In 1983 two doctors, one from each side of the world, decided to form a partnership, and so began a scientific adventure that would improve the odds that babies could be born healthy and whole. Neural tube defects that severely disabled or killed babies were epidemic in China (where the folk term was guai tai--roughly "monster baby"--for an infant whose embryonic neural tube doesn't completely close and whose head and neck may be misshapen or spine may protrude) and a significant problem in the United States, leading teams of researchers from the United States and China to combine forces to recruit more than 285,000 Chinese women and to follow nearly 250,000 pregnancies in an epidemiological study.
Sixteen thousand staff were involved in running the project, which encountered massive bureaucratic obstacles as well as cultural differences, politicking for study designs and funding, the crisis of Tiananmen Square, and testy debates over research ethics. Nevertheless, the researchers persevered in a collaboration that lasted more than three decades and led to landmark findings on the role of folic acid in preventing spina bifida. Fortifying cereal grain products with folic acid became routine in the United States and a growing number of nations around the world: that intervention was named one of the ten great public health achievements of the last decade.
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About the Author
Deborah Kowal is executive editor and a coauthor of Contraceptive Technology, now in its twentieth edition with more than two million copies in print. As a medical writer specializing in women's reproductive health, she has consulted with the US Centers for Disease Control and Prevention, the World Health Organization, and other organizations. For more than thirty years, she wrote the Public Health section in the World Book Encyclopedia's Science Year Annuals.
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The China-US Partnership to Prevent Spina Bifida
The Evolution of a Landmark Epidemiological Study
By Deborah Kowal
Vanderbilt University PressCopyright © 2015 Vanderbilt University Press
All rights reserved.
LOOKING FOR GOLD
The bus bumped along potholed roads. Near Beijing, the traffic had been heavy with masses of men and women riding bicycles, accompanied by the tinny bleat of bicycle bells. Outside the city limits, the traffic thinned markedly. Most of the passengers on the small bus glanced out the windows from time to time, but they were primarily interested in the strangers riding with them to Shunyi County, one of Beijing's suburbs. An observer would have quickly seen differences among the dozen or so passengers. In May 1983, before China began to rival the moneyed United States, the Chinese wore their poverty: skinny men and women cinched their belts around their waists to hold up threadbare clothes. In contrast, the Americans, even the modest visitors on the bus, wore the affluence of their country, then the world's shopping mall for consumer goods.
Godfrey Oakley, chief of the Birth Defects Branch at the US Centers for Disease Control (CDC), leaned forward as he spoke, his voice full of energy and volume, his speech laden with expletives, and his hands busy with gestures. Next to him, the reserved Yan Renying, professor of obstetrics and director of clinical teaching at the eminent Beijing Medical University (BMU), sat with her back straight and her shoulders squared. As they shared the hard bus seat, both Oakley and Yan Renying tried to conform to what little they knew of each other's cultural etiquettes. As they talked, this mismatched couple embarked upon a journey that would grow beyond the two-hour bus ride from Beijing to Shunyi County — beyond the awkward conversation between two people who knew so little of each other but sensed that they would come to ask so much of each other.
What prompted this unlikely partnership between Oakley and Yan Renying? Babies. The two physicians had spent their careers trying to discover why so many babies were born with handicapping or killing deformities. In China, birth defects were afflicting anywhere from 800,000 to 1.2 million infants annually. In the United States, birth defects were an underlying or contributing cause of almost one-quarter of infant deaths when Oakley and Yan Renying together puzzled over their mutual concern. One of the most common birth defects left babies' spines or brains incomplete. Doctors called the spinal deformity "spina bifida," and they called the brain deformity "anencephaly." Spina bifida and anencephaly were part of a constellation of congenital conditions called neural tube defects (NTDs). These big words meant little to mothers and fathers in China. A severely afflicted infant would be called guai tai — roughly translated as "monster baby" — a name that described how deformity greatly affected its appearance.
