Faculty Bibliography

BACKGROUND:Prenatal phthalate exposure has been linked to reductions in fetal growth in animal and laboratory studies, but epidemiologic evidence is equivocal. OBJECTIVE:Examine the association between prenatal phthalate metabolite mixtures and fetal growth and evaluate whether that association is modified by fetal sex or omega-3 intake during pregnancy. METHODS:Analyses included 604 singleton pregnancies from TIDES, a prospective pregnancy cohort with spot urine samples and questionnaires collected in each trimester. Pregnancy-averaged phthalate exposure estimates were calculated as the geometric means of specific-gravity corrected phthalate metabolites. Fetal growth outcomes included birthweight and length, and ultrasound-derived size and velocity of estimated fetal weight, femur length, abdominal and head circumferences in the second and third trimesters. We used a novel application of quantile g-computation to estimate the joint association between pregnancy-averaged phthalate exposure and fetal growth, and to examine effect modification of that association by infant sex or omega-3 intake during pregnancy. RESULTS:There were few statistically significant differences in birth size and fetal growth by exposure. A one-quartile increase in the phthalate mixture was modestly associated with reduced birthweight(β [95% confidence interval)]: -54.6 [-128.9, 19.7] grams; p = 0.15) and length (-0.2 [-0.6, 0.2] centimeters; p = 0.40). A one-quartile increase in the phthalate mixture was associated with reduced birth length in males (-0.5 [-1.0, 0.0] centimeters) but not for females (0.1 [-0.2, 0.3] centimeters); interaction p = 0.05. The phthalate metabolite mixture was inversely associated with ultrasound-derived fetal growth among those with adequate omega-3 intake. For example, a one-quartile increase in the phthalate mixture was associated with reduced abdominal circumference in the third trimesters in those with adequate omega-3 intake (-3.3 [-6.8, 0.1] millimeters) but not those with inadequate omega-3 intake (1.8 [-0.8, 4.5] millimeters); interaction p = 0.01. CONCLUSION/CONCLUSIONS:Prenatal phthalate exposure was not significantly associated with fetal growth outcomes, with some exceptions for certain subgroups.

Accumulating evidence suggests that maternal exposure to objectively stressful events and subjective distress during pregnancy may have intergenerational impacts on children's mental health, yet evidence is limited. In a multisite longitudinal cohort (N = 454), we used multi-variable linear regression models to evaluate the predictive value of exposure to stressful events and perceived distress in pregnancy for children's internalizing problems, externalizing problems, and adaptive skills at age 4. We also explored two- and three-way interactions between stressful events, distress, and child sex. Both objective and subjective maternal stress independently predicted children's behavior, with more stressful events and higher distress predicting more internalizing and externalizing problems and worse adaptability; stress types did not significantly interact. There was some evidence that more stressful events predicted higher externalizing behaviors only for girls. Three-way interactions were not significant. The current findings highlight the importance of considering the type of stress measurement being used (e.g., counts of objective event exposure or subjective perceptions), suggest prenatal stress effects may be transdiagnostic, and meet calls for rigor and reproducibility by confirming these independent main effects in a relatively large group of families across multiple U.S. regions. Results point to adversity prevention having a two-generation impact and that pre- and postnatal family-focused intervention targets may help curb the rising rates of children's mental health problems.

BACKGROUND:Gender diversity in young adolescents is understudied outside of referral clinics. We investigated gender diversity in an urban, ethnically diverse sample of adolescents from the general population and examined predictors and associated mental health outcomes. METHODS:The study was embedded in Generation R, a population-based cohort of children born between 2002 and 2006 in Rotterdam, the Netherlands (n = 5727). At ages 9-11 and 13-15 years, adolescents and/or their parents responded to two questions addressing children's contentedness with their assigned gender, whether they (a) 'wished to be the opposite sex' and (b) 'would rather be treated as someone from the opposite sex'. We defined 'gender-variant experience' when either the parent or child responded with 'somewhat or sometimes true' or 'very or often true'. Mental health was assessed at 13-15 years, using the Achenbach System of Empirically Based Assessment. RESULTS:Less than 1% of the parents reported that their child had gender-variant experience, with poor stability between 9-11 and 13-15 years. In contrast, 4% of children reported gender-variant experience at 13-15 years. Adolescents who were assigned female at birth reported more gender-variant experience than those assigned male. Parents with low/medium educational levels reported more gender-variant experience in their children than those with higher education. There were positive associations between gender-variant experience and symptoms of anxiety, depression, somatic complaints, rule-breaking, and aggressive behavior as well as attention, social, and thought problems. Similar associations were observed for autistic traits, independent of other mental difficulties. These associations did not differ by assigned sex at birth. CONCLUSIONS:Within this population-based study, adolescents assigned females were more likely to have gender-variant experience than males. Our data suggest that parents may not be aware of gender diversity feelings in their adolescents. Associations between gender diversity and mental health symptoms were present in adolescents.

