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  Lessons from the Womb

Five decades after medical researchers first started following the health of mothers and their newborns for an ambitious longitudinal study, Janet Hardy refuses to let go of her "babies," who are middle-aged now. Her hope: The data first gathered when they were in utero will yield tantalizing clues to the ailments that beset them today.

By Maria Blackburn
Illustration by Naomi Shea

Back in the late 1950s it wasn't difficult to convince 4,000 East Baltimore mothers-to-be to participate in the Collaborative Perinatal Project (CPP), a national state-of-the-art research study that tracked the growth and development of children from their first days in utero through second grade.

"Many of the people whose kids participated in the study told us, 'There's not much I can do for other people. This is something I can do,'" recalls Johns Hopkins' Janet Hardy, a pioneer in the field of pediatric public health who directed the Baltimore cohort of the 12-site study at Hopkins from 1957 until 1976. Nationally, the CPP followed about 60,000 pregnant women and their 58,000 children.

The hard part was getting the families to come back.

Doctors saw these children at least a half-dozen times at Hopkins during their seven or eight years in the study, which was designed to explore the origins of such neurological and sensory disorders as mental retardation, cerebral palsy, and learning disorders. At these visits they were weighed and measured; their hearing, vision, language, speech, and cognitive development were tested; and their parents were interviewed about their children's health and family life. Umbilical cord samples were taken at delivery, and prior to giving birth, their mothers visited Johns Hopkins Hospital about once a month for checkups and to give maternal blood samples. The blood was used for a serological study being done at the National Institutes of Health that explored the issue of maternal-fetal infection.

Being an unpaid participant in the CPP was a huge commitment, not to mention a "considerable inconvenience," says Hardy. Sometimes even the most well-meaning parents in these lower-middle-class families moved and left no forwarding address, missed appointments, or otherwise failed to keep up with the demands of the study.

Hardy refused to let the families slip away. She sent taxis to their doors to ferry them to doctor's appointments and always remembered to send birthday and Christmas cards. "Thank you for coming," Hardy and her staff always told the women. "Without your help there would be no study."

Due in part to her persistence, the CPP quickly yielded important insights into preventing brain damage in newborns with jaundice and preventing such birth defects as blindness and deafness. The comprehensive workups of newborns whose mothers were participating in the CPP created standards for hospitals regarding all newborn care. Over the next few years, other important findings came about: CPP researchers learned of the devastating effects rubella could have during the first and second trimester of pregnancy, and their findings helped the push for a vaccine. They found drugs that were unsafe for mothers to take during pregnancy. And they discovered more about the problems faced by teenage mothers and low-birth-weight babies. Their work had a great influence on the decline in the rate of infant mortality from 29.2 per 1,000 live births in 1950 to 7.2 in 1999.

Even when the children grew to adulthood, Hardy refused to let go. Working with colleagues at Hopkins in the late 1980s, she reconnected with several thousand mothers in the original Baltimore cohort and studied them, their children, and their grandchildren to learn more about how their environment influenced their health and development.

Today, at the age of 89, Hardy continues the work she started decades ago. The original CPP babies are middle-aged now and are likely suffering from some of the chronic diseases of midlife: type 2 diabetes, obesity, heart disease. Some could be schizophrenic or have other forms of mental illness. So Hardy and the researchers she inspired are reconnecting with original CPP participants and are hoping to find answers about when these diseases actually start.

"People told me this was a dead end," Hardy says of the CPP study. "They said it wasn't going to work. And these were some of my friends talking." "The more we look at complex disorders, the more we recognize that many adult diseases have their origins in childhood — many of them go back to in utero exposures," says Robert Yolken, director of the Stanley Division of Developmental Neurovirology at Johns Hopkins. "Dr. Hardy realized this in the 1950s — 30 or 40 years before other people did, and she was very interested in establishing a study whereby individuals would be followed literally from in the womb through adulthood."

In the 1950s, maternal and infant mortality and rates of premature births were high, and many children were being born with a broad range of neurological and neurosensory conditions. It was estimated that some 20 million Americans suffered from disabilities, including cerebral palsy, epilepsy, mental retardation, and defects of vision, hearing, learning, and communication.

