New ECHO Research Reveals Link Between Phthalate Exposure During Pregnancy and Multiple Health Outcomes in Children

Drew Day, PhD

Collaborative ECHO research led by Drew Day, PhD of Seattle Children’s Research Institute uses machine learning statistical algorithms to explore patterns of health outcomes in children. The researchers also investigated how exposures during pregnancy to phthalates—chemicals widely used in plastics that have previously been linked with preterm birth—can influence the development of multiple health conditions during childhood. This research, titled “Subpopulations of children with multiple chronic health outcomes in relation to chemical exposures in the ECHO-PATHWAYS consortium,” is published in Environment International.

Chronic health conditions, such as asthma and obesity, can develop together during childhood but are usually studied separately. The goal of this study was to use data from ECHO Cohort research sites across six U.S. cities to characterize “clusters,” or patterns, of obesity-related, lung health, and brain development outcomes in children and to investigate how these patterns relate to mothers’ exposures to phthalates during pregnancy.

ECHO researchers looked at 15 health outcomes in 1,092 children between the ages of 4 and 9 across six U.S. cities and collected measurements of phthalate exposure during pregnancy from 856 of these children’s mothers. Outcomes collected during this study included body mass index (BMI), IQ, anxiety, depression, irritability, learning disabilities, speech problems, asthma, wheeze, and nasal allergies. The researchers evaluated how children developed multiple outcomes and investigated how the probability of being in a particular group was affected by exposure to 15 plastic-associated phthalate chemicals during pregnancy. The researchers measured phthalate exposure during pregnancy using urine samples collected from 2007–2014 from mothers during late pregnancy.

The researchers identified three groups of children with a pattern of health outcomes that occurred together:

  1. A group of relatively healthy children;
  2. A group of children with lower IQs, elevated obesity, and slightly elevated asthma-related outcomes such as asthma, wheezing, and allergies; and
  3. Another group of children with high asthma-related outcomes along with elevated obesity and some increase in anxiety- and depression-related outcomes.

Compared to children in the healthy group, other groups had more male children, mothers with higher BMI and lower education attainment, and lower household incomes. The researchers found that children—particularly boys—were more likely to be in the third group if their mothers were exposed to phthalates during pregnancy.

These findings suggest that exposure to phthalates during pregnancy might be associated with an increased risk of developing not only asthma and related lung outcomes, but also obesity and mental health issues such as anxiety and depression. This study also suggests that low-income households are at higher risk for worse childhood health outcomes.

“The three patterns of health outcomes seen in this study reveal more about how pediatric diseases might arise together,” said Dr. Day. “The insights from this study could help inform future research on what biological processes contribute to these health outcome patterns as well as better treatments and interventions to enhance child health.”

This study’s multi-outcome approach can be used in future studies to identify public health risks that may affect central biological processes that result in multiple negative health outcomes. ECHO Cohort researchers are working to extend this method to include several additional U.S. research sites, which will allow them to evaluate whether similar patterns are observed in a larger dataset. Larger studies will also help researchers characterize how demographic differences like income and sex may influence the development of multiple health outcomes during childhood.

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ECHO Researchers Examine Fish Consumption and Supplement Use Among Pregnant People

Collaborative ECHO research led by Emily Oken, MD, MPH of Harvard Medical School and the Harvard Pilgrim Health Care Institute, and Kristen Lyall, ScD of Drexel University, investigates fish consumption and the use of omega-3 supplements among pregnant people.

This research, titled “Demographic and health characteristics associated with fish and n-3 fatty acid supplement intake during pregnancy: results from pregnancy cohorts in the ECHO program,” is published in Public Health Nutrition.

Omega-3 fatty acids, also known as n-3 fatty acids, are essential nutrients during pregnancy for supporting child health and neurodevelopment and may also improve other pregnancy outcomes. Fish intake is the primary source of these nutrients in the diet. Prior research on who eats fish and uses supplements during pregnancy has been limited, involving fewer participants and older data that may not represent current consumption.

