Association between maternal stress and child sleep quality: a nationwide ECHO prospective cohort study.

BACKGROUND: Childhood sleep quality is associated with physical, cognitive, and behavioral health and predicts later sleep quality; it has many determinants, including developmental exposures. OBJECTIVES: To examine associations between maternal stress during pregnancy and childhood sleep quality and determine whether postnatal stress mediates the association. METHOD: Data from the Environmental Influences on Child Health Outcomes cohort were used. Perceived Stress Scale (PSS) T-scores were the exposure measure. Outcome measures were preschool Child Behavior Checklist (CBCL) sleep syndrome scale and Patient-Reported Outcomes Measurement Information System Sleep Disturbance Parent Proxy short form 4a (PSD4a) T-scores at ages 4-8 years. Linear mixed-effects regression modeling was performed for each sleep outcome, adjusting for maternal age at delivery and education and child sex, gestational age at birth, and age at outcome ascertainment, with random intercepts for cohorts. RESULTS: Prenatal PSS score was associated with both CBCL (B = 0.09, 95% confidence interval [CI]: 0.06, 0.11; p < 0.01) and PSD4a (B = 0.07, 95% CI: 0.03, 0.12; p < 0.01) scores. Postnatal perceived stress mediated a proportion of the total effect of prenatal stress in both CBCL (66.3%) and PSD4a (95.9%) samples. CONCLUSIONS: Both pre- and postnatal maternal perceived stress appear to influence sleep quality during early life. IMPACT: Prenatal stress significantly associates with child sleep problems and disturbances at ages 4-8 years; postnatal maternal stress is a significant mediator of these associations. Research suggests a range of prenatal affective/distress exposures associated with child sleep problems, but the conclusions remain in doubt due to the mixture of exposures and outcomes employed. Ours is the first US-based effort to explore associations between perceived maternal stress during pregnancy and child sleep problems and disturbance in early and middle childhood. Even a small effect of a prevalent issue like psychosocial stress may have important public health implications at the population level.

Oxidative stress as a potential mechanism linking gestational phthalates exposure to cognitive development in infancy.

BACKGROUND: Gestational exposure to phthalates, endocrine disrupting chemicals widely used in consumer products, has been associated with poor recognition memory in infancy. Oxidative stress may represent one pathway linking this association. Hence, we examined whether exposure to phthalates was associated with elevated oxidative stress during pregnancy, and whether oxidative stress mediates the relationship between phthalate exposure and recognition memory. METHODS: Our analysis included a subset of mother-child pairs enrolled in the Illinois Kids Development Study (IKIDS, N = 225, recruitment years 2013-2018). Concentrations of 12 phthalate metabolites were quantified in 2nd trimester urine samples. Four oxidative stress biomarkers (8-isoprostane-PGF2α, 2,3-dinor-5,6-dihydro-8-isoPGF2α, 2,3-dinor-8-isoPGF2α, and prostaglandin-F2α) were measured in 2nd and 3rd trimester urine. Recognition memory was evaluated at 7.5 months, with looking times to familiar and novel stimuli recorded via infrared eye-tracking. Novelty preference (proportion of time looking at a novel stimulus when paired with a familiar one) was considered a measure of recognition memory. Linear mixed effect models were used to estimate associations between monoethyl phthalate (MEP), sum of di(2-ethylhexyl) phthalate metabolites (ΣDEHP), sum of di(isononyl) phthalate metabolites (ΣDINP), and sum of anti-androgenic phthalate metabolites (ΣAA) and oxidative stress biomarkers. Mediation analysis was performed to assess whether oxidative stress biomarkers mediated the effect of gestational phthalate exposure on novelty preference. RESULTS: The average maternal age at delivery was 31 years and approximately 50 % of participants had a graduate degree. A natural log unit increase in ΣAA, ΣDINP, and ΣDEHP was associated with a statistically significant increase in 8-isoPGF2α, 2,3-dinor-5,6-dihydro-8-isoPGF2α, and 2,3-dinor-8-isoPGF2α. The association was greatest in magnitude for ΣAA and 2,3-dinor-5,6-dihydro-8-isoPGF2α (ß = 0.45, 95 % confidence interval = 0.14, 0.76). The relationship between ΣAA, ΣDINP, ΣDEHP, and novelty preference was partially mediated by 2,3-dinor-8-isoPGF2α. CONCLUSIONS: Gestational exposure to some phthalates is positively associated with oxidative stress biomarkers, highlighting one mechanistic pathway through which these chemicals may impair early cognitive development.

