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Prenatal per- and poly-fluoroalkyl substances (PFAS) exposure may influence gestational outcomes through bioactive lipids─metabolic and inflammation pathway indicators. We estimated associations between prenatal PFAS exposure and bioactive lipids, measuring 12 serum PFAS and 50 plasma bioactive lipids in 414 pregnant women (median 17.4 weeks' gestation) from three Environmental influences on Child Health Outcomes Program cohorts. Pairwise association estimates across cohorts were obtained through linear mixed models and meta-analysis, adjusting the former for false discovery rates. Associations between the PFAS mixture and bioactive lipids were estimated using quantile g-computation. Pairwise analyses revealed bioactive lipid levels associated with PFDeA, PFNA, PFOA, and PFUdA (p < 0.05) across three enzymatic pathways (cyclooxygenase, cytochrome p450, lipoxygenase) in at least one combined cohort analysis, and PFOA and PFUdA (q < 0.2) in one linear mixed model. The strongest signature revealed doubling in PFOA corresponding with PGD2 (cyclooxygenase pathway; +24.3%, 95% CI: 7.3-43.9%) in the combined cohort. Mixture analysis revealed nine positive associations across all pathways with the PFAS mixture, the strongest signature indicating a quartile increase in the PFAS mixture associated with PGD2 (+34%, 95% CI: 8-66%), primarily driven by PFOS. Bioactive lipids emerged as prenatal PFAS exposure biomarkers, deepening insights into PFAS' influence on pregnancy outcomes.

BackgroundSynthetic chemicals are increasingly being recognized for potential independent contributions to preterm birth (PTB) and low birth weight (LBW). Bisphenols, parabens, and triclosan are consumer product chemicals that act via similar mechanisms including estrogen, androgen, and thyroid disruption and oxidative stress. Multiple cohort studies have endeavored to examine effects on birth outcomes, and systematic reviews have been limited due to measurement of 1-2 spot samples during pregnancy and limited diversity of populations.ObjectiveTo study the effects of prenatal phenols and parabens on birth size and gestational age (GA) in 3,619 mother-infant pairs from 11 cohorts in the NIH Environmental influences on Child Health Outcomes program.ResultsWhile many associations were modest and statistically imprecise, a 1-unit increase in log10 pregnancy averaged concentration of benzophenone-3 and methylparaben were associated with decreases in birthweight, birthweight adjusted for gestational age and SGA. Increases in the odds of being SGA were 29% (95% CI: 5%, 58%) and 32% (95% CI: 3%, 70%), respectively. Bisphenol S in third trimester was also associated with SGA (OR 1.52, 95% CI 1.08, 2.13). Associations of benzophenone-3 and methylparaben with PTB and LBW were null. In addition, a 1-unit increase in log10 pregnancy averaged concentration of 2,4-dichlorophenol was associated with 43% lower (95% CI: -67%, -2%) odds of low birthweight; the direction of effect was the same for the highly correlated 2,5-dichlorophenol, but with a smaller magnitude (-29%, 95% CI: -53%, 8%).DiscussionIn a large and diverse sample generally representative of the United States, benzophenone-3 and methylparaben were associated with lower birthweight as well as birthweight adjusted for gestational age and higher odds of SGA, while 2,4-dichlorophenol. These associations with smaller size at birth are concerning in light of the known consequences of intrauterine growth restriction for multiple important health outcomes emerging later in life.

The Environmental Influences on Child Health Outcomes (ECHO)-Wide Cohort Study (EWC), a collaborative research design comprising 69 cohorts in 31 consortia, was funded by the National Institutes of Health (NIH) in 2016 to improve children's health in the United States. The EWC harmonizes extant data and collects new data using a standardized protocol, the ECHO-Wide Cohort Data Collection Protocol (EWCP). EWCP visits occur at least once per life stage, but the frequency and timing of the visits vary across cohorts. As of March 4, 2022, the EWC cohorts contributed data from 60,553 children and consented 29,622 children for new EWCP data and biospecimen collection. The median (interquartile range) age of EWCP-enrolled children was 7.5 years (3.7-11.1). Surveys, interviews, standardized examinations, laboratory analyses, and medical record abstraction are used to obtain information in 5 main outcome areas: pre-, peri-, and postnatal outcomes; neurodevelopment; obesity; airways; and positive health. Exposures include factors at the level of place (e.g., air pollution, neighborhood socioeconomic status), family (e.g., parental mental health), and individuals (e.g., diet, genomics).