This study included 10,800 pregnant people enrolled by 23 ECHO Cohort study sites that collected information on fish consumption, and 12,646 participants at 35 sites that collected information on omega-3 supplement use. While the ECHO Program began 2016, some study sites had been collecting participant data for many years before. In this study, information on fish consumption and omega-3 supplement use was collected from pregnant participants from 1999 to 2020.

After collecting this information, the researchers sorted participant data based on how often they ate fish: never or less than once per month, once per month to less than once per week, one to two times per week, or more than twice per week. They then compared participant fish consumption and supplement use across various demographic and lifestyle factors, including age, race, ethnicity, education, weight, and smoking status.

The research team observed that about 25% of pregnant participants did not eat any fish or ate fish less than once per month, but older participants were more likely to eat fish. Participants who were non-Hispanic Black, non-Hispanic Asian, or Hispanic ate less fish on average than those who identified as non-Hispanic White. Participants categorized as overweight were also less likely to eat fish.

Omega-3 supplement use was also rare—with only 1 in 6 study participants reporting taking omega-3 supplements. Supplement use was more common in participants who were older and had more education, a lower body mass index (BMI), and a diet that included fish.

“This study observed that one-quarter of participants in this large nationwide dataset rarely or never consumed fish during pregnancy, and omega-3 supplement use was uncommon, even among those who did not consume fish,” Dr. Oken said.

Experts recommend that people need additional omega-3 fatty acids during pregnancy. Ongoing effective public health advice and resources to support clinicians are needed to encourage consumption of low-mercury fish during pregnancy and intake of omega-3 supplements among those who do not consume fish.

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New ECHO Research Study Relationship Between Maternal Education and Children’s Neurocognitive Development Over Time

Collaborative ECHO research led by Santiago Morales, PhD of the University of Southern California investigates the relationship between maternal education and children’s neurocognitive development over time. This research, titled “Maternal Education Prospectively Predicts Child Neurocognitive Function: An ECHO Study,” is published in Developmental Psychology.

ECHO researchers wanted to examine the relationship between changes in a mother’s education over time and their children’s later neurocognitive functioning, such as executive function and language skills. Studies to date have focused on early childhood outcomes and have treated a mother’s education as unchanging over time.

This study included 2,688 children, adolescents, and young adults from 3 to 20 years of age at ECHO research sites in 42 states across the U.S.

Mothers reported their own education levels during pregnancy and their child’s infancy, and again, years later when their children’s neurocognitive functions were also assessed. For both periods, the study categorized the mother’s education level into one of five groups—less than high school; high school or GED equivalent degree; some college, associate degree or trade school; bachelor’s degree; and graduate degree. The same categories were used to measure maternal education during childhood. Maternal education and income are two commonly used indicators of socioeconomic status. However, missing income data in this study prevented investigators from fully assessing the impact of socioeconomic status and income on neurocognitive skills.

Researchers also measured child participants’ cognitive abilities during childhood, adolescence, or young adulthood using the NIH Toolbox Cognition Battery. These tests assess aspects of cognition including language, memory, and problem solving. Test results created scores that reflected language skills, executive function, and overall brain function. The analysis included child participants who contributed at least one score.

This study found that a mother’s education level during pregnancy and infancy was associated with children’s language and executive function. Increases in maternal education were related to improved language performance but were not associated with executive functioning performance.

“These results suggest that further examining these associations can provide important insights that can help inform policies and interventions designed to foster neurocognitive development,” said Dr. Morales.

Future research can explore the factors involved in the suggested association between maternal education and a child’s neurocognitive development.

