Publications by authors named "Emily Oken"

394 Publications

Association of Mode of Obstetric Delivery With Child and Adolescent Body Composition.

JAMA Netw Open 2021 Oct 1;4(10):e2125161. Epub 2021 Oct 1.

Department of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts.

Importance: Although the literature on the association between birth by cesarean delivery and children's anthropometry has continued to increase, only a few studies have examined the association of cesarean delivery with measures of body composition assessed using dual-energy x-ray absorptiometry (DXA), which allows the differentiation of fat and lean mass overall and in specific regions of the body.

Objective: To investigate whether differences exist in DXA-measured body composition between children and adolescents born by cesarean delivery and those born by vaginal delivery.

Design, Setting, And Participants: This prospective cohort study included singleton children of mothers enrolled between April 1999 and July 2002 in Project Viva, a longitudinal prebirth cohort of mother-child pairs in Massachusetts. The children had at least 1 DXA scan at a follow-up visit during middle childhood (2007-2010) and/or early adolescence (2013-2016). Data analysis was performed from October 16, 2020, to May 9, 2021.

Exposures: Mode of delivery (cesarean vs vaginal).

Main Outcomes And Measures: Total lean mass index, total and truncal fat mass indexes, visceral adipose tissue (VAT), subcutaneous abdominal adipose tissue, and total abdominal adipose tissue (TAAT) were estimated using DXA. Multivariable linear regression models were used to estimate the association between mode of delivery and DXA-derived outcomes with adjustment for confounders. Stabilized inverse probability weights were used to control for potential selection bias owing to loss to follow-up.

Results: A total of 975 mother-child pairs were included in the study. The mean (SD) maternal age at study entry was 32.0 (5.5) years, and the mean (SD) self-reported prepregnancy body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) was 25.0 (5.4). Of the children included in the study, 491 (50%) were female; 212 (22%) were born by cesarean delivery and 763 (78%) by vaginal delivery. Body composition in middle childhood as measured by DXA did not differ by mode of delivery. In early adolescence, participants born by cesarean delivery had a significantly greater total lean mass index (β, 0.4; 95% CI, 0.0-0.7), total fat mass index (β, 0.6; 95% CI, 0.1-1.1), truncal fat mass index (β, 0.3; 95% CI, 0.0-0.5), VAT area (β, 4.7; 95% CI, 0.9-8.6), and TAAT area (β, 23.8; 95% CI, 0.8-46.8) in a model adjusted for child sex and age at the time of DXA measurements; maternal age, educational level, race and ethnicity, total gestational weight gain, and smoking status during pregnancy; birth-weight-per-gestational-age z score; and paternal BMI. Associations between mode of delivery and measures of adiposity were found for cesarean deliveries performed in the absence of labor (total fat mass index: β, 1.3; 95% CI, 0.3-2.3; truncal fat mass index: β, 0.6; 95% CI, 0.1-1.0; VAT area: β, 10.7; 95% CI, 3.1-18.3; TAAT area: β, 47.3; 95% CI, 2.3-92.2). There were no associations after adjustment for maternal self-reported prepregnancy BMI (total lean mass index: β, 0.2; 95% CI, -0.1 to 0.6; total fat mass index: β, 0.4; 95% CI, -0.1 to 0.9; truncal fat mass index: β, 0.2; 95% CI, -0.1 to 0.4; VAT area: β, 3.0; 95% CI, -0.6 to 6.7; TAAT area: β, 13.6; 95% CI, -8.2 to 35.3).

Conclusions And Relevance: In this cohort study, adolescents born by cesarean delivery had significantly higher measures of lean mass, fat mass, and central adiposity compared with those born by vaginal delivery, but associations did not remain after adjustment for the mothers' self-reported prepregnancy BMI. The findings suggest that the association between birth by cesarean delivery and adolescent adiposity may partly be explained by maternal self-reported prepregnancy BMI.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.25161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501392PMC
October 2021

Associations of maternal non-nutritive sweetener intake during pregnancy with offspring body mass index and body fat from birth to adolescence.

Int J Obes (Lond) 2021 Oct 5. Epub 2021 Oct 5.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.

Background/objective: The evidence that maternal non-nutritive sweetener (NNS) intake during pregnancy increases childhood obesity risk is conflicting. A potential reason for this is that all prior studies examined childhood body mass index (BMI) at only one timepoint and at different ages. We examined the extent to which NNS intake during pregnancy is associated with offspring BMI z-score and body fat longitudinally from birth to 18 years.

Subjects: A total of 1683 children from Project Viva, a prospective pre-birth cohort, were recruited from 1999 to 2002 in Massachusetts.

Methods: We assessed maternal NNS intake in the first and second trimesters of pregnancy using a semiquantitative food frequency questionnaire. Our outcomes were offspring BMI z-score, (at birth, infancy (median 6.3 months), early childhood (3.2 years), mid-childhood (7.7 years), and early adolescence (12.9 years)), sum of skinfolds (SS), fat mass index (FMI) measured by dual x-ray absorptiometry, and BMI z-score trajectory from birth to 18 years. We adjusted models for maternal pre-pregnancy BMI, age, race/ethnicity, education, parity, pre-pregnancy physical activity, smoking, and paternal BMI and education.

Results: A total of 70% of mothers were white and pre-pregnancy BMI was 24.6 ± 5.2 kg/m. The highest quartile of NNS intake (Q4: 0.98 ± 0.91 servings/day) was associated with higher BMI z-score in infancy (β 0.20 units; 95% CI 0.02, 0.38), early childhood (0.21; 0.05, 0.37), mid-childhood (0.21; 0.02, 0.40), and early adolescence (0.14; -0.07, 0.35) compared with Q1 intake (Q1: 0.00 ± 0.00 servings/day). Q4 was also associated with higher SS in early childhood (1.17 mm; 0.47, 1.88), mid-childhood (2.33 mm; 0.80, 3.87), and early adolescence (2.27 mm; -0.06, 4.60) and higher FMI in mid-childhood (0.26 kg/m; -0.07, 0.59). Associations of maternal NNS intake with offspring BMI z-score became stronger with increasing age from 3 to 18 years (P < 0.0001).

Conclusions: Maternal NNS intake during pregnancy is associated with increased childhood BMI z-score and body fat from birth to teenage years. This is relevant given the escalating obesity epidemic, and popularity of NNS.
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http://dx.doi.org/10.1038/s41366-021-00897-0DOI Listing
October 2021

Prenatal maternal phthalate exposures and trajectories of childhood adiposity from four to twelve years.

Environ Res 2021 Sep 23;204(Pt B):112111. Epub 2021 Sep 23.

Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Background/aim: Adiposity trajectories reflect dynamic process of growth and may predict later life health better than individual measures. Prenatal phthalate exposures may program later childhood adiposity, but findings from studies examining these associations are conflicting. We investigated associations between phthalate biomarker concentrations during pregnancy with child adiposity trajectories.

Methods: We followed 514 mother-child pairs from the Mexico City PROGRESS cohort from pregnancy through twelve years. We measured concentrations of nine phthalate biomarkers in 2nd and 3rd trimester maternal urine samples to create a pregnancy average using the geometric mean. We measured child BMI z-score, fat mass index (FMI), and waist-to-height ratio (WHtR) at three study visits between four and 12 years of age. We identified adiposity trajectories using multivariate latent class growth modeling, considering BMI z-score, FMI, and WHtR as joint indicators of latent adiposity. We estimated associations of phthalates biomarkers with class membership using multinomial logistic regression. We used quantile g-computation to estimate the potential effect of the total phthalate mixture and assessed effect modification by sex.

