Prenatal blood metals, per- and polyfluoroalkyl substances and antigen- or mitogen-stimulated cord blood lymphocyte proliferation and cytokine secretion.

BACKGROUND: Evidence suggests that prenatal per- and polyfluoroalkyl substances (PFAS) and metals, two classes of chemicals found ubiquitously in human populations, influence immune system development and response. OBJECTIVE: We evaluated whether first trimester blood PFAS and metals were associated with antigen- or mitogen-stimulated cord blood lymphocyte proliferation and cytokine secretion. METHODS: We measured six PFAS, as well as six nonessential and four essential metals, in first trimester blood from participants in the longitudinal pre-birth Project Viva cohort, recruited between 1999-2000 in eastern Massachusetts. We measured antigen- or mitogen-stimulated cord blood mononuclear cell proliferation responses (n=269-314) and cytokine secretion (n=217-302). We used covariate-adjusted least absolute shrinkage and selection operator (LASSO) for variable selection and multivariable regression to estimate associations with the immune markers. RESULTS: Each ng/mL of MeFOSAA was associated with a 3.6% (1.4, 5.8) higher lymphocyte proliferation response after stimulation with egg antigen, as well as 0.8 (0.7, 1.0) reduced odds of having IFN-γ detected in response to dust mite. Each ng/g increment of cesium was associated with 27.8% (-45.1, -4.9) lower IL-10 levels in response to dust mite. Each ng/g increment of mercury was associated with 12.0% (1.3, 23.8) higher IL-13 levels in response to mitogen PHA. Each ng/g increment of selenium and zinc was associated with 0.2% (0.01, 0.4) and 0.01% (0.002, 0.02) higher TNF-α in response to mitogen PHA, respectively. CONCLUSIONS: Prenatal metals and PFAS influence cord blood lymphocyte proliferation and cytokine secretion in ways that may increase risk for atopic disease in childhood.

Medication-Induced Weight Change Across Common Antidepressant Treatments : A Target Trial Emulation Study.

BACKGROUND: Antidepressants are among the most commonly prescribed medications, but evidence on comparative weight change for specific first-line treatments is limited. OBJECTIVE: To compare weight change across common first-line antidepressant treatments by emulating a target trial. DESIGN: Observational cohort study over 24 months. SETTING: Electronic health record (EHR) data from 2010 to 2019 across 8 U.S. health systems. PARTICIPANTS: 183 118 patients. MEASUREMENTS: Prescription data determined initiation of treatment with sertraline, citalopram, escitalopram, fluoxetine, paroxetine, bupropion, duloxetine, or venlafaxine. The investigators estimated the population-level effects of initiating each treatment, relative to sertraline, on mean weight change (primary) and the probability of gaining at least 5% of baseline weight (secondary) 6 months after initiation. Inverse probability weighting of repeated outcome marginal structural models was used to account for baseline confounding and informative outcome measurement. In secondary analyses, the effects of initiating and adhering to each treatment protocol were estimated. RESULTS: Compared with that for sertraline, estimated 6-month weight gain was higher for escitalopram (difference, 0.41 kg [95% CI, 0.31 to 0.52 kg]), paroxetine (difference, 0.37 kg [CI, 0.20 to 0.54 kg]), duloxetine (difference, 0.34 kg [CI, 0.22 to 0.44 kg]), venlafaxine (difference, 0.17 kg [CI, 0.03 to 0.31 kg]), and citalopram (difference, 0.12 kg [CI, 0.02 to 0.23 kg]); similar for fluoxetine (difference, -0.07 kg [CI, -0.19 to 0.04 kg]); and lower for bupropion (difference, -0.22 kg [CI, -0.33 to -0.12 kg]). Escitalopram, paroxetine, and duloxetine were associated with 10% to 15% higher risk for gaining at least 5% of baseline weight, whereas bupropion was associated with 15% reduced risk. When the effects of initiation and adherence were estimated, associations were stronger but had wider CIs. Six-month adherence ranged from 28% (duloxetine) to 41% (bupropion). LIMITATION: No data on medication dispensing, low medication adherence, incomplete data on adherence, and incomplete data on weight measures across time points. CONCLUSION: Small differences in mean weight change were found between 8 first-line antidepressants, with bupropion consistently showing the least weight gain, although adherence to medications over follow-up was low. Clinicians could consider potential weight gain when initiating antidepressant treatment. PRIMARY FUNDING SOURCE: National Institutes of Health.

Associations of street-view greenspace with Parkinson's disease hospitalizations in an open cohort of elderly US Medicare beneficiaries.

