Novel study at Brown shows how late-life health traces back to what happened in the womb

PROVIDENCE, R.I. [Brown University] — It makes sense that a viral infection during a pregnancy might negatively affect the fetus — but scientists now know that some effects of an adverse event during pregnancy may not be revealed for decades. On a more empowering note, scientists have found that low stress in pregnancy, consistent parenting in a child’s early years and quality preschool experiences reduce the risk of heart disease and mental illness in adulthood.

Those particular insights on how early life impacts future health, and many more, were made possible because of the New England Family Study, a one-of-a-kind research project launched in 1959 and continuing today.

“We now know that most diseases and conditions — from breast cancer to heart disease, to dementia, schizophrenia, asthma, reflux disorder — are a result of a combination of genetics and environmental factors,” said Brown University epidemiologist Stephen Buka, who directs the New England Family Study. “And a lot of those environmental influences happen really early, in utero or during the first year of life, and they alter physiological development in ways that later are expressed when a person is in their 40s, 50s and 60s.”

The study, which launched with the goal of understanding how conditions during pregnancy might contribute to neurodevelopmental problems in children, has followed a cohort of 17,000 pregnant women. The researchers studied the pregnant mothers as well as their children, evaluating health and development through the first seven years of life. Since then, the research team has continued to follow up with participants and has extended the study to include a third generation.

Because the study started evaluating some participants before they were born, the data offer insights into how different factors at the earliest moments of fetal development can impact a person’s health over their lifetime.

“The strength of the New England Family Study lies in learning from the same families over generations, from early development through aging,” said Buka, a professor of epidemiology who is the founding chair of the Department of Epidemiology at the Brown University School of Public Health. “There’s nothing quite like this in the world.”

Buka explains the significance in this way: Long-term studies have shown how diet, exercise and sleep are crucial for healthy aging, and how a lifetime of smoking or drinking alcohol contribute to health conditions. Yet there are people who drink and smoke and never exercise with no serious health problems, while others in excellent health develop heart disease or cancer. Part of the explanation for this disparity has to do with what happened to that healthy person even before they were born, Buka said. And if people are aware of their risks, there may be proactive actions they can take — medications or other therapeutic interventions — to reduce the severity or change the outcome.

He noted that data collected as part of the study, which has been funded by the National Institutes of Health, have allowed researchers to study a wide range of health conditions across the human lifespan and unlock key insights for healthy aging. Researchers have advanced scientific understanding of the development and treatment of cancer, heart disease, depression, schizophrenia, substance abuse and more. New England Family Study research has also identified early risks that contribute to the origins of ADHD, including lasting changes in brain structure, and those findings have contributed to establishing attention-deficit/hyperactivity disorder as a recognized medical condition.

The study has also informed interventions. For example, findings demonstrated how differences in learning styles that are apparent in the early years persist throughout adulthood, which has implications for effective provider-patient communication in asthma and diabetes management.

 “Study findings have implications for public policy and how we protect and care for pregnant people and their children to prevent conditions and illnesses from developing; service implications for health care, medicine and social services; and personal implications for all of us — advice and recommendations on what we can do to remain healthy and disease-free,” Buka said.

Three generations, improving the health of countless others

The New England Family Study originated from the National Collaborative Perinatal Project, which involved 12 research sites across the U.S. with the goal of understanding conditions during pregnancy that might contribute to childhood disorders such as epilepsy, cerebral palsy and blindness. Researchers were also interested in exposures that might alter the development of the fetus, such as infections, cigarette smoke and lead, as well as pregnancy complications.

The initial cohort of 17,000 pregnant participants donated blood samples, were assessed throughout prenatal care, and shared information about their health, medications and social circumstances. Researchers also collected samples from placental tissues and infant cord blood. These biological materials, which number around 800,000, remain in repositories at the National Institutes of Health.

Researchers examined how children were developing by recording their growth, height, weight, perceptual and motor skills, neurological behavior, and medical conditions, recorded observations and data at birth; at four, eight and twelve months; and at ages 3, 4 and 7 years.

In the 1980s, when the children entered their 20s, the research shifted into a different phase as Buka and other investigators at Brown and Harvard University followed up with the now-adult participants in Providence and Boston, expanding their focus to consider conditions that affect people in young adulthood, middle age and later. The researchers also extended the study to include the next generation.

Information collected from the same families is the best way to learn the causes of disease and conditions that develop across the lifespan, Buka said. During follow-up visits, researchers assess participants’ physical activity, memory and cardiovascular measures, focusing on the brain, heart and general well-being. In keeping with technological advancements, the team is now able to use cutting-edge tools to analyze DNA, RNA, proteins and metabolites.