Results: We identified three trajectories of child adiposity, a "low-stable", a "low-high", and a "high-high" group. A doubling of the sum of di (2-ethylhexyl) phthalate metabolites (ΣDEHP), was associated with 1.53 (1.08, 2.19) greater odds of being in the "high-high" trajectory in comparison to the "low-stable" group, whereas a doubling in di-isononyl phthalate metabolites (ΣDiNP) was associated with 1.43 (1.02, 2.02) greater odds of being in the "low-high" trajectory and mono (carboxy-isononyl) phthalate (MCNP) was associated with 0.66 (0.45, 97) lower odds of being in the "low-high" trajectory. No sex-specific associations or mixture associations were observed.

Conclusions: Prenatal concentrations of urinary DEHP metabolites, DiNP metabolites, and MCNP, a di-isodecyl phthalate metabolite, were associated with trajectories of child adiposity. The total phthalate mixture was not associated with early life child adiposity.
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http://dx.doi.org/10.1016/j.envres.2021.112111DOI Listing
September 2021

DNA methylation changes associated with prenatal mercury exposure: A meta-analysis of prospective cohort studies from PACE consortium.

Environ Res 2021 Sep 22;204(Pt B):112093. Epub 2021 Sep 22.

Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain; Spanish Consortium for Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain.

Mercury (Hg) is a ubiquitous heavy metal that originates from both natural and anthropogenic sources and is transformed in the environment to its most toxicant form, methylmercury (MeHg). Recent studies suggest that MeHg exposure can alter epigenetic modifications during embryogenesis. In this study, we examined associations between prenatal MeHg exposure and levels of cord blood DNA methylation (DNAm) by meta-analysis in up to seven independent studies (n = 1462) as well as persistence of those relationships in blood from 7 to 8 year-old children (n = 794). In cord blood, we found limited evidence of differential DNAm at cg24184221 in MED31 (β = 2.28 × 10, p-value = 5.87 × 10) in relation to prenatal MeHg exposure. In child blood, we identified differential DNAm at cg15288800 (β = 0.004, p-value = 4.97 × 10), also located in MED31. This repeated link to MED31, a gene involved in lipid metabolism and RNA Polymerase II transcription function, may suggest a DNAm perturbation related to MeHg exposure that persists into early childhood. Further, we found evidence for association between prenatal MeHg exposure and child blood DNAm levels at two additional CpGs: cg12204245 (β = 0.002, p-value = 4.81 × 10) in GRK1 and cg02212000 (β = -0.001, p-value = 8.13 × 10) in GGH. Prenatal MeHg exposure was associated with DNAm modifications that may influence health outcomes, such as cognitive or anthropometric development, in different populations.
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http://dx.doi.org/10.1016/j.envres.2021.112093DOI Listing
September 2021

Maternal diet quality during pregnancy and child cognition and behavior in a US cohort.

Am J Clin Nutr 2021 Sep 25. Epub 2021 Sep 25.

Dorothy J and Gerald R Friedman School of Nutrition and Science Policy at Tufts University.

Background: Maternal intake of several nutrients during pregnancy is linked to offspring cognition. The relationship between maternal dietary patterns and offspring cognition is less established.

Objective: To examine associations of maternal diet quality during pregnancy with child cognition and behavior.

Design: Among 1580 mother-child pairs in Project Viva, a prospective pre-birth cohort, we assessed maternal diet during pregnancy using food frequency questionnaires and evaluated diet quality using modified versions of the Mediterranean Diet Score (MDS-P) and Alternate Healthy Eating Index (AHEI-P). Child cognitive and behavioral outcomes were assessed using standardized tests and questionnaires at infancy, early and mid-childhood. We conducted multivariable linear regression analyses.

Results: Mothers were predominantly white, college-educated, and non-smokers. After adjustment for child age and sex and maternal sociodemographic and lifestyle characteristics, maternal high (6-9) vs. low (0-3) MDS-P during pregnancy was associated with higher child Kaufman Brief Intelligence Test (KBIT-II) nonverbal (mean difference for first trimester = 4.54; 95%CI: 1.53, 7.56) and verbal scores (3.78; 95%CI: 1.37, 6.19), and lower Behavioral Rating Inventory of Executive Function (BRIEF) Metacognition Index (-1.76; 95%CI: -3.25, -0.27), indicating better intelligence and fewer metacognition problems in mid-childhood. Maternal Q4 vs. Q1 AHEI-P during pregnancy was associated with higher Wide Range Assessment of Visual Motor Abilities matching scores in early childhood (mean difference for first trimester = 2.79; 95%CI: 0.55, 5.04), higher KBIT-II verbal scores (2.59; 95%CI: 0.13, 5.04) and lower BRIEF Global Executive Composite scores in mid-childhood (-1.61; 95%CI: -3.20, -0.01), indicating better visual spatial skills, verbal intelligence and executive function.

Conclusions: Maternal intake of a better quality diet during pregnancy was associated with better visual spatial skills in the offspring at early childhood, and better intelligence and executive function in the offspring at mid-childhood.
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http://dx.doi.org/10.1093/ajcn/nqab325DOI Listing
September 2021

The Role of Childhood Asthma in Obesity Development: A Nationwide U.S. Multi-cohort Study.

Epidemiology 2021 Sep 20. Epub 2021 Sep 20.

Department of Preventive Medicine, University of Southern California, Los Angeles, CA Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD Department of Civil and Environmental Engineering, Northeastern University, Boston, MA Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston MA Department of Pediatrics, Hackensack Meridian School of Medicine, Nutley NJ and the Albert Einstein College of Medicine, Bronx, NY Department of Pediatrics, University of North Carolina School of Medicine, Chapel Hill, NC Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN Departments of Pediatrics and Medicine, The University of Chicago, Chicago, IL University of Colorado, Anschutz Medical Campus, Aurora, CO Nell Hodgson Woodruff School of Nursing and Department of Family & Preventive Medicine, Emory University, Atlanta, GA Avera Research Institute, Sioux Falls, SD Kaiser Permanente Northern California Division of Research Department of Psychology The George Washington University, Washington, DC Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, United States; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA University of California, Davis, School of Medicine, CA Geisel School of Medicine, Dartmouth College, Hanover, NH Department of Pediatrics & Environmental and Occupational Health Sciences, University of Washington, WA Department of Psychiatry and Human Behavior and Department of Pediatrics, Brown Alpert Medical School and Women and Infants Hospital, Providence, RI. Department of Education, University of Oregon, Eugene, OR Division of Pediatric Pulmonary Medicine, Department of Pediatrics, University of Rochester Medical Center, Rochester, NY Department of Pediatrics, Oregon Health and Science University, Portland, OR Division of Clinical Immunology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY Departments of Psychiatry, Psychology, Neuroscience and Obstetrics and Gynecology, University of Rochester, NY Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY Department of Family and Preventive Medicine, University of Utah, Salt Lake City, UT Division of Allergy, Immunology, and Pulmonary Medicine, Department of PediatricsSt. Louis Children's Hospital, Washington University School of Medicine St. Louis, MO Departments of Pediatrics, Environmental Medicine and Population Health, New York University School of Medicine, NY Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY Department of Internal Medicine, University of Utah, Salt Lake City, UT Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY.

Rationale: Asthma and obesity often co-occur. It has been hypothesized that asthma may contribute to childhood obesity onset.

Objectives: To determine if childhood asthma is associated with incident obesity and examine the role of asthma medication in this association.

Methods: We studied 8716 children between ages 6-18.5 years who were non-obese at study entry participating in 18 U.S. cohorts of the Environmental influences on Child Health Outcomes program (among 7299 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: 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%CI: 4%, 44%) higher risk for subsequently developing obesity compared to 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 HR:-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.
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http://dx.doi.org/10.1097/EDE.0000000000001421DOI Listing
September 2021

Impact of paternal education on epigenetic ageing in adolescence and mid-adulthood: a multi-cohort study in the USA and Mexico.

Int J Epidemiol 2021 Sep 17. Epub 2021 Sep 17.

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Background: Both parental and neighbourhood socio-economic status (SES) are linked to poorer health independently of personal SES measures, but the biological mechanisms are unclear. Our objective was to examine these influences via epigenetic age acceleration (EAA)-the discrepancy between chronological and epigenetic ages.

