nondeaf women having a cesarean delivery. Conclusion Deaf women are not at increased risk of the majority of adverse pregnancy and neonatal outcomes. Obstetric care providers may use our findings in counseling this special population of prenatal patients.

BACKGROUND Infant leukaemia (IL) is extremely rare with fewer than 150 cases occurring each year in the United States. Little is known about its causes. However, recent evidence supports a role of de novo mutations in IL aetiology. Parental age has been associated with several adverse outcomes in offspring, including childhood cancers. Given the role of older parental age in de novo mutations in offspring, we carried out an analysis of parental age and IL. METHODS We evaluated the relationship between parental age and IL in a case-control study using registry data from New York, Minnesota, California, Texas, and Washington. Records from 402 cases [219 acute lymphoblastic leukaemia (ALL), 131 acute myeloid leukaemia (AML), and 52 other] and 45 392 controls born during 1981-2004 were analysed. Odds ratios (OR) and 95% confidence intervals (CI) were calculated by logistic regression. Estimates were adjusted for infant sex, birth year category, maternal race, state, and mutually adjusted for paternal or maternal age, respectively. RESULTS Infants with mothers' age ≥40 years had an increased risk of developing AML (OR 4.80, 95% CI 1.80, 12.76). In contrast, paternal age

Vitamin D deficiency among pregnant women is common. Compelling animal evidence suggests carcinogenic effects of vitamin D deficiency on the brains of offspring; however, the impact of circulating vitamin D [25(OH)D] on childhood brain tumor (CBT) risk has not been previously evaluated. Using linked birth-cancer registry data in Washington State, 247 CBT cases (

The authors sought to better understand the combined effects of pretransplant, transplant, and post-transplant factors in determining risks of serious cardiovascular disease after hematopoietic cell transplantation (HCT). Hospitalizations and deaths associated with serious cardiovascular outcomes were identified among 1379 Washington State residents who received HCT (57% allogeneic and 43% autologous) at a single center from 1985 to 2005, survived ≥ 2 years, and followed through 2008. Using a nested case-cohort design, relationships (hazard ratios [HRs]) between potential risk factors and outcomes were examined among affected survivors and a randomly selected subcohort (N = 509). After 7.0 years of median follow-up (range, 2.0 to 23.7), the 10-year cumulative incidence of ischemic heart disease, cardiomyopathy, stroke, and all-cause cardiovascular death was 3.8%, 6.0%, 3.5%, and 3.7%, respectively. In multivariable analysis, increased pretransplant anthracycline was associated with cardiomyopathy. Active chronic graft-versus-host disease was associated with cardiovascular death (HR, 4.0; 95% confidence interval, 1.1 to 14.7); risk was otherwise similar between autologous versus allogeneic HCT recipients. Independent of therapeutic exposures, pretransplant smoking, hypertension, dyslipidemia, diabetes, and obesity conferred additional risk of all outcomes except stroke (HR ≥ 1.5 for each additional risk factor, P < .03). Hypertension and dyslipidemia at 1 year with persistence of these conditions 2 or more years after HCT also were associated with independent risks of multiple outcomes. HCT survivors with preexisting or newly developed and persistent cardiovascular risk factors remain at greater risk of subsequent serious cardiovascular disease compared with other survivors, independent of chemo- and radiotherapy exposures. These survivors should receive appropriate follow-up and be considered for primary intervention.

Objective To identify barriers to life jacket use. Design Cross-sectional survey. Setting Nine public boat ramps in western Washington State, USA, August–November, 2008. Participants 675 adult boaters (>18 years) on motor boats Main outcome Low or no life jacket use (0–50% of time) versus high life jacket use (51–100% of time). Results Low/no life jacket use (0–50% of time) was associated with longer boat length (per foot, risk ratio [RR] 1.03, 95% CI 1.02 to 1.05), alcohol use (RR 1.11, 95% CI 1.01 to 1.20), perception of life jackets as ‘uncomfortable’ (RR 1.29, 95% CI 1.09 to 1.52), perceived greater level of swimming ability (RR 1.25, 95% CI 1.03 to 1.53 for ‘expert swimmer’) and possibly with lack of confidence that a life jacket may save one from drowning (RR 1.13, 95% CI 0.96 to 1.32). Low life jacket use was less likely when an inflatable life jacket was the primary life jacket used by a subject (RR 0.77, 95% CI 0.63 to 0.94), a child was onboard (RR 0.88, 95% CI 0.79 to 0.99) or if the respondent had taken a boating safety class (RR 0.94, 95% CI 0.87 to 1.01). Conclusions Life jacket use may increase with more comfortable devices, such as inflatable life jackets, and with increased awareness of their efficacy in preventing drowning. Boater education classes may be associated with increased life jacket use among adults.

