Faculty Bibliography

IMPORTANCE/UNASSIGNED:Gestational environmental chemical exposures are widespread. Some chemicals are known to adversely affect birth outcomes, but many remain understudied. OBJECTIVE/UNASSIGNED:To evaluate associations of gestational exposure to a priori identified chemicals in 10 classes with birth outcomes in a large, diverse US cohort. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:In the prospective Environmental influences on Child Health Outcomes Cohort study, 5318 mother-child pairs were enrolled from January 1, 2000, to December 31, 2021, with data on gestational urinary chemical concentrations, gestational age at birth, and birth weight. Statistical analysis was performed from January 2024 to February 2026. EXPOSURES/UNASSIGNED:In single, midgestation (median, 25 weeks [IQR, 21-30 weeks]) urine samples, concentrations of 113 analytes (chemicals or their metabolites) from 10 chemical classes were simultaneously measured: fungicides and herbicides (n = 11), insecticides (n = 20), halogenated phenols (n = 5), organophosphate esters (n = 10), benzophenones (n = 6), bisphenols (n = 14), parabens (n = 6), antimicrobials (n = 2), phthalates or alternative plasticizers (n = 32), and polycyclic aromatic hydrocarbons (PAHs) (n = 7). MAIN OUTCOMES AND MEASURES/UNASSIGNED:Linear mixed-effects regression models with a random effect for site were used to estimate covariate-adjusted differences in gestational age at birth (days) and birth weight-for-gestational age (BW-GA) z scores per IQR increase in urinary analyte concentrations. In secondary analyses, odds ratios (ORs) for preterm birth and small for gestational age (SGA) were estimated. RESULTS/UNASSIGNED:In the sample of 5318 mother-child pairs, most infants (2667 female [50%]; median gestational age at birth, 39.0 weeks [IQR, 38.0-40.0 weeks]) were born to college-educated (67% [3218 of 4785]), parous (56% [2815 of 5007]) mothers (median age at delivery, 30.7 years [IQR, 26.1-34.3 years]). A total of 43 of 113 analytes (38%) were detected in 50% or more of samples. Multiple phthalates or alternative plasticizers were associated with younger gestational age at birth or lower BW-GA z scores; for example, summed diisononyl phthalate metabolites were associated with a 0.6-day (95% CI, -1.0 to -0.1 days) younger gestational age (preterm birth OR, 1.16 [95% CI, 1.01-1.34]), and summed phthalate or alternative plasticizers were associated with a 0.06 (95% CI, -0.11 to -0.02) lower BW-GA z score (SGA OR, 1.09 [95% CI, 0.93-1.27]). Two halogenated phenols, benzophenone 8, bisphenol F, and several PAHs were associated with lower BW-GA z scores; for example, 1- and 9-hydroxphenanthrene were associated with a 0.04 (95% CI, -0.08 to -0.01) lower BW-GA z score (SGA OR, 1.13 [95% CI, 1.01-1.27]). CONCLUSIONS AND RELEVANCE/UNASSIGNED:This large cohort study of diverse US pregnancies found widespread exposure to 10 classes of environmental chemicals, many of which were associated with differences in gestational age at birth or lower BW-GA z scores. These findings indicate that reducing gestational exposure to chemicals, particularly phthalates or alternative plasticizers and PAHs, could promote healthy deliveries and better child outcomes.

Individuals are exposed to chemicals in daily life. Yet, few studies have examined the long-lasting joint effect of prenatal and childhood exposure to endocrine-disrupting chemical (EDC) on cognitive performance. We analyzed data from mother-child pairs from the Generation R birth cohort (The Netherlands, 2002-2006) with urinary levels of ten phthalate metabolites, bisphenol A, and five nonspecific organophosphate pesticides metabolites three times during pregnancy (n = 565) and at 5 years of age (n = 539). Child cognitive performance was assessed using the vocabulary, matrix reasoning, digit span, and coding subtests of the Wechsler Intelligence Scale at 13 years. Using hierarchical Bayesian kernel machine regression, we found that prenatal EDC mixture level at 75th percentile versus the median was associated with 0.33 decrease (95% credible interval: -0.60, -0.06) in verbal comprehension and with 0.26 decrease (-0.51, -0.02) in matrix reasoning scores, with di(2-ethyhexyl) phthalate and dibutyl phthalates as primary contributing chemicals to the mixture effect for matrix reasoning. Higher childhood levels of EDC mixture were associated with higher verbal scores, in contrast to the inverse associations observed for prenatal exposure, although this finding should be interpreted with caution due to potential exposure misclassification, selection bias, and residual confounding. Overall, our findings suggest that prenatal exposure to a mixture of plasticizers and pesticides may have a long-lasting adverse effect on offspring's cognition.