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New ECHO Study Finds No Statistically Significant Associations Between Small Molecules During Pregnancy and Childhood BMI

Collaborative ECHO research led by Rachel Kelly, PhD and Nicole Prince, PhD, of Brigham and Women’s Hospital and Harvard Medical School, and Donghai Liang, PhD, MPH of Emory University analyzes the relationship between small molecules in a mother’s blood during pregnancy and childhood BMI. This research, titled “Metabolomic Data Presents Challenges for Epidemiological Meta-Analysis: A Case Study of Childhood Body Mass Index from the ECHO Consortium,” is published in Metabolomics.

A child’s body mass index (BMI) can affect their future health. Some researchers are exploring the connection between factors during pregnancy and childhood BMI. Increasingly, researchers use molecular data to analyze the relationship between pregnancy and childhood health outcomes, sometimes combining molecular data from multiple study sites to increase the statistical power of these analyses.

In this study, ECHO researchers combined the results from multiple ECHO Cohort Study Sites to determine whether a relationship existed between small molecules in the mother’s blood during pregnancy and their child’s later BMI. It also aimed to use these data to test a framework for analyzing molecular data across multiple studies.

The study involved mothers in the second and third trimesters of pregnancy and their children from multiple study sites: the Atlanta ECHO Cohort, the New Hampshire Birth Cohort, and the Vitamin D Antenatal Asthma Reduction Trial. Pregnant participants from these sites provided blood samples, which were then used to measure a range of small molecules that provide information on each participant’s health and environment and the biological or genetic factors that could affect their pregnancy. These participants and their children were observed and assessed across pregnancy and the child’s early life. In this analysis, the authors used data from the aforementioned three study sites to evaluate the relationship between molecules measured during pregnancy and BMI at age 2, aiming to identify relationships that were consistent across all three.

The research team found that of all the small molecules tested, 20 showed up in all study sites, and 127 showed up in at least two. The study found that the levels of only six small molecules, primarily related to maternal diet, were associated with child BMI across all sites. However, statistical analysis across these study sites did not identify significant associations between these molecules and child BMI.

This study demonstrates some of the challenges of harmonizing molecular data across diverse study sites and highlights important considerations for researchers trying to conduct similar analyses.

“Differences in how molecular data were collected and measured between the sites in this study made it difficult to draw strong conclusions on the relationship between small molecules during pregnancy and childhood BMI,” Dr. Kelly said. “Future analyses could involve larger, more standardized studies that all use the same methods for sample collection and measurement of molecules present, which would improve the reliability and reproducibility of results.”

Many ECHO Cohort Study Sites are now measuring small molecules in mothers and children with a standardized approach under the ECHO Cohort Data Collection Protocol. ECHO researchers have an opportunity to use these data to power analyses that can explore the relationship between pregnancy health and child health outcomes.

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ECHO Researchers Find Link Between Phthalate Exposure and Preterm Birth, Estimate Potential Costs

 

Collaborative ECHO research led by Leonardo Trasande, MD, MPP of NYU Langone Health investigates the potential connections between phthalates, their metabolites in the urine of pregnant individuals, and birth outcomes. This research, titled “Prenatal phthalate exposure and adverse birth outcomes in the USA: a prospective analysis of births and estimates of attributable burden and costs,” is published in The Lancet Planetary Health.

Phthalates are widely used chemicals found in some consumer products, and previous research has linked phthalate exposure to preterm birth. In response, the use of di-2-ethylhexyl phthalate (DEHP), a common type of phthalate, has decreased in recent years. However, there is limited research on the effects of the replacement phthalates, and the costs associated with phthalate exposure remain unquantified.

The study included 5,006 mother-child pairs from 13 ECHO Cohort Study Sites across the U.S.  Researchers analyzed levels of 20 phthalate metabolites in urine samples collected at three different points during each participant’s pregnancy. Then, the team looked for associations between these metabolite levels and preterm birth. The team also investigated the differences between specific types of phthalates, comparing di-2-ethylhexyl phthalate (DEHP), a common type of phthalate, with several newer alternatives developed to replace it.

When the researchers grouped mothers based on the amount of DEHP metabolites (substances produced when the body breaks down DEHP) found in their urine, they found that the 10% with the highest levels had a 50% higher chance of giving birth before the 37th week of pregnancy compared to the 10% with the lowest levels.