Children with Down syndrome (DS), caused by constitutive trisomy of chromosome 21, have a 20-fold increased risk of acute lymphoblastic leukemia (DS-ALL) and 500-fold increased risk of acute megakaryoblastic leukemia (DS-AMKL). At least 10-15% of DS neonates are born with the pre-leukemic syndrome transient abnormal myelopoiesis (TAM). Trisomy 21 affects hematopoiesis and leukemia risk; however, the underlying mechanisms are not fully understood. Previous small-scale studies (sample N DNA was extracted from newborn dried bloodspots from 196 children born with DS and 442 non-DS controls from the California Biobank Program, and assayed using Illumina Infinium MethylationEPIC arrays containing >850,000 CpG probes. Data preprocessing was performed using the SeSAMe R package, and the conumee package confirmed trisomy 21 or euploidy in DS and non-DS subjects. Cell type deconvolution was performed, and blood cell proportions compared between DS and non-DS newborns using linear regression adjusting for covariates. ReFACTor principal components (PCs) were used to adjust for cell type heterogeneity and EPISTRUCTURE PCs to adjust for ancestry. Epigenome-wide association studies (EWAS) were performed overall, and stratified by ethnicity, using linear regression models adjusting for sex, plate, first six ReFACTor PCs, and first six ancestry-related PCs. Differentially methylated regions (DMRs) were evaluated using DMRcate and comb-p, with a consensus list of significant DMRs using the overlap. Deconvolution of blood cell proportions revealed highly significant (P Intriguingly, PC analysis and hierarchical clustering of DNA methylation data identified a subset of DS subjects (N=34/196, 17%) that clustered separately: these all had significantly higher nRBC proportions than other subjects and possibly represent DS neonates with TAM, although further investigation is needed for confirmation. Removing this cluster did not affect our main findings in our EWAS or DMR analyses. Constitutive trisomy 21 has profound effects on DNA methylation across the genome, in particular resulting in repression of known regulators of hematopoiesis including RUNX1 and FLI1. Our findings highlight potential mechanisms for the increased risk of both lymphoid and myeloid malignancies in children with DS. Disclosures No relevant conflicts of interest to declare.

Importance Birth defects affect approximately 1 in 33 children. Some birth defects are known to be strongly associated with childhood cancer (eg, trisomy 21 and acute leukemia). However, comprehensive evaluations of childhood cancer risk in those with birth defects have been limited in previous studies by insufficient sample sizes. Objectives To identify specific birth defect–childhood cancer (BD-CC) associations and characterize cancer risk in children by increasing number of nonchromosomal birth defects. Design, Setting, and Participants This multistate, population-based registry linkage study pooled statewide data on births, birth defects, and cancer from Texas, Arkansas, Michigan, and North Carolina on 10 181 074 children born from January 1, 1992, to December 31, 2013. Children were followed up to 18 years of age for a diagnosis of cancer. Data were retrieved between September 26, 2016, and September 21, 2017, and data analysis was performed from September 2, 2017, to March 21, 2019. Exposures Birth defects diagnoses (chromosomal anomalies and nonchromosomal birth defects) recorded by statewide, population-based birth defects registries. Main Outcomes and Measures Cancer diagnosis before age 18 years, as recorded in state cancer registries. Cox regression models were used to generate hazard ratios (HRs) and 95% CIs to evaluate BD-CC associations and the association between number of nonchromosomal defects and cancer risk. Results Compared with children without any birth defects, children with chromosomal anomalies were 11.6 (95% CI, 10.4-12.9) times more likely to be diagnosed with cancer, whereas children with nonchromosomal birth defects were 2.5 (95% CI, 2.4-2.6) times more likely to be diagnosed with cancer before 18 years of age. An increasing number of nonchromosomal birth defects was associated with a corresponding increase in the risk of cancer. Children with 4 or more major birth defects were 5.9 (95% CI, 5.3-6.4) times more likely to be diagnosed with cancer compared with those without a birth defect. In the analysis of 72 specific BD-CC patterns, 40 HRs were statistically significant (adjustedP Conclusions and Relevance Several significant and novel associations were observed between specific birth defects and cancers. Among children with nonchromosomal birth defects, the number of major birth defects diagnosed was significantly and directly associated with cancer risk. These findings could inform clinical treatment for children with birth defects and may elucidate mechanisms that lead to these complex outcomes.