Fetal growth is affected by exposure to both prenatal stress and environmental contaminants. The attacks on the World Trade Center (WTC) resulted in exposure to chemicals and psychological stress amongst New York City residents. We measured prenatal maternal stress and exposure to persistent organic pollutants (polybrominated diphenyl ethers, polychlorinated biphenyls, and polychlorinated dibenzo-p-dioxins (PCDDs)) in 108 participants from a Columbia University WTC birth cohort. Principal component (PC) analyses were conducted to characterize the mixture of exposure to the three groups of chemicals. We evaluated the associations between geographical exposures (proximity to the WTC disaster) and both chemical exposures (PCs) and stress (demoralization). We then evaluated the effect these exposures (PCs and stress) had on previously reported associations between geographical WTC exposure and birth outcomes (birth weight and birth length) in this study population to understand their individual roles in the observed associations. Geographical exposure via proximity to the WTC was associated with the PC reflecting higher PCDD exposure (PC3) (β = 0.60, 95% CI: 0.03, 1.18 for living/working within 2 miles of the WTC; and β = 0.73, 95% CI = 0.08, 1.38 for living within 2 miles of WTC). Previously reported reductions in birth weight and length associated with WTC proximity (β = -215.2, 95% CI: -416.2, -14.3 and β = -1.47, 95% CI: -2.6, -0.34, respectively) were attenuated and no longer significant for birth weight (β = -156.4, 95% CI: -358.2, 45.4) after adjusting for PC3, suggesting that PCDDs may act as partial mediators in this previously observed association. The results of this study can help focus future research on the long-term health effects of these prenatally exposed populations.

OBJECTIVES/OBJECTIVE:To assess the association between age of juice introduction and child anthropometry after the American Academy of Pediatrics changed their guidelines in 2017 to recommend delaying juice introduction until at least 12 months of age (previously 6 months), citing concerns of weight gain. STUDY DESIGN/METHODS:percentiles. Controlling for sociodemographic characteristics and parental BMI, we assessed the associations of age of juice introduction with child anthropometry. RESULTS:Prevalence of childhood obesity was 16.4% at 2-3 (n=1713) and 22.8% at 7-9 years (n=1283). Juice introduction at <6 versus ≥12 months was associated with higher weight-for-age Z score at 2-3 years (mean difference=0.21; 95% confidence interval 0.04-0.37). At 7-9 years, juice introduction at <6 versus ≥12 months was related to higher BMI-for-age (0.38; 0.12-0.64) and weight-for-age Z scores (0.27; 0.06-0.49). Risk of developing overweight/obesity and obesity was 1.54 (0.99-2.38) and 2.17 (1.11-4.23) times higher among children with juice introduced at <6 months. No associations were found with juice introduced at 6-<12 vs ≥12 months. CONCLUSIONS:Risk of developing overweight/obesity or obesity is higher among children introduced to juice before 6 months of age compared with ≥12 months.

BACKGROUND:Feeding problems are common in early childhood, and some evidence suggests that feeding problems may be associated with psychopathology. Few prospective studies have explored whether toddler feeding problems predict later psychopathology. METHODS:Mothers of 1,136 children from the Upstate KIDS cohort study provided data when children were 2.5 and 8 years of age. Food refusal (picky eating) and mechanical/distress feeding problems and developmental delays were assessed at 2.5 years. Child eating behaviors (enjoyment of food, food fussiness, and emotional under and overeating) and child psychopathology (attention-deficit/hyperactivity (ADHD), oppositional-defiant (OD), conduct disorder (CD), and anxiety/depression) symptoms were assessed at 8 years. RESULTS:Mechanical/distress feeding problems at age 2.5, but not food refusal problems, were associated with ADHD, problematic behavior (OD/CD), and anxiety/depression symptoms at 8 years in models adjusting for eating behaviors at 8 years and child and family covariates. Associations with mechanical/distress feeding problems were larger for ADHD and problematic behavior than anxiety/depression symptoms, though all were modest. Model estimates were similar for boys and girls. CONCLUSIONS:Much of the research on feeding problems focuses on picky eating. This study suggests that early mechanical and mealtime distress problems may serve as better predictors of later psychopathology than food refusal. Parents and pediatricians could monitor children with mechanical/distress feeding problems for signs of developing psychopathology.

RATIONALE/BACKGROUND:Asthma and obesity often co-occur. It has been hypothesized that asthma may contribute to childhood obesity onset. OBJECTIVES/OBJECTIVE:To determine if childhood asthma is associated with incident obesity and examine the role of asthma medication in this association. METHODS:We studied 8,716 children between ages 6 and 18.5 years who were nonobese at study entry participating in 18 US cohorts of the Environmental influences on Child Health Outcomes program (among 7,299 children with complete covariate data mean [SD] study entry age = 7.2 [1.6] years and follow up = 5.3 [3.1] years). MEASUREMENTS AND MAIN RESULTS/RESULTS:We defined asthma based on caregiver report of provider diagnosis. Incident obesity was defined as the first documented body mass index ≥95th percentile for age and sex following asthma status ascertainment. Over the study period, 26% of children had an asthma diagnosis and 11% developed obesity. Cox proportional hazards models with sex-specific baseline hazards were fitted to assess the association of asthma diagnosis with obesity incidence. Children with asthma had a 23% (95% confidence intervals [CI] = 4, 44) higher risk for subsequently developing obesity compared with those without asthma. A novel mediation analysis was also conducted to decompose the total asthma effect on obesity into pathways mediated and not mediated by asthma medication use. Use of asthma medication attenuated the total estimated effect of asthma on obesity by 64% (excess hazard ratios = 0.64; 95% CI = -1.05, -0.23). CONCLUSIONS:This nationwide study supports the hypothesis that childhood asthma is associated with later risk of obesity. Asthma medication may reduce this association and merits further investigation as a potential strategy for obesity prevention among children with asthma.

