How the Environmental influences on Child Health Outcome (ECHO) Cohort can spur discoveries in environmental epidemiology.

NIH's Environmental influences on Child Health Outcome (ECHO) program is an innovative, large, collaborative research initiative whose mission is to enhance the health of children for generations to come. The goal of the ECHO Cohort is to examine effects of a broad array of early environmental exposures on child health and development. It includes longitudinal data and biospecimens from over 100,000 children and family members from diverse settings across the U.S. ECHO investigators have published collaborative analyses showing associations of environmental exposures--primarily in the developmentally sensitive pre-, peri-, and post-natal periods--with preterm birth and childhood asthma, obesity, neurodevelopment, and positive health. Investigators have addressed health disparities, joint effects of environmental and social determinants, and effects of mixtures of chemicals. The ECHO Cohort is now entering its second 7-year cycle (2023-2030), which will add the preconception period to its current focus on prenatal through adolescence. Through a controlled access public use database, ECHO makes its deidentified data available to the general scientific community. ECHO Cohort data provide opportunities to fill major knowledge gaps in in environmental epidemiology, and to inform policies, practices, and programs to enhance child health.

Conceptual models for implementing solution-oriented team science in large research consortia.

Large translational research initiatives can strengthen efficiencies and support science with enhanced impact when practical conceptual models guide their design, implementation, and evaluation. The National Institutes of Health (NIH) Environmental influences on Child Health Outcomes (ECHO) program brings together data from 72 ongoing maternal-child cohort studies - involving more than 50,000 children and over 1200 investigators - to conduct transdisciplinary solution-oriented research that addresses how early environmental exposures influence child health. ECHO uses a multi-team system approach to consortium-wide data collection and analysis to generate original research that informs programs, policies, and practices to enhance children's health. Here, we share two conceptual models informed by ECHO's experiences and the Science of Team Science. The first conceptual model illuminates a system of teams and associated tasks that support collaboration toward shared scientific goals. The second conceptual model provides a framework for designing evaluations for continuous quality improvement of manuscript writing teams. Together, the two conceptual models offer guidance for the design, implementation, and evaluation of translational and transdisciplinary multi-team research initiatives.

Addressing the impact of opioids on women and children.

Women and children bear a substantial part of the burden of opioid overuse in the United States. Opioid use during pregnancy can lead to neonatal opioid withdrawal syndrome, and both the mothers and babies may be at higher risk of opioid use and its consequences later in the life course, setting up intergenerational cycles of opioid overuse. As part of the HEAL (Helping to End Addiction Long-term) Initiative of the National Institutes of Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the Environmental influences on Child Health Outcomes program are together launching observational and intervention research programs to interrupt these cycles, beginning with opportunities in pregnancy and the newborn period. The Eunice Kennedy Shriver National Institute of Child Health and Human Development has also launched programs to find alternatives to opioids for painful conditions in women of reproductive age, including a range of gynecologic conditions. These coordinated efforts promise to help turn the tide against the opioid crisis by providing the necessary evidence to improve care for women and children affected by these substances.

Maternal antibiotic use during pregnancy and childhood obesity at age 5 years.

OBJECTIVE: The benefits of antibiotic treatment during pregnancy are immediate, but there may be long-term risks to the developing child. Prior studies show an association between early life antibiotics and obesity, but few have examined this risk during pregnancy. SUBJECTS: To evaluate the association of maternal antibiotic exposure during pregnancy on childhood BMI-z at 5 years, we conducted a retrospective cohort analysis. Using electronic health record data from seven health systems in PCORnet, a national distributed clinical research network, we included children with same-day height and weight measures who could be linked to mothers with vital measurements during pregnancy. The primary independent variable was maternal outpatient antibiotic prescriptions during pregnancy (any versus none). We examined dose response (number of antibiotic episodes), spectrum and class of antibiotics, and antibiotic episodes by trimester. The primary outcome was child age- and sex-specific BMI-z at age 5 years. RESULTS: The final sample was 53,320 mother-child pairs. During pregnancy, 29.9% of mothers received antibiotics. In adjusted models, maternal outpatient antibiotic prescriptions during pregnancy were not associated with child BMI-z at age 5 years (ß = 0.00, 95% CI -0.03, 0.02). When evaluating timing during pregnancy, dose-response, spectrum and class of antibiotics, there were no associations of maternal antibiotics with child BMI-z at age 5 years. CONCLUSION: In this large observational cohort, provision of antibiotics during pregnancy was not associated with childhood BMI-z at 5 years.