Methods: We examined three USA-based [Coronary Artery Risk Disease in Adults (CARDIA) study, Fragile Families and Child Wellbeing Study (FFCWS) and Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS)] and one Mexico-based (Project Viva) cohort. DNA methylation was measured using Illumina arrays, personal/parental SES by questionnaire and neighbourhood disadvantage from geocoded address. In CARDIA, we examined the most strongly associated personal, parental and neighbourhood SES measures with EAA (Hannum's method) at study years 15 and 20 separately and combined using a generalized estimating equation (GEE) and compared with other EAA measures (Horvath's EAA, PhenoAge and GrimAge calculators, and DunedinPoAm).

Results: EAA was associated with paternal education in CARDIA [GEEs: βsome college = -1.01 years (-1.91, -0.11) and β
Conclusions: These findings suggest that EAA captures epigenetic impacts of paternal education independently of personal SES later in life. Longitudinal studies should explore these associations at different life stages and link them to health outcomes. EAA could be a useful biomarker of SES-associated health and provide important insight into the pathogenesis and prevention of chronic disease.
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http://dx.doi.org/10.1093/ije/dyab196DOI Listing
September 2021

Associations of midchildhood to early adolescence central adiposity gain with cardiometabolic health in early adolescence.

Obesity (Silver Spring) 2021 Sep 16. Epub 2021 Sep 16.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts, USA.

Objective: This study examined the associations of central adiposity gain from midchildhood to early adolescence with cardiometabolic health markers in early adolescence.

Methods: A total of 620 participants were studied in Project Viva. In midchildhood (mean age = 7.8 years) and early adolescence (12.9 years), waist circumference and dual-energy x-ray absorptiometry-measured visceral adipose tissue, subcutaneous abdominal adipose tissue, and trunk fat were obtained. Central adiposity gain was calculated as change per year between visits. Cardiometabolic health markers, including blood pressure, lipids, markers of insulin resistance, inflammation, and adipokines, were collected in early adolescence.

Results: Greater waist circumference gain was associated with higher log triglycerides (β 0.07 mg/dL; 95% CI: 0.02-0.13), log alanine aminotransferase (0.07 U/L; 95% CI: 0.03-0.12), log high-sensitivity C-reactive protein (0.43 mg/L; 95% CI: 0.28-0.58), and other cardiometabolic markers in early adolescence. Directly measured central adiposity gains were associated with higher systolic blood pressure z score in early adolescence (visceral adipose tissue [0.13 SD units; 95% CI: 0.04-0.23], subcutaneous abdominal adipose tissue [0.18 SD units; 95% CI: 0.04-0.31], and trunk fat [0.21 SD units; 95% CI: 0.06-0.36]). These associations were independent of baseline and change in total adiposity from midchildhood to early adolescence.

Conclusions: Monitoring central adiposity gain may enable identification and intervention in children vulnerable to developing cardiometabolic health risks.
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http://dx.doi.org/10.1002/oby.23261DOI Listing
September 2021

Regional and sociodemographic differences in average BMI among US children in the ECHO program.

Obesity (Silver Spring) 2021 Aug 31. Epub 2021 Aug 31.

Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, USA.

Objective: The aim of this study was to describe the association of individual-level characteristics (sex, race/ethnicity, birth weight, maternal education) with child BMI within each US Census region and variation in child BMI by region.

Methods: This study used pooled data from 25 prospective cohort studies. Region of residence (Northeast, Midwest, South, West) was based on residential zip codes. Age- and sex-specific BMI z scores were the outcome.

Results: The final sample included 14,313 children with 85,428 BMI measurements, 49% female and 51% non-Hispanic White. Males had a lower average BMI z score compared with females in the Midwest (β = -0.12, 95% CI: -0.19 to -0.05) and West (β = -0.12, 95% CI: -0.20 to -0.04). Compared with non-Hispanic White children, BMI z score was generally higher among children who were Hispanic and Black but not across all regions. Compared with the Northeast, average BMI z score was significantly higher in the Midwest (β = 0.09, 95% CI: 0.05-0.14) and lower in the South (β = -0.12, 95% CI: -0.16 to -0.08) and West (β = -0.14, 95% CI: -0.19 to -0.09) after adjustment for age, sex, race/ethnicity, and birth weight.

Conclusions: Region of residence was associated with child BMI z scores, even after adjustment for sociodemographic characteristics. Understanding regional influences can inform targeted efforts to mitigate BMI-related disparities among children.
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http://dx.doi.org/10.1002/oby.23235DOI Listing
August 2021

Analysis of Maternal Prenatal Weight and Offspring Cognition and Behavior: Results From the Promotion of Breastfeeding Intervention Trial (PROBIT) Cohort.

JAMA Netw Open 2021 Aug 2;4(8):e2121429. Epub 2021 Aug 2.

Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.

Importance: Prenatal experiences can influence fetal brain development.

Objective: To examine associations of maternal prenatal body mass index (BMI) with cognition and behavior of offspring born full-term.

Design, Setting, And Participants: This cohort study examined follow-up data from a breastfeeding promotion intervention at 31 hospitals and affiliated polyclinics in the Republic of Belarus. Participants included 11 276 children who were evaluated from birth (1996-1997) to adolescence (2017-2019), with maternal BMI information available in prenatal medical records.

Exposures: Maternal BMI, calculated as weight in kilograms divided by height in meters squared, after 35 weeks gestation; secondary analyses examined maternal BMI at other time points and paternal BMI.

Main Outcomes And Measures: Trained pediatricians assessed child cognition with the Wechsler Abbreviated Scales of Intelligence (WASI) at 6.5 years and the computerized self-administered NeuroTrax battery at 16 years, both with an approximate mean (SD) of 100 (15). Parents and teachers rated behaviors at 6.5 years using the Strengths and Difficulties Questionnaire (SDQ, range 0-40). Mixed-effects linear regression analyses corrected for clustering, adjusted for the randomized intervention group and baseline parental sociodemographic characteristics, and were considered mediation by child BMI.

Results: Among 11 276 participants, 9355 women (83%) were aged 20 to 34 years, 10 128 (89.8%) were married, and 11 050 (98.0%) did not smoke during pregnancy. Each 5-unit increase in of maternal late-pregnancy BMI (mean [SD], 27.2 [3.8]) was associated with lower offspring WASI performance intelligence quotient (IQ) (-0.52 points; 95% CI, -0.87 to -0.17 points) at 6.5 years and lower scores on 5 of 7 NeuroTrax subscales and the global cognitive score at 16 years (-0.67 points; 95% CI, -1.06 to -0.29 points). Results were similar after adjustment for sociodemographic characteristics, pregnancy complications, and paternal BMI and were not mediated by child weight. Higher late pregnancy maternal BMI was also associated with more behavioral problems reported on the SDQ by teachers but not associated with parent-reported behaviors (externalizing behaviors: 0.13 points; 95% CI, 0.02 to 0.24 points; and total difficulties: 0.14 points, 95% CI, -0.02 to 0.30 points). Results were similar for maternal BMI measured in the first trimester or postpartum. In contrast, higher 6.5-year paternal BMI was associated with slightly better child cognition (WASI verbal IQ: 0.42 points; 95% CI, 0.02 to 0.82 points; NeuroTrax executive function score: 0.68 points; 95% CI, 0.24 to 1.12 points) and fewer teacher-reported behavioral problems (total difficulties: -0.29 points; 95% CI, -0.46 to -0.11 points).

Conclusions And Relevance: This cohort study supports findings from animal experiments and human observational studies in settings with higher maternal BMI and obesity rates. Higher maternal prenatal BMI may be associated with poorer offspring brain development, although residual confounding cannot be excluded.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.21429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377565PMC
August 2021

Temporal trends of concentrations of per- and polyfluoroalkyl substances among adults with overweight and obesity in the United States: Results from the Diabetes Prevention Program and NHANES.