OBJECTIVE:Phthalates are recognized endocrine disruptors and emerging neurotoxicants. Prenatal exposure to di-2-ethylhexyl phthalate (DEHP) has been linked to adverse neurodevelopmental and neuropsychiatric outcomes, and maternal oxidative stress may play a mechanistic role in prenatal DEHP's neurotoxicity. MATERIALS AND METHODS/METHODS:Participants were drawn from the New York University Children's Health and Environment Study. Prenatal DEHP exposure and maternal lipid peroxidation were assessed using repeated creatinine-adjusted maternal urinary measurements across pregnancy, collected from January 2016-April 2020. Neonatal brain-derived neurotrophic factor (BDNF) was measured in cord serum (N = 337), and internalizing and externalizing problems were assessed at an average age of 2 years using the Child Behavior Checklist for Ages 1.5-5 (CBCL 1½-5) (N = 824). DEHP metabolites (mEHHP; mEOHP; mECPP) were averaged across pregnancy, and cumulative lipid peroxidation biomarkers (8-iso-PGF2α; 15-PGF2α; 8,15-PGF2α; MDA) were estimated using area-under-the-curve values from linear mixed-effects spline models. Partial least squares path modeling evaluated direct and indirect associations using latent constructs for DEHP exposure, lipid peroxidation, CBCL 1½-5, and socioeconomic status; other covariates were modeled as single variables. Sex differences were assessed using bootstrapping and sex-stratified models, adjusting for maternal and child age, parity, pre-pregnancy body mass index, cotinine exposure, and socioeconomic status. RESULTS:Prenatal DEHP exposure was positively associated with maternal lipid peroxidation in all models (β's = 0.11-0.27). Sex-stratified analyses showed that prenatal DEHP exposure was positively associated with CBCL 1½-5 in male children only (β = 0.11), but not with BDNF in either sex. Maternal lipid peroxidation was not associated with BDNF or CBCL 1½-5 in either sex. CONCLUSION/CONCLUSIONS:Prenatal DEHP exposure is associated with maternal oxidative stress and total behavioral problems in male children only, but maternal oxidative stress does not mediate these relationships. Alternative upstream mechanisms may underlie both maternal oxidative stress and neurobehavioral outcomes. Future studies should investigate endocrine, metabolic, and epigenetic pathways to clarify DEHP neurotoxicity.

BACKGROUND:Individuals are ubiquitously exposed to bisphenols and phthalates, common plasticizers that may affect neurodevelopment. We examined associations of prenatal and childhood bisphenol and phthalate exposure with internalizing and externalizing problems from early childhood through adolescence. METHODS:Within the Generation R study, prenatal urinary concentrations of bisphenol A (BPA) and phthalate metabolites were assessed in early, mid- and late pregnancy and in childhood at age 6 years. Pregnancy levels were averaged and used in analyses. Internalizing and externalizing problems were reported by parents at child age 3, 6, 10 and 14 years and by children at ages 10 and 14 years. Mother-child dyads with at least one prenatal exposure measure and one internalizing or externalizing problem score during follow-up were included (n = 1361). Among children with childhood exposure measures, n = 651 had at least one internalizing or externalizing problem score. Associations were examined using linear mixed models. Mixture analysis was performed for self-reported scores at age 14 with G-computation. FINDINGS/RESULTS: = 0.12, 95%CI: 0.04, 0.20). No associations with BPA were found. G-computation showed positive, but non-significant, associations for the same metabolites as in single chemical analyses. CONCLUSIONS:Associations of BPA and phthalate exposure with internalizing and externalizing problem scores in adolescents were largely null, associations with childhood phthalate exposure were less consistent and harder to interpret.