Seasonal and weather variation of sleep and physical activity in 12-14-year-old children.

Background: Understanding variation in physical activity (PA) and sleep is necessary to develop novel intervention strategies targeting adolescents' health behaviors. We examined the extent to which PA and sleep vary by aspects of the physical environment. Participants: We performed a cross-sectional analysis of 669 adolescents in the Project Viva cohort. Methods: We estimated total PA, sleep duration, sleep efficiency, and sleep midpoint timing from wrist accelerometers. We used multivariable linear regression models and generalized estimated equations to assess associations of PA and sleep with season and daily weather conditions obtained from the National Oceanic and Atmospheric Administration archive. Results: Mean age was 12.9 (SD 0.6) years; 51% were female and 68% were white. Mean sleep duration was 466 (SD 42) min per night and total PA was 1,652 (SD 431) counts per min per day. Sleep midpoint time was 41 (95% CI: 27 to 54) min later in summer, 28 (95% CI: -41 to -14) min earlier in spring, and 29 (95% CI: -43 to -15) min earlier in autumn compared to winter. Higher temperature and longer day length both were associated with small reductions of nightly sleep duration. Adolescents were less physically active during winter and on rainy and short sunlight days. There was an inverse U-shaped relationship between PA and mean temperature. Conclusions: Season was associated with large changes in sleep timing, and smaller changes in other sleep and PA measurements. Given the importance of sleep and circadian alignment, future health behavioral interventions may benefit by targeting "season-specific" interventions.

Association of Maternal Prepregnancy Weight with Offspring Adiposity Throughout Adulthood over 37 Years of Follow-up.

OBJECTIVE: This study aimed to determine the relation of maternal prepregnancy weight with offspring BMI across adulthood from almost 40 years of follow-up. METHODS: BMI was measured in Framingham Heart Study Offspring cohort participants between 1971 and 2008. The association of maternal prepregnancy weight category (ascertained via direct measure and questionnaire) with serial offspring BMI, overweight, obesity, and change in BMI over time was tested, adjusted for age, sex, and a BMI genetic risk score; secondary models additionally adjusted for physical activity, dietary factors, smoking, education, and familial relatedness. RESULTS: Among 863 participants at initial assessment (83 exposed and 780 controls), mean (SD) age was 33 (10) years, 53% were female, and mean BMI was 24.5 (4.1) kg/m2 . Exposed offspring BMI was higher at every examination cycle, ranging from 1.5 (0.5) to 3.0 (0.5) kg/m2 (P < 0.001), with larger differences at later assessments. The rate of increase in offspring BMI over time was higher in exposed offspring before the age of 50 years (ß [SE] = 0.07 [0.02] kg/m2 per year; P = 0.004) but not after the age of 50 years (-0.05 [0.04] kg/m2 per year; P = 0.2). CONCLUSIONS: Maternal prepregnancy weight is associated with greater offspring BMI throughout adulthood, with more rapid weight acceleration in early and midadulthood.

Maternal corticotropin-releasing hormone is associated with LEP DNA methylation at birth and in childhood: an epigenome-wide study in Project Viva.

BACKGROUND: Corticotropin-releasing hormone (CRH) plays a central role in regulating the secretion of cortisol which controls a wide range of biological processes. Fetuses overexposed to cortisol have increased risks of disease in later life. DNA methylation may be the underlying association between prenatal cortisol exposure and health effects. We investigated associations between maternal CRH levels and epigenome-wide DNA methylation of cord blood in offsprings and evaluated whether these associations persisted into mid-childhood. METHODS: We investigated mother-child pairs enrolled in the prospective Project Viva pre-birth cohort. We measured DNA methylation in 257 umbilical cord blood samples using the HumanMethylation450 Bead Chip. We tested associations of maternal CRH concentration with cord blood cells DNA methylation, adjusting the model for maternal age at enrollment, education, maternal race/ethnicity, maternal smoking status, pre-pregnancy body mass index, parity, gestational age at delivery, child sex, and cell-type composition in cord blood. We further examined the persistence of associations between maternal CRH levels and DNA methylation in children's blood cells collected at mid-childhood (n = 239, age: 6.7-10.3 years) additionally adjusting for the children's age at blood drawn. RESULTS: Maternal CRH levels are associated with DNA methylation variability in cord blood cells at 96 individual CpG sites (False Discovery Rate <0.05). Among the 96 CpG sites, we identified 3 CpGs located near the LEP gene. Regional analyses confirmed the association between maternal CRH and DNA methylation near LEP. Moreover, higher maternal CRH levels were associated with higher blood-cell DNA methylation of the promoter region of LEP in mid-childhood (P < 0.05, ß = 0.64, SE = 0.30). CONCLUSION: In our cohort, maternal CRH was associated with DNA methylation levels in newborns at multiple loci, notably in the LEP gene promoter. The association between maternal CRH and LEP DNA methylation levels persisted into mid-childhood.

