Environmental Influences on Child Health Outcomes (ECHO) - PATHWAYS - Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE)

Pregnant women are exposed daily to multiple chemical and non-chemical stressors, including air pollutants, phthalates, and psychosocial stress. The Developmental Origins of Health and Disease model (DOHaD) states that exposure to these stressors in pregnancy affects fetal development in a manner that impacts offspring health across the life course. Yet epidemiologic data in these areas is limited, particularly with U.S. samples. It is also poorly understood whether these exposures prenatally affect childhood neurodevelopment and airway health in an independent or combined manner, and likely moderators of effects, such as the sex of the child, are infrequently addressed. We propose to unify three diverse extant pregnancy cohorts: TIDES (N=717, 2010-12), GAPPS (N=1133, 2012-16), and CANDLE (N=1385, 2007-11), for a combined sample size of 3235 mother-child dyads in the PATHWAYS study. PATHWAYS will investigate how chemical (air pollutants and phthalates) and non-chemical (psychosocial stress) exposures during pregnancy are related to placental gene expression (transcriptome) and childhood neurodevelopment and airway health (at ages 4-6, 8-9, and 10-11 years). Each cohort has rich resources of prenatal data and banked specimens (urine, blood, and placenta) that will be harmonized for the PATHWAYS study and will contribute to the ECHO consortium. We will develop a national model with high spatiotemporal resolution of key air pollutants and assess urinary markers of maternal exposure. A composite measure will capture multilevel maternal psychosocial stress across pregnancy, and urinary phthalate and blood stress hormone [Corticotropin-releasing hormone (CRH)] levels in the second and third trimesters will provide individual assessment of those exposures in potential critical periods. We will characterize the placental transcriptome using RNA sequencing (RNA-Seq) and will assess neurodevelopment and airway health prospectively into middle childhood. PATHWAYS will examine how these prenatal exposures are related to the placental transcriptome and child health outcomes in main effect and interactive models, with emphasis on sex-specific associations. For both neurodevelopment and airway health, we propose to measure both phenotypic precursors of health outcomes (i.e. fluid cognition, lung function growth), which yield dimensional tests of proposed associations, as well as clinically meaningful and policy relevant outcomes (i.e. asthma, mental health). Our study is powered to assess interactive effects of chemical and non-chemical stressors and will be the first study to characterize how prenatal environmental exposures relate to placental transcriptome pathways in relation to childhood health outcomes. This represents a significant scientific advance in testing DOHaD hypotheses. Major contributions to the ECHO Consortium include: 1) the development of a state of the art national model of air pollution, 2) a large, diverse pregnancy cohort with extensive biorepositories and extant prenatal and postnatal biomarkers, placental transcriptome, psychosocial and environmental data, and 3) an experienced, interdisciplinary team that will contribute meaningfully to the ECHO program of work.The sequencing data in this submission pertains only to the 794 subjects from the CANDLE study for whom placental tissue transcriptomics was performed. ]]>
The following inclusion/exclusion criteria are based on the CANDLE study, from which the placenta samples were obtained, and is copied verbatim from their whitepaper (https://candlestudy.uthsc.edu/wp-content/uploads/sites/5/2020/06/CANDLE-White-Paper-2015.pdf) The study population included women, recruited during their second trimesters of pregnancy, and the children who were born at the birth visit. The Urban Child Institute (UCI) CANDLE Study considered a woman eligible for participation if she met all the following criteria: was a Shelby County residentwas pregnant between 16 and 28 weeks gestationwas between the ages of 16 and 40could speak and understand Englishhad a singleton pregnancyhad plans to deliver at one of the five participating health care settings in Shelby County. Exclusions chronic hypertension requiring therapy or vascular disease requiring therapymaternal red-cell alloimmunization except Rhesus (Rh) factorhemoglobinopathy, including sickle-cell trait and severe iron-deficiency anemia (hemoglobin less than 9)insulin dependent diabetesappreciable renal or cardiopulmonary diseaseprolapsed or ruptured membranesoligohydramnios; complete placenta previaendocrine diseasecollagen disease (e.g., lupus erythematosus or scleroderma) active or chronic hepatitisrenal diseasepulmonary or heart disease requiring therapeutic medication or limitation of physical activitymajor fetal anomaly (e.g., aneuploidy, major organ-system defect)human immunodeficiency virus. ]]>
The following study history pertains to the CANDLE study, from which the placenta samples were obtained, and is copied verbatim from their whitepaper. Study recruitment occurred in two stages. The first stage of recruitment took place between December 2006 and August 2008 at the UT (University of Tennessee) Medical Group clinic, where the project recruited pregnant patients via discussions with clinic staff. The UTHSC project coordinator asked each eligible patient to participate in the study while the patient was in the UT Medical Group clinic during her regular obstetric appointment. UCI CANDLE Study staff at UTHSC asked each woman who met screening criteria to participate; if she agreed, the UTHSC project coordinator provided her with a consent form. CANDLE required each woman under the age of 18 to have a legally authorized representative cosign the consent form. CANDLE enrolled a total of 344 women from the UT Medical Group clinic through August 2008. The second stage of recruitment started in September 2007 and lasted until July 2011. The purpose of the second stage was to increase the study sample and to improve distribution across the county. The second stage of recruitment focused on community sources, including mailings to obstetric practices, flyers in obstetric practices, referrals by friends and relatives, and television advertisements. During the second stage of recruitment, CANDLE enrolled an additional 1,160 women. During this recruitment wave, women telephoned the UTHSC recruitment center, which screened them for eligibility. The recruiters provided consent forms and obtained signatures, and eligibility was confirmed at the woman's in-person enrollment visit (M1, or first maternal or baseline visit). CANDLE required each woman under the age of 18 to have a legally authorized representative cosign the consent form. Out of 5,228 women who were screened for eligibility through both waves of recruitment, 3,320 (63 percent) met inclusion criteria, and 1,503 (45 percent) agreed to participate in the study. The institutional review boards at UTHSC and the three hospital systems (for the five health care settings) at which enrollees planned to deliver reviewed and approved this study.The CANDLE participants were recontacted in 2016 by ECHO PATHWAYS to recruit infants and children born in the parent study for further transcriptomics analysis of banked placental samples. Of the 1385 available subjects, 794 consented to transcriptomics analysis as well as data sharing. ]]>