Use, limitations, and future directions of mixtures approaches to understand the health impacts of weather- and climate change-related exposures, an under-studied aspect of the exposome.

The exposome concept aims to account for the comprehensive and cumulative effects of physical, chemical, biological, and psychosocial influences on biological systems. To date, limited exposome research has explicitly included climate change-related exposures. We define these exposures as those that will intensify with climate change, including direct effects like extreme heat, tropical cyclones, wildfires, downstream effects like air pollution, power outages, and limited or contaminated food and water supplies. These climate change-related exposures can occur individually or simultaneously. Here, we discuss the concept of a climate mixture, defined as three or more simultaneous climate change-related exposures, in the context of the exposome. In a motivating climate mixture example, we consider the impact of a co-occurring tropical cyclone, power outage, and flooding on respiratory hospitalizations. We identify current gaps and future directions for assessing the effect of climate mixtures on health. Mixtures methods allow us to incorporate climate mixtures into exposomics.

Exploring relationships between smoke exposure, housing characteristics, and preterm birth in California.

Pregnant people are vulnerable to air pollution exposure, including risk of preterm birth, low birth weight, and stillbirth. Understanding the infiltration of outdoor wildfire smoke into a residential space is critical for the accurate assessment of wildfire smoke exposure and associated health effects in pregnant people. Relying on ambient measurements of wildfire smoke alone can result in exposure misclassification. In this study, we examine the role of physical housing characteristics in the relationship between smoke exposure and preterm birth. In particular, we examine the effect of home size, year of construction, cooling type, and renovation status, as effect modifiers in the relationship between smoke exposure during pregnancy and preterm birth from 2007 to 2015 in California. To do this, we combined data on home characteristics from the California Tax Assessor, birth outcomes from the California birth records database, and the number of smoke days for each pregnancy from theNOAA (National Oceanic and Atmospheric Administration) Hazard Mapping System (HMS). We estimated the association between smoke day exposures and odds of preterm birth using logistic regression models and stratified by air basin and housing characteristics. Our findings reveal that cooling type and renovation status are key factors modifying the smoke exposure-preterm birth relationship. Notably, we found elevated associations for people living in unrenovated homes, those using evaporative cooling systems, and those using central air conditioning units. While we observed elevated odds of preterm birth associated with increasing smoke day exposure for residents of large and new homes, this effect does not significantly differ across home size and age quartiles. This study highlights the need to further examine the relative roles of housing characteristics as well as factors not measured here including behavioral factors, time spent outdoors, window use, and occupational exposures in driving adverse birth outcomes related to wildfire smoke exposure.

Mediating effects of inequitable gender norms on intimate partner violence and contraceptive use in a cluster randomized control trial in Niger.