A number of retrospective studies had previously linked cerebral palsy and mental retardation with dysfunctional pregnancy, labor, and delivery. Other retrospective research suggested these problems could be caused by genetic factors, maternal-fetal viral infection, drugs, and cigarette smoking. In 1951, two researchers even coined the phrase "the continuum of reproductive wastage" to refer to the idea that many pregnancy problems were the cause of unfavorable outcomes for babies.

Hardy was among those who recognized the value of embarking on a large, longitudinal study of mothers-to-be and their children — an ambitious project that would involve researchers at a dozen major medical centers. "This was exactly what was needed," Hardy says of the CPP.

The feeling was hardly unanimous. The CPP's length and breadth — not to mention its collaborative nature and $100 million price tag — made it controversial. Many researchers at the time believed that smaller studies — not one large one — would lead to more answers. Critics were vocal in their doubting of the CPP's success. "People told me this was a dead end," Hardy says of the study, which was funded by the National Institute of Neurological Diseases and Blindness. "They said it wasn't going to work. And these were some of my friends talking."

"It's very expensive to do a study like this, and it's difficult to carry out in its implementation," says Jonas Ellenberg, who was chief of the biometry branch of the National Institute of Neurological Disorders and Stroke, part of the NIH, during the CPP study. What made the CPP stand out, he says, was that it allowed for the collection of lots of data and had a specific, yet still broad, focus. "Most medical research is driven by hypotheses and would tend to have a narrow focus," says Ellenberg, currently associate dean for research program development at the University of Pennsylvania's School of Medicine.

"The CPP did have hypotheses, but the mechanics for the design of the study allowed for an extraordinarily broad access to data that was not hypothesis-driven. The primary goal of the project was to look at causes of cerebral palsy, but at the end of the day there was a long list of medical and clinical outcomes examined that were not talked about at the beginning of the study."

Hardy looks at the CPP's balance between a narrow and broad focus as akin to the recipe for soup. "It seems to me a really good vegetable soup depends on having a basic broth that provides a sort of starting point," she says. "From there you can go in all sorts of directions to make the perfect soup."

The 400-plus specialized publications and presentations that came out of the CPP are the variations on the basic vegetable soup. The CPP population and database represents the broth. "And a very rich broth it was, too," Hardy adds.

In September 1964, seven years into the CPP, Hardy and her team began seeing a number of very sick, very strange looking babies being born to participating mothers. Their skin was yellow from jaundice and dotted with purple lesions, their livers and spleens were enlarged, and their bodies were puffy and swollen with fluid.

Janet Hardy (left) with Anne Duggan and William Eaton, two of the Hopkins researchers who will carry on her work.
Photo by Keith Weller
The cause was congenital rubella, a virus their mothers had experienced early in pregnancy. Hardy and her team were aware of the virus — thousands of rubella babies were being born at U.S. hospitals in 1964 and 1965. But the outbreak among Baltimore newborns in the CPP gave the researchers a perfect opportunity not only to study rubella but also to document how an infection spreads from mother to fetus. Working with John L. Sever at the NIH, Hardy and her team were able to show — using sera samples and viral cultures they had taken for the CPP — how rubella is transferred in utero.

"This was one of the really strong parts of the CPP," Hardy says. "We had all kinds of mothers and newborns — we were able to identify mothers who had antibodies to rubella and mothers who didn't and we had babies in the nursery with clinical symptoms. Using the data we had, we were not only able to identify rubella but other infectious agents."

The nationwide rubella epidemic would leave an estimated 20,000 to 30,000 children with disabilities that ranged from blindness and deafness to severe mental retardation. But the Hopkins CPP team's contributions to understanding how the virus spread helped educate health care providers about the disease and assisted in the effort to get federal funding to support the introduction of a rubella vaccine.

When the CPP ended in 1976, researchers at other institutions moved on to new projects and new subjects. But Hardy could not. She was too curious and had too many questions about how a child's environment influences his or her life.

During the CPP, Hardy had observed that women who had their first babies as teens were at higher risk for pregnancy complications than older mothers, and that their surviving children faced substantial health and developmental risks. What could be done to help these women and children and others like them? And what kind of adults would the CPP babies become: Would they go to college or have babies young? Would they become self-sufficient or live on public assistance?