Environ Int 2021 12 29;157:106789. Epub 2021 Jul 29.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA. Electronic address:

Background: Understanding the temporal trends and change of concentrations of per- and polyfluoroalkyl substances (PFAS) is important to evaluate the health impact of PFAS at both the individual- and population-level, however, limited information is available for pre-diabetic adults in the U.S.

Objectives: Determine trends and rate of change of plasma PFAS concentrations in overweight or obese U.S. adults and evaluate variation by sex, race/ethnicity, and age.

Methods: We described temporal trends of plasma PFAS concentrations using samples collected in 1996-1998, 1999-2001, and 2011-2012 from 957 pre-diabetic adults enrolled in the Diabetes Prevention Program (DPP) trial and Outcomes Study (DPPOS) and compared to serum concentrations from the National Health and Nutrition Examination Survey (NHANES 1999-2000, 2003-2016, adults with BMI ≥ 24 kg/m). We examined associations between participants' characteristics and PFAS concentrations and estimated the rate of change using repeated measures in DPP/DPPOS assuming a first-order elimination model.

Results: Longitudinal measures of PFAS concentrations in DPP/DPPOS individuals were comparable to NHANES cross-sectional populational means. Plasma concentrations of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid, perfluorohexanesulfonic acid (PFHxS), N-ethyl-perfluorooctane sulfonamido acetic acid (EtFOSAA), and N-methylperfluorooctane sulfonamido acetic acid (MeFOSAA) started to decline after the year 2000 and concentrations of perfluorononanoic acid (PFNA) increased after 2000 and, for NHANES, decreased after 2012. We consistently observed higher PFOS, PFHxS and PFNA among male, compared to female, and higher PFOS and PFNA among Black, compared to white, participants. The estimated time for concentrations to decrease by half ranged from 3.39 years for EtFOSAA to 17.56 years for PFHxS.

Discussion: We observed a downward temporal trend in plasma PFOS concentrations that was consistent with the timing for U.S. manufacturers' phaseout. Male and Black participants consistently showed higher PFOS and PFNA than female and white participants, likely due to differences in exposure patterns, metabolism or elimination kinetics.
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http://dx.doi.org/10.1016/j.envint.2021.106789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490287PMC
December 2021

Early Life Exposure to Green Space and Mid-childhood Cognition in the Project Viva Cohort (Massachusetts, USA).

Am J Epidemiol 2021 Jul 23. Epub 2021 Jul 23.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, Massachusetts, USA.

The association between early life greenness and child cognition is not well understood. Using prospective data from Project Viva (n=857) from 1999 to 2010, we examined associations of early life greenness exposure with mid-childhood cognition. We estimated residential greenness at birth, early childhood (median age 3.1y), and mid-childhood (7.8y) using 30m resolution Landsat satellite imagery [Normalized Difference Vegetation Index]. In early childhood and mid-childhood, we administered standardized assessments of verbal and nonverbal intelligence, visual-motor abilities, and visual memory. We used natural splines to examine associations of early life-course greenness with mid-childhood cognition, adjusting for age, sex, race, income, neighborhood socioeconomic status, maternal intelligence, and parental education. At lower levels of greenness (greenness<0.6), greenness exposure at early childhood was associated with a 0.48% increase in non-verbal intelligence and 2.64% increase in visual memory in mid-childhood. The association between early childhood greenness and mid-childhood visual memory was observed after further adjusting for early childhood cognition and across different methodologies, while the association with non-verbal intelligence was not. No other associations between early life-course greenness and mid-childhood cognition were found. Early childhood greenness was nonlinearly associated with higher mid-childhood visual memory. Our findings highlight the importance of nonlinear associations between greenness and cognition.
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http://dx.doi.org/10.1093/aje/kwab209DOI Listing
July 2021

Dietary fat intake during early pregnancy is associated with cord blood DNA methylation at IGF2 and H19 genes in newborns.

Environ Mol Mutagen 2021 Aug 31;62(7):388-398. Epub 2021 Jul 31.

Division of Environmental Health Sciences, University of California, Berkeley School of Public Health, Berkeley, Berkeley, California, USA.

Maternal fat intake during pregnancy affects fetal growth, but mechanisms underlying this relationship are unclear. We performed an exploratory study of the associations of fat consumption during pregnancy with cord blood DNA methylation of the insulin-like growth factor 2 (IGF2) and H19 genes. We used data from 96 uncomplicated full-term pregnancies of mothers of whom majority had normal body mass index (BMI) (66%) in Project Viva, a prospective pre-birth cohort. We assessed maternal diet with validated food frequency questionnaires during the first and second trimesters and measured DNA methylation in segments of the IGF2- and H19-differentially methylated regions (DMRs) by pyrosequencing DNA extracted from umbilical cord blood samples. Mean (SD) age was 32.8 (4.1) years and prepregnancy BMI was 24.0 (4.4) kg/m . Mean DNA methylation was 56.3% (3.9%) for IGF2-DMR and 44.6% (1.9%) for H19-DMR. Greater first trimester intake of omega-6 polyunsaturated fat (effect per 1% of calories at the expense of carbohydrates) was associated with lower DNA methylation of IGF2-DMR (-1.2%; 95% confidence interval [CI]: -2.2%, -0.2%) and higher DNA methylation at H19-DMR (0.8%; 95% CI: 0.3%, 1.3%). On the other hand, greater first trimester intake of omega-3 polyunsaturated fat was associated with lower DNA methylation of the H19-DMR (-4.3%; 95% CI: -7.9%, -0.8%). We did not find significant associations of IGF2 and H19 methylation with IGF2 cord blood levels. Our findings suggest that early prenatal fat intake (omega-3, omega-6, and saturated fatty acids) may influence DNA methylation at the IGF2 and H19 locus, which could impact fetal development and long-term health.
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http://dx.doi.org/10.1002/em.22452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8364885PMC
August 2021

Prenatal and childhood exposure to per- and polyfluoroalkyl substances (PFAS) and child executive function and behavioral problems.

Environ Res 2021 Jul 6;202:111621. Epub 2021 Jul 6.

Center for Environmental Research and Children's Health, University of California, Berkeley School of Public Health, Berkeley, CA, USA; Division of Epidemiology, University of California, Berkeley School of Public Health, Berkeley, CA, USA.

Early life exposure to per- and polyfluoroalkyl substances (PFAS) may adversely impact neurodevelopment, but epidemiological findings are inconsistent. In the Project Viva pre-birth cohort, we examined associations of prenatal and childhood PFAS plasma concentrations with parent and teacher assessments of children's behavior problems [Strengths and Difficulties Questionnaire (SDQ)] and executive function abilities [Behavior Rating Inventory of Executive Function (BRIEF)] at age 6-10 years (sample sizes 485-933). PFAS concentrations in pregnant Project Viva mothers (in 1999-2002) and children at ages 6-10 (in 2007-10) were similar to concentrations at similar time points in women and children in the nationally representative U.S. National Health and Nutrition Examination Survey. We observed no consistent associations of prenatal PFAS concentrations with behavior or executive function. Childhood concentrations of perfluorooctanoate (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonate (PFHxS), perfluorononanoate (PFNA) and perfluorodecanoate (PFDA) were associated with higher parent-rated SDQ Total Difficulties scores (mean = 6.7, standard deviation (SD) = 4.9), suggesting greater behavioral problems (top (Q4) versus bottom (Q1) quartile PFOA: 1.5, 95% confidence interval (CI): 0.3, 2.7; PFOS: 1.4, 95% CI: 0.3, 2.5; PFHxS: 1.2, 95% CI: 0.1, 2.3; PFNA: 1.2, 95% CI: 0.1, 2.2; PFDA: 1.1, 95% CI: 0.0, 1.1); teacher-rated SDQ scores did not show associations. Higher childhood PFOS was associated with higher (indicating more problems) parent-rated BRIEF General Executive Composite (GEC) scores (standardized to mean = 50, SD = 10) (Q4 vs. Q1: 2.4, 95% CI: 0.2, 4.6), while teacher BRIEF GEC scores indicated more problems among children with higher PFHxS (Q4 vs. Q1: 3.5, 95% CI: -0.8, 6.3). There were no consistent patterns of sexual dimorphism in associations. In a cohort of U.S. children, we observed cross-sectional associations of childhood PFAS concentrations with greater behavioral and executive function problems, but no consistent associations with prenatal PFAS.
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http://dx.doi.org/10.1016/j.envres.2021.111621DOI Listing
July 2021

Genetic Interactions with Intrauterine Diabetes Exposure in Relation to Obesity: The EPOCH and Project Viva Studies.

