Faculty Bibliography

Pregnant women are widely exposed to organophosphate (OP) pesticides, which are potentially neurotoxicant for the developing fetus. We aimed to identify principal demographic and dietary predictors of OP pesticide exposure among 450 pregnant women participating in the New York University Children's Health and Environment Study (enrolled 2016-19). Urinary concentrations of six dialkyl phosphate (DAP) metabolites (3 dimethyl (DM) metabolites and 3 diethyl (DE) metabolites) of OP pesticides were determined at three time points across pregnancy. At mid-gestation, the Diet History Questionnaire II was used to assess women's dietary intake over the past year. Demographic characteristics were obtained using questionnaires and/or electronic health records. We used linear mixed models to evaluate the associations of demographic and food groups with DAP metabolite levels, and partial-linear single-index (PLSI) models to analyze the contribution proportions of food groups to DAP metabolite concentrations and the dose-response relationships between them. We observed that pregnant women in NYC had lower levels of OP pesticide metabolites than pregnant populations in Europe, Asia, and other regions in the U.S. Having lower pre-pregnancy body mass index and being Asian, employed, and single were associated with higher DAP metabolite concentrations. Fruit and grain intakes were associated with higher ∑DM, ∑DE, and ∑DAP levels. ∑DE concentrations increased 9.0% (95% confidence interval (CI) = 1.2%, 17.4%) per two-fold increase in dairy consumption, whereas ∑DE concentrations decreased 1.8% (95%CI = -3.1%, -0.4%) per two-fold increase in seafood consumption. The PLSI model indicated that among the food mixture, fruit and grains were the main food groups contributed to higher levels of ∑DAP, while meat contributed to lower levels of ∑DAP. The contribution proportions of fruit, grains, and meat were 18.7%, 17.9%, and 39.3%, respectively. Our results suggest that fruit, grains, and meat are major dietary components associated with OP pesticide exposure in urban pregnant women.

OBJECTIVE:To investigate whether deoxyribonucleic acid (DNA) methylation at birth and in childhood differ by conception using assisted reproductive technologies (ART) or ovulation induction compared with those in children conceived without fertility treatment. DESIGN/METHODS:Upstate KIDS is a matched exposure cohort which oversampled on newborns conceived by treatment. SETTING/METHODS:New York State (excluding New York City). PATIENT(S)/METHODS:This analysis included 855 newborns and 152 children at approximately 9 years of age. INTERVENTION(S)/METHODS:None. MAIN OUTCOME MEASURE(S)/METHODS:DNA methylation levels were measured using the Illumina EPIC platform. Single CpG and regional analyses at imprinting genes were conducted. RESULT(S)/RESULTS:Compared to no fertility treatment, ART was associated with lower mean DNA methylation levels at birth in 11 CpGs (located in/near SYCE1, SPRN, KIAA2013, MYO1D, GET1/WRB-SH4BGR, IGF1R, SORD, NECAB3/ACTL10, and GET1) and higher mean methylation level in 1 CpG (KLK4; all false discovery rate P<.05). The strongest association (cg17676129) was located at SYCE1, which codes for a synaptonemal complex that plays a role in meiosis and therefore infertility. This CpG remained associated with newborn hypomethylation when the analysis was limited to those conceived with ICSI, but this may be because of underlying male infertility. In addition, nine regions in maternally imprinted genes (IGF1R, PPIEL, SVOPL GNAS, L3MBTL, BLCAP, HYMAI/PLAGL1, SNU13, and MEST) were observed to have decreased mean DNA methylation levels among newborns conceived by ART. In childhood, hypomethylation of the maternally imprinted gene, GNAS, persisted. No CpGs or regions were associated with ovulation induction. CONCLUSION(S)/CONCLUSIONS:ART but not ovulation induction was associated with hypomethylation at birth, but only one difference at an imprinting region appeared to persist in childhood.