7046 Background: Infections are a major complication of hematopoietic cell transplantation (HCT). Few studies have compared the incidence of late infections occurring ≥2y post-HCT to other cancer patients and the general population. Methods: Single center records of ≥2y HCT survivors who were Washington residents treated from 1992-2009 (n = 1,792; median age 46y; 53% allogeneic; 90% hematologic malignancies) were linked to the state’s hospital discharge and death registries. Individuals randomly selected from the state cancer registry (n = 5,455, non-HCT) and driver’s license files (n = 16,340, DOL) who survived ≥2y formed two comparison groups, matched on sex, age, year, and cancer diagnosis (non-HCT group only). Based on hospital and death registry codes, incidence rate ratios (IRR) with confidence intervals (CI) of infections by organism type and organ system were estimated using Poisson regression. Results: With 6y (range 2-20) median follow up, the incidence rate (per 1000 person-y) of all infections was 65 in HCT survivors vs. 40 in the non-HCT group (IRR 1.6, 95% CI 1.3-1.9). In contrast, the DOL group’s infection rate was 7 (HCT vs. DOL IRR 10.0, 95% CI 8.3-12.1). Specifically, bacterial and fungal infections were each 70% more common in HCT vs non-HCT cancer survivors (IRRs 1.7; p < 0.01). Differences in viral infection rates were more modest (IRR 1.4, p = 0.07). Infections attributed to staphylococcus, streptococcus, and non-Candida fungi including Aspergillus were twice as common in the HCT vs. non-HCT cancer survivors (IRRs 2.1-2.3; p < 0.05). IRRs for nervous system, respiratory, and musculoskeletal infections between these 2 groups were 1.9-2.8 (p < 0.05). Among potentially vaccine-preventable organisms, the IRR was 3.2 (95% CI 2.2-4.6). While the absolute incidences decreased with time, the relative risks in almost all categories were even greater when restricted to ≥5y HCT vs. non-HCT cancer survivors. Conclusions: ≥2y HCT survivors had a significantly increased incidence of infections vs. matched non-HCT cancer survivors. Providers caring for long-term HCT survivors should maintain high vigilance for infections in this population and ensure adherence to HCT antimicrobial prophylaxis and vaccination guidelines.

Background : Acute leukemia is the most common cancer in children under 15 years of age; 80% are acute lymphoblastic leukemia (ALL) and 17% are acute myeloid leukemia (AML). Childhood leukemia shows further diversity based on cytogenetic and molecular characteristics, which may relate to distinct etiologies. Case–control studies conducted worldwide, particularly of ALL, have collected a wealth of data on potential risk factors and in some studies, biospecimens. There is growing evidence for the role of infectious/immunologic factors, fetal growth, and several environmental factors in the etiology of childhood ALL. The risk of childhood leukemia, like other complex diseases, is likely to be influenced both by independent and interactive effects of genes and environmental exposures. While some studies have analyzed the role of genetic variants, few have been sufficiently powered to investigate gene–environment interactions. Objectives : The Childhood Leukemia International Consortium (CLIC) was established in 2007 to promote investigations of rarer exposures, gene–environment interactions and subtype-specific associations through the pooling of data from independent studies. Methods : By September 2012, CLIC included 22 studies (recruitment period: 1962–present) from 12 countries, totaling approximately 31000 cases and 50000 controls. Of these, 19 case–control studies have collected detailed epidemiologic data, and DNA samples have been collected from children and child–parent trios in 15 and 13 of these studies, respectively. Two registry-based studies and one study comprising hospital records routinely obtained at birth and/or diagnosis have limited interview data or biospecimens. Conclusions : CLIC provides a unique opportunity to fill gaps in knowledge about the role of environmental and genetic risk factors, critical windows of exposure, the effects of gene–environment interactions and associations among specific leukemia subtypes in different ethnic groups.

Background The presence of a congenital anomaly is associated with increased childhood cancer risk, likely due to large effects of Down syndrome and chromosomal anomalies for leukemia. Less is known about associations with presence of non-chromosomal anomalies. Methods Records of children diagnosed with cancer at