Prenatal phthalate exposure and adverse birth outcomes in the USA: a prospective analysis of births and estimates of attributable burden and costs.

BACKGROUND: Phthalates are synthetic chemicals widely used in consumer products and have been identified to contribute to preterm birth. Existing studies have methodological limitations and potential effects of di-2-ethylhexyl phthalate (DEHP) replacements are poorly characterised. Attributable fractions and costs have not been quantified, limiting the ability to weigh trade-offs involved in ongoing use. We aimed to leverage a large, diverse US cohort to study associations of phthalate metabolites with birthweight and gestational age, and estimate attributable adverse birth outcomes and associated costs. METHODS: In this prospective analysis we used extant data in the US National Institutes of Health Environmental influences on Child Health Outcomes (ECHO) Program from 1998 to 2022 to study associations of 20 phthalate metabolites with gestational age at birth, birthweight, birth length, and birthweight for gestational age z-scores. We also estimated attributable adverse birth outcomes and associated costs. Mother-child dyads were included in the study if there were one or more urinary phthalate measurements during the index pregnancy; data on child's gestational age and birthweight; and singleton delivery. FINDINGS: We identified 5006 mother-child dyads from 13 cohorts in the ECHO Program. Phthalic acid, diisodecyl phthalate (DiDP), di-n-octyl phthalate (DnOP), and diisononyl phthalate (DiNP) were most strongly associated with gestational age, birth length, and birthweight, especially compared with DEHP or other metabolite groupings. Although DEHP was associated with preterm birth (odds ratio 1·45 [95% CI 1·05-2·01]), the risks per log10 increase were higher for phthalic acid (2·71 [1·91-3·83]), DiNP (2·25 [1·67-3·00]), DiDP (1·69 [1·25-2·28]), and DnOP (2·90 [1·96-4·23]). We estimated 56 595 (sensitivity analyses 24 003-120 116) phthalate-attributable preterm birth cases in 2018 with associated costs of US$3·84 billion (sensitivity analysis 1·63- 8·14 billion). INTERPRETATION: In a large, diverse sample of US births, exposure to DEHP, DiDP, DiNP, and DnOP were associated with decreased gestational age and increased risk of preterm birth, suggesting substantial opportunities for prevention. This finding suggests the adverse consequences of substitution of DEHP with chemically similar phthalates and need to regulate chemicals with similar properties as a class. FUNDING: National Institutes of Health.

Neighborhood Opportunity and Vulnerability and Incident Asthma Among Children.

Background: The extent to which physical and social attributes of neighborhoods play a role in childhood asthma remains understudied. Objective: To examine associations of neighborhood-level opportunity and social vulnerability measures with childhood asthma incidence. Design, Setting, and Participants: This cohort study used data from children in 46 cohorts participating in the Environmental Influences on Child Health Outcomes (ECHO) Program between January 1, 1995, and August 31, 2022. Participant inclusion required at least 1 geocoded residential address from birth and parent or caregiver report of a physician's diagnosis of asthma. Participants were followed up to the date of asthma diagnosis, date of last visit or loss to follow-up, or age 20 years. Exposures: Census tract-level Child Opportunity Index (COI) and Social Vulnerability Index (SVI) at birth, infancy, or early childhood, grouped into very low (<20th percentile), low (20th to <40th percentile), moderate (40th to <60th percentile), high (60th to <80th percentile), or very high (≥80th percentile) COI or SVI. Main Outcomes and Measures: The main outcome was parent or caregiver report of a physician's diagnosis of childhood asthma (yes or no). Poisson regression models estimated asthma incidence rate ratios (IRRs) associated with COI and SVI scores at each life stage. Results: The study included 10 516 children (median age at follow-up, 9.1 years [IQR, 7.0-11.6 years]; 52.2% male), of whom 20.6% lived in neighborhoods with very high COI and very low SVI. The overall asthma incidence rate was 23.3 cases per 1000 child-years (median age at asthma diagnosis, 6.6 years [IQR, 4.1-9.9 years]). High and very high (vs very low) COI at birth, infancy, or early childhood were associated with lower subsequent asthma incidence independent of sociodemographic characteristics, parental asthma history, and parity. For example, compared with very low COI, the adjusted IRR for asthma was 0.87 (95% CI, 0.75-1.00) for high COI at birth and 0.83 (95% CI, 0.71-0.98) for very high COI at birth. These associations appeared to be attributable to the health and environmental and the social and economic domains of the COI. The SVI during early life was not significantly associated with asthma incidence. For example, compared with a very high SVI, the adjusted IRR for asthma was 0.88 (95% CI, 0.75-1.02) for low SVI at birth and 0.89 (95% CI, 0.76-1.03) for very low SVI at birth. Conclusions: In this cohort study, high and very high neighborhood opportunity during early life compared with very low neighborhood opportunity were associated with lower childhood asthma incidence. These findings suggest the need for future studies examining whether investing in health and environmental or social and economic resources in early life would promote health equity in pediatric asthma.

