Prenatal exposure to per- and polyfluoroalkyl substances and infant growth and adiposity: the Healthy Start Study

Background: Prenatal exposures to certain per- and polyfluoroalkyl substances (PFAS) have been linked to lower weight and adiposity at birth but greater weight and adiposity in childhood. We hypothesized that faster growth in early infancy may be associated with maternal PFAS concentrations. Methods: Among 415 mother-infant pairs in a longitudinal cohort study, we estimated associations between maternal pregnancy serum concentrations of six PFAS and offspring weight and adiposity at ~5 months of age, and growth in early infancy. Linear and logistic regression models were adjusted for potential confounders including maternal pre-pregnancy body mass index. Effect modification by infant sex was evaluated. We evaluated potential confounding by correlated exposures via multipollutant linear regression and elastic net penalized regression. Results: Associations between maternal PFAS concentrations and infant weight and adiposity differed by offspring sex. In male infants, maternal perfluorooctanoate and perfluorononanoate were positively associated with adiposity, with percent fat mass increases of 1.5–1.7% per ln-ng/mL increase in PFAS (median adiposity at ~5 months: 24.6%). Maternal perfluorooctane sulfonate (PFOS) and perfluorohexane sulfonate (PFHxS) were associated with lower weight-for-age z-score among female infants only (−0.26 SD per ln-ng/mL PFOS, 95% CI −0.43, −0.10; −0.17 SD per ln-ng/mL PFHxS, 95% CI −0.33, −0.01). In analyses pooled by sex, 2-(N-methyl-perfluorooctane sulfonamido) acetate above vs. below the limit of detection was associated with greater odds of rapid growth in weight-for-age (odds ratio [OR] 2.2, 95% CI 1.1, 4.3) and weight-for-length (OR 3.3, 95% CI 1.8, 6.2). Multipollutant models generally confirmed the results and strengthened some associations. Discussion: We observed sex- and chemical-specific associations between maternal serum PFAS concentrations and infant weight and adiposity. Multipollutant models suggested confounding by correlated PFAS with opposing effects. Although maternal PFAS concentrations are inversely associated with infant weight and adiposity at birth, rapid gain may occur in infancy, particularly in fat mass

Prenatal exposure to ambient air pollution and traffic and indicators of adiposity in early childhood: the Healthy Start study

Background: Prenatal exposure to ambient air pollution and traffic have been related to a lower birth weight and may be associated with greater adiposity in childhood. We aimed to examine associations of maternal exposure to ambient air pollution and traffic during pregnancy with indicators of adiposity in early childhood. Methods: We included 738 participants of the Colorado-based Healthy Start study whose height, weight, waist circumference and/or fat mass were measured at age 4–6 years. We estimated residential exposure to ambient concentrations of fine particulate matter (PM2.5) and ozone (O3) averaged by trimester and throughout pregnancy via inverse distance-weighted interpolation of central site monitoring data. We assessed the distance to the nearest major roadway and traffic density in multiple buffers surrounding the participants’ homes. Associations of prenatal exposure to air pollution and traffic with overweight, waist circumference, percent fat mass and fat mass index (FMI) were assessed by logistic and linear regression. Results: Associations of exposure to PM2.5 and O3 at the residential address during pregnancy with percent fat mass and FMI at age 4–6 years were inconsistent across trimesters. For example, second trimester PM2.5 was associated with a higher percent fat mass (adjusted difference 0.70% [95% CI 0.05, 1.35%] per interquartile range (IQR; 1.3 µg/m3) increase), while third trimester PM2.5 was associated with a lower percent fat mass (adjusted difference −1.17% [95% CI −1.84, −0.50%] per IQR (1.3 µg/m3) increase). Residential proximity to a highway during pregnancy was associated with higher odds of being overweight at age 4–6 years. We observed no associations of prenatal exposure to PM2.5 and O3 with overweight and waist circumference. Conclusions: We found limited evidence of associations of prenatal exposure to ambient PM2.5 and O3 with indicators of adiposity at age 4–6 years. Suggestive relationships between residential proximity to a highway during pregnancy and greater adiposity merit further investigation

Exposure to ambient air pollution during pregnancy and inflammatory biomarkers in maternal and umbilical cord blood: The Healthy Start study

