sion possible. Our reason for attending to this implementation process is that it offers a powerful benchmark for examining the work in the clinic. We will argue that the recurring problems that families and geneticists en- countered in the clinic were largely hardwired into the way the expansion of newborn screening was implemented. The setup of newborn screening affected which conditions could be screened, how quickly parents could be informed of the results, who would help them interpret and understand the results, who would pay for screening, and what the ensuing medical care would be like. Newborn screening advocates considered evidence selectively while acknowledging that they did not have the answers for some scientifi c issues that would be crucial for implementation. They ig- nored pertinent characteristics of the US healthcare system and left many aspects of executing expanded newborn screening up to local actors, re- gardless of whether these actors were up to the task. They presumed a standard script in which a patient would be identifi ed with and treated for a life- threatening condition, but many patients with metabolic disorders now face ambiguous conditions or disorders for which treatment remains insuffi cient. The expansion of newborn screening with its priorities and si- lences thus set the stage for interactional uncertainties when geneticists discussed screening results with parents.
The Origins of Newborn Screening
Medical review articles invariably locate the origins of newborn screen- ing in the work of Robert Guthrie, a microbiologist and screening advo- cate.3 While experts agree that Guthrie initiated newborn screening, opin-
ions are mixed as to whether his approach struck the appropriate balance between science and advocacy. Over time, Guthrie’s work has come to sig- nify a historical lesson of either a successful public health initiative or the dangers of unbridled screening. The story goes like this.
After the birth of a child with mental retardation and a niece diag- nosed with phenylketonuria (PKU), Guthrie became active in the local chapter of the National Association for Retarded Children (NARC, now the Arc of the United States4). Parent activists founded this grassroots
organization in the 1950s to fi ght discrimination against children with mental retardation in public schools and to provide alternatives to insti- tutional care. The organization counted physicians among its members and its advisory boards, but they were primarily involved because of per-
sonal and family experiences with mental retardation. While serving as vice president of a local NARC chapter, Guthrie was approached by a di- rector of a local children’s rehabilitation center who was looking for an easier way to check phenylalanine levels in children with PKU who had been put on a restricted diet. People with PKU, a rare autosomal recessive genetic condition, are defi cient in the enzyme needed to break down the amino acid phenylalanine. Consequently, phenylalanine builds up in the body and may cause mental retardation and other symptoms. A phenylal- anine restrictive diet was an experimental form of PKU treatment devel- oped in Britain and published in the early 1950s.5
Guthrie’s original research was on cancer, but he shifted his research to PKU screening as a way to prevent some types of mental retardation. He and his assistant, Ada Susi, developed a bacterial inhibition assay that enabled presymptomatic diagnosis of PKU using neonatal blood. Guthrie realized that if plasma phenylalanine levels could identify affected chil- dren, the technique could also be used as a screening method for undiag- nosed children. The attraction of developing a screening method was that the condition could be discovered prior to the onset of irreversible symp- toms and mental retardation might be prevented. In the method Guthrie developed, blood was collected via a heel stick prior to hospital discharge and then blotted on a piece of fi lter paper and mailed to a laboratory. There, a technician punched out a small disk of fi lter paper and placed it on an agar gel plate containing bacteria and a bacterial growth inhibitor. If the sample contained extra phenylalanine, the inhibition was overcome and the bacteria grew. The amount of growth, visible to the eye within a day, was proportional to the phenylalanine level. The screen was inter- preted by comparing the diameter of the growth colony on each sample disk to the colonies of a series of reference disks with standard phenylal- anine content. In healthy people, phenylalanine levels are usually under 120 µmol / L, but the assay was sensitive enough to detect serum phenyl- alanine levels of 180–240 µmol / L. When an elevated level was detected, the laboratory notifi ed the infant’s physician, who explained the result to the family. Before Guthrie’s assay, the only alternative screening method was the urine ferric chloride test developed by Willard Centerwall in 1957, which measured phenylpyruvic acid based on fresh urine in a diaper. This “wet diaper” or “nappy” test was relatively unreliable, although the US Children’s Bureau, housed in the Department of Health, Education, and Welfare, had recommended it as the preferred testing method for infants at risk for PKU (e.g., infants with affected siblings) prior to the Guthrie
inhibition assay because no better option was available.6 The wet diaper
test was only reliable six to eight weeks after birth, when brain damage might already have occurred, and thus was not suitable for population screening.7
In 1961, President John F. Kennedy made federal funding available for research about mental retardation, and Guthrie’s PKU research drew the attention of the Children’s Bureau. The idea of trying to prevent mental retardation rather than rehabilitating affl icted patients was appealing to the Children’s Bureau, which funded a pilot study in 1962 that screened 400,000 infants in 29 states for PKU. The study used Guthrie’s bacterial inhibition assay to test blood and urine for phenylalanine, and established the superiority of the blood test over the urine test. Guthrie’s major tech- nological contribution to PKU screening was thus to create a test that would screen for phenylalanine levels in the blood rather than in the urine and to develop bloodspot technology which facilitated an easy screening infrastructure. Once the hospital- laboratory connections had been estab- lished, most states involved in the Guthrie fi eld trials continued to screen for PKU after the end of the study. By 1964, four states had laws requir- ing PKU screening.