BackgroundPreterm birth is the leading cause of infant morbidity and mortality worldwide. Elevated levels of oxidative stress have been associated with an increased risk of delivering before term. However, most studies testing this hypothesis have been conducted in racially and demographically homogenous study populations, which do not reflect the diversity within the United States.ObjectiveWe leveraged 4 cohorts participating in the Environmental Influences on Child Health Outcomes Program to conduct the largest study to date examining biomarkers of oxidative stress and preterm birth (N=1916). Furthermore, we hypothesized that elevated oxidative stress would be associated with higher odds of preterm birth, particularly preterm birth of spontaneous origin.Study designThis study was a pooled analysis and meta-analysis of 4 birth cohorts spanning multiple geographic regions in the mainland United States and Puerto Rico (208 preterm births and 1708 full-term births). Of note, 8-iso-prostaglandin-F2α, 2,3-dinor-5,6-dihydro-8-iso-prostaglandin-F2α (F2-IsoP-M; the major 8-iso-prostaglandin-F2α metabolite), and prostaglandin-F2α were measured in urine samples obtained during the second and third trimesters of pregnancy. Logistic regression was used to calculate adjusted odds ratios and 95% confidence intervals for the associations between averaged biomarker concentrations for each participant and all preterm births, spontaneous preterm births, nonspontaneous preterm births (births of medically indicated or unknown origin), and categories of preterm birth (early, moderate, and late). Individual oxidative stress biomarkers were examined in separate models.ResultsApproximately 11% of our analytical sample was born before term. Relative to full-term births, an interquartile range increase in averaged concentrations of F2-IsoP-M was associated with higher odds of all preterm births (odds ratio, 1.29; 95% confidence interval, 1.11-1.51), with a stronger association observed for spontaneous preterm birth (odds ratio, 1.47; 95% confidence interval, 1.16-1.90). An interquartile range increase in averaged concentrations of 8-iso-prostaglandin-F2α was similarly associated with higher odds of all preterm births (odds ratio, 1.19; 95% confidence interval, 0.94-1.50). The results from our meta-analysis were similar to those from the pooled combined cohort analysis.ConclusionHere, oxidative stress, as measured by 8-iso-prostaglandin-F2α, F2-IsoP-M, and prostaglandin-F2α in urine, was associated with increased odds of preterm birth, particularly preterm birth of spontaneous origin and delivery before 34 completed weeks of gestation.

BackgroundPer- and polyfluoroalkyl substances (PFAS) are persistent and ubiquitous chemicals associated with risk of adverse birth outcomes. Results of previous studies have been inconsistent. Associations between PFAS and birth outcomes may be affected by psychosocial stress.ObjectivesWe estimated risk of adverse birth outcomes in relation to prenatal PFAS concentrations and evaluate whether maternal stress modifies those relationships.MethodsWe included 3,339 participants from 11 prospective prenatal cohorts in the Environmental influences on the Child Health Outcomes (ECHO) program to estimate the associations of five PFAS and birth outcomes. We stratified by perceived stress scale scores to examine effect modification and used Bayesian Weighted Sums to estimate mixtures of PFAS.ResultsWe observed reduced birth size with increased concentrations of all PFAS. For a 1-unit higher log-normalized exposure to perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexane sulfonic acid (PFHxS), we observed lower birthweight-for-gestational-age z-scores of β=-0.15 [95% confidence interval (CI): -0.27, -0.03], β=-0.14 (95% CI: -0.28, -0.002), β=-0.22 (95% CI: -0.23, -0.10), β=-0.06 (95% CI: -0.18, 0.06), and β=-0.25 (95% CI: -0.37, -0.14), respectively. We observed a lower odds ratio (OR) for large-for-gestational-age: ORPFNA=0.56 (95% CI: 0.38, 0.83), ORPFDA=0.52 (95% CI: 0.35, 0.77). For a 1-unit increase in log-normalized concentration of summed PFAS, we observed a lower birthweight-for-gestational-age z-score [-0.28; 95% highest posterior density (HPD): -0.44, -0.14] and decreased odds of large-for-gestational-age (OR=0.49; 95% HPD: 0.29, 0.82). Perfluorodecanoic acid (PFDA) explained the highest percentage (40%) of the summed effect in both models. Associations were not modified by maternal perceived stress.DiscussionOur large, multi-cohort study of PFAS and adverse birth outcomes found a negative association between prenatal PFAS and birthweight-for-gestational-age, and the associations were not different in groups with high vs. low perceived stress. This study can help inform policy to reduce exposures in the environment and humans. https://doi.org/10.1289/EHP10723.