Hepatotoxicity of Statins as Determined by Serum Alanine Aminotransferase in a Pediatric Cohort With Dyslipidemia.

OBJECTIVE: The aim of the study was to evaluate the hepatotoxicity of statins, as determined by serum alanine aminotransferase (ALT), in children and adolescents with dyslipidemia in real-world clinical practice. STUDY DESIGN: Clinical and laboratory data were prospectively collected between September 2010 and March 2014. We compared ALT levels between patients prescribed versus not prescribed 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins), and then compared ALT before and after initiation of statins. RESULTS: Over the 3.5-year observation period, there were 2704 ALT measurements among 943 patients. The mean age was 14 years; 54% were boys, 47% obese, and 208 patients were treated with statins. Median follow-up after first ALT was 18 months. The mean (SD) ALT in statin and non-statin users was 23 (20) U/L and 28 (28) U/L, respectively. In models adjusted for age, sex, and race, ALT was 2.1 U/L (95% CI 0.1 to 4.4; P = 0.04) lower among statin users, which was attenuated after adjustment for weight category. Patients started on statins during the observation period did not demonstrate an increase in ALT over time (ALT 0.9 U/L [95% confidence interval -5.2 to 3.4] increase per year; P = 0.7). CONCLUSIONS: In our study population, we did not observe a higher burden of ALT elevations among pediatric patients on statins as compared to those with dyslipidemia who are not on statins, supporting the hepatic safety of statin use in childhood.

Early Antibiotic Exposure and Weight Outcomes in Young Children.

: media-1vid110.1542/5839981580001PEDS-VA_2018-0290Video Abstract OBJECTIVES: To determine the association of antibiotic use with weight outcomes in a large cohort of children. METHODS: Health care data were available from 2009 to 2016 for 35 institutions participating in the National Patient-Centered Clinical Research Network. Participant inclusion required same-day height and weight measurements at 0 to <12, 12 to <30, and 48 to <72 months of age. We assessed the association between any antibiotic use at <24 months of age with BMI z score and overweight or obesity prevalence at 48 to <72 months (5 years) of age, with secondary assessments of antibiotic spectrum and age-period exposures. We included children with and without complex chronic conditions. RESULTS: Among 1 792 849 children with a same-day height and weight measurement at <12 months of age, 362 550 were eligible for the cohort. One-half of children (52%) were boys, 27% were African American, 18% were Hispanic, and 58% received ≥1 antibiotic prescription at <24 months of age. At 5 years, the mean BMI z score was 0.40 (SD 1.19), and 28% of children had overweight or obesity. In adjusted models for children without a complex chronic condition at 5 years, we estimated a higher mean BMI z score by 0.04 (95% confidence interval [CI] 0.03 to 0.05) and higher odds of overweight or obesity (odds ratio 1.05; 95% CI 1.03 to 1.07) associated with obtaining any (versus no) antibiotics at <24 months. CONCLUSIONS: Antibiotic use at <24 months of age was associated with a slightly higher body weight at 5 years of age.

Supporting healthful lifestyles during pregnancy: a health coach intervention pilot study.