Buka, who leads the Brown research team, has been joined by Jill Goldstein, a clinical neuroscientist and professor at Harvard Medical School and the Department of Psychiatry at Massachusetts General Hospital. The team has been able to sustain participation with more than 4,000 cohort members, some at multiple times at different ages, and Buka estimates that the team has conducted around 5,000 assessments. They continue to reach out to study participants to add even more information to their database.

“Studies are usually conducted when people have already developed Alzheimer’s disease and other disorders of aging,” said Goldstein, a principal investigator of the New England Family Study. “We have the advantage of being able to continuously follow a large group of people prior to illness and perform advanced tests to identify red flags, patterns and other signs. That’s practically unheard of. The data from the New England Family Study is an absolute gold mine.”

Research with real-world benefits

Ongoing New England Family Study projects by researchers at Brown and Harvard include studies of how mood and anxiety, memory, information processing and brain function change with age; an investigation into early causes and preventive measures for breast cancer and other types of cancer; and efforts to understand how early-life factors may contribute to the risk of adult heart disease, its co-occurrence with depression and Alzheimer’s disease, and how this differs by sex.

Study participants not only have the opportunity to learn about their physiology and brain function, but also, in some cases, receive personalized recommendations for how to reduce their risks.

As part of one proposed study, participants will be screened for biomarker and brain changes, or clues in blood or other fluids, that can indicate the potential onset of Alzheimer’s disease or dementia even before a person is experiencing symptoms.

“This study is uniquely poised to help us answer some important questions about the development of Alzheimer’s and dementia,” said Dr. Ted Huey, the associate director of Brown’s Center for Alzheimer’s Disease Research and director of the Memory and Aging Program at Butler Hospital. “We know there are disparities in incidence and prevalence of Alzheimer’s and dementia. This study allows us the opportunity to investigate the biological basis of these disparities, as well as the impact of social determinants of health. It’s remarkable.”

Participants will be able to learn about their risk for Alzheimer’s and dementia and about resources available to help them manage their condition, Huey said, including the option to enroll in one of the many clinical trials at Butler.

Another study led by Buka and Brown physician-scientist Dr. Charles Eaton, which is funded by a federal grant and involves 1,500 participants, is exploring the mechanisms that may cause premature, low-weight babies to be at risk for heart disease in middle age.

 “The theory is that a fetus that is not adequately nourished in the womb, for whatever reason, may react physiologically by limiting development of certain systems, including its cardiovascular system,” Buka said.

 The results of the study may influence proactive medical treatment for high-risk, growth-restricted babies, Buka said, to help prevent the development of heart disease later in life.

 Goldstein is leading New England Family Study projects that include prenatal immune and stress antecedents of sex differences in the risk for depression and heart disease; discoveries that have led to the development of a novel neuromodulation treatment targeted to the brain circuitry that regulates mood, anxiety and cardiac tone through the vagus nerve; a clinical algorithm for identifying women who are at risk of developing Alzheimer's disease; and tools to identify immunological red flags for major depression that may provide clues to why women and men respond differently to antidepressants.

 “The study participants are directly contributing to the development of new diagnostic tools and therapies on conditions ranging from depression to the risk for Alzheimer’s disease,” Goldstein said. 

Participants have described many benefits of being a part of the long-running New England Family Study. From a practical perspective, the brain scans, heart monitoring and laboratory results have detected unknown health problems leading to improved diagnosis and treatment. Access to records from early childhood have helped participants document long-term disorders such as depression, ADHD or learning disabilities. And results of assessments in mid-adulthood have been used to track changes in cognitive abilities and brain and cardiovascular function to help understand risk factors for Alzheimer’s disease and potentially other disorders of aging.

 Some members are motivated to continue to participate out of respect for their parents, or respect for the scientific process. One participant recently spoke about his experience at a data conference at Brown.

 “I had faint memories of participating even as a young boy,” said Jason, who shared only his first name. “When I was contacted again [by the researchers] in the 90s, I jumped at the opportunity. At the time, I didn’t know the impact the study was having globally, but I knew that what they were discovering was of serious value.”

 Buka confirmed that Jason’s sentiments echo those he’s heard from many participants.

 “They know they’re special,” Buka said. “People have told us that participating in the study gives their life special meaning; that they feel like they’re making a contribution to society, to the world. We want them to know: They really are unique, and we’re so grateful.”