All babies with anencephaly died. Children with spina bifida who survived their infancy endured a range of problems, from a poor gait to paralysis to early death. In the early 1980s, when Oakley and his team first traveled to China, spina bifida and other NTDs annually killed or paralyzed between three hundred thousand and four hundred thousand babies across the globe. In China, about 100,000 infants were born with spina bifida or anencephaly each year. In the United States, where the death rate from NTDs was one-tenth of that in China, fewer couples faced the traumatic loss of a fetus or newborn. However, of the US-born infants that survived "the first twenty-four hours of life with the most common form of NTD — spina bifida, 75 percent will have varying degrees of paralysis from permanent damage to the spinal cord and spinal nerves, and 20 percent will have moderate or severe mental retardation." What happened during early childhood is suggested by a study from Dublin, Ireland, showing that of those NTD-affected infants born alive between 1976 and 1987, 60 percent died before age five. Of those who survived to age five, having undergone a mean of five surgeries since birth, more than half lived with severe disability and another quarter with less severe forms of disability.
Oakley and Yan Renying found themselves on the same bus that day because they were attending the first European-Chinese Conference on Perinatal Surveillance. Perinatal surveillance is the set of tools for investigating health problems from pregnancy through the first month after birth — the time when the potential for life can be so frighteningly fragile. The scientists attending the meeting were tracking not only the health problems but also the threats contributing to the problems.
For spina bifida and other NTDs, the threats were taking root at the beginning of pregnancy and perhaps even before then. Before many women know that they are pregnant, circumstances have already determined the outcome of their pregnancies. A substantial part of the difficulty in preventing spina bifida and other NTDs is that the neural tube develops within a month after conception. The multiplying cells are not yet a baby, not yet a fetus. At the point of discovery that the period is late, the growing cluster is an embryo. Even within this short span of time, the embryo has undergone a significant journey. When the father's sperm fertilized the mother's egg, the two together formed the zygote, which split into two cells, then four, then eight. This mass of doubling cells traveled through the mother's fallopian tubes for six days, and finally settled into her womb.
At this stage, the embryo resembles a flat disk, not a human, but it carries out the vital task of forming the cell layers that will develop into the major organs needed to sustain life. Soon the shape of the disk shifts from two dimensions to three. A primitive groove forms and deepens, and the ridges at the sides grow higher. With the deepening and the pushing up of tissue, the sides of the groove gradually connect together, starting high in what will become a neck and then extending upward and downward, eventually forming a long tube. Because this tube is made of nerve cells, it is called the neural tube.
By the end of the third week, the embryo's heart begins to beat. So small, the size of a grain of rice, the embryo seems in danger of being crushed by the weight of the mother's tissues. But that is not the risk. The risk lies in those invisible things to which the growing embryonic cells are exposed, or not exposed, during this period of exquisite sensitivity. By the end of the fourth week, the long neural tube closes to form the spinal cord and, at the top end of the tube, the immature brain. Occasionally, the neural tube does not close, and the fetus sustains any of an array of defects. These are aptly named neural tube defects. As with many objective medical terms, however, the name "neural tube defect" describes only the anatomical problem, not the many related physical, mental, social, emotional, and life-altering or life-denying problems associated with the condition.
When the top end of the neural tube fails to develop into a brain, the result is anencephaly. The Chinese say the afflicted infant, often lacking the frontal bones of the skull, resembles a frog in shape. Anencephaly usually ends in a stillbirth, although some infants are born alive, sometimes appearing beautifully normal and then dying within a few days because no brain is present to coordinate the life-sustaining functions of organs. When the tube opens somewhere below the level of the brain, the result is spina bifida. In "closed" forms of spina bifida, the vulnerable spinal cord may be covered by only a thin layer of meninges or dimpled skin instead of protective bony vertebrae. "Open" forms of spina bifida do not have even these paltry coverings, and the naked brain or spinal cord extrudes from the body. In rural areas of northern China at the time, the death rate for open spina bifida was 100 percent.