BACKGROUND: Excessive gestational weight gain (GWG) is associated with adverse health outcomes in both the mother and child. Many previous lifestyle interventions in women with excess weight during pregnancy encouraging appropriate GWG have been unsuccessful, and there remains no consensus about the content, format, or theoretical framework of GWG interventions. We assessed the feasibility and acceptability of a remote health coach intervention to promote healthful lifestyle behaviors and appropriate GWG among overweight pregnant women. METHODS: At one northeastern US clinic, we enrolled 30 overweight (pre-pregnancy BMI ≥ 25 kg/m2) pregnant women at a median gestation of 12.5 weeks (IQR: 11-15) into a one-arm trial. We connected participants with a health coach to provide behavioral support to help participants adopt healthful lifestyles during pregnancy. Health coaches contacted participants by phone every 2-3 weeks to monitor goals, and sent emails and text messages between calls. Participants completed baseline (N = 30) and follow-up (N = 26) surveys at the end of the intervention (36 weeks gestation), as well as follow-up phone interviews (N = 18). RESULTS: Among 30 participants, median age was 32 years (IQR: 28-33), median self-reported pre-pregnancy BMI was 27.3 kg/m2 (IQR: 25.7-31.1), and 17/30 were white, 9/30 African-American, and 3/30 Asian. Three-quarters (22/29) of participants completed at least a college degree. Although 25/30 participants reported in baseline surveys that they worried about being able to lose the weight postpartum that they expected to gain during pregnancy, just 12/26 participants reported the same at follow-up (P < 0.001). In follow-up surveys, 21/26 participants reported that health coaches were helpful in keeping them motivated, and 22/26 thought the phone conversations helped them face problems and find solutions. Based on qualitative assessment, several themes emerged in follow-up interviews about the quality of the intervention including accountability and support from health coaches. Participants also expressed desire for more visual resources and integration with standard clinical care to improve the intervention. CONCLUSIONS: We demonstrated feasibility and high participant satisfaction with our remote health coach intervention during pregnancy. We identified areas in which we could refine the intervention for inclusion in a full-scale RCT, such as integration with clinical care and additional visual resources. TRIAL REGISTRATION: Retrospectively registered at ClinicalTrials.gov ( NCT03080064 , 3/14/2017).

Maternal intake of pesticide residues from fruits and vegetables in relation to fetal growth.

OBJECTIVES: To examine the associations of maternal intake of fruits and vegetables (FVs), considering pesticide residue levels, with fetal growth. METHODS: We studied 1777 mothers (1275 white, 502 non-white) and their infants from Project Viva, a prospective pre-birth cohort (1999-2002). We categorized FVs as containing high or low pesticide residues using data from the US Department of Agriculture. We then used a food frequency questionnaire to estimate each participant's intake of high and low pesticide residue FVs in the first and second trimester. The primary outcomes were small-for-gestational-age (SGA; <10th percentile in birth-weight-for-gestational-age), large-for-gestational-age (LGA; ≥10th percentile in birth-weight-for-gestational-age) and preterm birth (gestational age <37 weeks). We also evaluated whether the associations between high pesticide residue FV intake and birth outcomes were modified by race/ethnicity. RESULTS: 5.5% of newborns were SGA, 13.7% were LGA, and 7.3% were preterm. Intakes of high or low pesticide residue FVs, regardless of pregnancy trimester, were not associated with risks of SGA, LGA, or preterm birth. In addition, the associations of high pesticide FV intake with SGA and LGA were not modified by race/ethnicity. However, we observed heterogeneity in the relationship between first trimester high pesticide FV intake and risk of preterm birth by race/ethnicity (P value for interaction = 0.01), although this relationship did not persist after correction for multiple comparisons (Bonferroni corrected level of significance: P < 2.8 × 10-3). CONCLUSIONS: There were no clear associations between high or low pesticide FV intake during pregnancy with SGA, LGA or preterm birth.

Development and testing of a novel survey to assess Stakeholder-driven Community Diffusion of childhood obesity prevention efforts.

BACKGROUND: Involving groups of community stakeholders (e.g., steering committees) to lead community-wide health interventions appears to support multiple outcomes ranging from policy and systems change to individual biology. While numerous tools are available to measure stakeholder characteristics, many lack detail on reliability and validity, are not context specific, and may not be sensitive enough to capture change over time. This study describes the development and reliability of a novel survey to measure Stakeholder-driven Community Diffusion via assessment of stakeholders' social networks, knowledge, and engagement about childhood obesity prevention. METHODS: This study was completed in three phases. Phase 1 included conceptualization and online survey development through literature reviews and expert input. Phase 2 included a retrospective study with stakeholders from two completed whole-of-community interventions. Between May-October 2015, 21 stakeholders from the Shape Up Somerville and Romp & Chomp interventions recalled their social networks, knowledge, and engagement pre-post intervention. We also assessed one-week test-retest reliability of knowledge and engagement survey modules among Shape Up Somerville respondents. Phase 3 included survey modifications and a second prospective reliability assessment. Test-retest reliability was assessed in May 2016 among 13 stakeholders involved in ongoing interventions in Victoria, Australia. RESULTS: In Phase 1, we developed a survey with 7, 20 and 50 items for the social networks, knowledge, and engagement survey modules, respectively. In the Phase 2 retrospective study, Shape Up Somerville and Romp & Chomp networks included 99 and 54 individuals. Pre-post Shape Up Somerville and Romp & Chomp mean knowledge scores increased by 3.5 points (95% CI: 0.35-6.72) and (- 0.42-7.42). Engagement scores did not change significantly (Shape Up Somerville: 1.1 points (- 0.55-2.73); Romp & Chomp: 0.7 points (- 0.43-1.73)). Intraclass correlation coefficients (ICCs) for knowledge and engagement were 0.88 (0.67-0.97) and 0.97 (0.89-0.99). In Phase 3, the modified knowledge and engagement survey modules included 18 and 25 items, respectively. Knowledge and engagement ICCs were 0.84 (0.62-0.95) and 0.58 (0.23-0.86). CONCLUSIONS: The survey measures upstream stakeholder properties-social networks, knowledge, and engagement-with good test-retest reliability. Future research related to Stakeholder-driven Community Diffusion should focus on prospective change and survey validation for intervention effectiveness.