INTRODUCTION: Protective associations of greenspace with Parkinson's disease (PD) have been observed in some studies. Visual exposure to greenspace seems to be important for some of the proposed pathways underlying these associations. However, most studies use overhead-view measures (e.g., satellite imagery, land-classification data) that do not capture street-view greenspace and cannot distinguish between specific greenspace types. We aimed to evaluate associations of street-view greenspace measures with hospitalizations with a PD diagnosis code (PD-involved hospitalization). METHODS: We created an open cohort of about 45.6 million Medicare fee-for-service beneficiaries aged 65 + years living in core based statistical areas (i.e. non-rural areas) in the contiguous US (2007-2016). We obtained 350 million Google Street View images across the US and applied deep learning algorithms to identify percentages of specific greenspace features in each image, including trees, grass, and other green features (i.e., plants, flowers, fields). We assessed yearly average street-view greenspace features for each ZIP code. A Cox-equivalent re-parameterized Poisson model adjusted for potential confounders (i.e. age, race/ethnicity, socioeconomic status) was used to evaluate associations with first PD-involved hospitalization. RESULTS: There were 506,899 first PD-involved hospitalizations over 254,917,192 person-years of follow-up. We found a hazard ratio (95% confidence interval) of 0.96 (0.95, 0.96) per interquartile range (IQR) increase for trees and a HR of 0.97 (0.96, 0.97) per IQR increase for other green features. In contrast, we found a HR of 1.06 (1.04, 1.07) per IQR increase for grass. Associations of trees were generally stronger for low-income (i.e. Medicaid eligible) individuals, Black individuals, and in areas with a lower median household income and a higher population density. CONCLUSION: Increasing exposure to trees and other green features may reduce PD-involved hospitalizations, while increasing exposure to grass may increase hospitalizations. The protective associations may be stronger for marginalized individuals and individuals living in densely populated areas.

Trends of Antihypertensive Prescription Among US Adults From 2010 to 2019 and Changes Following Treatment Guidelines: Analysis of Multicenter Electronic Health Records.

BACKGROUND: Guidelines for the use of antihypertensives changed in 2014 and 2017. To understand the effect of these guidelines, we examined trends in antihypertensive prescriptions in the United States from 2010 to 2019 using a repeated cross-sectional design. METHODS AND RESULTS: Using electronic health records from 15 health care institutions for adults (20-85 years old) who had ≥1 antihypertensive prescription, we assessed whether (1) prescriptions of beta blockers decreased after the 2014 Eighth Joint National Committee (JNC 8) report discouraged use for first-line treatment, (2) prescriptions for calcium channel blockers and thiazide diuretics increased among Black patients after the JNC 8 report encouraged use as first-line therapy, and (3) prescriptions for dual therapy and fixed-dose combination among patients with blood pressure ≥140/90 mm Hg increased after recommendations in the 2017 Hypertension Clinical Practice Guidelines. The study included 1 074 314 patients with 2 133 158 prescription episodes. After publication of the JNC 8 report, prescriptions for beta blockers decreased (3% lower in 2018-2019 compared to 2010-2014), and calcium channel blockers increased among Black patients (20% higher in 2015-2017 and 41% higher in 2018-2019, compared to 2010-2014), in accordance with guideline recommendations. However, contrary to guidelines, dual therapy and fixed-dose combination decreased after publication of the 2017 Hypertension Clinical Practice Guidelines (9% and 11% decrease in 2018-2019 for dual therapy and fixed-dose combination, respectively, compared to 2015-2017), and thiazide diuretics decreased among Black patients after the JNC 8 report (6% lower in 2018-2019 compared to 2010-2014). CONCLUSIONS: Adherence to guidelines on prescribing antihypertensive medication was inconsistent, presenting an opportunity for interventions to achieve better blood pressure control in the US population.

Food, nutrition, and autism: from soil to fork.

Food and nutrition-related factors have the potential to impact development of autism spectrum disorder (ASD) and quality of life for people with ASD, but gaps in evidence exist. On 10 November 2022, Tufts University's Friedman School of Nutrition Science and Policy and Food and Nutrition Innovation Institute hosted a 1-d meeting to explore the evidence and evidence gaps regarding the relationships of food and nutrition with ASD. This meeting report summarizes the presentations and deliberations from the meeting. Topics addressed included prenatal and child dietary intake, the microbiome, obesity, food-related environmental exposures, mechanisms and biological processes linking these factors and ASD, food-related social factors, and data sources for future research. Presentations highlighted evidence for protective associations with prenatal folic acid supplementation and ASD development, increases in risk of ASD with maternal gestational obesity, and the potential for exposure to environmental contaminants in foods and food packaging to influence ASD development. The importance of the maternal and child microbiome in ASD development or ASD-related behaviors in the child was reviewed, as was the role of discrimination in leading to disparities in environmental exposures and psychosocial factors that may influence ASD. The role of child diet and high prevalence of food selectivity in children with ASD and its association with adverse outcomes were also discussed. Priority evidence gaps identified by participants include further clarifying ASD development, including biomarkers and key mechanisms; interactions among psychosocial, social, and biological determinants; interventions addressing diet, supplementation, and the microbiome to prevent and improve quality of life for people with ASD; and mechanisms of action of diet-related factors associated with ASD. Participants developed research proposals to address the priority evidence gaps. The workshop findings serve as a foundation for future prioritization of scientific research to address evidence gaps related to food, nutrition, and ASD.