Some common alternatives to DEHP were associated with an even higher risk of preterm birth. Women exposed to the highest amounts of these alternative chemicals—phthalic acid, di-isodecyl phthalate (DIDP), di-n-octyl phthalate (DnOP), and diisononyl phthalate (DiNP)—had twice the risk of preterm birth compared to those with little to no exposure to these alternatives. The team also calculated the costs associated with phthalate exposure.

“The number of premature births in the U.S. that could be linked to phthalate exposure in 2018 was between 24,000 and 120,000, potentially costing between $1.6 billion and $8.1 billion in medical expenses over the lifetime of the children,” Dr. Trasande said.

Future research could look at how exposure to replacement phthalates affects child development after birth. The European Union has prohibited the use of certain phthalates in some consumer products—as have California and a few other U.S. states.

Read the research summary here.

New ECHO Research Highlights Gaps in Literature Studying Role of Fathers in Child Development

Collaborative ECHO research led by Elena Jansen, PhD of Johns Hopkins School of Medicine, and Kristine Marceau, PhD of the College of Health and Human Sciences at Purdue University reviewed existing literature on what is known about a father’s role in child development, highlighting how a father’s history and personal characteristics can influence their child’s health and wellbeing. This research, titled “The Role of Fathers in Child Development from Preconception to Postnatal Influences: Opportunities for the National Institutes of Health Environmental influences on Child Health Outcomes (ECHO) Program,” is published in Developmental Psychobiology.

While few studies on parental health and child development include fathers in any substantial way, a growing body of literature emphasizes their vital role—even before birth. This literature review studied existing research on the role of fathers in child development. It evaluated the quality of this research, focusing on three outcome areas of the ECHO Program: obesity, neurodevelopment, and positive health. The review also discussed how the ECHO Program can address gaps in the literature by designing studies that address unanswered questions.

The review first described data collected by the ECHO Cohort and identified critical gaps in the research related to the role of fathers in ECHO’s five key health outcome areas. After understanding the program’s data collection methods, the research team analyzed multiple research papers categorized into three broad stages of child development—preconception, prenatal, and postnatal.

This review focused on which previously studied characteristics or behaviors of fathers have been connected to children’s development. It demonstrated how studying the effect of fathers on child development has revealed additional insights into children’s health outcomes, including reasons for declines in physical or mental health. Compared to the pregnancy and pre-pregnancy stages, this study allowed researchers to better understand a father’s role once a baby is born.

“One unique aspect of this work is describing how fathers can impact the child by first influencing the mother, for example, by helping her follow healthy behaviors, such as cooking or helping to cook healthy meals and eating healthy food himself,” Dr. Jansen said.

This literature review also revealed gaps in the research community’s understanding of the father’s role in child development, highlighting the need to incorporate maternal and paternal reported data on fathers’ characteristics. While many studies offer insights into the role of fathers, often fathers do not provide this information themselves, or existing data do not allow researchers to compare the roles of fathers and mothers.

Additionally, the study team proposed a new conceptual model to guide future inquiry considering paternal influences, and suggest methods researchers can use to help fill in some knowledge gaps.

“Our model can help guide other researchers to focus on the pieces of the puzzle that we currently know very little about,” Dr. Jansen said. “It may help explain how each parent interacts with their child and which influence has a stronger impact or is more prevalent for which parent.”

With more data becoming available from the ECHO Program, information on fathers’ characteristics can be connected to the rich data on family characteristics, mothers’ influences, and child development. Additional data will be gathered to provide further insights and answer remaining questions.

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New ECHO Research Finds No Association Between Arsenic Exposure and Birth Outcomes

Collaborative ECHO research led by Jonathan Lewis, MHS, Emily Knapp, PhD, MHS, and Amii Kress, PhD, MPH of Johns Hopkins Bloomberg School of Public Health investigates the relationship between arsenic exposure and certain birth outcomes. This research, titled “Associations Between Area-Level Arsenic Exposure and Adverse Birth Outcomes: An ECHO-Wide Cohort Analysis,” is published in Environmental Research.