Developing a National-Scale Exposure Index for Combined Environmental Hazards and Social Stressors and Applications to the Environmental Influences on Child Health Outcomes (ECHO) Cohort.

Tools for assessing multiple exposures across several domains (e.g., physical, chemical, and social) are of growing importance in social and environmental epidemiology because of their value in uncovering disparities and their impact on health outcomes. Here we describe work done within the Environmental influences on Child Health Outcomes (ECHO)-wide Cohort Study to build a combined exposure index. Our index considered both environmental hazards and social stressors simultaneously with national coverage for a 10-year period. Our goal was to build this index and demonstrate its utility for assessing differences in exposure for pregnancies enrolled in the ECHO-wide Cohort Study. Our unitless combined exposure index, which collapses census-tract level data into a single relative measure of exposure ranging from 0-1 (where higher values indicate higher exposure to hazards), includes indicators for major air pollutants and air toxics, features of the built environment, traffic exposures, and social determinants of health (e.g., lower educational attainment) drawn from existing data sources. We observed temporal and geographic variations in index values, with exposures being highest among participants living in the West and Northeast regions. Pregnant people who identified as Black or Hispanic (of any race) were at higher risk of living in a "high" exposure census tract (defined as an index value above 0.5) relative to those who identified as White or non-Hispanic. Index values were also higher for pregnant people with lower educational attainment. Several recommendations follow from our work, including that environmental and social stressor datasets with higher spatial and temporal resolutions are needed to ensure index-based tools fully capture the total environmental context.

Associations between social, biologic, and behavioral factors and biomarkers of oxidative stress during pregnancy: Findings from four ECHO cohorts.

BACKGROUND: Lower 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. METHODS: Leveraging 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. RESULTS: Numerous 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. CONCLUSIONS: Oxidative 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.

Drinking water contaminants in California and hypertensive disorders in pregnancy.

Environmental pollutants have been associated with hypertensive disorders in pregnancy including gestational hypertension, preeclampsia, and eclampsia, though few have focused on drinking water contamination. Water pollution can be an important source of exposures that may contribute to adverse pregnancy outcomes. METHODS: We linked water quality data on 13 contaminants and two violations from the California Communities Environmental Health Screening Tool to birth records from vital statistics and hospital discharge records (2007-2012) to examine the relationship between drinking water contamination and hypertensive disorders in pregnancy. We examined contaminants in single- and multipollutant models. Additionally, we examined if the relationship between water contamination and hypertensive disorders in pregnancy differed by neighborhood poverty, individual socioeconomic status, and race/ethnicity. RESULTS: Arsenic, nitrate, trihalomethane, hexavalent chromium, and uranium were detected in a majority of water systems. Increased risk of hypertensive disorders in pregnancy was modestly associated with exposure to cadmium, lead, trihalomethane, and hexavalent chromium in drinking water after adjusting for covariates in single pollutant models with odds ratios ranging from 1.01 to 1.08. In multipollutant models, cadmium was consistent, lead and trihalomethane were stronger, and additional contaminants were associated with hypertensive disorders in pregnancy including trichloroethylene, 1,2-Dibromo-3-chloropropane, nitrate, and tetrachloroethylene. Other contaminants either showed null results or modest inverse associations. The relationship between water contaminants and hypertensive disorders in pregnancy did not differ by neighborhood poverty. CONCLUSIONS: We found increased risk of hypertensive disorders in pregnancy associated with exposure to several contaminants in drinking water in California. Results for cadmium, lead, trihalomethane, and hexavalent chromium were robust in multipollutant models.

Exposure to formaldehyde and asthma outcomes: A systematic review, meta-analysis, and economic assessment.