Birth outcomes in relation to neighborhood food access and individual food insecurity during pregnancy in the Environmental Influences on Child Health Outcomes (ECHO)-wide cohort study.

BACKGROUND: Limited access to healthy foods, resulting from residence in neighborhoods with low-food access or from household food insecurity, is a public health concern. Contributions of these measures during pregnancy to birth outcomes remain understudied. OBJECTIVES: We examined associations between neighborhood food access and individual food insecurity during pregnancy with birth outcomes. METHODS: We used data from 53 cohorts participating in the nationwide Environmental Influences on Child Health Outcomes-Wide Cohort Study. Participant inclusion required a geocoded residential address or response to a food insecurity question during pregnancy and information on birth outcomes. Exposures include low-income-low-food-access (LILA, where the nearest supermarket is >0.5 miles for urban or >10 miles for rural areas) or low-income-low-vehicle-access (LILV, where few households have a vehicle and >0.5 miles from the nearest supermarket) neighborhoods and individual food insecurity. Mixed-effects models estimated associations with birth outcomes, adjusting for socioeconomic and pregnancy characteristics. RESULTS: Among 22,206 pregnant participants (mean age 30.4 y) with neighborhood food access data, 24.1% resided in LILA neighborhoods and 13.6% in LILV neighborhoods. Of 1630 pregnant participants with individual-level food insecurity data (mean age 29.7 y), 8.0% experienced food insecurity. Residence in LILA (compared with non-LILA) neighborhoods was associated with lower birth weight [ß -44.3 g; 95% confidence interval (CI): -62.9, -25.6], lower birth weight-for-gestational-age z-score (-0.09 SD units; -0.12, -0.05), higher odds of small-for-gestational-age [odds ratio (OR) 1.15; 95% CI: 1.00, 1.33], and lower odds of large-for-gestational-age (0.85; 95% CI: 0.77, 0.94). Similar findings were observed for residence in LILV neighborhoods. No associations of individual food insecurity with birth outcomes were observed. CONCLUSIONS: Residence in LILA or LILV neighborhoods during pregnancy is associated with adverse birth outcomes. These findings highlight the need for future studies examining whether investing in neighborhood resources to improve food access during pregnancy would promote equitable birth outcomes.

Cross-sectional and prospective associations of early childhood circulating metals with early and mid-childhood cognition in the Project Viva cohort.

BACKGROUND: Relatively little is known about the immediate and prospective neurodevelopmental impacts of joint exposure to multiple metals (i.e., metal mixtures) in early childhood. OBJECTIVES: To estimate associations of early childhood (∼3 years of age) blood metal concentrations with cognitive test scores at early and mid-childhood (∼8 years of age). METHODS: We studied children from the Project Viva cohort. We measured erythrocyte concentrations of seven essential (Co, Cu, Mg, Mn, Mo, Se, and Zn) and eight non-essential metals (As, Ba, Cd, Cs, Hg, Pb, Sn, and Sr) in early childhood blood samples. Trained research assistants administered cognitive tests assessing vocabulary, visual-motor ability, memory, and general intelligence (standard deviations: ∼10 points), in early and mid-childhood. We employed multivariable linear regression to examine associations of individual metals with test scores adjusting for confounders, other concurrently measured metals, and first-trimester maternal blood metals. We also estimated joint associations and explored interaction between metals in mixture analyses. RESULTS: We analyzed 349 children (median whole blood Pb ∼1 µg/dL). In cross-sectional analyses, each doubling of Pb was associated with lower visual-motor function (mean difference: -2.43 points, 95% confidence interval (CI): -4.01, -0.86) and receptive vocabulary, i.e., words understood (-1.45 points, 95% CI: -3.26, 0.36). Associations of Pb with mid-childhood cognition were weaker and less precise by comparison. Mg was positively associated with cognition in cross-sectional but not prospective analyses, and cross-sectional associations were attenuated in a sensitivity analysis removing adjustment for concurrent metals. We did not observe joint associations nor interactions. DISCUSSION: In this cohort with low blood Pb levels, increased blood Pb was robustly associated with lower cognitive ability in cross-sectional analyses, even after adjustment for prenatal Pb exposure, and regardless of adjustment for metal co-exposures. However, associations with mid-childhood cognition were attenuated and imprecise, suggesting some buffering of Pb neurotoxicity in early life. WHAT THIS STUDY ADDS: Relatively few studies have comprehensively separated the effects of neurotoxic metals such as lead (Pb) from pre- and postnatal co-occurring metals, nor examined persistence of associations across childhood. In a cohort of middle-class children, we found higher early childhood (∼3 y) blood Pb was associated with lower scores on cognitive tests, independent of other metals and prenatal blood Pb. However, early childhood Pb was only weakly associated with cognition in mid-childhood (∼8 y). Our results suggest the effects of low-level Pb exposure may attenuate over time in some populations, implying the presence of factors that may buffer Pb neurotoxicity in early life.