Prenatal n-3 long-chain fatty acid status and offspring metabolic health in early and mid-childhood: results from Project Viva.

Higher maternal and biomarker levels of n-3 long-chain polyunsaturated fatty acids (LCPUFAs) have been associated with improved perinatal outcomes and may also influence offspring metabolic health. Past studies were not powered to examine metabolic outcomes and few have specifically targeted metabolically vulnerable populations. We examined the associations of prenatal n-3 LCPUFA status with markers of metabolic health in early and mid-childhood in the full population as well as stratified by maternal glucose tolerance. Our data consisted of 1418 mother-child dyads from Project Viva, a longitudinal, prospective pre-birth cohort enrolled in eastern Massachusetts. We assessed maternal dietary intake of fish and n-3 LCPUFA in mid-pregnancy using a validated food frequency questionnaire. N-3 LCPUFA levels were quantified in maternal second trimester and umbilical cord plasma using liquid-gas chromatography. We assessed offspring anthropometry, adiposity, and blood pressure at early (median age: 3.2 years) and mid-childhood (median age: 7.7 years); and assayed blood samples collected at these visits for metabolic biomarkers. We report here multivariable effect estimates and 95% CI. Early childhood BMI z-score was on average 0.46 (1.03) units and waist circumference 51.3 (3.7) cm. At mid-childhood these measures were 0.39 (1.00) units and 60.0 (8.3) cm, respectively. Higher cord plasma DHA levels were associated with lower BMI z-score ((Q)uartile 4 vs. Q1: -0.21, 95% CI: -0.38, -0.03), waist circumference (Q4 vs. Q1: -0.63, 95% CI: -1.27, 0.00 cm), and leptin levels (Q4 vs. Q1: -0.36, 95% CI: -0.77, 0.05 ng/mL) in early childhood. These associations were strongest and reached significance in offspring of women with isolated hyperglycemia vs. better or worse glycemic status. Higher maternal DHA + EPA (Q4 vs. Q1: -1.59, 95% CI: -2.80, -0.38 µg/mL) and fish (≥3 vs. 0 portions/week: -2.18, 95% CI: -3.90, -0.47 µg/mL) intake was related to lower adiponectin in early childhood. None of these associations persisted with mid-childhood outcomes. We did not find associations with any of the other outcomes. This study supports early and possibly transient effects of prenatal n-3 LCPUFA status on anthropometric measures and adipokine levels. It also raises the possibility that offspring of women with isolated hyperglycemia derive the most benefits from higher n-3 LCPUFA status.

US adolescents at risk for not meeting physical activity recommendations by season.

BACKGROUND: We sought to identify regional and seasonal variation in not meeting physical activity (PA) recommendations of ≥60 min a day of moderate-to-vigorous PA (MVPA) and 3 h of vigorous PA per week (VPA) in a longitudinal cohort of United States (US) adolescents. METHODS: Participants in the Growing Up Today Study 2, a prospective study of 10,918 adolescents, self-reported season-specific weekly hours of MVPA and VPA from 2004 through 2011. To assess variation in PA by climate, we grouped the contiguous US into nine climatically consistent geographic regions. We also examined MVPA and VPA by season, sex, ethnicity, weight status, and age group. RESULTS: The majority (85%) of adolescents did not meet the MVPA recommendation, and 91% did not meet the VPA recommendation, for one or more seasons over the four study years. Across all climate regions, adolescents were two times more likely to not meet the MVPA recommendation during the winter compared to summer (odds ratio 2.02, 95% confidence interval: 1.96-2.08). CONCLUSION: Regardless of climate region, gender, ethnicity, or age group, adolescents were more likely not to meet MVPA or VPA recommendations in the winter than the summer. Adolescents may benefit from interventions aimed at increasing PA in the winter.