One of the two main reasons infants with open spina bifida die is from infection entering the open lesion on the back. The other main reason they die is that almost all the infants develop hydrocephalus. In the hydrocephalus associated with spina bifida, cerebrospinal fluid — the fluid that cushions and protects the brain — cannot exit the brain cavity. The way out is blocked. If the blockage is not removed, fluid pressure builds, gradually squeezing the brain against the skull and causing brain cells to die, which leads to mental retardation and then death. Some forms of the less severe, closed spina bifida may cause no detectable problems until an event, an injury perhaps, discloses the vulnerable anatomy. Other forms leave the individual weak or paralyzed. If the lesion is high up on the spinal cord, the child usually requires a wheelchair. If the lesion is lower down on the spinal cord, the child may one day walk, but experience other problems with bladder and bowel control. In spina bifida occulta, an invisible lesion delays walking and creates gait disturbances and pain. Some individuals with the milder disabilities may live for years. At least, that has been the case in the United States, where medical technology keeps babies from dying of infection inside the open neural structures, where surgical techniques bring as much repair and wholeness as possible, and where rehabilitative services support the disabled. Most people with spina bifida need treatment for bladder and skin infections, to which they are more susceptible, and many need surgeries to close the opening that exposes neural tissues, to place and replace shunts for hydrocephalus, to untether the spinal cord, and to manage problems with the hips, feet, or spine. These fixes are expensive. Beyond these treatment costs lie expenses for braces and wheelchairs, for catheters inserted as often as six times a day to empty the bladder, for diapers and bowel management programs along with adaptive bathroom equipment, and for the rigid routine to maintain skin integrity. Beyond the cost in dollars is an emotional toll on both the individuals affected by spina bifida and their parents; they are sometimes depressed, often feeling isolated, and always working hard to get through a day.
Medical advances and rehabilitative services, however, were not available in China in the late twentieth century (and are not available today, three decades later, for many Chinese families). The nation was not rich enough, its generally available medical technology not advanced enough, and its resource-poor families not supported enough to care for such disabled babies and children. The parents, frightened and heartbroken, did not have the means to prevent the dangers of infection or overcome the physical impairments. And being poor, they lived in enclaves with no health providers trained in the complex medical needs of severely affected infants and children. When Oakley visited China, the nation was still feeling the consequences of public health strategies initiated by Chairman Mao Zedong. Many academically credentialed physicians had been replaced by minimally trained "barefoot doctors." Although the focus on the most basic level of primary care reduced problems such as infectious diseases, the shift in how monies were allocated left the higher-level tertiary care services underfunded. The medical system was left unable to provide sufficient infrastructure in technology, medical education, research, and personnel to address chronic ailments and impairments. With care and treatment falling desperately short, and with physiology precluding cure because nerve tissue cannot be repaired or replaced, something had to be done to prevent babies from developing NTDs in the first place — to find what stopped the neural tube from zipping shut during its delicate development.
During the 1960s and 1970s, researchers were beginning to gather a body of evidence about the causes of birth defects. They suspected that some NTDs might be due to genetic abnormalities, but it would be three decades before the human genome project would produce enough information to give people hope of finding the genetic keys to birth defects. Other NTDs were thought to be due to infections such as rubella and chickenpox, environmental causes such as radiation, substances such as alcohol and medications, chemicals such as herbicides, or workplace exposures. Studies seemed to suggest weak links to lead in drinking water and toxic exposures from a father's occupation. Other studies identified risk factors having to do with the mother's lifestyle, such as obesity, overheating during pregnancy, and poor diet.
Truth be told, most of the world's babies are born in nations similar to China — with regions of poverty lacking needed medical resources, and with a pile of other equally pressing problems to worry parents and communities. The common folk in China, the United Kingdom, and other places suffering NTD epidemics did not need a scientific approach to tell them what they knew to be true: the people most likely to have babies with NTDs were the poor, who could barely afford to feed themselves, and when they could, it was with low-quality food. The defect appeared in families who lived in colder climates part of the year, where they faced frozen soil and a long period of dormant vegetation; in families who had to put their food in storage for the long, hard winter, subsisting on cabbage, potatoes, or other hardy, pale vegetables; and in families whose babies were born as the leaves fell from trees and as plants withered with the autumn changes — those families whose babies who had been conceived in the dead of winter.