Associations of Prenatal Per- and Polyfluoroalkyl Substance (PFAS) Exposures with Offspring Adiposity and Body Composition at 16-20 Years of Age: Project Viva.

BACKGROUND: Findings on the associations between prenatal PFAS exposures and offspring adiposity are inconsistent. Whether such associations may extend to adolescence is especially understudied. OBJECTIVES: We investigated associations of prenatal PFAS exposures with offspring adiposity and body composition at 16-20 years of age. METHODS: We studied 545 mother-child pairs in the prospective prebirth cohort Project Viva (Boston, Massachusetts). We measured six PFAS (PFOA, PFOS, PFNA, PFHxS, EtFOSAA, and MeFOSAA) in maternal early pregnancy (median age=9.6wk, range: 5.7-19.6 wk) plasma samples. At the late adolescence visit (median age=17.4 y, range: 15.9-20.0 y), we obtained anthropometric measures and assessed body composition using bioelectrical impedance analysis and dual-energy X-ray absorptiometry. We examined associations of individual PFAS with obesity [i.e., age- and sex-specific body mass index (BMI) ≥95th percentile] and adiposity and body composition using multivariable Poisson and linear regression models, respectively. We assessed PFAS mixture effects using Bayesian kernel machine regression (BKMR) and quantile g-computation. We used fractional-polynomial models to assess BMI trajectories (at 3-20 years of age) by prenatal PFAS levels. RESULTS: Thirteen percent (n=73) of the children had obesity in late adolescence. After multivariable adjustment, higher prenatal PFAS concentrations were associated with higher obesity risk [e.g., 1.59 (95% CI: 1.19, 2.12), 1.24 (95% CI: 0.98, 1.57), and 1.49 (95% CI: 1.11, 1.99) times the obesity risk per doubling of PFOS, PFOA, and PFNA, respectively]. BKMR showed an interaction between PFOA and PFOS, where the positive association between PFOS and obesity was stronger when PFOA levels were lower. Each quartile increment of the PFAS mixture was associated with 1.52 (95% CI: 1.03, 2.25) times the obesity risk and 0.52 (95% CI: -0.02, 1.06) kg/m2 higher BMI. Children with higher prenatal PFOS, EtFOSAA, and MeFOSAA concentrations had higher rates of BMI increase starting from 9-11 years of age. DISCUSSION: Prenatal PFAS exposures may have obesogenic effects into late adolescence. https://doi.org/10.1289/EHP12597.

Infant Feeding Practices and Metal Concentrations in Children's Blood.

This cohort study assesses the association between 4 infant feeding practices and concentrations of 8 nonessential and 7 essential metals in red blood cells.

Prenatal and Childhood Per- and Polyfluoroalkyl Substance (PFAS) Exposures and Blood Pressure Trajectories From Birth to Late Adolescence in a Prospective US Prebirth Cohort.

Background Evidence is limited regarding the associations of prenatal and childhood per- and polyfluoroalkyl substance (PFAS) exposures with blood pressure (BP) trajectories in children. Methods and Results Participants are from Project Viva, a prospective prebirth cohort in eastern Massachusetts. We measured PFAS in early-pregnancy maternal (median, 9.6 weeks) and midchildhood (median, 7.7 years) plasma samples. We conducted standardized BP measurements at 6 research visits: birth, infancy (median, 6.3 months), early childhood (median, 3.2 years), midchildhood (median, 7.7 years), early adolescence (median, 12.9 years), and late adolescence (median, 17.5 years). We used linear regression to examine associations of individual PFASs with BP at each visit, linear spline mixed-effects regression to model BP trajectories, and a mixture approach to estimate PFAS exposure burden. We included 9036 BP measures from 1506 participants. We observed associations between particular individual prenatal PFASs and child BP at specific time points, for example, prenatal 2-(N-ethyl-perfluorooctane sulfonamido) acetate (EtFOSAA) and 2-(N-methyl-perfluorooctane sulfonamido) acetate (MeFOSAA) with higher systolic BP at birth; prenatal perfluorooctane sulfonate (PFOS) and EtFOSAA with lower diastolic BP in infancy; and prenatal PFOS, perfluorooctanoate (PFOA), and EtFOSAA with higher systolic BP at midchildhood. No prenatal or childhood PFAS was consistently associated with BP across all visits. Diastolic BP trajectories from 0 to 20 years differed slightly by prenatal PFOA, perfluorohexane sulfonate (PFHxS), and perfluorononanoate (PFNA) (P values 0.01-0.09). Diastolic BP trajectories from 6 to 20 years differed slightly by midchildhood PFHxS and MeFOSAA (P-values 0.03-0.08). Prenatal or childhood PFAS mixture burden scores were not associated with BP. Conclusions We found associations of prenatal and childhood PFAS exposures with BP at specific time points between birth and late adolescence but no consistent associations across all time points or PFAS types.