Previous research has demonstrated that the Reaching Married Adolescents intervention (RMA) was associated with changes in inequitable gender norms, intimate partner violence (IPV), and modern contraceptive use. This study seeks to understand if changes in inequitable gender norms mediate the RMA intervention's effects on contraceptive use and intimate partner violence (IPV). A four-arm cluster randomized control trial was conducted to evaluate effects of the RMA intervention (household visits, small groups, combination, control) on married adolescent girls and their husbands in Dosso, Niger (baseline: 1042 dyads; 24m follow-up: 737 dyads; 2016-2019). Mediation was assessed using inverse odds ratio weighting. In the small group intervention, of the total effect on IPV prevalence (8% reduction), indirect effects via inequitable gender norms is associated with a 2% decrease (95% CI: -0.07, 0.12) and direct effects with a 6% decrease (95% CI: -0.20, -0.02). For household visits, of the total effect on contraceptive use (20% increase), the indirect effect accounts for an 11% decrease (95% CI: -0.18, -0.01) and direct effect, a 32% increase (95% CI: 0.13, 0.44); similar to findings for the combination arm. This experimental evidence informs the value of changing underlying social norms to reduce IPV and increase contraception use.

The Camp fire and perinatal health: An example of the generalized synthetic control method to identify susceptible windows of exposure.

BACKGROUND: The November 2018 Camp fire was the most destructive wildfire in California history, but its effects on reproductive health are not known. METHODS: We linked California birth records from 2017-2019 to daily smoke levels using U.S. EPA Air Quality System (AQS) PM2.5 data and NOAA Hazard Mapping System smoke plume polygons during the Camp fire. In the main analysis, pregnancies were considered exposed if they had median AQS PM2.5 levels above 50 µg/m3 for at least 7 days during November 8-22, 2018. We calculated rates of preterm birth and the infant sex ratio based on week of conception and used the generalized synthetic control method to estimate the average treatment effect on the treated and to propose a novel approach to identify potential critical weeks of exposure during pregnancy. RESULTS: We found associations between Camp fire-related smoke exposure and rates of preterm birth, with a risk difference (RD) = 0.005, 95% CI 0.001, 0.010. Exposure during week 10 of pregnancy was consistently associated with increased preterm birth (RD = 0.030, 95% CI 0.004, 0.056). We did not observe differences in the infant sex ratio. CONCLUSIONS: Camp fire smoke exposure was associated with increased rates of preterm birth, with sensitive windows in the first trimester.

Fluoride-related changes in the fetal cord blood proteome; a pilot study.

BACKGROUND: Fluoride exposure during pregnancy has been associated with various effects on offspring, including changes in behavior and IQ. To provide clues to possible mechanisms by which fluoride may affect human fetal development, we completed proteomic analyses of cord blood serum collected from second-trimester pregnant women residing in northern California, USA. OBJECTIVE: To identify changes in cord blood proteins associated with maternal serum fluoride concentration in pregnant women. METHODS: The proteomes of 19 archived second-trimester cord blood samples from women living in northern California, USA, and having varied serum fluoride concentrations, were analyzed by quantitative mass spectrometry. The 327 proteins that were quantified were characterized by their abundance relative to maternal serum fluoride concentration, and subjected to pathway analyses using PANTHER and Ingenuity Pathway Analysis processes. RESULTS: Pathway analyses showed significant increases in process related to reactive oxygen species and cellular oxidant detoxification, associated with increasing maternal serum fluoride concentrations. Pathways showing significant decreases included complement cascade, suggesting alterations in alterations in process associated with inflammation. CONCLUSION: Maternal fluoride exposure, as measured by serum fluoride concentrations in a small, but representative sample of women from northern California, USA, showed significant changes in the second trimester cord blood proteome relative to maternal serum fluoride concentration.

The COVID-19 Pandemic Period, SARS-CoV-2 Infection, and Perinatal Health.

This cohort study assesses population-level associations of COVID-19 with birth parent and infant health, distinguishing the COVID-19 pandemic period from individual SARS-CoV-2 infection.

Ambient Environment and the Epidemiology of Preterm Birth.

Preterm birth (PTB) is associated with substantial mortality and morbidity. We describe environmental factors that may influence PTB risks. We focus on exposures associated with an individual's ambient environment, such as air pollutants, water contaminants, extreme heat, and proximities to point sources (oil/gas development or waste sites) and greenspace. These exposures may further vary by other PTB risk factors such as social constructs and stress. Future examinations of risks associated with ambient environment exposures would benefit from consideration toward multiple exposures - the exposome - and factors that modify risk including variations associated with the structural genome, epigenome, social stressors, and diet.