The COVID-19 pandemic-and its associated restrictions-have changed many behaviors that can influence environmental exposures including chemicals found in commercial products, packaging and those resulting from pollution. The pandemic also constitutes a stressful life event, leading to symptoms of acute traumatic stress. Data indicate that the combination of environmental exposure and psychological stress jointly contribute to adverse child health outcomes. Within the Environmental influences on Child Health Outcomes (ECHO)-wide Cohort, a national consortium initiated to understand the effects of environmental exposures on child health and development, our objective was to assess whether there were pandemic-related changes in behavior that may be associated with environmental exposures. A total of 1535 participants from nine cohorts completed a survey via RedCap from December 2020 through May 2021. The questionnaire identified behavioral changes associated with the COVID-19 pandemic in expected directions, providing evidence of construct validity. Behavior changes reported by at least a quarter of the respondents include eating less fast food and using fewer ultra-processed foods, hair products, and cosmetics. At least a quarter of respondents reported eating more home cooked meals and using more antibacterial soaps, liquid soaps, hand sanitizers, antibacterial and bleach cleaners. Most frequent predictors of behavior change included Hispanic ethnicity and older age (35 years and older). Respondents experiencing greater COVID-related stress altered their behaviors more than those not reporting stress. These findings highlight that behavior change associated with the pandemic, and pandemic-related psychological stress often co-occur. Thus, prevention strategies and campaigns that limit environmental exposures, support stress reduction, and facilitate behavioral change may lead to the largest health benefits in the context of a pandemic. Analyzing biomarker data in these participants will be helpful to determine if behavior changes reported associate with measured changes in exposure.

Participants in biomonitoring studies who receive personal exposure reports seek information to reduce exposures. Many chemical exposures are driven by systems-level policies rather than individual actions; therefore, change requires engagement in collective action. Participants' perceptions of collective action and use of report-back to support engagement remain unclear. We conducted virtual focus groups during summer 2020 in a diverse group of peripartum people from cohorts in the Environmental influences on Child Health Outcomes (ECHO) Program (N = 18). We assessed baseline exposure and collective action experience, and report-back preferences. Participants were motivated to protect the health of their families and communities despite significant time and cognitive burdens. They requested time-conscious tactics and accessible information to enable action to reduce individual and collective exposures. Participant input informed the design of digital report-back in the cohorts. This study highlights opportunities to shift responsibility from individuals to policymakers to reduce chemical exposures at the systems level.

BackgroundLower socioeconomic status (SES) and elevated psychosocial stress are known contributors to adverse pregnancy outcomes; however, biological mechanisms linking these factors to adverse pregnancy outcomes are not well-characterized. Oxidative stress may be an important, yet understudied mechanistic pathway. We used a pooled study design to examine biological, behavioral, and social factors as predictors of prenatal oxidative stress biomarkers.MethodsLeveraging four pregnancy cohorts from the Environmental influences on Child Health Outcomes (ECHO) Program spanning multiple geographic regions across the United States (U.S.) (N = 2082), we measured biomarkers of oxidative stress in urine samples at up to three time points during pregnancy, including 8-isoprostane-prostaglandin F2α (8-isoPGF2α), its major metabolite, 2,3-dinor-5,6-dihydro-15-F2t-isoprostane, and prostaglandin F2α (PGF2α). Maternal age, pre-pregnancy body mass index, marital/partnered status, parity, and smoking status were included as biological and behavioral factors while race/ethnicity, maternal education, and stressful life events were considered social factors. We examined associations between each individual biological, behavioral, and social factor with oxidative stress biomarkers using multivariable-adjusted linear mixed models.ResultsNumerous biological, behavioral, and social factors were associated with elevated levels of 8-isoPGF2α, its major metabolite, and PGF2α. Pregnant people who were current smokers relative to non-smokers or had less than a high school education relative to a college degree had 11.04% (95% confidence interval [CI] = -1.97%, 25.77%) and 9.13% (95% CI = -1.02%, 20.32%) higher levels of 8-isoPGF2α, respectively.ConclusionsOxidative stress biomarkers are elevated among pregnant people with higher socioeconomic disadvantage and may represent one pathway linking biological, behavioral, and social factors to adverse pregnancy and child health outcomes, which should be explored in future work.

