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.

Breastfeeding and risk of childhood brain tumors: a report from the Childhood Cancer and Leukemia International Consortium.

PURPOSE: Studies report mixed findings regarding the association of breastfeeding with childhood brain tumors (CBT), the leading causes of cancer-related mortality in young people. Our objective was to determine whether breastfeeding is associated with CBT incidence. METHODS: We pooled data on N = 2610 cases with CBT (including 697 cases with astrocytoma, 447 cases with medulloblastoma/primitive neuroectodermal tumor [PNET], 167 cases with ependymoma) and N = 8128 age- and sex-matched controls in the Childhood Cancer and Leukemia International Consortium. We computed unconditional logistic regression models to estimate the odds ratio (OR) and 95% confidence interval (CI) of CBT, astrocytoma, medulloblastoma/PNET, and ependymoma according to breastfeeding status, adjusting for study, sex, mode of delivery, birthweight, age at diagnosis/interview, maternal age at delivery, maternal educational attainment, and maternal race/ethnicity. We evaluated any breastfeeding versus none and breastfeeding ≥ 6 months versus none. We subsequently performed random effects meta-analysis to confirm our findings, identify potential sources of heterogeneity, and evaluate for outliers or influential studies. RESULTS: Breastfeeding was reported by 64.8% of control mothers and 64.5% of case mothers and was not associated with CBT (OR 1.04, 95% CI 0.94-1.15), astrocytoma (OR 1.01, 95% CI 0.87-1.17), medulloblastoma/PNET (OR 1.11, 95% CI 0.93-1.32), or ependymoma (OR 1.06, 95% CI 0.81-1.40). Results were similar when we restricted to breastfeeding ≥ 6 months and in meta-analyses. CONCLUSION: Our data suggest that breastfeeding does not protect against CBT.

Infant feeding practices and childhood acute leukemia: Findings from the Childhood Cancer & Leukemia International Consortium.

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.

Morbidity and rehospitalization postpartum among women with epilepsy and their infants: A population-based study.

OBJECTIVE: 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. METHODS: 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 mortality <2 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. RESULTS: 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. CONCLUSION: 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.

Hospitalization and mortality outcomes in the first 5 years after a childhood cancer diagnosis: a population-based study.

PURPOSE: Children with cancer are frequently hospitalized. However, hospitalization and death by disease category are not well defined < 5 years from diagnosis. METHODS: We conducted a retrospective cohort study using linked cancer registry-hospital discharge-vital records to identify cancer cases < 20 years at diagnosis during 1987-2012 (n = 4,567) and comparison children without cancer, matched on birth year and sex (n = 45,582). Data linkage identified serious morbidities resulting in cancer- and non-cancer-related hospitalizations or deaths < 5 years from diagnosis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated to compare relative hospitalization and mortality by disease category and after excluding cancer-related outcomes. Among cancer cases, relative risks of these outcomes for children with solid tumors compared with children with leukemia/lymphoma were also estimated. RESULTS: Greater rates of all-cause hospitalization (281.5/1,000 vs. 6.2/1,000 person years) and death (40.7/1,000 vs. 0.15/1,000 person years) were observed in childhood cancer cases than comparators and across all diagnosis categories. Increased hospitalization (31.0/1,000 vs. 6.2/1,000 person years; HR 5.0, 95% CI 4.5-5.5) and death (1.0/1,000 vs. 0.15/1,000 person years; HR 10.4, 95% CI 5.6-19.1) rates remained when cancer-related outcomes were excluded. Although HRs for hospitalization and death did not differ greatly by treatment era, absolute rates of hospitalization were greater (1987-1999: 233.3/1,000; 2000-2012: 320.0/1,000 person years) and death were lesser (1987-1999: 46.3/1,000; 2000-2012: 36.8/1,000 person years) in the later treatment era among cases. Children with solid tumors were less likely to have a cancer-related hospitalization than were those with leukemia/lymphoma (RR 0.91, 95% CI 0.84-0.98). CONCLUSION: Even after excluding cancer-related diagnoses, children with cancer experience greater rates of hospitalization and death in all disease categories. Results may guide future toxicity mitigation initiatives and inform anticipatory guidance for families of children with cancer.

Sex differences in associations between birth characteristics and childhood cancers: a five-state registry-linkage study.

BACKGROUND: 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. METHODS: 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 < 0.01) by sex was evaluated for each characteristic in each cancer. RESULTS: Males comprised > 50% of cases for all cancers, except Wilms tumor (49.6%). Sex interacted with a number of risk factors (all p-interaction < 0.01) including gestational age for ALL (female, 40 vs. 37-39 weeks OR: 0.84, 95% CI 0.73-0.97) and ependymoma (female, 40 vs. 37-39 OR: 1.78, 95% CI 1.14-2.79; female, ≥ 41 OR: 2.01. 95% CI 1.29-3.14), birth order for AML (female, ≥ 3rd vs. 1st OR: 1.39, 95% CI 1.01-1.92), maternal education for Hodgkin lymphoma (male, any college vs. < high school[HS] OR: 1.47, 95% CI 1.03-2.09) and Wilms tumor (female, any college vs. HS OR: 0.74, 95% CI 0.59-0.93), maternal race/ethnicity for neuroblastoma (male, black vs. white OR: 2.21, 95% CI 1.21-4.03; male, Hispanic vs. white OR: 1.86, 95% CI 1.26-2.75; female, Asian/Pacific Islander vs. white OR: 0.28, 95% CI 0.12-0.69), and paternal age (years) for hepatoblastoma in males (< 24 vs. 25-29 OR: 2.17, 95% CI 1.13-4.19; ≥ 35 vs. 25-29 OR: 2.44, 95% CI 1.28-4.64). CONCLUSIONS: These findings suggest etiologic heterogeneity by sex for childhood cancers for gestational age, maternal education, and race/ethnicity and paternal age.