Background: Air pollution exposure during pregnancy has been associated with adverse pregnancy and birth outcomes. Inflammation has been proposed as a potential link. We estimated associations between air pollution exposure during pregnancy and inflammatory biomarkers in maternal and cord blood. We evaluated whether maternal inflammation was associated with infant outcomes. Methods: Among 515 mother-infant dyads in the Healthy Start study (2009–2014), trimester-long, 7- and 30-day average concentrations of particulate matter ≤2.5 μm (PM2.5) and ozone (O3) during pregnancy were estimated, using inverse-distance-weighted interpolation. Inflammatory biomarkers were measured in maternal blood in mid-pregnancy (C-reactive protein [CRP], Interleukin [IL]-6, and tumor necrosis factor-α [TNFα]) and in cord blood at delivery (CRP, IL-6, IL-8, IL-10, monocyte chemoattractant protein-1 [MCP-1], and TNFα). We used linear regression to estimate associations between pollutants and inflammatory biomarkers and maternal inflammatory biomarkers and infant weight and body composition. Results: There were positive associations between PM2.5 during certain exposure periods and maternal IL-6 and TNFα. There were negative associations between recent O3 and maternal CRP, IL-6, and TNFα and positive associations between trimester-long O3 exposure and maternal inflammatory biomarkers, though some 95% confidence intervals included the null. Patterns were inconsistent for associations between PM2.5 and O3 and cord blood inflammatory biomarkers. No consistent associations between maternal inflammatory biomarkers and infant outcomes were identified. Conclusions: Air pollution exposure during pregnancy may impact maternal inflammation. Further investigations should examine the health consequences for women and infants of elevated inflammatory biomarkers associated with air pollution exposure during pregnancy

Prenatal exposure to traffic and ambient air pollution and infant weight and adiposity: The Healthy Start study

Background: Prenatal exposures to ambient air pollution and traffic have been associated with adverse birth outcomes, and may also lead to an increased risk of obesity. Obesity risk may be reflected in changes in body composition in infancy. Objective: To estimate associations between prenatal ambient air pollution and traffic exposure, and infant weight and adiposity in a Colorado-based prospective cohort study. Methods: Participants were 1125 mother-infant pairs with term births. Birth weight was recorded from medical records and body composition measures (fat mass, fat-free mass, and adiposity [percent fat mass]) were evaluated via air displacement plethysmography at birth (n = 951) and at ~5 months (n = 574). Maternal residential address was used to calculate distance to nearest roadway, traffic density, and ambient concentrations of fine particulate matter (PM2.5) and ozone (O3) via inverse-distance weighted interpolation of stationary monitoring data, averaged by trimester and throughout pregnancy. Adjusted linear regression models estimated associations between exposures and infant weight and body composition. Results: Participants were urban residents and diverse in race/ethnicity and socioeconomic status. Average ambient air pollutant concentrations were generally low; the median, interquartile range (IQR), and range of third trimester concentrations were 7.3 μg/m3 (IQR: 1.3, range: 3.3–12.7) for PM2.5 and 46.3 ppb (IQR: 18.4, range: 21.7–63.2) for 8-h maximum O3. Overall there were few associations between traffic and air pollution exposures and infant outcomes. Third trimester O3 was associated with greater adiposity at follow-up (2.2% per IQR, 95% CI 0.1, 4.3), and with greater rates of change in fat mass (1.8 g/day, 95% CI 0.5, 3.2) and adiposity (2.1%/100 days, 95% CI 0.4, 3.7) from birth to follow-up. Conclusions: We found limited evidence of an association between prenatal traffic and ambient air pollution exposure and infant body composition. Suggestive associations between prenatal ozone exposure and early postnatal changes in body composition merit further investigation

Power and sample size analysis for longitudinal mixed models of health in populations exposed to environmental contaminants: a tutorial

Background: When evaluating the impact of environmental exposures on human health, study designs often include a series of repeated measurements. The goal is to determine whether populations have different trajectories of the environmental exposure over time. Power analyses for longitudinal mixed models require multiple inputs, including clinically significant differences, standard deviations, and correlations of measurements. Further, methods for power analyses of longitudinal mixed models are complex and often challenging for the non-statistician. We discuss methods for extracting clinically relevant inputs from literature, and explain how to conduct a power analysis that appropriately accounts for longitudinal repeated measures. Finally, we provide careful recommendations for describing complex power analyses in a concise and clear manner. Methods: For longitudinal studies of health outcomes from environmental exposures, we show how to [1] conduct a power analysis that aligns with the planned mixed model data analysis, [2] gather the inputs required for the power analysis, and [3] conduct repeated measures power analysis with a highly-cited, validated, free, point-and-click, web-based, open source software platform which was developed specifically for scientists. Results: As an example, we describe the power analysis for a proposed study of repeated measures of per- and polyfluoroalkyl substances (PFAS) in human blood. We show how to align data analysis and power analysis plan to account for within-participant correlation across repeated measures. We illustrate how to perform a literature review to find inputs for the power analysis. We emphasize the need to examine the sensitivity of the power values by considering standard deviations and differences in means that are smaller and larger than the speculated, literature-based values. Finally, we provide an example power calculation and a summary checklist for describing power and sample size analysis. Conclusions: This paper provides a detailed roadmap for conducting and describing power analyses for longitudinal studies of environmental exposures. It provides a template and checklist for those seeking to write power analyses for grant applications