Mixtures of Metals and Micronutrients in Early Pregnancy and Cognition in Early and Mid-Childhood: Findings from the Project Viva Cohort.

BACKGROUND: The developing fetal brain is sensitive to many environmental exposures. However, the independent and joint effects of prenatal exposure to metals and micronutrients on child cognition are not well understood. OBJECTIVES: Our aim was to evaluate associations of first-trimester (∼10 wk) maternal erythrocyte concentrations of mixtures of nonessential and essential metals and micronutrients with early (∼3 y) and mid-childhood (∼8 y) cognitive test scores in Project Viva, a prebirth cohort in Boston, Massachusetts, USA. METHODS: We measured concentrations of five essential metals (Cu, Mg, Mn, Se, Zn) and two micronutrients (vitamin B12 and folate), together termed the "nutrient mixture," as well as six nonessential metals (As, Ba, Cd, Cs, Hg, Pb), together termed the "neurotoxic mixture," in first-trimester (∼10 wk) maternal erythrocytes (metals) or plasma (micronutrients). We assessed visual-motor function and receptive vocabulary in early childhood (∼3 y), and visual-motor function, visual memory, and fluid and crystallized intelligence in mid-childhood (∼8 y). We employed adjusted quantile g-computation and linear regression to estimate mixture and individual component associations, respectively. RESULTS: Analyses included 900 mother-child pairs (74% college graduates; 52% male children). In mixture analyses, a quartile increase in the nutrient mixture was associated with a mean difference in early childhood receptive vocabulary score of 1.58 points [95% confidence interval (CI): 0.06, 3.10], driven by Zn and Se. A quartile increase in the neurotoxic mixture was associated with a mean difference in mid-childhood visual-motor score of -3.01 points (95% CI: -5.55, -0.47), driven by Ba and Cs. Linear regressions supported quantile g-computation findings for mixture component contributions. DISCUSSION: Maternal circulating concentrations of several essential (Zn and Se) and nonessential (Ba and Cs) metals were associated with some domains of child cognition. In this folate-replete cohort, first-trimester circulating concentrations of known neurotoxic metals, such as Pb, were not associated with child cognition. https://doi.org/10.1289/EHP12016.

Quantitative fluoride imaging of teeth using CaF emission by laser induced breakdown spectroscopy.

In this work, we propose the use of molecular emission of calcium fluoride (CaF) by laser induced breakdown spectroscopy (LIBS) to obtain quantitative fluoride distribution images of teeth. LIBS has proved to be an efficient technique to detect low amounts of fluoride in solids, and human teeth have the advantage being a matrix rich in calcium. We used new calibration material from sintered hydroxyapatite pellets doped with fluoride to determine the optimized LIBS conditions of argon flow at 1 L min-1 and using the green emission bands of CaF in 530 nm, and obtained a calibration curve between 0 and 400 µg g-1, and LOD of 18 µg g-1. This methodology was applied within a rat model of fluoride exposure and showed increasing tooth-fluoride with increased exposure dose. To demonstrate applicability of this method in human teeth, we quantified fluoride distribution in teeth from three children from non-fluorinated and fluorinated water regions. Samples from children living in fluoridated water regions showed higher fluoride concentrations in dentine formed after birth, compared to a child from a non-fluoridated region. Teeth have been used as biomarkers for environmental exposure and this new method opens the opportunity in epidemiology research to study critical windows of early life exposure to fluoride as well.

Prenatal Exposure to Per- and Polyfluoroalkyl Substances and Childhood Autism-related Outcomes.