PKU screening was met with resistance by some public health re- searchers and metabolic researchers who doubted that population screen- ing for a rare disease such as PKU was effi cient. Metabolic experts ad- vising the California Department of Public Health, for example, argued against the state coordinating a fi eld trial because the mechanism of PKU, the reliability of the Guthrie test, and the effectiveness of dietary treat- ment were unknown.8 Since treating PKU with a low- phenylalanine diet
had only been introduced in the United States in the mid- 1950s, relatively few infants had aged suffi ciently to predict their cognitive and develop- mental functioning while on the diet. Although the diet suggested bio- chemical success insofar as it lowered phenylalanine levels, its long- term impact on mental retardation was unknown. Only in 1967 did the Chil- dren’s Bureau fund a study that established the long- term physical and cognitive benefi ts of a low- phenylalanine diet when initiated early on. In addition, controversy remained for more than a decade about when to start the diet and how long the patient should stay on it.
The California state advisers also argued that the vast majority of men- tally retarded people did not suffer from PKU and that this community needed social support rather than scientifi c intervention.9 Indeed, research
less than 1 percent of institutionalized mentally retarded people had PKU. Screening for PKU was thus unlikely to make a dent in this population. This low yield posed a problem for population screening. In Massachu- setts, newborn screening proponents were fortunate because the program identifi ed the fi rst case of PKU after only 1,000 infants were screened and found nine cases in the fi rst 53,000 samples. It then took another 50,000 samples to fi nd the 10th case. If it had taken this long to fi nd the fi rst case, enthusiasm for screening might have been dampened. Massachusetts became the fi rst state to pass legislation mandating newborn screening for PKU and the only state without organized medical opposition to this legislation.10 In Washington, DC, no infants were diagnosed within the fi rst
three years of mandatory screening, and health offi cials concluded that they had better use for the resources.
Generally, the American Medical Association (AMA) and its state orga- nizations opposed mandatory screening as an infringement of physicians’ rights to regulate their professional practice. The AMA was concerned about regulatory intrusions into the patient- physician relationship. By the early 1960s, the AMA had been fi ghting government intrusion for several decades on various fronts—including public health clinics, private insur- ance, Medicare and Medicaid legislation—to preserve physician autonomy and a lucrative fee- for- service system.11 In 1967, the American Academy of
Pediatrics cautioned against adopting underdeveloped screening programs too quickly.12
In the face of such resistance, Guthrie, the son of a salesman, became an “evangelist” for universal PKU screening.13 He circumvented professional
objections by working directly with parents, legislators, and the press, and encouraged the National Association for Retarded Children to develop model legislation and lobby for state laws mandating newborn screen- ing. A nameless sociologist hired by the National Academy of Sciences in the early 1970s documented the tug of war between the medical profes- sion and the local ARC chapters to infl uence legislators in 12 states.14 In
Florida, a woman whose child’s PKU was not detected early pushed for a bill mandating screening. She teamed up with Maxine Baker, who had been elected to the Florida House of Representatives, to introduce a bill. Although the state medical association opposed the bill, the Florida Chap- ter of the Association for Retarded Children and some pediatricians sup- ported it. In 1965, a bill was passed that made PKU screening in Florida voluntary. In 1971, an amended law made PKU screening mandatory since the voluntary screening was an insuffi cient incentive to screen infants.15
Grassroots mobilization generated legislative successes in spite of re- sistance from organized medicine. By 1965, 27 states mandated newborn screening and by 1973, an additional 16 states followed suit. An important aspect of this early legislation was that in most states informed consent was bypassed. Parents could object to the screening, but already in 1975 one source stated that “parents are frequently not informed of the test or their right to object.”16 Furthermore, only 25 of the 43 states provided for
medical treatment in their legislation, and only 7 states provided treat- ment free of charge.