Water Fluoridation and Birth Outcomes in California.

BACKGROUND: There is a lack of research on the relationship between water fluoridation and pregnancy outcomes. OBJECTIVES: We assessed whether hypothetical interventions to reduce fluoride levels would improve birth outcomes in California. METHODS: We linked California birth records from 2000 to 2018 to annual average fluoride levels by community water system. Fluoride levels were collected from consumer confidence reports using publicly available data and public record requests. We estimated the effects of a hypothetical intervention reducing water fluoride levels to 0.7 ppm (the current level recommended by the US Department of Health and Human Services) and 0.5 ppm (below the current recommendation) on birth weight, birth-weight-for-gestational age z-scores, gestational age, preterm birth, small-for-gestational age, large-for-gestational age, and macrosomia using linear regression with natural cubic splines and G-computation. Inference was calculated using a clustered bootstrap with Wald-type confidence intervals. We evaluated race/ethnicity, health insurance type, fetal sex, and arsenic levels as potential effect modifiers. RESULTS: Fluoride levels ranged from 0 to 2.5 ppm, with a median of 0.51 ppm. There was a small negative association on birth weight with the hypothetical intervention to reduce fluoride levels to 0.7 ppm [-2.2g; 95% confidence interval (CI): -4.4, 0.0] and to 0.5 ppm (-5.8g; 95% CI: -10.0, -1.6). There were small negative associations with birth-weight-for-gestational-age z-scores for both hypothetical interventions (0.7 ppm: -0.004; 95% CI: -0.007, 0.000 and 0.5 ppm: -0.006; 95% CI: -0.013, 0.000). We also observed small negative associations for risk of large-for-gestational age for both the hypothetical interventions to 0.7 ppm [risk difference (RD)=-0.001; 95% CI: -0.002, 0.000 and 0.5 ppm (-0.001; 95% CI: -0.003, 0.000)]. We did not observe any associations with preterm birth or with being small for gestational age for either hypothetical intervention. We did not observe any associations with risk of preterm birth or small-for-gestational age for either hypothetical intervention. CONCLUSION: We estimated that a reduction in water fluoride levels would modestly decrease birth weight and birth-weight-for-gestational-age z-scores in California. https://doi.org/10.1289/EHP13732.

Fluoride-related changes in the fetal cord blood proteome; a pilot study.

Background: Fluoride exposure during pregnancy has been associated with various effects on offspring, including changes in behavior and IQ. To provide clues to possible mechanisms by which fluoride affects human fetal development, we completed proteomic analyses of cord blood serum collected from second-trimester pregnant women residing in Northern California with either high or low fluoride exposure, as identified by maternal serum fluoride concentrations. Objective: To identify changes in cord blood proteins associated with maternal serum fluoride concentration in pregnant women living in Northern California. Methods: The proteomes of 19 archived second-trimester cord blood samples representing highest and lowest serum fluoride concentrations from a cohort of 48 women living in Northern California, previously analyzed for serum, urine and amniotic fluoride concentrations, were characterized by mass spectrometry. Proteins highly correlated to maternal serum fluoride concentrations were identified, and further compared in a group of samples from women with the highest serum fluoride to the group with the lowest maternal serum fluoride concentrations. Results: Nine cord blood proteins were significantly correlated with maternal serum fluoride concentrations. Six of these proteins, including apolipoprotein B-100, delta homolog 1, coagulation factor X, mimecan, plasma kallikrein, and vasorin, were significantly decreased in the cord blood from women with the highest serum fluoride levels. Conclusion: Changes in the relative amounts of second trimester cord blood proteins included proteins associated with the development of the fetal hematopoetic system.

Pregnancy exposure to PM2.5 from wildland fire smoke and preterm birth in California.