Researchers captured proxy exposure to arsenic using a residential history of arsenic violations from the preconception period throughout pregnancy, a time when environmental influences could disrupt fetal growth.  Violations were used as a proxy for arsenic exposure. The study used data from 15,000 mother-child pairs at 51 research sites across the U.S., focusing on children born in 2006 or later. In 2006, the Environmental Protection Agency (EPA) revised the enforceable standard for arsenic concentrations in drinking water to 10 parts per billion.

Low birth weight, gestational age at birth, preterm birth, and birth size were not found to be associated with potential arsenic exposure in areas with violations. However, infants whose mothers experienced continuous exposure to arsenic from three months before conception through birth exhibited a statistically significant increase in birth weight compared to those born in areas without violations.

In future studies, researchers aim to improve the identification of the community water systems that serve ECHO participants. Future research could also consider ECHO participants’ exposure to arsenic in foods and from other sources of drinking water.

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ECHO Research Explores Potential Value of Nutrition Data Collected from Pregnancy Through Adolescence for Understanding Child Health

Collaborative ECHO research led by Megan Bragg, PhD, RD and Kristen Lyall, ScD of the A.J. Drexel Autism Institute highlights the opportunity for researchers to access the large amount of diet information already collected from the ECHO Cohort. This research, titled “Opportunities for examining child health impacts of early-life nutrition in the ECHO Program: Maternal and child dietary intake data from pregnancy to adolescence”, is published in Current Developments in Nutrition.

This study aimed to describe dietary intake data available in the ECHO Program as of August 2022, from pregnancy through adolescence, including estimated sample sizes, and to highlight the potential for future analyses of nutrition and child health. As of that date, 66 ECHO Cohort Study Sites across the country had collected diet information using a variety of methods, including dietary recalls, food frequency questionnaires, and questionnaires about supplement use. Diet information from these study sites is especially useful because it has been collected from a large group of diverse people, and because many families provided information more than once over the course of pregnancy and childhood.

Often, data collected on diet provide only a snapshot that can’t address how early-life diet affects later child health outcomes. The ECHO Cohort Consortium is addressing these challenges by gathering information over time about the dietary habits of individuals during pregnancy and childhood from a large, diverse group of participants.

“Researchers need information about what people eat during pregnancy and childhood from a large, diverse group of people in order to answer questions about nutrition,” said Dr. Bragg. “ECHO is unique because study sites have collected and continue to collect this information.”

Information from over 33,000 pregnancies and more than 31,000 children in the ECHO Program is now accessible to researchers. This de-identified data is publicly available to researchers through the National Institute of Child Health and Human Development Data and Specimen Hub (DASH) to encourage broad use to answer important questions about nutrition and child health.

Access the brief flash talk from one of the authors in the following video:

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New ECHO Research Characterizes Children Born Preterm into Four Neurobehavioral Profiles Based on a Combination of Health Outcomes

Collaborative ECHO research led by Marie Camerota, PhD of the Warren Alpert Medical School of Brown University studies the health outcomes of children born preterm and characterizes them into four neurobehavioral profiles. This research, titled “Neurodevelopmental and behavioral outcomes of very preterm infants: latent profile analysis in the Environmental influences on Child Health Outcomes (ECHO) Program,” is published in Pediatric Research.

Birth outcomes for infants born very preterm have steadily improved over the past several decades. More children born at earlier gestational ages are surviving into childhood, however, it is unclear how being born very preterm may influence neurodevelopmental or behavioral problems.