BACKGROUND:Exposure to phthalates is ubiquitous across the United States. While phthalates have anti-androgenic effects in men, there is little research on their potential impacts on sex hormone concentrations in women and that also take into account menopausal status. METHODS:Cross-sectional data on urinary phthalate metabolites, serum sex hormones, and relevant covariates were obtained from the National Health and Nutrition Examination Survey 2013-14 and 2015-16. Women over the age of 20 who were not pregnant or breastfeeding and had not undergone oophorectomy were included (n = 698 premenopausal, n = 557 postmenopausal). Weighted multivariable linear and Tobit regression models stratified by menopausal status were fit with natural log-transformed phthalate concentrations and sex hormone outcomes adjusting for relevant covariates. RESULTS:Phthalate metabolites were associated with differences in sex hormone concentrations among postmenopausal women only. Di-2-ethylhexyl phthalate (DEHP) was associated with lower serum estradiol and bioavailable testosterone concentrations. Specifically, a doubling of DEHP concentrations was associated with 5.9% (95% Confidence Interval (CI): 0.2%, 11.3%) lower estradiol and 6.2% (95% CI: 0.0%, 12.1%) lower bioavailable testosterone concentrations. In contrast, 1,2-cyclohexane dicarboxylic acid di-isononyl ester (DINCH) was associated with higher free testosterone, bioavailable testosterone, and free androgen index. Finally, di-2-ethylhexyl terephthalate (DEHTP) was associated with a higher testosterone-to-estradiol ratio. None of these results retained statistical significance when adjusted for multiple comparisons. CONCLUSIONS:DEHP, DINCH, and DEHTP were associated with differences in serum sex hormone concentrations among postmenopausal women, highlighting the need for further research into the safety of these chemicals.

IMPORTANCE/OBJECTIVE:Exposure to phthalates may affect fetal growth, but previous studies are inconsistent and have not explored the trimester-specific effects of phthalates on repeated measures of fetal growth. OBJECTIVE:To assess the associations of maternal phthalate metabolites urine concentrations with fetal growth measures and birth outcomes and identify potential windows of vulnerability to exposure. DESIGN/METHODS:Population-based prospective cohort study, the Generation R Study (2002-2006). Data analysis was performed from November 2019 to June 2020. SETTING/METHODS:Rotterdam, the Netherlands. PARTICIPANTS/METHODS:1379 pregnant women. EXPOSURES/UNASSIGNED:Maternal phthalate metabolites urine concentrations in first, second and third trimester. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Fetal head circumference, length and weight measured in the second and third trimester by ultrasound and at birth and preterm birth and small size for gestational age at birth. RESULTS:Higher pregnancy-averaged phthalic acid, low molecular weight phthalate (LMWP), high molecular weight phthalate (HMWP) and di-2-ethylhexylphthalate (DEHP) concentrations tended to be associated with lower fetal weight SDS across gestation. The associations of phthalic acid and LMWP with fetal weight became stronger as pregnancy progressed (differences -0.08 (95% CI -0.14 to -0.02) SDS and -0.09 (95% CI -0.16 to -0.02) SDS at 40 weeks per interquartile range increase in phthalic acid and LMWP, respectively). Higher concentrations of specific LMWP, HMWP and DEHP metabolites were also associated with smaller head circumference and lower length SDS at birth and an increased risk of preterm birth and small size for gestational age at birth (p-values < 0.05). We observed differences by timing of exposure in these associations. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:Higher maternal phthalate metabolites urine concentrations seem to be related with fetal growth restriction and preterm birth. Phthalates may have trimester specific effects on fetal growth and birth outcomes. Further studies are needed to explore the underlying mechanisms and long-term consequences.

OBJECTIVE:The purpose of this study was to investigate the associations of urinary phthalates and bisphenols at age 6 years old with body fat and cardiovascular risk factors at 6 and 10 years and with the change from 6 to 10 years. METHODS:Among 471 Dutch children, the phthalates and bisphenols urinary concentrations at 6 years and BMI, fat mass index, android fat mass, blood pressure, glucose, insulin, and lipids blood concentrations at 6 and 10 years were measured. RESULTS:An interquartile range increase in di-n-octyl phthalate (DNOP) metabolites concentrations at 6 years was associated with an increased risk of overweight at 6 and 10 years (odds ratio: 1.44; 95% CI: 1.11-1.87, and 1.43; 95% CI: 1.09-1.86, respectively). Also, higher DNOP metabolites concentrations were associated with higher fat mass index at 6 years, higher systolic blood pressure at 10 years, a decrease in high-density lipoprotein cholesterol, and an increase in triglycerides concentrations from 6 to 10 years (P < 0.05). Higher total bisphenols and bisphenol A concentrations were associated with a decrease in BMI from 6 to 10 years (P < 0.01). CONCLUSIONS:DNOP metabolites are associated with overweight and an adverse cardiovascular profile in childhood. Total bisphenols and bisphenol A are associated with a decrease in BMI from 6 to 10 years.

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.