Pediatr Rep 2021 Jun 1;13(2):279-288. Epub 2021 Jun 1.

Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045, USA.

To examine whether BMI-associated genetic risk variants modify the association of intrauterine diabetes exposure with childhood BMI z-scores, we assessed the interaction between 95 BMI-associated genetic variants and in utero exposure to maternal diabetes among 459 children in the Exploring Perinatal Outcomes among Children historical prospective cohort study (n = 86 exposed; 373 unexposed) in relation to age- and sex-standardized childhood BMI z-scores (mean age = 10.3 years, standard deviation = 1.5 years). For the genetic variants showing a nominally significant interaction, we assessed the relationship in an additional 621 children in Project Viva, which is an independent longitudinal cohort study, and used meta-analysis to combine the results for the two studies. Seven of the ninety-five genetic variants tested exhibited a nominally significant interaction with in utero exposure to maternal diabetes in relation to the offspring BMI z-score in EPOCH. Five of the seven variants exhibited a consistent direction of interaction effect across both EPOCH and Project Viva. While none achieved statistical significance in the meta-analysis after accounting for multiple testing, three variants exhibited a nominally significant interaction with in utero exposure to maternal diabetes in relation to offspring BMI z-score: rs10733682 near (interaction β = 0.39; standard error (SE) = 0.17), rs17001654 near (β = 0.53; SE = 0.22), and rs16951275 near (β = 0.37; SE = 0.17). BMI-associated genetic variants may enhance the association between exposure to in utero diabetes and higher childhood BMI, but larger studies of in utero exposures are necessary to confirm the observed nominally significant relationships.
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http://dx.doi.org/10.3390/pediatric13020036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293453PMC
June 2021

Prospective associations of mid-childhood plasma per- and polyfluoroalkyl substances and pubertal timing.

Environ Int 2021 11 23;156:106729. Epub 2021 Jun 23.

Center for Outcomes Research and Evaluation, Maine Medical Center Research Institute, Portland, ME, USA; Pediatric Endocrinology and Diabetes, Maine Medical Center, Portland, ME, USA.

Background: Exposure to per- and polyfluoroalkyl substances (PFAS) may disrupt pubertal timing. Higher PFAS plasma concentrations have been associated with later pubertal timing in girls, but cross-sectional findings may be explained by reverse causation.

Objectives: To assess prospective associations between PFAS plasma concentrations in mid-childhood and markers of pubertal timing in male and female adolescents.

Methods: We studied 640 children in Project Viva, a Boston-area prospective cohort. We examined associations of plasma concentrations of 6 PFAS measured at mean 7.9 (SD 0.8) years (2007-2010) with markers of pubertal timing. Parents reported a 5-item pubertal development score at early adolescence (mean 13.1 (SD 0.8) years) and reported age at menarche annually. We calculated age at peak height velocity using research and clinical measures of height. We used sex-specific linear and Cox proportional hazards regression to estimate associations of single PFAS with outcomes, and we used Bayesian Kernel Machine Regression (BKMR) to estimate associations of the PFAS mixture with outcomes.

Results: Plasma concentrations were highest for perfluorooctane sulfonate (PFOS) [median (IQR) 6.4(5.6) ng/mL], followed by perfluorooctanoate (PFOA) [4.4(3.0) ng/mL]. In early adolescence, girls were further along in puberty than boys [pubertal development score mean (SD) 2.9 (0.7) for girls and 2.2(0.7) for boys; age at peak height velocity mean (SD) 11.2y (1.0) for girls and 13.1y (1.0) for boys]. PFAS was associated with later markers of pubertal timing in girls only. For example, each doubling of PFOA was associated with lower pubertal development score (-0.18 units; 95% CI: -0.30, -0.06) and older age at peak height velocity (0.23 years; 95% CI: 0.06, 0.40)]. We observed similar associations for PFOS, perfluorodecanoate (PFDA), and the PFAS mixture. PFAS plasma concentrations were not associated with age at menarche or markers of pubertal timing in boys.

Discussion: Higher PFAS plasma concentrations in mid-childhood were associated with later onset of puberty in girls.
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http://dx.doi.org/10.1016/j.envint.2021.106729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380705PMC
November 2021

Prenatal exposure to a mixture of elements and neurobehavioral outcomes in mid-childhood: Results from Project Viva.

Environ Res 2021 10 21;201:111540. Epub 2021 Jun 21.

Department of Environmental Health, Boston University School of Public Health, Boston, MA, USA.

Background: Lead (Pb), manganese (Mn), selenium (Se) and methylmercury (MeHg) can be neurotoxic individually, despite Mn and Se also being essential elements. Little is known about the joint effects of essential and non-essential elements on neurobehavior, particularly for prenatal exposures.

Objectives: To evaluate associations of prenatal exposure to multiple elements with executive function and neurobehavior in children.

Methods: Participants included 1009 mother-child pairs from the Project Viva pre-birth cohort. We estimated maternal erythrocyte Pb, Mn, Se, and Hg concentrations prenatally. In 6-11-year old children (median 7.6 years), parents and teachers rated children's executive function-related behaviors using the Behavior Rating Inventory of Executive Function (BRIEF) Global Executive Composite score and behavioral difficulties using the Strengths and Difficulties Questionnaire (SDQ) total difficulties score. We evaluated associations of element mixtures with neurobehavior using Bayesian kernel machine regression (BKMR), multivariable linear regression, and quantile g-computation.

Results: Median erythrocyte Pb, Mn, Se, and Hg concentrations were 1.1 μg/dL, 33.1 μg/L, 204.5 ng/mL, and 3.1 ng/g, respectively. Findings from BKMR and quantile g-computation models both showed worse (higher) parent-rated BRIEF and SDQ z-scores with higher concentrations of the mixture, although estimates were imprecise. When remaining elements were set at their median within BKMR models, increases in Pb and Se from the 25th to 75th percentile of exposure distributions were associated with 0.08 (95% CI: 0.02, 0.19) and 0.07 (95% CI: 0.03, 0.16) standard deviation increases in parent-rated BRIEF scores, and 0.08 (95% CI: 0.02, 0.17) and 0.05 (95% CI: 0.03, 0.13) standard deviation increases in SDQ scores, respectively. There was no evidence of element interactions.

Discussion: Although associations were small in magnitude, we found a trend of worsening neurobehavioral ratings with increasing prenatal exposure to an element mixture. However, we may be observing a limited range of dose-dependent impacts given the levels of exposure within our population.
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http://dx.doi.org/10.1016/j.envres.2021.111540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502495PMC
October 2021

Early pregnancy exposure to metal mixture and birth outcomes - A prospective study in Project Viva.

Environ Int 2021 11 17;156:106714. Epub 2021 Jun 17.

Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, Berkeley, CA, USA. Electronic address:

Background: Prenatal exposure to metals has been individually associated with birth outcomes. However, little is known about the effect of metal mixture, particularly at low exposure levels.

Objectives: To estimate individual and joint effects of metal mixture components on birth outcomes.