BackgroundPrenatal exposure to individual per‑ and poly‑fluoroalkyl substances (PFAS) and psychosocial stressors have been associated with reductions in fetal growth. Studies suggest cumulative or joint effects of chemical and non-chemical stressors on fetal growth. However, few studies have examined PFAS and non-chemical stressors together as a mixture, which better reflects real life exposure patterns. We examined joint associations between PFAS, perceived stress, and depression, and fetal growth using two approaches developed for exposure mixtures.MethodsPregnant participants were enrolled in the Chemicals in Our Bodies cohort and Illinois Kids Development Study, which together make up the ECHO.CA.IL cohort. Seven PFAS were previously measured in 2nd trimester maternal serum samples and were natural log transformed for analyses. Perceived stress and depression were assessed using self-reported validated questionnaires, which were converted to t-scores using validated methods. Quantile g-computation and Bayesian kernel machine regression (BKMR) were used to assess joint associations between PFAS, perceived stress and depression t-scores and birthweight z-scores (N = 876).ResultsIndividual PFAS, depression and perceived stress t-scores were negatively correlated with birthweight z-scores. Using quantile g-computation, a simultaneous one quartile increase in all PFAS, perceived stress and depression t-scores was associated with a slight reduction in birthweight z-scores (mean change per quartile increase = -0.09, 95% confidence interval = -0.21,0.03). BKMR similarly indicated that cumulative PFAS and stress t-scores were modestly associated with lower birthweight z-scores. Across both methods, the joint association appeared to be distributed across multiple exposures rather than due to a single exposure.ConclusionsOur study is one of the first to examine the joint effects of chemical and non-chemical stressors on fetal growth using mixture methods. We found that PFAS, perceived stress, and depression in combination were modestly associated were lower birthweight z-scores, which supports prior studies indicating that chemical and non-chemical stressors are jointly associated with adverse health outcomes.

Studies have shown that prenatal stress can negatively impact neurodevelopment, but little is known about its effect on early cognitive development. We assessed the impact of prenatal stress on cognition in 152 7.5-month-old infants using Cohen's Perceived Stress Scale (PSS), maternal telomere length (MTL), and a Stressful Life Events (SLE) Scale. A visual recognition memory task consisting of nine blocks, each with one familiarization trial (two identical stimuli) followed by two test trials (one familiar stimulus, one novel), was administered. Outcomes assessed included: average time looking at stimuli (measure: processing speed), time to reach looking time criterion (measure: attention), and the proportion of time looking at the novel stimulus (measure: recognition memory). We examined the association of each stress measure with each outcome adjusted for infant age and sex, which of the two stimuli in each set was novel, household income, and maternal age, education, and IQ. Higher prenatal stress was associated with shorter looking durations [PSS (β = -1.6, 95% CI: -2.5, -0.58); SLE (β = 0.58, 95% CI: -0.08, 1.24); MTL (β = 1.81, 95% CI: 0.18, 3.44)] and longer time to reach criterion [PSS (β = 9.1, 95% CI: 1.6, 16.6); SLE (β = 12.2, 95% CI: 1.9, 24.1); MTL (β = -23.1, 95% CI: -45.3, -0.9)], suggesting that higher prenatal stress is associated with decreased visual attention in infancy.