Ambient air pollution during pregnancy and cardiometabolic biomarkers in cord blood

Background/Objectives: Prenatal air pollution exposure has been associated with adverse childhood cardiometabolic outcomes. It is unknown whether evidence of metabolic disruption associated with air pollution is identifiable at birth. We examined exposure to prenatal ambient air pollution and cord blood cardiometabolic biomarkers among 812 mother-infant pairs in the Healthy Start study. Methods: Using inverse-distance-weighted interpolation of ambient concentrations obtained from stationary monitors, we estimated daily particulate matter ≤2.5 micrometers PM2.5 and ozone O3 concentrations at participant residences. Daily estimates were averaged by trimester, full-pregnancy, and the 7 and 30 days prior to delivery. Associations of air pollution with the following cord blood biomarkers were estimated via multivariable linear regression: glucose, insulin, glucose/insulin ratio GIR, leptin, high-density lipoprotein HDL cholesterol, non-HDL cholesterol, free fatty acids, and triglycerides. Results: In this Denver-based cohort, PM2.5 concentrations were lower than in many US urban areas, but O3 concentrations regularly exceeded federal air quality standards. Higher O3 concentrations during pregnancy were consistently associated with higher insulin and lower GIR in cord blood. For example, an interquartile range increase in full pregnancy O3 6.3 parts per billion [ppb] was associated with 0.13 log-IU/ml 95% confidence interval [CI] = 0.04, 0.22 higher cord blood insulin, after adjusting for PM2.5 and other confounders. We found positive, but generally nonsignificant, associations between PM2.5 and leptin and isolated associations between pollutants during certain exposure periods and lipids. Conclusions: In this cohort with moderately high O3 exposure, prenatal concentrations of O3 were positively associated with cord blood insulin. Future studies should examine the implications for offspring long-term health

Combined environmental and social exposures during pregnancy and associations with neonatal size and body composition: The Healthy Start study

Background: Prenatal environmental and social exposures have been associated with decreased birth weight. However, the effects of combined exposures (CEs) in these domains are not fully understood. Here we assessed multi-domain exposures for participants in the Healthy Start study (Denver, CO) and tested associations with neonatal size and body composition. Methods: In separate linear regression models, we tested associations between neonatal outcomes and three indices for exposures. Two indices were developed to describe exposures to environmental hazards (ENV) and social determinants of health (SOC). A third index CEs in both domains (CE = ENV/10 × SOC/10). Index scores were assigned to mothers based on address at enrollment. Birth weight and length were measured at delivery, and weight-for-length z-scores were calculated using a reference distribution. Percent fat mass was obtained by air displacement plethysmography. Results: Complete data were available for 897 (64%) participants. Median (range) ENV, SOC, and CE values were 31.9 (7.1-63.2), 36.0 (2.8-75.0), and 10.9 (0.4-45.7), respectively. After adjusting for potential confounders, 10-point increases in SOC and CE were associated with 27.7 g (95% confidence interval [CI] = 12.4, 42.9 g) and 56.3 g (19.4-93.2 g) decreases in birth weight, respectively. SOC and CE were also associated with decreases in percent fat mass. Conclusions: CEs during pregnancy were associated with lower birth weight and percent fat mass. Evidence of a potential synergistic effect between ENV and SOC suggests a need to more fully consider neighborhood exposures when assessing neonatal outcomes

Vaccination Trends and Family-Level Characteristics Associated With Incomplete or Delayed Childhood Immunizations: The Healthy Start Study

Purpose: Assess family-level factors associated with childhood immunization schedule adherence. Design: Prospective cohort; Setting; The Healthy Start study enrolled 1,410 pregnant women in Denver, Colorado 2009-2014 Subjects: Children with available vaccination data in medical records (0-6 years old) Measures: Vaccine schedule completion and compliance Analysis: Logistic regression comparing family-level factors that differ based on vaccine schedule adherence Results: Most immunizations required in Colorado for school entry were below national completion goals with 61.8% of participants (n = 532/861) completing the full vaccination series. Most participants received the first dose of individual vaccines on time (73.5% - 90.7%), but fewer received all doses on time (21.0% - 39.5%). Factors associated with not completing the vaccination series (OR [95% CI]) included: in-utero exposure to cigarette smoke (1.97 [1.41, 2.75]), single parent household (1.70 [1.21, 2.38]), children identified as non-White (Hispanic 1.40 [1.01, 1.94]; Black 1.88 [1.24, 2.85]; Other 2.17 [1.34, 3.49]), mothers not working outside the home (1.98 [1.46, 2.67]), and household income <$70,000 per year (<$40,000 1.93 [1.35, 2.75]; $40,000-$70,000 1.64 [1.09, 2.46]). Conversely, families with more educated mothers (0.47 [0.29, 0.76]) and older parents (0.97 [0.94, 0.99]) were significantly more likely to complete the series. Conclusions: These findings may help identify groups at risk of immunization schedule non-adherence and may be used to target education/advocacy campaigns to reduce hesitancy and increase access in these populations