Outcomes of children born at a gestational age of less than 33 weeks (“very pre-term”) vary significantly, with some children showing few neurodevelopmental concerns and others showing significant impairment. Most prior research has looked at single outcomes—for example, whether a child born preterm had a lower neurodevelopmental score or higher levels of behavior problems. Understanding how these different outcomes may group together can help researchers and healthcare providers provide more comprehensive treatment plans for children born very preterm.

This study included more than 2,000 babies who were born at less than 33 weeks gestational age from three ECHO Cohort Study Sites. When these children reached the age of two years, researchers conducted a neurodevelopmental assessment and a motor exam on the children while parents completed questionnaires about their children’s behavior. ECHO researchers looked for patterns in these data to understand whether there were groups of children with similar strengths and weaknesses.

Researchers found evidence for four different neurobehavioral profiles based on different combinations of cognitive, motor, and behavioral outcomes of children at the age of two. These profiles range from few or no developmental concerns to severe impairment in one or more domains. The study placed about 85% of children into one of two groups with no/mild developmental delay and a low prevalence of behavioral problems. The remaining 15% fell into one of two profiles with more serious neurodevelopmental problems with (5%) or without (10%) co-occurring behavior problems.

“This study helps us better understand outcomes for children following a very pre-term birth and shows that it is important to measure both neurodevelopmental and behavioral outcomes for children born preterm,” Dr. Camerota said. “The different groups of children we described might require different types of follow-up services or interventions. Therefore, the results of this study could potentially be used to develop personalized interventions for children following a very pre-term birth.”

More research is needed to understand why some preterm children develop neurodevelopmental and/or behavioral problems and others do not. To do this, future studies may study risk factors in pregnancy, the perinatal period, and in early infancy.

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ECHO Researchers Evaluate New Scale for Measuring Pandemic-related Traumatic Stress in Children and Adults

Courtney K. Blackwell, PhD

Collaborative ECHO research led by Courtney K. Blackwell, PhD of Northwestern University evaluated COVID-19 pandemic-related traumatic stress in a large sample of children and adults. In March 2020, ECHO researchers developed the Pandemic-related Traumatic Stress Scale (PTSS) to measure stress related to the COVID-19 pandemic. The PTSS can be used to identify children and adults with higher levels of traumatic stress and who may need additional mental health support. This research, titled “Development and Psychometric Validation of the Pandemic-related Traumatic Stress Scale for Children and Adults,” is published in Psychological Assessment.

The study included 17,830 children and adults from 47 ECHO Cohort study sites representing all 50 states, Washington, DC, and Puerto Rico. Researchers split the sample into four groups including 1,656 pregnant or postpartum individuals; 11,483 adult caregivers; 1,795 adolescents aged 13 to 21; and 2,896 children aged 3 to 12.

Between April 2020 and August 2021, adolescents and adult caregivers (including pregnant or postpartum individuals) completed surveys about their pandemic-related traumatic stress, depressive symptoms, anxiety, general stress, and life satisfaction. Caregivers of children aged 3-12 reported on the behaviors observed in their child.

On average, caregivers had the highest levels of pandemic-related traumatic stress, followed by adolescents, pregnant or postpartum individuals, and children. Within these groups, the researchers found additional differences related to age and gender. Adolescents, females, and caregivers of children under 5 had higher PTSS scores on average than younger children, males, and caregivers of children 5 and older, respectively. Higher levels of pandemic-related traumatic stress were associated with greater symptoms of distress and lower life satisfaction.

The researchers found that the PTSS is a reliable way to measure pandemic-related traumatic stress in the context of the COVID-19 pandemic. Researchers and doctors can use this scale to distinguish general stress, depression, and anxiety from traumatic stress, helping them to identify people who may need more support to improve their mental health.

“The PTSS can be used beyond the immediate COVID-19 pandemic context,” said Dr. Blackwell. “Unlike previous measures that capture traumatic stress reactions to a single event, the PTSS was developed to evaluate potential traumatic stress reactions to ongoing large-scale threats. In the future, the PTSS could be adapted to evaluate reactions to other acute onset stressors with lengthy durations.”

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