BackgroundInfants whose mothers experience greater psychosocial stress and environmental chemical exposures during pregnancy may face greater rates of preterm birth, lower birth weight, and impaired neurodevelopment.MethodsECHO.CA.IL is composed of two cohorts, Chemicals in Our Bodies (CIOB; n = 822 pregnant women and n = 286 infants) and Illinois Kids Development Study (IKIDS; n = 565 mother-infant pairs), which recruit pregnant women from San Francisco, CA and Urbana-Champaign, IL, respectively. We examined associations between demographic characteristics and gestational age, birth weight z-scores, and cognition at 7.5 months across these two cohorts using linear models. We also examined differences in biomarkers of exposure to per- and polyfluoroalkyl substances (PFAS), measured in second-trimester serum, and psychosocial stressors by cohort and participant demographics.ResultsTo date, these cohorts have recruited over 1300 pregnant women combined. IKIDS has mothers who are majority white (80%), whereas CIOB mothers are racially and ethnically diverse (38% white, 34% Hispanic, 17% Asian/Pacific Islander). Compared to CIOB, median levels of PFOS, a specific PFAS congener, are higher in IKIDS (2.45 ng/mL versus 1.94 ng/mL), while psychosocial stressors are higher among CIOB. Across both cohorts, women who were non-white and single had lower birth weight z-scores relative to white women and married women, respectively. Demographic characteristics are not associated with cognitive outcomes at 7.5 months.ConclusionsThis profile of the ECHO.CA.IL cohort found that mothers and their infants who vary in terms of socioeconomic status, race/ethnicity, and geographic location are similar in many of our measures of exposures and cognitive outcomes. Similar to past work, we found that non-white and single women had lower birth weight infants than white and married women. We also found differences in levels of PFOS and psychosocial stressors based on geographic location.

BackgroundInfants whose mothers experience greater psychosocial stress and environmental chemical exposures during pregnancy may face greater rates of preterm birth, lower birth weight, and impaired neurodevelopment.MethodsECHO.CA.IL is composed of two cohorts, Chemicals in Our Bodies (CIOB; n = 822 pregnant women and n = 286 infants) and Illinois Kids Development Study (IKIDS; n = 565 mother-infant pairs), which recruit pregnant women from San Francisco, CA and Urbana-Champaign, IL, respectively. We examined associations between demographic characteristics and gestational age, birth weight z-scores, and cognition at 7.5 months across these two cohorts using linear models. We also examined differences in biomarkers of exposure to per- and polyfluoroalkyl substances (PFAS), measured in second-trimester serum, and psychosocial stressors by cohort and participant demographics.ResultsTo date, these cohorts have recruited over 1300 pregnant women combined. IKIDS has mothers who are majority white (80%), whereas CIOB mothers are racially and ethnically diverse (38% white, 34% Hispanic, 17% Asian/Pacific Islander). Compared to CIOB, median levels of PFOS, a specific PFAS congener, are higher in IKIDS (2.45 ng/mL versus 1.94 ng/mL), while psychosocial stressors are higher among CIOB. Across both cohorts, women who were non-white and single had lower birth weight z-scores relative to white women and married women, respectively. Demographic characteristics are not associated with cognitive outcomes at 7.5 months.ConclusionsThis profile of the ECHO.CA.IL cohort found that mothers and their infants who vary in terms of socioeconomic status, race/ethnicity, and geographic location are similar in many of our measures of exposures and cognitive outcomes. Similar to past work, we found that non-white and single women had lower birth weight infants than white and married women. We also found differences in levels of PFOS and psychosocial stressors based on geographic location.

