Faculty Bibliography

Acetaminophen is among the most common over-the-counter medications used during pregnancy. Given inconsistent findings from both experimental and epidemiological studies on associations between use and adverse health outcomes, further research is warranted. To address this, our objective was to assess the relationship between prenatal acetaminophen use and birth outcomes. We studied 8957 mother-infant pairs from 36 pediatric study sites participating in the Environmental influences on Child Health Outcomes (ECHO) program. After imputation and inverse probability weighting, we used regression models to examine the relationship between acetaminophen during pregnancy and the following outcomes: (1) preterm birth, (2) birthweight, (3) small-for-gestational age (SGA), and (4) large-for-gestational-age (LGA). Approximately 59% of mothers reported using acetaminophen at any point during their pregnancy (n = 5257). After adjustment for relevant covariates, prenatal acetaminophen use was associated with lower odds of LGA (adjusted odds ratio (aOR): 0.87; 95% CI: 0.79, 0.96). Prenatal acetaminophen use was not associated with preterm birth (aOR: 0.99; 95% CI: 0.86, 1.14), birthweight (aβ: -7.52 g; 95% CI: -27.80, 12.77) or SGA (aOR: 1.02; 95% CI: 0.88, 1.18). Based on these findings, future research should test for dose-response, trimester-specific exposures, and factors affecting individual responses.

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.

Growing evidence links prenatal air pollution with early behavioral outcomes, yet U.S. studies remain sparse. We analyzed data from 8370 mother-child dyads from 28 Environmental influences on Child Health Outcomes (ECHO) Cohort sites. Prenatal nitrogen dioxide (NO₂), fine particulate (PM_2.5), and ozone (O₃) levels were estimated using residential addresses. Caregiver-reported Child Behavior Checklist for ages 1.5-5 (CBCL/1.5-5) assessed internalizing and externalizing problems. Covariate-adjusted linear mixed-effects models estimated associations between pollutants and CBCL/1.5-5 T-scores. Child sex, socioeconomic neighborhood conditions, and prenatal depressive symptoms were evaluated as potential modifiers. Each interquartile range increase in pregnancy-average PM_2.5 was associated with higher externalizing (β_{externalizing} = 0.52, 95% confidence intervals: 0.15-0.90) and internalizing (β_{internalizing} = 0.45, 0.07-0.83) T-scores. Trimester-specific associations were observed: first-trimester PM_2.5 was associated with externalizing (β_{externalizing} = 0.39, 0.08-0.70) and second-trimester PM_2.5 with internalizing (β_{internalizing} = 0.32, 0.01-0.64) T-scores. Third-trimester NO₂ was linked to higher behavioral T-scores (β_{externalizing} = 0.52, 0.03-1.01; β_{internalizing} = 0.51, 0.00-1.01). Associations for O₃ were nonsignificant. Children from the lowest-opportunity neighborhoods exhibited stronger positive associations for NO₂. Males and children whose mothers reported lower prenatal depressive symptoms showed stronger inverse associations for O₃. Overall, prenatal PM_2.5 and NO₂ exposures may be associated with modest increases in early behavioral problems, potentially affecting many children given widespread exposure.

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.

PURPOSE/OBJECTIVE:Our goals were to: 1) examine the occurrence of behavioral and emotional symptoms in children on the autism spectrum in a large national sample, stratifying by sex, and 2) evaluate whether children with increased autism-related social communication deficits also experience more behavioral and emotional problems. METHODS: Participants (n = 7,998) were from 37 cohorts from the Environmental influences on Child Health Outcomes (ECHO) Program. Cross-sectional information on demographic factors, parent-report of an ASD diagnosis by clinician, Social Responsiveness Scale (SRS) scores, and Child Behavior Checklist (CBCL) scores were obtained for children aged 2.5-18 years by surveys. We examined mean differences in CBCL Total Problems and DSM-oriented subscale scores by autism diagnosis and by child sex. Analyses using logistic regression were conducted to examine whether autism was associated with higher CBCL scores. We further examined if these relationships differed by child age category (< 6 years, 6-11 years, 12 + years). The relationships between SRS score and CBCL total and subscale scores were examined using quantile regression models, with analyses adjusted for child sex and age. RESULTS: In ECHO, 553 youth were reported by a parent to have a clinician diagnosis of autism spectrum disorder (ASD) (432 [78%] boys and 121 [22%] girls). Youth on the spectrum had higher mean CBCL raw scores on Total Problems and all DSM-oriented subscales compared to those not on the spectrum (all p < 0.0001). Analyses adjusted for sex and stratified by age group indicated that higher odds of autism diagnosis were associated with total, depression, anxiety, and attention-deficit/hyperactivity disorder (ADHD) scales in the top 30% of the CBCL score distribution. Autistic girls were more likely to have parent-reported depression and anxiety compared to autistic boys. In quantile regression analyses, we observed evidence of stronger associations between SRS and CBCL for those in higher quantiles of CBCL total problems scale score (beta representing 1-unit change in SRS associated with 1-unit increase in CBCL total problems scale score), among children in the 70-90th percentile (β = 1.60, p < 0.01), or top 10th percentile (β = 2.43, p < 0.01) of the CBCL total problems scale score distribution. Similar findings were seen for the DSM-oriented depression, anxiety, and ADHD subscales. CONCLUSION/CONCLUSIONS: Results from this large national sample suggest increased behavioral and emotional problems among autistic children compared to non-autistic children throughout early life. Among children on the spectrum this may warrant increased monitoring for co-occurring behavioral and emotional problems.

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/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.

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.