OBJECTIVE:We previously found that antibiotic use at <24 months of age was associated with slightly higher body weight at 5 years of age. In this study, we examine associations of early life antibiotic prescriptions with weight outcomes at 108 to 132 months of age ("10 years"). METHODS:We used electronic health record data from 2009 through 2016 from 10 health systems in PCORnet, a national distributed clinical research network. We examined associations of any (vs no) antibiotics at <24 months of age with body mass index z-score (BMI-z) at 10 years adjusted for confounders selected a priori. We further examined dose response (number of antibiotic episodes) and antibiotic spectrum (narrow and broad). RESULTS:Among 56,727 included children, 57% received any antibiotics at <24 months; at 10 years, mean (standard deviation) BMI-z was 0.54 (1.14), and 36% had overweight or obesity. Any versus no antibiotic use at <24 months was associated with a slightly higher BMI-z at 10 years among children without a complex chronic condition (β 0.03; 95% confidence interval [CI] 0.01, 0.05) or with a complex chronic condition (β 0.09; 95% CI 0.03, 0.15). Any versus no antibiotic use was not associated with odds of overweight or obesity at 10 years among children without (odds ratio 1.02; 95% CI 0.97, 1.07) or with a complex chronic condition (odds ratio 1.07; 95% CI 0.96, 1.19). CONCLUSIONS:The small and likely clinically insignificant associations in this study are consistent with our previous 5-year follow-up results, suggesting that, if this relationship is indeed causal, early increases in weight are small but maintained over time.

OBJECTIVE: The aim of this study is to model the association between gestational age at birth and early child development through 3 years of age. STUDY DESIGN/METHODS: Development of 5,868 children in Upstate KIDS (New York State; 2008-2014) was assessed at 7 time points using the Ages and Stages Questionnaire (ASQ). The ASQ was implemented using gestational age corrected dates of birth at 4, 8, 12, 18, 24, 30, and 36 months. Whether children were eligible for developmental services from the Early Intervention Program was determined through linkage. Gestational age was based on vital records. Statistical models adjusted for covariates including sociodemographic factors, maternal smoking, and plurality. RESULTS: Compared with gestational age of 39 weeks, adjusted odds ratios (aOR) and 95% confidence intervals of failing the ASQ for children delivered at <32, 32-34, 35-36, 37, 38, and 40 weeks of gestational age were 5.32 (3.42-8.28), 2.43 (1.60-3.69), 1.38 (1.00-1.90), 1.37 (0.98-1.90), 1.29 (0.99-1.67), 0.73 (0.55-0.96), and 0.51 (0.32-0.82). Similar risks of being eligible for Early Intervention Program services were observed (aOR: 4.19, 2.10, 1.29, 1.20, 1.01, 1.00 [ref], 0.92, and 0.78 respectively for <32, 32-34, 37, 38, 39 [ref], 40, and 41 weeks). CONCLUSION/CONCLUSIONS: Gestational age was inversely associated with developmental delays for all gestational ages. Evidence from our study is potentially informative for low-risk deliveries at 39 weeks, but it is notable that deliveries at 40 weeks exhibited further lower risk.

Declining life expectancy and increasing all-cause mortality in the United States have been associated with unhealthy behaviors, socioecological factors, and preventable disease. A growing body of basic science, clinical research, and population health evidence points to the benefits of healthy behaviors, environments and policies to maintain health and prevent, treat, and reverse the root causes of common chronic diseases. Similarly, innovations in research methodologies, standards of evidence, emergence of unique study cohorts, and breakthroughs in data analytics and modeling create new possibilities for producing biomedical knowledge and clinical translation. To understand these advances and inform future directions research, The Lifestyle Medicine Research Summit was convened at the University of Pittsburgh on December 4-5, 2019. The Summit's goal was to review current status and define research priorities in the six core areas of lifestyle medicine: plant-predominant nutrition, physical activity, sleep, stress, addictive behaviors, and positive psychology/social connection. Forty invited subject matter experts (1) reviewed existing knowledge and gaps relating lifestyle behaviors to common chronic diseases, such as cardiovascular disease, diabetes, many cancers, inflammatory- and immune-related disorders and other conditions; and (2) discussed the potential for applying cutting-edge molecular, cellular, epigenetic and emerging science knowledge and computational methodologies, research designs, and study cohorts to accelerate clinical applications across all six domains of lifestyle medicine. Notably, federal health agencies, such as the Department of Defense and Veterans Administration have begun to adopt "whole-person health and performance" models that address these lifestyle and environmental root causes of chronic disease and associated morbidity, mortality, and cost. Recommendations strongly support leveraging emerging research methodologies, systems biology, and computational modeling in order to accelerate effective clinical and population solutions to improve health and reduce societal costs. New and alternative hierarchies of evidence are also be needed in order to assess the quality of evidence and develop evidence-based guidelines on lifestyle medicine. Children and underserved populations were identified as prioritized groups to study. The COVID-19 pandemic, which disproportionately impacts people with chronic diseases that are amenable to effective lifestyle medicine interventions, makes the Summit's findings and recommendations for future research particularly timely and relevant.