BACKGROUND: Every major federal regulation in the United States requires an economic analysis estimating its benefits and costs. Benefit-cost analyses related to regulations on formaldehyde exposure have not included asthma in part due to lack of clarity in the strength of the evidence. OBJECTIVES: 1) To conduct a systematic review of evidence regarding human exposure to formaldehyde and diagnosis, signs, symptoms, exacerbations, or other measures of asthma in humans; and 2) quantify the annual economic benefit for decreases in formaldehyde exposure. METHODS: We developed and registered a protocol in PROSPERO (Record ID #38766, CRD 42016038766). We conducted a comprehensive search of articles published up to April 1, 2020. We evaluated potential risk of bias for included studies, identified a subset of studies to combine in a meta-analysis, and rated the overall quality and strength of the evidence. We quantified economics benefit to children from a decrease in formaldehyde exposure using assumptions consistent with EPA's proposed formaldehyde rule. RESULTS: We screened 4,821 total references and identified 150 human studies that met inclusion criteria; of these, we focused on 90 studies reporting asthma status of all participants with quantified measures of formaldehyde directly relevant to our study question. Ten studies were combinable in a meta-analysis for childhood asthma diagnosis and five combinable for exacerbation of childhood asthma (wheezing and shortness of breath). Studies had low to probably-low risk of bias across most domains. A 10-µg/m3 increase in formaldehyde exposure was associated with increased childhood asthma diagnosis (OR = 1.20, 95% CI: [1.02, 1.41]). We also found a positive association with exacerbation of childhood asthma (OR = 1.08, 95% CI: [0.92, 1.28]). The overall quality and strength of the evidence was rated as "moderate" quality and "sufficient" for asthma diagnosis and asthma symptom exacerbation in both children and adults. We estimated that EPA's proposed rule on pressed wood products would result in 2,805 fewer asthma cases and total economic benefit of $210 million annually. CONCLUSION: We concluded there was "sufficient evidence of toxicity" for associations between exposure to formaldehyde and asthma diagnosis and asthma symptoms in both children and adults. Our research documented that when exposures are ubiquitous, excluding health outcomes from benefit-cost analysis can underestimate the true benefits to health from environmental regulations.

Racial and geographic variation in effects of maternal education and neighborhood-level measures of socioeconomic status on gestational age at birth: Findings from the ECHO cohorts.

Preterm birth occurs at excessively high and disparate rates in the United States. In 2016, the National Institutes of Health (NIH) launched the Environmental influences on Child Health Outcomes (ECHO) program to investigate the influence of early life exposures on child health. Extant data from the ECHO cohorts provides the opportunity to examine racial and geographic variation in effects of individual- and neighborhood-level markers of socioeconomic status (SES) on gestational age at birth. The objective of this study was to examine the association between individual-level (maternal education) and neighborhood-level markers of SES and gestational age at birth, stratifying by maternal race/ethnicity, and whether any such associations are modified by US geographic region. Twenty-six ECHO cohorts representing 25,526 mother-infant pairs contributed to this disseminated meta-analysis that investigated the effect of maternal prenatal level of education (high school diploma, GED, or less; some college, associate's degree, vocational or technical training [reference category]; bachelor's degree, graduate school, or professional degree) and neighborhood-level markers of SES (census tract [CT] urbanicity, percentage of black population in CT, percentage of population below the federal poverty level in CT) on gestational age at birth (categorized as preterm, early term, full term [the reference category], late, and post term) according to maternal race/ethnicity and US region. Multinomial logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CIs). Cohort-specific results were meta-analyzed using a random effects model. For women overall, a bachelor's degree or above, compared with some college, was associated with a significantly decreased odds of preterm birth (aOR 0.72; 95% CI: 0.61-0.86), whereas a high school education or less was associated with an increased odds of early term birth (aOR 1.10, 95% CI: 1.00-1.21). When stratifying by maternal race/ethnicity, there were no significant associations between maternal education and gestational age at birth among women of racial/ethnic groups other than non-Hispanic white. Among non-Hispanic white women, a bachelor's degree or above was likewise associated with a significantly decreased odds of preterm birth (aOR 0.74 (95% CI: 0.58, 0.94) as well as a decreased odds of early term birth (aOR 0.84 (95% CI: 0.74, 0.95). The association between maternal education and gestational age at birth varied according to US region, with higher levels of maternal education associated with a significantly decreased odds of preterm birth in the Midwest and South but not in the Northeast and West. Non-Hispanic white women residing in rural compared to urban CTs had an increased odds of preterm birth; the ability to detect associations between neighborhood-level measures of SES and gestational age for other race/ethnic groups was limited due to small sample sizes within select strata. Interventions that promote higher educational attainment among women of reproductive age could contribute to a reduction in preterm birth, particularly in the US South and Midwest. Further individual-level analyses engaging a diverse set of cohorts are needed to disentangle the complex interrelationships among maternal education, neighborhood-level factors, exposures across the life course, and gestational age at birth outcomes by maternal race/ethnicity and US geography.