Inherited genetic susceptibility to acute lymphoblastic leukemia in Down syndrome.

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.

Association of Antidepressant Continuation in Pregnancy and Infant Birth Weight.

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; <2500 g), and macrosomia (>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.

Maternal Gestational Weight Gain in Relation to Antidepressant Continuation in Pregnancy.

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..

Assessment of the Accuracy of Identification of Selected Disabilities and Conditions in Hospital Discharge Data for Pregnant Women.

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 preexisting 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 <50% for some conditions, PPVs were 87%-100% for all conditions except intellectual disability (67%). Many physical conditions had complete verification and no underreporting. CONCLUSIONS: These results are helpful for new studies using historical data comparing outcomes among women with and without these conditions and to inform interpretation of results from earlier studies. Assessment of the accuracy of disabilities as identified by ICD version 10 codes is warranted.

Birthweight and all-cause mortality after childhood and adolescent leukemia: a cohort of children with leukemia from Denmark, Norway, Sweden, and Washington State.

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 (<2500 g) and 19% were high (≥4000 g) birthweight. Compared with average weight, hazard ratios (HRs) of death associated with low birthweight varied by age at leukemia diagnosis: 1.5 (95% confidence interval (CI): 0.7, 3.2) for patients 0-1 year old, 1.6 (95% CI: 1.0, 2.6) for >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.

Obstetrical and infant outcomes among women with neoplasms during pregnancy.

PURPOSE: 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. METHODS: 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 < 2 years post-delivery were compared separately for each group by multivariable regressions to estimate risk ratios (RR) and 95% confidence intervals (CI). RESULTS: Women with either condition had increased anemia, cesarean, and preterm delivery; their infants were more often < 2,500 g or jaundiced. Women with benign conditions had increased gestational diabetes (RR = 1.20; 95% CI 1.12-1.28) and preeclampsia (RR = 1.27; 95% CI 1.18-1.36); their infants had increased malformations (RR = 1.29; 95% CI 1.19-1.38). Women with neoplasms more often were hospitalized seven or more days or rehospitalized; their infants' hospitalizations were also longer. CONCLUSION: Malignant and benign neoplasms were associated with several adverse outcomes. Reasons for relationships of benign neoplasms with gestational diabetes, preeclampsia, and congenital malformations merit further study.

Antidepressant continuation in pregnancy and risk of gestational diabetes.

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 to 2014 to women enrolled in Kaiser Permanente Washington, an integrated health care 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 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.

Hospitalization and mortality among pediatric cancer survivors: a population-based study.

PURPOSE: We examined serious long-term outcomes among childhood cancer survivors using population-based data. METHODS: 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 < 20 years at diagnosis (n = 3,152) and a sample of comparison children within birth cohorts, with assessment by cancer type and child/family characteristics. RESULTS: During follow-up (9 years median), 12% of survivors had hospitalizations; 4% died. Greatest absolute risks/1,000 person-years were for hospitalization/deaths due to cancers (8.1), infection (6.2), injuries (6.0), and endocrine/metabolic disorders (5.8). Hazard ratios (HR) and 95% confidence intervals (CI) for hospitalization (2.7, 95% CI 2.4-3.0) and any-cause death (14.7, 95% CI 11.3-19.1) were increased, and for all cause-specific outcomes examined, most notably cancer- (35.1, 95% CI 23.7-51.9), hematological- (6.7, 95% CI 5.3-8.5), nervous system- (6.4, 95% CI 5.2-7.8), and circulatory- (5.2, 95% CI 4.1-6.5) related outcomes. Hospitalizations occurred more often among females and those receiving radiation, with modest differences by urban/rural birth residence and race/ethnicity. Cause-specific outcomes varied by cancer type. CONCLUSIONS: This study suggests increased risks for the rarely-studied outcomes of long-term fracture and injury, and confirms increased risks of selected other conditions among survivors. Multi-state pooling of population-based data would increase the ability to evaluate outcomes for uncommon cancer types and by racial/ethnic groups under-represented in many studies.

A Population-based Study of Perinatal Infection Risk in Women with and without Systemic Lupus Erythematosus and their Infants.

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.

Advanced parental age as risk factor for childhood acute lymphoblastic leukemia: results from studies of the Childhood Leukemia International Consortium.