Methods: We used data from 1,391 mother-infant pairs in Project Viva (1999-2002). We measured 11 metals in maternal 1st trimester erythrocyte; abstracted birth weight from medical records; calculated gestational age from last menstrual period or ultrasound; and obtained birth length (n = 729) and head circumference (n = 791) from research measurements. We estimated individual and joint effects of metals using multivariable linear and Bayesian kernel machine regressions.

Results: In both single metal and metal mixture analyses, exposure to higher concentrations of arsenic was associated with lower birth weight in males, zinc with higher head circumference in females, and manganese with higher birth length in sex-combined analysis. We also observed sex-specific metal interactions with birth outcomes. Arsenic and manganese showed a synergistic association with birth weight in males, in whom an interquartile range (IQR) increase in arsenic was associated with 25.3 g (95% CI: -79.9, 29.3), 47.9 g (95% CI: -98.0, 2.1), and 72.2 g (95% CI: -129.8, -14.7) lower birth weight when manganese concentrations were at 25th, 50th, and 75th percentiles, respectively. Lead and zinc showed an antagonistic association with head circumference in males, where an IQR increase in lead was associated with 0.18 cm (95% CI: -0.35, -0.02), 0.10 cm (95% CI: -0.25, 0.04), 0.03 cm (95% CI: -0.2, 0.14) smaller head circumference when zinc concentrations were at 25th, 50th, and 75th percentiles, respectively. Exposure to higher concentrations of arsenic was also associated with lower gestational age in males when concentrations of manganese and lead were higher.

Discussion: Maternal erythrocyte concentrations of arsenic, manganese, lead, and zinc were individually and interactively associated with birth outcomes. The associations varied by infant sex and exposure level of other mixture components.
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http://dx.doi.org/10.1016/j.envint.2021.106714DOI Listing
November 2021

SPR perspectives: Environmental influences on Child Health Outcomes (ECHO) Program: overcoming challenges to generate engaged, multidisciplinary science.

Pediatr Res 2021 Jun 15. Epub 2021 Jun 15.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.

The US National Institutes of Health-funded Environmental influences on Child Health Outcomes (ECHO) Program brings together 69 cohorts and over 57,000 children from across the nation to address five key pediatric outcome areas with high public health impact: pre-, peri-, and postnatal outcomes; upper and lower airway health; obesity; neurodevelopment; and positive health. We describe (1) the ECHO Program infrastructure that was designed to facilitate collaboration across over 1200 investigators and support the development of a cohort-wide data collection protocol and (2) the many challenges that were overcome in rapidly launching this large-scale program. Guided by a commitment to transparency, team science, and end user stakeholder engagement, ECHO successfully launched a unified study protocol and is working across disciplines to generate high-impact, solution-oriented research to improve children's lives for generations to come. IMPACT: Many children in the United States experience chronic health conditions or do not reach their developmental potential. The Environmental influences on Child Health Outcomes (ECHO) Program brings together 69 existing cohort studies comprising over 57,000 children to identify modifiable aspects of the early environment associated with pediatric outcomes with high public health impact: pre-, peri-, and postnatal outcomes; upper and lower airway health; obesity; neurodevelopment; and positive health. We describe the collaborative, team science-informed approach by which over 1200 investigators convened to form the ECHO Program and foster solution-oriented research to improve the health of children for generations to come.
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http://dx.doi.org/10.1038/s41390-021-01598-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204620PMC
June 2021

Early pregnancy essential and non-essential metal mixtures and gestational glucose concentrations in the 2nd trimester: Results from project viva.

Environ Int 2021 10 10;155:106690. Epub 2021 Jun 10.

Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA, USA; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA. Electronic address:

Metals are involved in glucose metabolism, and some may alter glycemic regulation. However, joint effects of essential and non-essential metals on glucose concentrations during pregnancy are unclear. This study explored the joint associations of pregnancy exposures to essential (copper, magnesium, manganese, selenium, zinc) and non-essential (arsenic, barium, cadmium, cesium, lead, mercury) metals with gestational glucose concentrations using 1,311 women enrolled 1999-2002 in Project Viva, a Boston, MA-area pregnancy cohort. The study measured erythrocyte metal concentrations from 1 trimester blood samples and used glucose concentrations measured 1 h after non-fasting 50-gram glucose challenge tests (GCT) from clinical gestational diabetes screening at 26-28 weeks gestation. Bayesian Kernel Machine Regression (BKMR) and quantile-based g-computation were applied to model the associations of metal mixtures-including their interactions-with glucose concentrations post-GCT. We tested for reproducibility of BKMR results using generalized additive models. The BKMR model showed an inverse U-shaped association for barium and a linear inverse association for mercury. Specifically, estimated mean glucose concentrations were highest around 75th percentile of barium concentrations [2.1 (95% confidence interval: -0.2, 4.4) mg/dL higher comparing to the 25th percentile], and each interquartile range increase of erythrocyte mercury was associated with 1.9 mg/dL lower mean glucose concentrations (95% credible interval: -4.2, 0.4). Quantile g-computation showed joint associations of all metals, essential-metals, and non-essential metals on gestational glucose concentrations were all null, however, we observed evidences of interaction for barium and lead. Overall, we found early pregnancy barium and mercury erythrocytic concentrations were associated with altered post-load glucose concentrations in later pregnancy, with potential interactions between barium and lead.
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http://dx.doi.org/10.1016/j.envint.2021.106690DOI Listing
October 2021

Air Pollution, Neonatal Immune Responses, and Potential Joint Effects of Maternal Depression.

Int J Environ Res Public Health 2021 05 11;18(10). Epub 2021 May 11.

Department of Social and Behavioral Sciences, The Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.

Prenatal maternal exposure to air pollution may cause adverse health effects in offspring, potentially through altered immune responses. Maternal psychosocial distress can also alter immune function and may increase gestational vulnerability to air pollution exposure. We investigated whether prenatal exposure to air pollution is associated with altered immune responses in cord blood mononuclear cells (CBMCs) and potential modification by maternal depression in 463 women recruited in early pregnancy (1999-2001) into the Project Viva longitudinal cohort. We estimated black carbon (BC), fine particulate matter (PM), residential proximity to major roadways, and near-residence traffic density, averaged over pregnancy. Women reported depressive symptoms in mid-pregnancy (Edinburgh Postnatal Depression Scale) and depression history by questionnaire. Immune responses were assayed by concentrations of three cytokines (IL-6, IL-10, and TNF-α), in unstimulated or stimulated (phytohemagglutinin (PHA), cockroach extract (Bla g 2), house dust mite extract (Der f 1)) CBMCs. Using multivariable linear or Tobit regression analyses, we found that CBMCs production of IL-6, TNF-a, and IL-10 were all lower in mothers exposed to higher levels of PM during pregnancy. A suggestive but not statistically significant pattern of lower cord blood cytokine concentrations from ever (versus never) depressed women exposed to PM, BC, or traffic was also observed and warrants further study.
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http://dx.doi.org/10.3390/ijerph18105062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150899PMC
May 2021

Maternal Midpregnancy Leptin and Adiponectin Levels as Predictors of Autism Spectrum Disorders: A Prenatal Cohort Study.

J Clin Endocrinol Metab 2021 Sep;106(10):e4118-e4127

Harvard Medical School, Boston, Massachusetts 02115, USA.

Context: Autism spectrum disorders (ASDs) are a group of conditions characterized by impaired social function and repetitive behaviors. Their etiology is largely unknown.

Objective: This work aims to examine the associations of maternal second-trimester and cord blood leptin and adiponectin levels with ASDs in offspring.

Methods: We used data from 1164 mother-child pairs enrolled in Project Viva, a prospective prebirth cohort. We used logistic regression analysis to examine the associations of leptin and adiponectin levels in maternal second-trimester blood and cord blood obtained at birth with ASDs. Additionally, we examined the association of maternal prepregnancy body mass index (BMI) as an exposure. Main outcome measures included doctor-diagnosed ASDs reported by mothers using questionnaires in midchildhood and early adolescence.