Multilevel social factors and NICU quality of care in California.

OBJECTIVE: Our objective was to incorporate social and built environment factors into a compendium of multilevel factors among a cohort of very low birth weight infants to understand their contributions to inequities in NICU quality of care and support providers and NICUs in addressing these inequities via development of a health equity dashboard. STUDY DESIGN: We examined bivariate associations between NICU patient pool and NICU catchment area characteristics and NICU quality of care with data from a cohort of 15,901 infants from 119 NICUs in California, born 2008-2011. RESULT: NICUs with higher proportion of minority racial/ethnic patients and lower SES patients had lower quality scores. NICUs with catchment areas of lower SES, higher composition of minority residents, and more household crowding had lower quality scores. CONCLUSION: Multilevel social factors impact quality of care in the NICU. Their incorporation into a health equity dashboard can inform providers of their patients' potential resource needs.

Environmental pollution and social factors as contributors to preterm birth in Fresno County.

BACKGROUND: Environmental pollution exposure during pregnancy has been identified as a risk factor for preterm birth. Most studies have evaluated exposures individually and in limited study populations. METHODS: We examined the associations between several environmental exposures, both individually and cumulatively, and risk of preterm birth in Fresno County, California. We also evaluated early (< 34 weeks) and spontaneous preterm birth. We used the Communities Environmental Health Screening Tool and linked hospital discharge records by census tract from 2009 to 2012. The environmental factors included air pollution, drinking water contaminants, pesticides, hazardous waste, traffic exposure and others. Social factors, including area-level socioeconomic status (SES) and race/ethnicity were also evaluated as potential modifiers of the relationship between pollution and preterm birth. RESULTS: In our study of 53,843 births, risk of preterm birth was associated with higher exposure to cumulative pollution scores and drinking water contaminants. Risk of preterm birth was twice as likely for those exposed to high versus low levels of pollution. An exposure-response relationship was observed across the quintiles of the pollution burden score. The associations were stronger among early preterm births in areas of low SES. CONCLUSIONS: In Fresno County, we found multiple pollution exposures associated with increased risk for preterm birth, with higher associations among the most disadvantaged. This supports other evidence finding environmental exposures are important risk factors for preterm birth, and furthermore the burden is higher in areas of low SES. This data supports efforts to reduce the environmental burden on pregnant women.

Social disadvantage and the black-white disparity in spontaneous preterm delivery among California births.

We examined the contribution of social disadvantage to the black-white disparity in preterm birth. Analyses included linked vital and hospital discharge records from 127,358 black and 615,721 white singleton California births from 2007-11. Odds ratios (OR) were estimated by 4 logistic regression models for 2 outcomes: early (<32 wks) and moderate (32-36 wks) spontaneous preterm birth (ePTB, mPTB), stratified by 2 race-ethnicity groups (blacks and whites). We then conducted a potential impact analysis. The OR for less than high school education (vs. college degree) was 1.8 (95% confidence interval 1.6, 2.1) for ePTB among whites but smaller for the other 3 outcome groups (ORs 1.3-1.4). For all 4 groups, higher census tract poverty was associated with increased odds (ORs 1.03-1.05 per 9% change in poverty). Associations were less noteworthy for the other variables (payer, and tract percent black and Gini index of income inequality). Setting 3 factors (education, poverty, payer) to 'favorable' values was associated with lower predicted probability of ePTB (25% lower among blacks, 31% among whites) but a 9% higher disparity, compared to probabilities based on observed values; for mPTB, respective percentages were 28% and 13% lower probability, and 17% lower disparity. Results suggest that social determinants contribute to preterm delivery and its disparities, and that future studies should focus on ePTB and more specific factors related to social circumstances.