BACKGROUND: Wildfires in the Western United States are a growing and significant source of air pollution that is eroding decades of progress in air pollution reduction. The effects on preterm birth during critical periods of pregnancy are unknown. METHODS: We assessed associations between prenatal exposure to wildland fire smoke and risk of preterm birth (gestational age < 37 weeks). We assigned smoke exposure to geocoded residence at birth for all live singleton births in California conceived 2007-2018, using weekly average concentrations of particulate matter ≤ 2.5 µm (PM2.5) attributable to wildland fires from United States Environmental Protection Agency's Community Multiscale Air Quality Model. Logistic regression yielded odds ratio (OR) for preterm birth in relation to increases in average exposure across the whole pregnancy, each trimester, and each week of pregnancy. Models adjusted for season, age, education, race/ethnicity, medical insurance, and smoking of the birthing parent. RESULTS: For the 5,155,026 births, higher wildland fire PM2.5 exposure averaged across pregnancy, or any trimester, was associated with higher odds of preterm birth. The OR for an increase of 1 µg/m3 of average wildland fire PM2.5 during pregnancy was 1.013 (95 % CI:1.008,1.017). Wildland fire PM2.5 during most weeks of pregnancy was associated with higher odds. Strongest estimates were observed in weeks in the second and third trimesters. A 10 µg/m3 increase in average wildland fire PM2·5 in gestational week 23 was associated with OR = 1.034; 95 % CI: 1.019, 1.049 for preterm birth. CONCLUSIONS: Preterm birth is sensitive to wildland fire PM2.5; therefore, we must reduce exposure during pregnancy.

Regional and racial/ethnic inequalities in public drinking water fluoride concentrations across the US.

BACKGROUND: Although the US Centers for Disease Control and Prevention (CDC) considers fluoridation of community water systems (CWSs) to be a major public health achievement responsible for reducing dental disease, recent epidemiologic evidence suggests that chronic exposure to population-relevant levels of fluoride may also be associated with adverse child neurodevelopmental outcomes. To our knowledge, a nationally representative database of CWS fluoride concentration estimates that can be readily linked to US epidemiologic cohorts for further study is not publicly available. Our objectives were to evaluate broad regional and sociodemographic inequalities in CWS fluoride concentrations across the US, and to determine if county-level racial/ethnic composition was associated with county-level CWS fluoride. METHODS: We generated CWS-level (N = 32,495) and population weighted county-level (N = 2152) fluoride concentration estimates using over 250,000 routine compliance monitoring records collected from the US Environmental Protection Agency's (EPA) Third Six Year Review (2006-2011). We compared CWS-level fluoride distributions across subgroups including region, population size served, and county sociodemographic characteristics. In county-level spatial error models, we also evaluated geometric mean ratios (GMRs) of CWS fluoride per 10% higher proportion of residents belonging to a given racial/ethnic subgroup. RESULTS: 4.5% of CWSs (serving >2.9 million residents) reported mean 2006-2011 fluoride concentrations ≥1500 µg/L (the World Health Organization's guideline for drinking water quality). Arithmetic mean, 90th, and 95th percentile contaminant concentrations were greatest in CWSs reliant on groundwater, located in the Southwest and Eastern Midwest, and serving Semi-Urban, Hispanic communities. In fully adjusted spatial error models, the GMR (95% CI) of CWS fluoride per a 10% higher proportion of county residents that were Hispanic/Latino was 1.16 (1.10, 1.23). IMPACT STATEMENT: We find that over 2.9 million US residents are served by public water systems with average fluoride concentrations exceeding the World Health Organization's guidance limit. We also find significant inequalities in community water system fluoride concentration estimates (2006-2011) across the US, especially for Hispanic/Latino communities who also experience elevated arsenic and uranium in regulated public drinking water systems. Our fluoride estimates can be leveraged in future epidemiologic studies to assess the potential association between chronic fluoride exposure and related adverse outcomes.