BACKGROUND/UNASSIGNED:Phthalates, widely used as plasticizers, have been associated with adverse pregnancy outcomes, including preterm birth (PTB). This analysis quantifies the global burden of PTB associated with exposure to di (2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DINP). METHODS/UNASSIGNED:A disease burden model was constructed using 2018 exposure estimates from available population-level biomonitoring surveys and meta-analyses in regions lacking such surveys. Hazard ratios (HRs) for PTB associated with phthalate exposure were derived from a previous cohort study and applied to regional exposure distributions, and a search from 2016 to 2026 was completed to identify uncertainty intervals for effect estimates. PTB-attributable outcome estimates were obtained from the Institute for Health Metrics and Evaluation's. Phthalate-associated PTB outcomes were calculated using a population attributable fraction approach. FINDINGS/UNASSIGNED:In 2018, 1.97 million DEHP-attributable PTBs (8.74% of global PTBs) were estimated, alongside 74,000 deaths, 6.69 million years of life lost (YLLs) and 1.22 million years of life lived with disability (YLDs). 1.93 million of these incident PTBs, 72,500 deaths, 6.56 million YLLs, and 1.20 million YLDs could be linked to plastics. The highest absolute burden was estimated in the Middle East and South Asia, representing over 54% of estimated attributable PTBs, followed by Africa at 26%. Attributable morbidity and mortality trends differed in accordance with underlying regional patterns of burden. Estimates were similar for DiNP (64,000 deaths, 1.88 million PTB cases, 5.77 YLLs, 1.35 YLDs, and PAF of 8.32%). To account for uncertainties in extrapolating effect estimates from the US, effect estimates from four previous global meta-analyses were also used to calculate uncertainty intervals. Uncertainty intervals revealed as low as 4 times lower estimates for DEHP, and 10 times lower DiNP estimates, highlighting the need for further investigation to refine DiNP associated morbidity and mortality. INTERPRETATION/UNASSIGNED:This model presents the first global estimate of the PTB burden linked to exposure to certain phthalates. Burden was estimated to be disproportionate in South Asia, the Middle East, and Africa. Implementing regulatory measures to limit exposure to phthalates as a class could help reduce the global PTB burden, particularly in and areas with high PTB risk, limited regulations, and growing plastics industries. FUNDING/UNASSIGNED:Funding was provided by Beyond Petrochemicals and National Institutes of Health grant number: P2CES033423.

BACKGROUND:The role of maternal and fetal characteristics in determining kidney size in early childhood remains largely unexplored. This study aims to evaluate the association between birth weight and kidney size in children aged one to six years and explore other children and maternal determinants in a United States cohort. METHODS:We analyzed data from 892 mother-child pairs enrolled in the New York University Children's Health and Environment Study (CHES). Renal sonographic measurements were taken from one to six years of age. Kidney size outcomes included average kidney length, width, depth, total kidney volume (TKV), adjusted kidney length (kidney length/body length), and adjusted TKV (TKV/body surface area). Maternal determinants include age, demographic characteristics, pre-pregnancy BMI, lifestyle, pregnancy complications, and diet during pregnancy. Fetal determinants included sex, birth weight for gestational age z-score, and gestational age at delivery. Anthropometric z change and breastfeeding duration were also considered. Associations were examined using crude and covariate-adjusted linear mixed models. RESULTS:Birth weight z-score and anthropometric z change were observed positively associated with all measures except adjusted kidney length. Female children had smaller average kidney length and TKV, and breastfeeding duration was negatively associated with average kidney depth and TKV. Children of non-Hispanic Black mothers and parous mothers had smaller kidney measures. CONCLUSION/CONCLUSIONS:In NYU CHES, we found that early childhood kidney size measures were consistently influenced by birth weight z-scores and changes in postnatal weight gain z-scores. Additionally, we observed racial differences and the influence of breastfeeding duration on kidney size. TRIAL REGISTRATION/BACKGROUND:Not applicable.