She didn't know the answers. But she knew where to find them.

When Baltimore CPP families completed the study, Hardy and her staff would always present them with a certificate of participation. They'd also ask for a way to get in touch in the future. "We never believed it was over," Hardy says of the CPP study. "Each step was always leading to the next."

It's not easy to have an infant. It's even harder to have an infant when you are not so far from childhood yourself.

"What struck me during the CPP was that we had known for years that children born to elderly mothers had problems, but there had been no major focus on young mothers," Hardy says. "When we looked at our data, we realized that mothers under the age of 18 were at extremely high risk from pregnancy loss, their children died at a higher proportion in the first year of life, and their children had lower IQs and more developmental problems. We had the information that the situation was bad, so we wanted to do something about it."

Janet Hardy
"An Extraordinary
Role Model"

Born: January 14, 1916

Education: BS, University of British Columbia (1937); MDCM from McGill University (1941). Decided on a career in medicine after her father, an internist, once told her, "No daughter of mine is ever going to be a physician."

Career Highlights: Served on the pediatric house staff at Johns Hopkins Hospital (1942-1945), where she was charged with developing the hospital's first neonatology ward; consultant to state of Maryland Health Department (1946-1950), where she helped develop a statewide transport system for premature and at-risk newborn infants; worked for Baltimore City Health Department (1951-1957), first as director of maternal and child health, ultimately as assistant commissioner of health for preventive medicine; director of Johns Hopkins Collaborative Perinatal Study (1957-1976); director of the Office of Continuing Medical Education at JHMI (1974-1981); director of Johns Hopkins Adolescent Pregnancy Programs (1975-1985); director of Johns Hopkins Children and Youth Programs (1982-1985); fifth woman to achieve rank of full professor on the Hopkins medical faculty.

Family: Married to Johns Hopkins associate professor Paul H. Hardy for 66 years; has two children and three grandchildren. The couple reared their family on a 35-acre farm in Glen Arm, Maryland, where she raised horses, kept a garden, and canned her own jams and vegetables. Says Anne Duggan: "She's an extraordinary role model for how you can really have it all. She's an incredible researcher, wife, mother, grandmother, homemaker, gardener. And she has always made it look effortless."

Working with the late Theodore King, former chair of Hopkins' Department of Gynecology and Obstetrics, and other colleagues, Hardy put together the Johns Hopkins Adolescent Pregnancy and Parenting Programs in 1976. The project looked at teaching parenting skills to teens and teaching and evaluating pregnancy prevention methods. "It was a special clinical program that was very supportive and focused on health and parenting education," Hardy recalls.

Several years later, Hardy became aware of new research by Laurie Schwab Zabin, a professor of population and family health sciences at the Bloomberg School of Public Health, that showed that pregnancy prevention efforts needed to reach teenagers earlier than previously thought. The two worked with city children's advocate Rosalie Streett to develop the Hopkins Pregnancy Prevention Program. The innovative school-linked program was implemented at a Baltimore City high school and a junior high. The program, which blended social support, education, and access to birth control for young men and women, succeeded in decreasing the pregnancy rate among participants by 30 percent while pregnancy rates at schools without the program grew 58 percent.

Zabin calls Hardy a dedicated, dogged researcher, someone who not only has curiosity but also has the ability to get the right people together for a project and find the funding to make it work. "When she decided something was going to be done, she totally threw herself into it, picked very carefully who she was going to do it with, and did it," Zabin says. "She's always been a person who saw what the next step could be."

Then there was the question of how the CPP participants, their children, and grandchildren were faring. After approximately 25 years since her last contact with CPP mothers and children, Hardy decided it was time for a follow-up. In 1988, together with the late Sam Shapiro of the Bloomberg School's Department of Health Policy and Management, Hardy reconnected with a random sample of 2,694 CPP participants for the Pathways to Adulthood Study. The goal: to see how their environment and health had influenced their development.

"Clearly the question was what had happened to the mothers and the children, and why did it happen," Hardy says. Because of the fine relationship her CPP staff had with participants, Hardy had little trouble finding the children, who were now between the ages of 27 and 33.