Extending Nontargeted Discovery of Environmental Chemical Exposures during Pregnancy and Their Association with Pregnancy Complications-A Cross-Sectional Study.

BACKGROUND: Nontargeted analysis (NTA) methods identify novel exposures; however, few chemicals have been quantified and interrogated with pregnancy complications. OBJECTIVES: We characterized levels of nine exogenous and endogenous chemicals in maternal and cord blood identified, selected, and confirmed in prior NTA steps, including linear and branched isomers perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), monoethylhexyl phthalate, 4-nitrophenol, tetraethylene glycol, tridecanedioic acid, octadecanedioic acid, and deoxycholic acid. We evaluated relationships between maternal and cord levels and between gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy in a diverse pregnancy cohort in San Francisco. METHODS: We collected matched maternal and cord serum samples at delivery from 302 pregnant study participants from the Chemicals in Our Bodies cohort in San Francisco. Chemicals were identified via NTA and quantified using targeted approaches. We calculated distributions and Spearman correlation coefficients testing the relationship of chemicals within and between the maternal and cord blood matrices. We used adjusted logistic regression to calculate the odds of GDM and hypertensive disorders of pregnancy associated with an interquartile range increase in maternal chemical exposures. RESULTS: We detected linear PFOS, PFHxS, octadecanedioic acid, and deoxycholic acid in at least 97% of maternal samples. Correlations ranged between -0.1 and 0.9. We observed strong correlations between cord and maternal levels of PFHxS, linear PFOS, and branched PFOS (coefficient=0.9, 0.8, and 0.8, respectively). An interquartile range increase in linear and branched PFOS, tridecanedioic acid, octadecanedioic acid, and deoxycholic acid was associated with increased odds ratio (OR) of GDM [OR=1.33 (95% CI: 0.89, 2.01), 1.24 (95% CI: 0.86, 1.80), 1.26 (95% CI: 0.93, 1.73), 1.24 (95% CI: 0.86, 1.80), and 1.23 (95% CI: 0.87, 1.75), respectively]. Tridecanedioic acid was positively associated with hypertensive disorders of pregnancy [OR=1.28 (95% CI: 0.90, 1.86)]. DISCUSSION: We identified both exogenous and endogenous chemicals seldom quantified in pregnant study participants that were also related to pregnancy complications and demonstrated the utility of NTA to identify chemical exposures of concern. https://doi.org/10.1289/EHP11546.

Pregnancy-associated systemic gene expression compared to a pre-pregnancy baseline, among healthy women with term pregnancies.

Background: Pregnancy is known to induce extensive biological changes in the healthy mother. Little is known, however, about what these changes are at the molecular level. We have examined systemic expression changes in protein-coding genes and long non-coding (lnc) RNAs during and after pregnancy, compared to before pregnancy, among healthy women with term pregnancies. Methods: Blood samples were collected from 14 healthy women enrolled in our prospective pregnancy cohort at 7 time-points (before, during and after pregnancy). Total RNA from frozen whole blood was used for RNA sequencing. Following raw read alignment and assembly, gene-level counts were obtained for protein-coding genes and long non-coding RNAs. At each time-point, cell type proportions were estimated using deconvolution. To examine associations between pregnancy status and gene expression over time, Generalized Estimating Equation (GEE) models were fitted, adjusting for age at conception, and with and without adjusting for changes in cell type proportions. Fold-changes in expression at each trimester were examined relative to the pre-pregnancy baseline. Results: Numerous immune-related genes demonstrated pregnancy-associated expression, in a time-dependent manner. The genes that demonstrated the largest changes in expression included several that were neutrophil-related (over-expressed) and numerous immunoglobulin genes (under-expressed). Estimated cell proportions revealed a marked increase in neutrophils, and less so of activated CD4 memory T cells, during pregnancy, while most other cell type proportions decreased or remained unchanged. Adjusting for cell type proportions in our model revealed that although most of the expression changes were due to changes in cell type proportions in the bloodstream, transcriptional regulation was also involved, especially in down-regulating expression of type I interferon inducible genes. Conclusion: Compared to a pre-pregnancy baseline, there were extensive systemic changes in cell type proportions, gene expression and biological pathways associated with different stages of pregnancy and postpartum among healthy women. Some were due to changes in cell type proportions and some due to gene regulation. In addition to providing insight into term pregnancy among healthy women, these findings also provide a "normal" reference for abnormal pregnancies and for autoimmune diseases that improve or worsen during pregnancy, to assess deviations from normal.