The Environmental influences on Child Health Outcomes (ECHO) Program is a research initiative funded by the National Institutes of Health that capitalizes on existing cohort studies to investigate the impact of early life environmental factors on child health and development from infancy through adolescence. In the initial stage of the program, extant data from 70 existing cohort studies are being uploaded to a database that will be publicly available to researchers. This new database will represent an unprecedented opportunity for researchers to combine data across existing cohorts to address associations between prenatal chemical exposures and child neurodevelopment. Data elements collected by ECHO cohorts were determined via a series of surveys administered by the ECHO Data Analysis Center. The most common chemical classes quantified in multiple cohorts include organophosphate pesticides, polychlorinated biphenyls, polybrominated diphenyl ethers, environmental phenols (including bisphenol A), phthalates, and metals. For each of these chemicals, at least four ECHO cohorts also collected behavioral data during infancy/early childhood using the Child Behavior Checklist. For these chemicals and this neurodevelopmental assessment (as an example), existing data from multiple ECHO cohorts could be pooled to address research questions requiring larger sample sizes than previously available. In addition to summarizing the data that will be available, the article also describes some of the challenges inherent in combining existing data across cohorts, as well as the gaps that could be filled by the additional data collection in the ECHO Program going forward.

Summary: Children in America today are at an unacceptably high risk of developing neurodevelopmental disorders that affect the brain and nervous system including autism, attention deficit hyperactivity disorder, intellectual disabilities, and other learning and behavioral disabilities. These are complex disorders with multiple causes—genetic, social, and environmental. The contribution of toxic chemicals to these disorders can be prevented. Approach: Leading scientific and medical experts, along with children’s health advocates, came together in 2015 under the auspices of Project TENDR: Targeting Environmental Neuro-Developmental Risks to issue a call to action to reduce widespread exposures to chemicals that interfere with fetal and children’s brain development. Based on the available scientific evidence, the TENDR authors have identified prime examples of toxic chemicals and pollutants that increase children’s risks for neurodevelopmental disorders. These include chemicals that are used extensively in consumer products and that have become widespread in the environment. Some are chemicals to which children and pregnant women are regularly exposed, and they are detected in the bodies of virtually all Americans in national surveys conducted by the U.S. Centers for Disease Control and Prevention. The vast majority of chemicals in industrial and consumer products undergo almost no testing for developmental neurotoxicity or other health effects. Conclusion: Based on these findings, we assert that the current system in the United States for evaluating scientific evidence and making health-based decisions about environmental chemicals is fundamentally broken. To help reduce the unacceptably high prevalence of neurodevelopmental disorders in our children, we must eliminate or significantly reduce exposures to chemicals that contribute to these conditions. We must adopt a new framework for assessing chemicals that have the potential to disrupt brain development and prevent the use of those that may pose a risk. This consensus statement lays the foundation for developing recommendations to monitor, assess, and reduce exposures to neurotoxic chemicals. These measures are urgently needed if we are to protect healthy brain development so that current and future generations can reach their fullest potential.

Children in America today are at an unacceptably high risk of developing neurodevelopmental disorders that affect the brain and nervous system including autism, attention deficit hyperactivity disorder, intellectual disabilities, and other learning and behavioral disabilities. These are complex disorders with multiple causes—genetic, social, and environmental. The contribution of toxic chemicals to these disorders can be prevented. Approach: Leading scientific and medical experts, along with children’s health advocates, came together in 2015 under the auspices of Project TENDR: Targeting Environmental Neuro-Developmental Risks to issue a call to action to reduce widespread exposures to chemicals that interfere with fetal and children’s brain development. Based on the available scientific evidence, the TENDR authors have identified prime examples of toxic chemicals and pollutants that increase children’s risks for neurodevelopmental disorders. These include chemicals that are used extensively in consumer products and that have become widespread in the environment. Some are chemicals to which children and pregnant women are regularly exposed, and they are detected in the bodies of virtually all Americans in national surveys conducted by the U.S. Centers for Disease Control and Prevention. The vast majority of chemicals in industrial and consumer products undergo almost no testing for developmental neurotoxicity or other health effects. Conclusion: Based on these findings, we assert that the current system in the United States for evaluating scientific evidence and making health-based decisions about environmental chemicals is fundamentally broken. To help reduce the unacceptably high prevalence of neurodevelopmental disorders in our children, we must eliminate or significantly reduce exposures to chemicals that contribute to these conditions. We must adopt a new framework for assessing chemicals that have the potential to disrupt brain development and prevent the use of those that may pose a risk. This consensus statement lays the foundation for developing recommendations to monitor, assess, and reduce exposures to neurotoxic chemicals. These measures are urgently needed if we are to protect healthy brain development so that current and future generations can reach their fullest potential.