BACKGROUND: Epidemiologic evidence linking prenatal exposure to per- and polyfluoroalkyl substances (PFAS) with altered neurodevelopment is inconclusive, and few large studies have focused on autism-related outcomes. We investigated whether blood concentrations of PFAS in pregnancy are associated with child autism-related outcomes. METHODS: We included 10 cohorts from the National Institutes of Health (NIH)-funded Environmental influences on Child Health Outcomes (ECHO) program (n = 1,429). We measured 14 PFAS analytes in maternal blood collected during pregnancy; eight analytes met detection criteria for analysis. We assessed quantitative autism-related traits in children via parent report on the Social Responsiveness Scale (SRS). In multivariable linear models, we examined relationships of each PFAS (natural log-transformed) with SRS scores. We further modeled PFAS as a complex mixture using Bayesian methods and examined modification of these relationships by child sex. RESULTS: Most PFAS in maternal blood were not associated with child SRS T-scores. Perfluorononanoic acid (PFNA) showed the strongest and most consistent association: each 1-unit increase in ln-transformed PFNA was associated with greater autism-related traits (adjusted ß [95% confidence interval (CI)] = 1.5 [-0.1, 3.0]). The summed mixture, which included six PFAS detected in >70% of participants, was not associated with SRS T-scores (adjusted ß [95% highest posterior density interval] = 0.7 [-1.4, 3.0]). We did not observe consistent evidence of sex differences. CONCLUSIONS: Prenatal blood concentrations of PFNA may be associated with modest increases in child autism-related traits. Future work should continue to examine the relationship between exposures to both legacy and emerging PFAS and additional dimensional, quantitative measures of childhood autism-related outcomes.

Associations of Prenatal First Trimester Essential and Nonessential Metal Mixtures with Body Size and Adiposity in Childhood.

BACKGROUND: Prenatal nonessential metals may contribute to postnatal adiposity, whereas essential metals may have metabolic benefits. We evaluated joint and individual associations between prenatal metals and childhood adiposity. METHODS: We measured concentrations of six nonessential (arsenic, barium, cadmium, cesium, lead, and mercury) and four essential (magnesium, manganese, selenium, and zinc) metals in first trimester maternal blood from a prebirth cohort. We collected anthropometric measures in early childhood, mid-childhood, and early adolescence including subscapular+tricep skinfold thickness (mm) (N = 715-859), waist circumference (cm) (N = 717-882), and body mass index (BMI) (z-score) (N = 716-875). We measured adiposity in mid-childhood and early adolescence using bone densitometry total- and trunk- fat mass index (kg/m 2 ) (N = 511-599). We estimated associations using adjusted quantile g-computation and linear regression. RESULTS: The nonessential metal mixture was associated with higher total (ß = 0.07, 95% CI = 0.01, 0.12) and trunk fat mass index (ß = 0.12, CI = 0.02, 0.22), waist circumference (ß = 0.01, CI = 0.00, 0.01), and BMI (ß = 0.24, CI = 0.07, 0.41) in mid-childhood, and total fat mass index (ß = 0.07, CI = 0.01, 0.14), and BMI (ß = 0.19, CI = 0.02, 0.37) in early adolescence. The essential metal mixture was associated with lower early adolescence total-(ß = -0.11, CI = -0.17, -0.04) and trunk- fat mass index (ß = -0.13, CI = -0.21, -0.05), subscapular+tricep skinfold thickness (ß = -0.02, CI = -0.03, -0.00), waist circumference (ß = -0.003, CI = -0.01, -0.00), and BMI (ß = -0.16, CI = -0.28, -0.04). Cadmium and cesium were individually associated with childhood adiposity at different timepoints. CONCLUSIONS: Prenatal first-trimester essential metals were associated with lower childhood adiposity, whereas nonessential metals were associated with higher adiposity into adolescence.

Early pregnancy essential and non-essential metal mixtures and maternal antepartum and postpartum depressive symptoms.