OBJECTIVE:To estimate the prevalence of perinatal cannabis use (ie, before and/or during pregnancy); document the frequency, modes, and motivations for use; and identify predictors of perinatal cannabis use. METHODS:Six states in the Pregnancy Risk Assessment Monitoring System, a state-specific, population-based surveillance system, administered a supplemental questionnaire on perinatal cannabis use in 2016-2018. Women with live births were surveyed 2-6 months postpartum about behaviors ≤3 months preconception and during pregnancy. Demographic, psychosocial, and behavioral characteristics were examined in relation to perinatal cannabis use using multinomial regression models. Those who: (1) never used cannabis, (2) only used in preconception period, and (3) used in both preconception and prenatal periods were compared. RESULTS:Among 6428 respondents, 379 (5.8%) used cannabis preconceptionally only and 466 (4.4%) used in both the preconception and prenatal periods. Among those using prenatally, most reported smoking as their single mode (87.1%), with the two most common reasons being stress (83.8%) and nausea/vomiting (79.2%). Marital status, race/ethnicity, socioeconomic status, parity, and cigarette and alcohol use were significantly associated with perinatal cannabis use. Single (vs partnered) women were more likely to use cannabis prenatally (odds ratio = 2.4, 95% confidence interval: 1.5, 3.9) and non-Hispanic Black (vs White) women were less likely to use prenatally (odds ratio = 0.4, 95% confidence interval: 0.2, 0.8). CONCLUSIONS:Using a population-based sample of US births in six states, several demographic, psychosocial, and behavioral characteristics were identified in relation to perinatal cannabis use. These data are valuable for counseling in prenatal care and investigations of health effects.

While definitions vary, endocrine-disrupting chemicals (EDCs) have two fundamental features: their disruption of hormone function and their contribution to disease and disability. The unique vulnerability of children to low-level EDC exposures has eroded the notion that only the dose makes the thing a poison, requiring a paradigm shift in scientific and policy practice. In this review, we discuss the unique vulnerability of children as early as fetal life and provide an overview of epidemiological studies on programming effects of EDCs on neuronal, metabolic, and immune pathways as well as on endocrine, reproductive, and renal systems. Building on this accumulating evidence, we dispel and address existing myths about the health effects of EDCs with examples from child health research. Finally, we provide a list of effective actions to reduce exposure, and subsequent harm that are applicable to individuals, communities, and policy-makers. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

CONTEXT/BACKGROUND:Accelerating evidence of endocrine-related morbidity has raised alarm about the ubiquitous use of phthalates in the human environment, but studies have not directly evaluated mortality in relation to these exposures. OBJECTIVES/OBJECTIVE:To evaluate associations of phthalate exposure with mortality, and quantify attributable mortality and lost economic productivity in 2013-4 among 55-64 year olds. DESIGN/METHODS:This nationally representative cohort study included 5303 adults aged 20 years or older who participated in the US National Health and Nutrition Examination Survey 2001-2010 and provided urine samples for phthalate metabolite measurements. Participants were linked to mortality data from survey date through December 31, 2015. Data analyses were conducted in July 2020. MAIN OUTCOME MEASURES/METHODS:Mortality from all causes, cardiovascular disease, and cancer. RESULTS:Multivariable models identified increased mortality in relation to high-molecular weight (HMW) phthalate metabolites, especially those of di-2-ethylhexylphthalate (DEHP). Hazard ratios (HR) for continuous HMW and DEHP metabolites were 1.14 (95% CI 1.06-1.23) and 1.10 (95% CI 1.03-1.19), respectively, with consistently higher mortality in the third tertile (1.48, 95% CI 1.19-1.86; and 1.42, 95% CI 1.13-1.78). Cardiovascular mortality was significantly increased in relation to a prominent DEHP metabolite, mono-(2-ethyl-5-oxohexyl)phthalate. Extrapolating to the population of 55-64 year old Americans, we identified 90,761-107,283 attributable deaths and $39.9-47.1 billion in lost economic productivity. CONCLUSIONS:In a nationally representative sample, phthalate exposures were associated with all-cause and cardiovascular mortality, with societal costs approximating $39 billion/year or more. While further studies are needed to corroborate observations and identify mechanisms, regulatory action is urgently needed.