Oakley's team at the CDC specialized in the epidemiology of birth defects, and their greatest interest was spina bifida and other NTDs. "I had heard that the rates may be high in China, but I doubted it," Oakley recalled. "On that first trip to China, one of the things they had us do was visit hospitals. I sat down in a county hospital that had what looked like an obstetrics logbook. I think missionaries out of England, who were obsessed with logbooks, had said, 'Put these ten items down,' so the Chinese did. I started counting babies mentally, a hundred births per page. All the mothers were the same age, about twenty-four, and I thought, 'Gee whiz,' that is the absolute best age to have a child without Down syndrome. But here were all these babies with spina bifida and anencephaly." He quickly calculated the rate in his head, feeling a rising sense of alarm.
Yan Renying came to the international conference armed with data from a pilot project in Shunyi County, where she and her colleagues had found a high rate of infant death. It was the first population-based study conducted in China. The researchers counted fifty deaths out of nearly two thousand pregnancies. One-third of the deaths and many of the complications among newborns had been caused by birth defects. The most common were NTDs. In Shunyi County, which was probably little different from many other places in China, seven babies out of every thousand were born with NTDs. Because China's doors had been closed to the outside world during the previous decade, Yan Renying had had no way of comparing her findings with that of other countries. During her career, she had delivered numerous babies with birth defects, including infants with spina bifida, anencephaly, and other rare defects of the brain and spinal cord. These were experiences shared by many doctors in certain regions of China. These events were sad, but was their frequency unusual?
The data confirmed Oakley's fears: "China may have an epidemic of NTDs." As one of the world's experts in the birth defect, he well knew the rate at which it appeared in other populations. The numbers Yan Renying reported were high. Very high. Oakley quickly seized on the implications of Yan Renying's data, which indicated that the rate in Shunyi County was seven times higher than the rate in the United States. "I thought that could make it seven times easier to do a study in China," he said, especially given China's massive population.
Oakley was aware of an earlier study suggesting, but not proving, that a vitamin called folic acid might prevent a large proportion of spina bifida occurrences and those of other NTDs. Science does not give up its secrets easily. Finding answers requires repeatedly studying substantial numbers of people, gradually building a body of evidence to suggest that the statistical results may be meaningful enough to direct a course of action. So far, the hope that a simple vitamin could interrupt the complex interplay of genes and environment that stopped anatomical development before the brain and spine were complete was no more than a hypothesis, one that had been weakly tested by a study with enough faults that its finding was hardly reliable.
Oakley wanted to test the hypothesis by conducting a randomized controlled trial (RCT), a rigorously designed study that could give the most reliable results. He had spent the last few years trawling for funding, hawking to agencies the idea of running such a clinical trial. But with a small fraction of the US population at risk, attaining the statistical power to get meaningful findings would have demanded an excessively lengthy trial in order to collect enough cases (a case is the countable instance in the population or group of a particular condition under study, and is part of a dataset; it is not the actual person with the condition). Moreover, the costs of running RCTs in the United States involved ghastly sums.
Excerpted from The China-US Partnership to Prevent Spina Bifida by Deborah Kowal. Copyright © 2015 Vanderbilt University Press. Excerpted by permission of Vanderbilt University Press.
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Table of Contents
1 Looking for Gold 1
2 Barefoot Doctors and Shoe-Leather Epidemiologists 13
3 Trust, Control, and Funding 38
4 Suspicion and Doubt 62
5 Squeezed 86
6 Atlas of Heartache 109
7 Hungarians and Changed Plans 130
8 The Community Intervention 148
9 Data Cleaning 164
10 Road's End? 183
11 Lessons Learned 197