BACKGROUND: Mood disorders are common during and after pregnancy, and environmental metals may contribute to increased risk. Antepartum metal exposures have not been well characterized in relation to maternal depression. We evaluated the extent to which early pregnancy erythrocyte concentrations of essential and non-essential metals were prospectively associated with antepartum and postpartum depressive symptoms. METHODS: Participants were 1226 women in Project Viva, a longitudinal cohort recruited during pregnancy (1999-2002). We measured concentrations of 11 metals in maternal first trimester erythrocytes (arsenic, barium, cadmium, cesium, copper, mercury, magnesium, manganese, lead, selenium, zinc). Using the Edinburgh Postnatal Depression Scale (EPDS), we assessed elevated depressive symptoms (≥13; 0-30 scale) at mid-pregnancy and at 6 and 12 months postpartum. We applied latent class mixed modeling to identify symptom trajectories. Adjusting for maternal sociodemographics and co-exposures, we examined associations between the metal mixture and depressive symptoms using logistic (for EPDS≥13)/multinomial (for symptom trajectories) regression and quantile g-computation. RESULTS: In this cohort of moderately high socioeconomic status participants (e.g., 72 % college graduate), low-level metal concentrations were weakly to moderately correlated (Spearman: -0.24 to 0.59); the prevalence of depressive symptoms ranged from 9 % (mid-pregnancy) to 6 % (12 months postpartum); and three trajectories (stable low; elevated mid-pregnancy, then decreasing; moderate mid-pregnancy, then increasing) best fit the EPDS data. The early pregnancy erythrocyte metal mixture was not associated with maternal depressive symptoms in logistic, multinomial, or mixture models. For individual metals, most confidence intervals (CI) included the null. There was weak evidence that arsenic, lead, and selenium were moderately associated with elevated odds of depressive symptoms and/or trajectories. However, the odds ratios (95 % CI) per doubling of these three metals were imprecise [e.g., arsenic: 1.13 (0.94, 1.40) for EPDS≥13 at six months postpartum; lead: 1.19 (0.80, 1.77) for EPDS≥13 at mid-pregnancy; selenium: 2.35 (0.84, 6.57) for elevated mid-pregnancy, then decreasing versus stable low trajectory]. DISCUSSION: We did not observe strong, consistent evidence of associations between early pregnancy erythrocyte metal concentrations and subsequent maternal antepartum and postpartum depressive symptoms.

Prenatal Antidepressant Exposures and Autism Spectrum Disorder or Traits: A Retrospective, Multi-Cohort Study.

Prenatal antidepressant exposure has been associated with increased risk for neurodevelopmental disorders in childhood, including autism spectrum disorder (ASD). The current study utilized multi-cohort data from the Environmental influences on Child Health Outcomes (ECHO) program (N = 3129) to test for this association, and determine whether the association remained after adjusting for maternal prenatal depression and other potential confounders. Antidepressants and a subset of selective serotonin reuptake inhibitors (SSRIs) were examined in relation to binary (e.g., diagnostic) and continuous measures of ASD and ASD related traits (e.g., social difficulties, behavior problems) in children 1.5 to 12 years of age. Child sex was tested as an effect modifier. While prenatal antidepressant exposure was associated with ASD related traits in univariate analyses, these associations were statistically non-significant in models that adjusted for prenatal maternal depression and other maternal and child characteristics. Sex assigned at birth was not an effect modifier for the prenatal antidepressant and child ASD relationship. Overall, we found no association between prenatal antidepressant exposures and ASD diagnoses or traits. Discontinuation of antidepressants in pregnancy does not appear to be warranted on the basis of increased risk for offspring ASD.

Non-essential and essential trace element mixtures and kidney function in early pregnancy - A cross-sectional analysis in project viva.

Some trace elements are established nephrotoxicants, yet their associations with kidney function remain understudied in the context of pregnancy, a time of substantial change in kidney physiology and function. We aimed to estimate the individual and joint associations of trace element mixtures with maternal kidney function during the 1st trimester of pregnancy (mean 9.7 gestational weeks). 1040 women from Project Viva contributed blood samples which were assessed for erythrocyte non-essential [arsenic (As), cadmium (Cd), cesium (Cs), mercury (Hg), lead (Pb)] and essential [barium (Ba), magnesium (Mg), manganese (Mn), selenium (Se), and Zinc (Zn)] trace elements, and plasma creatinine for kidney function. We estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration (eGFRCKD-EPI) equation without race-adjustment factors. We examined associations of eGFRCKD-EPI with individual trace elements using multivariable linear regression and their mixtures using quantile-based g-computation, adjusting for sociodemographics, pregnancy characteristics, and diet. Participants in our study were predominantly White (75%), college graduates (72%), and had household income >$70,000/year (63%). After adjusting for covariates, higher Pb (ß -3.51 ml/min/1.73 m2; 95% CI -5.83, -1.18) concentrations were associated with lower eGFRCKD-EPI, while higher Mg (ß 10.53 ml/min/1.73 m2; 95% CI 5.35, 15.71), Se (ß 5.56 ml/min/1.73 m2; 95% CI 0.82, 10.31), and Zn (ß 5.88 ml/min/1.73 m2; 95% CI 0.51, 11.26) concentrations were associated with higher eGFRCKD-EPI. In mixture analyses, higher non-essential trace elements mixture concentration was associated with reduced eGFRCKD-EPI (Ψ -1.03 ml/min/1.73 m2; 95% CI: 1.92, -0.14). Conversely, higher essential trace elements mixture concentration was associated with higher eGFR (Ψ 1.42; 95% CI: 0.48, 2.37). Exposure to trace elements in early pregnancy may influence women's kidney function although reverse causation cannot be eliminated in this cross-sectional analysis. These findings have important implications for long-term cardiovascular and postpartum kidney health that warrant additional studies.