Oxidative stress, an imbalance between reactive oxygen species and antioxidants, has been linked to impaired placental function and suboptimal fetal growth, yet trimester-specific associations remain poorly understood. We examined 561 mother-infant pairs from The Infant Development and Environmental Study (TIDES), measuring maternal urinary biomarkers of DNA oxidation (8- hydroxydeoxyguanosine (8-OHdG)), lipid peroxidation (malondialdehyde (MDA), and F2-isoprostanes), and protein oxidation (dityrosine (diY)) at first and second trimesters. Using generalized linear models, we examined prospective associations between oxidative stress and ultrasound-derived growth velocities. Early pregnancy oxidative stress biomarkers were persistently associated with reduced second and third trimester growth velocities. First trimester lipid peroxidation markers (8-PGF2α, 15-PGF2α, and 8,15-PGF2α) were associated with slower estimated fetal weight growth velocity in both second trimester (-0.81, -0.93, and -1.72 g/week per log-unit increase, respectively) and third trimester (-4.25, -5.60, and -6.74 g/week). Similarly, first trimester 8-OHdG and diY were associated with both second trimester (-1.31 and -1.17 g/week, respectively) and third trimester estimated fetal weight velocity (-8.01 and -6.75 g/week, respectively). Second trimester 8-OHdG and MDA were associated with slower third trimester estimated fetal weight velocity (-8.57 and -9.25 g/week, respectively). These results provide novel insights into trimester-specific associations between oxidative stress and fetal growth.

BACKGROUND:Pregnant women are widely exposed to organophosphate esters (OPEs). Few studies have examined how gestational OPE exposures may influence child growth rates, which are important predictors of subsequent cardiometabolic health. METHODS:Among 4566 mother-child dyads from 14 sites within the Environmental influences on Child Health Outcomes (ECHO) Cohort, we evaluated associations of gestational urinary concentrations of nine OPE metabolites with early and mid-childhood rates of change in age- and sex-standardized weight (WAZ), height (HAZ), and body mass index (BMIZ). Using linear mixed models, we estimated associations between each OPE metabolite and each growth measure separately in early childhood (2-5 years; n = 4321) and mid-childhood (6-10 years; n = 2504). We evaluated effect modification by child sex and maternal pre-pregnancy BMI. RESULTS:. DISCUSSION/CONCLUSIONS:In this large, diverse sample of U.S. children, gestational exposure to OPEs was associated with child growth rates, but the direction and magnitude differed by OPE biomarker and developmental period (early- or mid-childhood).

Environmental exposures can have adverse associations with perinatal health and birth outcomes. This study aimed to identify the overlap and association between urban areas of environmental risk and adverse perinatal health indicator hotspots in New York City. We examined 2101 census tracts representing 575,257 births from 2016 to 2020 recorded by the New York City Bureau of Vital Statistics looking at preterm birth, adolescent pregnancy, and pre-pregnancy obesity rates. The Getis-Ord Gi* statistic was used to identify geospatial hotspots of adverse indicators. We used multivariable logistic regression to assess associations between areas of environmental risk and odds of indicator hotspot status and Poisson regression to assess associations of hotspot overlap. Overall, 54.6% of environmental risk areas were hotspots for at least one adverse perinatal indicator, accounting for 63.7% of preterm birth hotspots, 93.7% of adolescent pregnancy hotspots, and 67.3% of pre-pregnancy obesity hotspots. Compared with non-risk areas, risk areas had greater odds of being a hotspot of preterm birth (aOR = 2.11; 95% CI 1.60-2.78), adolescent pregnancy (aOR = 32.8; 21.8-49.4), and pre-pregnancy obesity (aOR = 3.15; 2.56-3.87). Environmental risk areas were expected to have 3.36 times the number of overlapping hotspots after adjusting for parental birthplace and parity. The overlap between environmental risk areas and hotspots of adverse perinatal health indicators and the associations with individual indicators and overlapping hotspots suggest that environmental risk area designation may be a useful measure of perinatal health vulnerability for targeted community interventions.