Violence Related to Daily Water and Sanitation Needs in South Africa.

There is a critical lack of research on violence experienced by women when meeting their daily water and sanitation needs. This short report describes the cumulative lifetime incidence of exposure to violence when using the toilet or collecting water (water, sanitation, and hygiene [WASH]-related violence) and identifies associated health and behavioral risks. Data from 1,870 participants collected in 2013-2015 from a longitudinal cohort of young women in rural South Africa were included in this analysis. We found that exposure to WASH-related violence was high: 25.9% experienced violence when collecting water or when using the toilet. Those who experienced violence were more likely to report pregnancy, an older partner, unprotected sex, experience of intimate partner violence, engaging in transactional sex, depressive symptoms, and anxiety. Future research should investigate the location and type of violence experienced and examine how WASH-related violence is related to health outcomes to identify gender-centered WASH interventions that reduce violence exposure.

Birth Outcomes in Relation to Prenatal Exposure to Per- and Polyfluoroalkyl Substances and Stress in the Environmental Influences on Child Health Outcomes (ECHO) Program.

BACKGROUND: Per- 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. OBJECTIVES: We estimated risk of adverse birth outcomes in relation to prenatal PFAS concentrations and evaluate whether maternal stress modifies those relationships. METHODS: We 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. RESULTS: We 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 ß=-0.15 [95% confidence interval (CI): -0.27, -0.03], ß=-0.14 (95% CI: -0.28, -0.002), ß=-0.22 (95% CI: -0.23, -0.10), ß=-0.06 (95% CI: -0.18, 0.06), and ß=-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. DISCUSSION: Our 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.

Comparing Two-way Fixed Effects and New Estimators for Difference-in-Differences: A Simulation Study and Empirical Example.

BACKGROUND: Two-way fixed effects methods have been used to estimate effects of policies adopted in different places over time, but they can provide misleading results when effects are heterogeneous or dynamic, and alternate methods have been proposed. METHODS: We compared methods for estimating the average treatment effect on the treated (ATT) under staggered adoption of policies, including two-way fixed effects, group-time ATT, cohort ATT, and target-trial approaches. We applied each method to assess the impact of Medicaid expansion on preterm birth using the National Center for Health Statistics' birth records. We compared each estimator's performance in a simulation parameterized to mimic the empirical example. We generated constant, heterogeneous, and dynamic effects and calculated bias, mean squared error, and confidence interval coverage of each estimator across 1000 iterations. RESULTS: Two-way fixed effects estimated that Medicaid expansion increased the risk of preterm birth (risk difference [RD], 0.12; 95% CI = 0.02, 0.22), while the group-time ATT, cohort ATT, and target-trial approaches estimated protective or null effects (group-time RD, -0.16; 95% CI = -0.58, 0.26; cohort RD, -0.02; 95% CI = -0.46, 0.41; target trial RD, -0.16; 95% CI = -0.59, 0.26). In simulations, two-way fixed effects performed well when treatment effects were constant and less well under heterogeneous and dynamic effects. CONCLUSIONS: We demonstrated why new approaches perform better than two-way fixed effects when treatment effects are heterogeneous or dynamic under a staggered policy adoption design, and created simulation and analysis code to promote understanding and wider use of these methods in the epidemiologic literature.