Prenatal Exposure to Tobacco and Offspring Neurocognitive Development in the Healthy Start Study

Objective: To explore the associations between prenatal exposure to tobacco and neurocognitive development, in the absence of prematurity or low birth weight. Study design: We followed mother-child pairs within Healthy Start through 6 years of age. Children were born at ≥37 weeks of gestation with a birth weight of ≥2500 g. Parents completed the Third Edition Ages and Stages Questionnaire (n = 246) and children completed a subset of the National Institutes of Health Toolbox Cognition Battery (n = 200). The Ages and Stages Questionnaire domains were dichotomized as fail/monitor and pass. Maternal urinary cotinine was measured at approximately 27 weeks of gestation. Separate logistic regression models estimated associations between prenatal exposure to tobacco (cotinine below vs above the limit of detection) and the Ages and Stages Questionnaire domains. Separate linear regression models estimated associations between prenatal exposure to tobacco and fully corrected T-scores for inhibitory control, cognitive flexibility, and receptive language, as assessed by the National Institutes of Health Toolbox. A priori covariates included sex, maternal age, maternal education, daily caloric intake during pregnancy, race/ethnicity, household income, maternal psychiatric disorders, and, in secondary models, postnatal exposure to tobacco. Results: Compared with unexposed offspring, exposed offspring were more likely to receive a fail/monitor score for fine motor skills (OR, 3.9; 95% CI, 1.5-10.3) and decreased inhibitory control (B: −3.0; 95% CI, −6.1 to −0.7). After adjusting for postnatal exposure, only the association with fine motor skills persisted. Conclusions: Prenatal and postnatal exposures to tobacco may influence neurocognitive development, in the absence of preterm delivery or low birth weight. Increased developmental screening may be warranted for exposed children

Cross-sectional associations between serum PFASs and inflammatory biomarkers in a population exposed to AFFF-contaminated drinking water

Background: Per- and polyfluoroalkyl substances (PFASs) are widespread and persistent environmental contaminants. Exposure to several PFASs has been associated with altered immune function in humans, including autoimmune disease and impaired response to vaccination. However, changes to the profile of inflammatory biomarkers in adults exposed to PFASs has not been extensively described. Objective: To estimate cross-sectional associations between serum PFASs and markers of inflammation among adults in a population exposed to aqueous film forming foam (AFFF)-contaminated drinking water. Methods: We quantified concentrations of 48 PFASs in non-fasting serum samples from 212 non-smoking adults. In the same serum samples, we measured concentrations of ten pro- and anti-inflammatory cytokines. We restricted analysis to seven PFASs detected in >85% of participants and the following four cytokines detected in ≥30% of participants: interleukin [IL]-1β, IL-6, IL-10, and tumor necrosis factor [TNF]-α. We fit multiple linear regression or logistic regression models, adjusted for potential confounders, to estimate associations between concentrations of each PFAS and either continuous or categorical (above vs below limit of detection) concentrations of each cytokine. We additionally applied Bayesian kernel machine regression to describe the combined effect of the PFAS mixture on each cytokine outcome. Results: Certain PFAS concentrations in this sample were elevated compared to a US nationally representative sample; median levels of PFHxS, ΣPFOS and ΣPFOA in this sample were 13.8, 2.1 and 1.7 times higher, respectively, than medians observed in the U.S. sample. Higher concentrations of multiple PFASs were significantly associated with lower odds of detectable IL-1β. Weaker associations were observed with other cytokines. In general, perfluoroalkyl carboxylic acids had inverse associations with TNF-α, whereas the perfluoroalkyl sulfonic acids showed positive associations. Conclusions: We observed preliminary evidence of altered inflammatory profiles among adults with elevated serum concentrations of PFASs due to contaminated drinking water. Modifications to inflammatory pathways may be one mechanism by which PFAS exposures produce adverse health effects in humans, but this finding requires verification in longitudinal studies as well as phenotypic anchoring to immune function outcomes