Associations Between Prenatal Blood Metals and Vitamins and Cord Blood Peptide Hormone Concentrations.

Background: Nonessential metals have endocrine disrupting properties, interfere with cellular processes, generate reactive oxygen and deplete antioxidants, while essential metals and vitamins act as antioxidants. The extent to which prenatal metals and vitamins are associated with cord blood hormones involved in maternal and fetal metabolic and growth processes is unknown. Methods: We measured six nonessential (arsenic, barium, cadmium, cesium, lead, mercury) and four essential (magnesium, manganese, selenium, zinc) metals and trace elements, and two vitamins (B12 and folate) in first trimester blood from participants in the longitudinal pre-birth Project Viva cohort, who were recruited between 1999-2002 in eastern Massachusetts. We measured adiponectin, C-peptide, IGF-1, IGF-2, IGFBP-3, insulin, and leptin concentrations in cord blood (~n=695). We used covariate-adjusted quantile g-computation for mixtures and linear regression for individual exposures to estimate associations with cord blood peptide hormones. Results: The essential metal mixture (magnesium, manganese, selenium, zinc) was associated with higher IGF-1 (ß=3.20 ng/ml per quartile, 95% CI: 0.39, 6.01), IGF-2 (ß=10.93 ng/ml, 95% CI: 0.08, 21.79), and leptin (ß=1.03 ng/ml, 95% CI: 0.25, 1.80). Magnesium was associated with higher leptin (ß=2.90 ng/ml, 95% CI: 0.89, 4.91), while B12 was associated with lower adiponectin, IGF-2, and leptin, but higher C-peptide. Other individual nonessential metals were associated with cord blood hormones. Conclusions: Our findings suggest that some prenatal metals and vitamins are associated with cord blood hormones, which may influence growth and development.

Cleaning of anthropometric data from PCORnet electronic health records using automated algorithms.

Objective: To demonstrate the utility of growthcleanr, an anthropometric data cleaning method designed for electronic health records (EHR). Materials and Methods: We used all available pediatric and adult height and weight data from an ongoing observational study that includes EHR data from 15 healthcare systems and applied growthcleanr to identify outliers and errors and compared its performance in pediatric data with 2 other pediatric data cleaning methods: (1) conditional percentile (cp) and (2) PaEdiatric ANthropometric measurement Outlier Flagging pipeline (peanof). Results: 687 226 children (<20 years) and 3 267 293 adults contributed 71 246 369 weight and 51 525 487 height measurements. growthcleanr flagged 18% of pediatric and 12% of adult measurements for exclusion, mostly as carried-forward measures for pediatric data and duplicates for adult and pediatric data. After removing the flagged measurements, 0.5% and 0.6% of the pediatric heights and weights and 0.3% and 1.4% of the adult heights and weights, respectively, were biologically implausible according to the CDC and other established cut points. Compared with other pediatric cleaning methods, growthcleanr flagged the most measurements for exclusion; however, it did not flag some more extreme measurements. The prevalence of severe pediatric obesity was 9.0%, 9.2%, and 8.0% after cleaning by growthcleanr, cp, and peanof, respectively. Conclusion: growthcleanr is useful for cleaning pediatric and adult height and weight data. It is the only method with the ability to clean adult data and identify carried-forward and duplicates, which are prevalent in EHR. Findings of this study can be used to improve the growthcleanr algorithm.

A Cross-validated Ensemble Approach to Robust Hypothesis Testing of Continuous Nonlinear Interactions: Application to Nutrition-Environment Studies.

Gene-environment and nutrition-environment studies often involve testing of high-dimensional interactions between two sets of variables, each having potentially complex nonlinear main effects on an outcome. Construction of a valid and powerful hypothesis test for such an interaction is challenging, due to the difficulty in constructing an efficient and unbiased estimator for the complex, nonlinear main effects. In this work we address this problem by proposing a Cross-validated Ensemble of Kernels (CVEK) that learns the space of appropriate functions for the main effects using a cross-validated ensemble approach. With a carefully chosen library of base kernels, CVEK flexibly estimates the form of the main-effect functions from the data, and encourages test power by guarding against over-fitting under the alternative. The method is motivated by a study on the interaction between metal exposures in utero and maternal nutrition on children's neurodevelopment in rural Bangladesh. The proposed tests identified evidence of an interaction between minerals and vitamins intake and arsenic and manganese exposures. Results suggest that the detrimental effects of these metals are most pronounced at low intake levels of the nutrients, suggesting nutritional interventions in pregnant women could mitigate the adverse impacts of in utero metal exposures on children's neurodevelopment.