Advanced parental age has been associated with adverse health effects in the offspring including childhood (0-14 years) 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 1-5 years 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.

Association of endometrial hyperplasia and cancer with a history of gestational diabetes.

PURPOSE: Excess circulating insulin may contribute to endometrial cancer (EC) development; studies suggest increased risk of EC associated with type 2 diabetes. We investigated whether gestational diabetes is associated with increased risk of EC and its precursor, endometrial hyperplasia (EH). METHODS: We conducted a population-based, case-control study of women in Washington State. Cases were women with a hospital discharge record indicating the presence of EH/EC who could be linked to a prior delivery hospitalization or birth record from 1987 to 2013 (n = 593). Controls were randomly selected from remaining deliveries, frequency matched 10:1 on delivery year and maternal age at delivery (n = 5,743). Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: After adjustment for race/ethnicity, maternal age at delivery, and delivery year, EH/EC was associated with a history of gestational diabetes (OR 1.73, 95% CI 1.27-2.35). This association was present for both EH and EC (OR 1.61, 95% CI 1.00-2.60 and OR 1.80, 95% CI 1.22-2.65, respectively). After adjustment for prepregnancy body mass index, the OR for EH/EC was attenuated and became statistically non-significant (OR 1.22, 95% CI 0.87-1.72), except in women <50 years old at the time of case ascertainment (OR 1.49, 95% CI 1.00-2.20). Associations were slightly stronger for EC than EH. CONCLUSIONS: We observed an association between EH/EC and a history of gestational diabetes specific to younger women. Future studies focusing on the relationships between gestational diabetes, obesity, and EC, including age at diagnosis, are warranted.

Daughters of Mothers Who Smoke: A Population-based Cohort Study of Maternal Prenatal Tobacco use and Subsequent Prenatal Smoking in Offspring.

BACKGROUND: Prenatal exposure to tobacco is associated with adverse health outcomes for the mother and child, and has been associated with an increased risk of tobacco smoking and nicotine dependence in offspring. The objective of this study was to examine the risk of prenatal smoking, among daughters, associated with maternal prenatal smoking. METHODS: We used a population-based cohort study design, with linked vital records data of mothers and daughters delivering 1984-96 and 1996-2013, respectively, in Washington State. The exposure of interest was mothers' prenatal smoking (any vs. no smoking at any time during pregnancy), while the outcome was daughters' prenatal smoking (similarly assessed). We used multivariable log-binomial regression to obtain estimates of the relative risk (RR) and 95% confidence interval (CI). RESULTS: Daughters exposed to maternal prenatal smoking were more likely to smoke during their pregnancy, compared to unexposed daughters (RR 1.78, 95% CI 1.72, 1.84, adjusted for the year the daughter delivered, her marital status and educational attainment, and the mothers' race/ethnicity). CONCLUSIONS: In this relatively young population, we found that daughters exposed to maternal prenatal smoking have an increased risk of smoking later on during their own pregnancy, emphasizing the importance of exposures during the prenatal period. The mechanisms leading to prenatal smoking are multifactorial and likely include behavioural, genetic, epigenetic and environmental factors. An understanding of this risk factor for prenatal smoking may guide health care providers to better target smoking cessation interventions to at-risk populations.

Parental Age and Risk of Infant Leukaemia: A Pooled Analysis.

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 <20 was associated with increased risk of ALL (OR 3.69, 95% CI 1.62, 8.41). CONCLUSION: This study demonstrates increased risk of infant ALL in relation to young paternal age. Given record linkage, there is little concern with recall or selection bias, although data are lacking on MLL gene status and other potentially important variables. Parent of origin effects, de novo mutations, and/or carcinogenic exposures may be involved in IL aetiology.

Parental Tobacco Smoking and Acute Myeloid Leukemia: The Childhood Leukemia International Consortium.

The association between tobacco smoke and acute myeloid leukemia (AML) is well established in adults but not in children. Individual-level data on parental cigarette smoking were obtained from 12 case-control studies from the Childhood Leukemia International Consortium (CLIC, 1974-2012), including 1,330 AML cases diagnosed at age <15 years and 13,169 controls. We conducted pooled analyses of CLIC studies, as well as meta-analyses of CLIC and non-CLIC studies. Overall, maternal smoking before, during, or after pregnancy was not associated with childhood AML; there was a suggestion, however, that smoking during pregnancy was associated with an increased risk in Hispanics (odds ratio = 2.08, 95% confidence interval (CI): 1.20, 3.61) but not in other ethnic groups. By contrast, the odds ratios for paternal lifetime smoking were 1.34 (95% CI: 1.11, 1.62) and 1.18 (95% CI: 0.92, 1.51) in pooled and meta-analyses, respectively. Overall, increased risks from 1.2- to 1.3-fold were observed for pre- and postnatal smoking (P < 0.05), with higher risks reported for heavy smokers. Associations with paternal smoking varied by histological type. Our analyses suggest an association between paternal smoking and childhood AML. The association with maternal smoking appears limited to Hispanic children, raising questions about ethnic differences in tobacco-related exposures and biological mechanisms, as well as study-specific biases.