Results: The cumulative incidence of ASDs was 3.4%. Maternal prepregnancy BMI (per 5 points) was positively associated with ASDs in a logistic regression model adjusted for maternal race/ethnicity, education, smoking status and child sex (adjusted odds ratio [OR] 1.38; 95% CI, 1.06-1.79). Higher second-trimester adiponectin was associated with lower odds of ASD in offspring (unadjusted OR 0.49; 95% CI, 0.30-0.78; and OR 0.54; 95% CI, 0.32-0.91 after adjusting for maternal race/ethnicity, education, child sex, OR 0.55; 95% CI, 0.33-0.93 after adjusting for BMI, gestational weight gain, gestational diabetes, and smoking status). Maternal leptin and cord blood leptin and adiponectin levels were not associated with ASDs.

Conclusion: Prepregnancy BMI and adiponectin during pregnancy may be useful as a tool to monitor the risk of autism. Increasing adiponectin levels prenatally may play a role in the prevention of ASDs.
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http://dx.doi.org/10.1210/clinem/dgab378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475238PMC
September 2021

Diet and erythrocyte metal concentrations in early pregnancy-cross-sectional analysis in Project Viva.

Am J Clin Nutr 2021 08;114(2):540-549

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.

Background: Dietary sources of metals are not well established among pregnant women in the United States.

Objective: We aimed to perform a diet-wide association study (DWAS) of metals during the first trimester of pregnancy.

Methods: In early pregnancy (11.3 ± 2.8 weeks of gestation), 1196 women from Project Viva (recruited 1999-2002 in eastern Massachusetts) completed a validated FFQ (135 food items) and underwent measurements of erythrocyte metals [arsenic (As), barium, cadmium, cesium (Cs), copper, mercury (Hg), magnesium, manganese, lead (Pb), selenium (Se), zinc]. The DWAS involved a systematic evaluation and visualization of all bivariate relations for each food-metal combination. For dietary items with strong associations with erythrocyte metals, we applied targeted maximum likelihood estimations and substitution models to evaluate how hypothetical dietary interventions would influence metals' concentrations.

Results: Participants' mean ± SD age was 32.5 ± 4.5 y and prepregnancy BMI was 24.8 ± 5.4 kg/m2; they were mostly white (75.9%), college graduates (72.4%), married or cohabitating (94.6%), had a household income >$70,000/y (63.5%), and had never smoked (67.1%). Compared with other US-based cohorts, the overall diet quality of participants was above average, and concentrations of erythrocyte metals were lower. The DWAS identified significant associations of several food items with As, Hg, Pb, Cs, and Se; for example, As was higher for each SD increment in fresh fruit (11.5%; 95% CI: 4.9%, 18.4%), white rice (17.9%; 95% CI: 9.4%, 26.9%), and seafood (50.9%; 95% CI: 42.8%, 59.3%). Following the guidelines for pregnant women to consume ≤3 servings/wk of seafood was associated with lower As (-0.55 ng/g; 95% CI: -0.82, -0.28 ng/g) and lower Hg (-2.67 ng/g; 95% CI: -3.55, -1.80 ng/g). Substituting white rice with bread, pasta, tortilla, and potato was also associated with lower As (35%-50%) and Hg (35%-70%).

Conclusions: Our DWAS provides a systematic evaluation of diet-metals relations. Prenatal diet may be an important source of exposures to metals.
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http://dx.doi.org/10.1093/ajcn/nqab088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326032PMC
August 2021

The associations of phthalate biomarkers during pregnancy with later glycemia and lipid profiles.

Environ Int 2021 10 6;155:106612. Epub 2021 May 6.

School of Global Public Health, New York University, NY, USA.

Background: Pregnancy induces numerous cardiovascular and metabolic changes. Alterations in these sensitive processes may precipitate long-term post-delivery health consequences. Studies have reported associations between phthalates and metabolic complications of pregnancy, but no study has investigated metabolic outcomes beyond pregnancy.

Objectives: To examine associations of exposure to phthalates during pregnancy with post-delivery metabolic health.

Design: We quantified 15 urinary phthalate biomarker concentrations during the second and third trimesters among 618 pregnant women from Mexico City. Maternal metabolic health biomarkers included fasting blood measures of glycemia [glucose, insulin, Homeostatic Model Assessment of Insulin Resistance [HOMA-IR], % hemoglobin A1c (HbA1c%)] and lipids (total, high-density lipoprotein (HDL), low-density lipoprotein (LDL) cholesterol, triglycerides), at 4-5 and 6-8 years post-delivery. To estimate the influence of the phthalates mixture, we used Bayesian weighted quantile sum regression and Bayesian kernel machine regression; for individual biomarkers, we used linear mixed models.

Results: As a mixture, higher urinary phthalate biomarker concentrations during pregnancy were associated with post-delivery concentrations of plasma glucose (interquartile range [IQR] difference: 0.13 SD, 95%CrI: 0.05, 0.20), plasma insulin (IQR difference: 0.06 SD, 95%CrI: -0.02, 0.14), HOMA-IR (IQR difference: 0.08 SD, 95% CrI: 0.01, 0.16), and HbA1c% (IQR difference: 0.15 SD, 95%CrI: 0.05, 0.24). Associations were primarily driven by mono-2-ethyl-5-carboxypentyl terephthalate (MECPTP) and the sum of dibutyl phthalate biomarkers (∑DBP). The phthalates mixture was associated with lower HDL (IQR difference: -0.08 SD, 95%CrI: -0.16, -0.01), driven by ∑DBP and monoethyl phthalate (MEP), and higher triglyceride levels (IQR difference: 0.15 SD, 95%CrI: 0.08, 0.22), driven by MECPTP and MEP. The overall mixture was not associated with total cholesterol and LDL. However, ∑DBP and MEP were associated with lower and higher total cholesterol, respectively, and MECPTP and ∑DBP were associated with lower LDL.

Conclusions: Phthalate exposure during pregnancy is associated with adverse long-term changes in maternal metabolic health. A better understanding of timing of the exact biological changes and their implications on metabolic disease risk is needed.
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http://dx.doi.org/10.1016/j.envint.2021.106612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292182PMC
October 2021

Contributions of asthma, rhinitis and IgE to exhaled nitric oxide in adolescents.

ERJ Open Res 2021 Apr 19;7(2). Epub 2021 Apr 19.

Division of Pulmonary, Critical Care and Sleep Medicine, Dept of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.

Exhaled nitric oxide fraction ( ) is an indicator of allergic airway inflammation. However, it is unknown how asthma, allergic rhinitis (AR) and allergic sensitisation relate to , particularly among adolescents and in overlapping conditions. We sought to determine the associations between asthma, AR, and aeroallergen immunoglobulin (Ig)E and in adolescents. We measured among 929 adolescents (aged 11-16 years) in Project Viva, an unselected prebirth cohort in Massachusetts, USA. We defined asthma as ever asthma physician diagnosis plus wheezing in the past year or taking asthma medications in the past month, AR as a physician diagnosis of hay fever or AR, and aeroallergen IgE as any IgE >0.35 IU·mL among 592 participants who provided blood samples. We examined associations of asthma, AR and IgE with percent difference in in linear regression models adjusted for sex, race/ethnicity, age and height, maternal education and smoking during pregnancy, and household/neighbourhood demographics. Asthma (14%) was associated with 97% higher (95% CI 70-128%), AR (21%) with 45% higher (95% CI 28-65%), and aeroallergen IgE (58%) with 102% higher (95% CI 80-126%) compared to those without each condition, respectively. In the absence of asthma or AR, aeroallergen IgE was associated with 75% higher (95% CI 52-101), while asthma and AR were not associated with in the absence of IgE. The link between asthma and AR with is limited to those with IgE-mediated phenotypes. may be elevated in those with allergic sensitisation alone, even in the absence of asthma or AR.
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http://dx.doi.org/10.1183/23120541.00945-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053905PMC
April 2021

Residential PM exposure and the nasal methylome in children.