There was the baby who, though tiny and brain damaged at birth, went on to lead an independent life and have a family. There was the girl with the high IQ who won a full scholarship to college. There were babies who grew up to be doctors, lawyers, and small business owners, and babies who grew up to continue the poverty cycle, live on welfare, and go to prison.

"It was amazing to see as the children developed and the families made their way in life," Hardy says. "So many of them turned out to be successful."

Hardy's follow-up study found that living with both parents, remaining free from poverty, and good behavior in and out of school were all predictors of successful adult lives among this inner-city population, which was largely African American. She also found a strong link between a woman's age when she first gives birth and how her children do later on in life. Those born to mothers in their late 20s were more likely to get high school diplomas, stay off public assistance, and avoid teenage pregnancies in their own lives than were the children of teenage mothers.

It was more than curiosity that brought Hardy back to the CPP data several years ago. "We were beginning to hear of findings, particularly from a researcher named David Barker in England, that there was definitive evidence between perinatal factors and chronic diseases such as diabetes, heart disease, and hypertension, yet there were very few databases that included detailed prospective data from the mother's pregnancy through the children's development to adulthood," Hardy says. The original CPP data, which included a collection of 60,000 frozen sera samples, could be a goldmine.

Now Hardy just needed Hopkins researchers who were interested in the next step — following the participants to middle age. Says Duggan: "[Janet] realized the incredible value [of continuing] to follow the cohort but [knew] it was never going to happen unless she took action to pass along to a next generation of researchers what she had done."

William Eaton, chair of the Department of Mental Health at the Bloomberg School of Public Health, has been interested in life course studies for most of his career and immediately saw the value of continuing the CPP. "We have studied thousands of generations of fruit flies . . . and hundreds of generations of rodents, but [there's not been] a single intensive study of even one generation of humans," he says. "Following up on the CPP is one of the first opportunities we have to do that."

"We have studied hundreds of generations of rodents ... but [there's not been] a single intensive study of even one generation of humans." —William Eaton Along with Duggan, Eaton has been spearheading the effort to embark on the latest follow-up. They've just completed a pilot study proving that they are able to reconnect with participants, and they are still finding research specialists to sign on to the project and plan to apply for funding in February.

Yolken, the Hopkins neurovirologist, had already used sera samples from the CPP for some of his work, including a recent study that found an increased incidence in schizophrenia among adults whose mothers had herpes simplex virus II when they were pregnant. He signed on to the follow-up of the now middle-aged "CPP babies" because he knows the richness of the data that was already available and he's eager to see where new data might lead. "The collaborative perinatal study was probably the best study of its kind that's ever been done," Yolken says. "I don't think any study since then has really characterized that many children and also collected prenatal and cord blood samples that were stored in an archive."

And then there's the opportunity of working with Hardy, whom Yolken calls an "oral historian" of the CPP. "Dr. Hardy has been an incredible resource," he says. "She has an incredible memory and anytime I've had questions about what a particular variable means I simply ask her. I can get information from her that's not documented, or if it is documented I haven't been able to find it from other sources."

Hardy is thrilled that Eaton, Duggan, and other researchers at Hopkins have agreed to carry on her work. "I'm just so fortunate to have it in better hands than mine," she says. "I no longer have any feeling of ownership. I guess it's analogous to having one's children grow up."

And yet, even Hardy doubts she will ever really be able to leave the CPP behind. She's curious about what the new findings might be and professes a desire to see the completion of the most recent follow-up. "They have a wonderful opportunity to do a quick and dirty study to answer some of the current hypotheses about the development of midlife chronic disease," Hardy says. "Does it start in utero? If so, why? And what are the mediating factors along the way? You have a confluence of the database, a population, and rather urgent scientific questions. For my money, that makes for a very exciting situation."

However, Hardy admits she has one regret. "I only wish I could see it done," she says.

Eaton considers Hardy's words for a moment and laughs. "That's a lot of crap," he says. "She's just talking. She is going to be here."

Maria Blackburn is a senior writer at Johns Hopkins Magazine.

Return to November 2005 Table of Contents

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