Environ Int 2021 08 16;153:106505. Epub 2021 Apr 16.

Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, MA, USA; Channing Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

Rationale: PMinduced adverse effects on respiratory health may be driven by epigenetic modifications in airway cells. The potential impact of exposure duration on epigenetic alterations in the airways is not yet known.

Objectives: We aimed to study associations of fine particulate matter PM exposure with DNA methylation in nasal cells.

Methods: We conducted nasal epigenome-wide association analyses within 503 children from Project Viva (mean age 12.9 y), and examined various exposure durations (1-day, 1-week, 1-month, 3-months and 1-year) prior to nasal sampling. We used residential addresses to estimate average daily PM at 1 km resolution. We collected nasal swabs from the anterior nares and measured DNA methylation (DNAm) using the Illumina MethylationEPIC BeadChip. We tested 719,075 high quality autosomal CpGs using CpG-by-CpG and regional DNAm analyses controlling for multiple comparisons, and adjusted for maternal education, household smokers, child sex, race/ethnicity, BMI z-score, age, season at sample collection and cell-type heterogeneity. We further corrected for bias and genomic inflation. We tested for replication in a cohort from the Netherlands (PIAMA).

Results: In adjusted analyses, we found 362 CpGs associated with 1-year PM (FDR < 0.05), 20 CpGs passing Bonferroni correction (P < 7.0x10) and 10 Differentially Methylated Regions (DMRs). In 445 PIAMA participants (mean age 16.3 years) 11 of 203 available CpGs replicated at P < 0.05. We observed differential DNAm at/near genes implicated in cell cycle, immune and inflammatory responses. There were no CpGs or regions associated with PM levels at 1-day, 1-week, or 1-month prior to sample collection, although 2 CpGs were associated with past 3-month PM.

Conclusion: We observed wide-spread DNAm variability associated with average past year PM exposure but we did not detect associations with shorter-term exposure. Our results suggest that nasal DNAm marks reflect chronic air pollution exposure.
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http://dx.doi.org/10.1016/j.envint.2021.106505DOI Listing
August 2021

Longitudinal associations of fruit juice intake in infancy with DXA-measured abdominal adiposity in mid-childhood and early adolescence.

Am J Clin Nutr 2021 07;114(1):117-123

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.

Background: Excessive abdominal adiposity is associated with health risks in children and adults. Higher consumption of fruit juice and other sources of fructose has been shown to promote weight gain and specifically visceral adiposity in adulthood.

Objectives: We aimed to examine the longitudinal associations of fruit juice intake in infancy with visceral adiposity in mid-childhood and early adolescence.

Methods: We analyzed data from 783 participants in Project Viva, a US prebirth cohort. Our exposure was fruit juice intake at 1 y old. We measured visceral adipose tissue (VAT), subcutaneous abdominal adipose tissue (SAAT), and total abdominal adipose tissue (TAAT) in mid-childhood (mean age 7.8 ± 0.7 y) and early adolescence (13 ± 0.8 y) using DXA. We examined longitudinal associations of fruit juice intake at 1 y with VAT, SAAT, and TAAT area sex-specific standard deviation scores (SDSs) in mid-childhood and early adolescence using linear mixed models. We adjusted for child age at outcome, sex, race/ethnicity, age and BMI z-score at 1 y-questionnaire, maternal prepregnancy BMI, level of education, and prenatal sugar-sweetened beverage intake, paternal BMI, and median household income at birth.

Results: After adjusting for child and parental covariates, each serving (120 mL) per day of fruit juice intake at 1 y was associated with persistently greater VAT area SDS (β = 0.08; 95% CI: 0.03, 0.13) at both timepoints in boys and girls. The association of fruit juice intake with VAT appeared stronger than that with SAAT (β = 0.05; 95% CI: 0.00, 0.09) and TAAT (β = 0.05; 95% CI: 0.01, 0.10).

Conclusions: Higher fruit juice intake in infancy was associated with greater abdominal adiposity, particularly VAT, in mid-childhood and early adolescence. Our findings support limiting fruit juice intake in infancy, which can have later impact on visceral adiposity in childhood and adolescence.Clinical Trial Registry number: NCT02820402 (https://clinicaltrials.gov/ct2/show/NCT02820402).
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http://dx.doi.org/10.1093/ajcn/nqab043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246602PMC
July 2021

Cesarean delivery and metabolic health and inflammation biomarkers during mid-childhood and early adolescence.

Pediatr Res 2021 Apr 6. Epub 2021 Apr 6.

Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.

Background: We assessed differences in plasma levels of metabolic health and inflammation biomarkers during mid-childhood and early adolescence between children born by cesarean section vs. vaginal delivery.

Methods: Mother-child pairs (N = 942) enrolled during pregnancy in obstetric practices and child follow-up started at birth. Risk biomarkers were assessed in blood samples collected at the mild-childhood (median = 7 years) and early adolescence (median = 13 years) in-person visits.

Results: Two hundred and six children (22%) were born by cesarean section. There were no significant differences in biomarker levels between children born by cesarean and children born vaginally in mid-childhood. However, adolescents born by cesarean section had significantly lower adiponectin [% difference (95% confidence interval (CI)) = -11.3 (-18.1, -4.0) µg/mL] compared to vaginal delivery. We also found some suggestion of higher insulin resistance [insulin levels % difference (95% CI) = 11.5 (-0.40, 25.0) µU/mL and HOMA-IR (homeostatic model assessment of insulin resistance) % difference (95% CI) = 9.1 (-2.30, 21.8) U] in adolescents born by cesarean section compared to those born vaginally.

Conclusions: We found suggestive evidence that adolescents born by cesarean section show differences in certain metabolic health biomarkers relative to adolescents born by vaginal delivery. Further studies are needed to reevaluate these associations since the clinical significance of these differences is unclear.

Impact: Multiple studies show that children born by cesarean section are at higher risk of obesity compared to those born vaginally. It is unclear yet to what extent this elevated risk may extend to a more adverse profile of biomarkers of metabolic health and inflammation. Adolescents born by cesarean section show small differences in adiponectin and insulin relative to adolescents born by vaginal delivery. Adolescents born by cesarean section may be at higher risk to a more adverse profile of biomarkers of metabolic health and inflammation, but the clinical significance of these differences is uncertain.
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http://dx.doi.org/10.1038/s41390-021-01503-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492770PMC
April 2021

DNA methylation architecture of the ACE2 gene in nasal cells of children.

Sci Rep 2021 03 29;11(1):7107. Epub 2021 Mar 29.

Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has led to the global coronavirus disease 2019 (COVID-19) pandemic. SARS-CoV-2 enters cells via angiotensin-Converting Enzyme 2 (ACE2) receptors, highly expressed in nasal epithelium with parallel high infectivity. The nasal epigenome is in direct contact with the environment and could explain COVID-19 disparities by reflecting social and environmental influences on ACE2 regulation. We collected nasal swabs from anterior nares of 547 children, measured DNA methylation (DNAm), and tested differences at 15 ACE2 CpGs by sex, age, race/ethnicity and epigenetic age. ACE2 CpGs were differentially methylated by sex with 12 sites having lower DNAm (mean = 12.71%) and 3 sites greater DNAm (mean = 1.45%) among females relative to males. We observed differential DNAm at 5 CpGs for Hispanic females (mean absolute difference = 3.22%) and lower DNAm at 8 CpGs for Black males (mean absolute difference = 1.33%), relative to white participants. Longer DNAm telomere length was associated with greater ACE2 DNAm at 11 and 13 CpGs among males (mean absolute difference = 7.86%) and females (mean absolute difference = 8.21%), respectively. Nasal ACE2 DNAm differences could contribute to our understanding COVID-19 severity and disparities reflecting upstream environmental and social influences. Findings need to be confirmed among adults and patients with risk factors for COVID-19 severity.
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http://dx.doi.org/10.1038/s41598-021-86494-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007733PMC
March 2021
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