In the decades after PKU screening began, various tests were gradu- ally added to newborn screening to justify the low yield of PKU screen- ing and the extensive infrastructure required. Using the same technology, Guthrie and other researchers developed screening tests for congenital adrenal hyperplasia, hypothyroidism, and toxoplasmosis. The intervening decades also saw the advent of two- tiered screening to lower the likeli- hood of false positives.17 With a successful demonstration of two- tiered
screening for congenital hypothyroidism, screening for other conditions such as hemoglobinopathy followed.
From the 1970s through the 1990s, there were various attempts to strengthen universal newborn screening in a more systematic fashion. The federal government initiated legislation in 1976 to support screening for genetic diseases and provided limited funding to pay for screening costs and research. The federal government also developed standards for labo- ratories and screening tests. The Council of Regional Networks for Genetic Services distinguished fi ve system components of newborn screening that included the screening itself, follow- up for positive results, diagnosis, long- term therapy, and an evaluation of the entire system to make sure that benefi ts were realized for the newborn, family, and society.18 This approach
spelled out algorithms, technical requirements, regulatory structures, and quality assurance monitoring for each component of the entire system. Still, newborn screening remained largely a state responsibility with indi- vidual states choosing the panel of screening targets and organizing pay- ment, education programs, opt- out policies, and follow- up procedures.
PKU Screening as a Cautionary Tale
Universal screening for PKU was the fi rst large- scale population screen- ing program in the United States. It became a cornerstone public health
initiative that required close collaboration with healthcare professionals and a well- developed infrastructure integrating laboratories, state health agencies, hospitals, clinical centers, and families. In the following decades, various stakeholders retold the story of the implementation of PKU screening to make broader points about genetic screening, expanded new- born screening, and even the eternal nature- nurture debate.19 PKU and
later sickle cell disease became good case studies through which to think about genetics and screening. Rather quickly, some medical professionals drew a cautionary lesson from the introduction of PKU screening. Evalu- ated against the standards of contemporary biomedical innovations, these professionals argued, the advocates for PKU screening had been lucky. Considering the scientifi c unknowns, the program might easily have failed in its main goal of preventing mental retardation. Proponents had been advocating screening for a condition that was not well understood.
Population screening required a reassessment of PKU. One key issue was the relationship between elevated phenylalanine levels and mental retardation. Once screening began, researchers found that elevated phe- nylalanine levels did not automatically result in mental retardation. Some infants whose newborn screens displayed slightly elevated phenylalanine levels had older siblings with similarly elevated phenylalanine levels but without mental retardation.20 Later, researchers distinguished between
classic PKU and benign hyperphenylalanine, the latter of which did not require dietary modifi cation. In addition, some children who did not have PKU still developed mental retardation because their mothers, who had PKU, did not follow the recommended diet during gestation: the children were affected because of the teratogenic effect of phenylalanine.21 Ma-
ternal PKU was considered an unintended consequence of the success of screening and resulting deinstitutionalization of people with PKU. Few women with PKU gave birth when spending their lives in institutions, yet after screening and early intervention, many of these women went on to have children. According to medical professionals, such women risked undermining the benefi ts of screening if their phenylalanine levels were high during pregnancy: “Given average reproductive rates, the frequency of new cases of PKU- related mental retardation could return to its for- mer level after only one generation if no treatment is available to protect their offspring.”22
The promotion of PKU screening also depended on the success of the low- phenylalanine diet as an effective treatment. Yet understand- ings of dietary regulation were somewhat rudimentary when mandatory
screening was implemented. Some children with false positive results or with what later was recognized as hyperphenylalanine were put on low- phenylalanine diets unnecessarily, depriving them of a crucial amino acid for proper development, which, paradoxically, could also lead to men- tal retardation.23 Furthermore, the benefi ts of detection might have been
squandered if the test was performed too early (in the fi rst hours of life) or too late (month three or four). In addition, the accuracy of the Guth- rie test was not established until 1974. To avoid false negatives, the cutoff point for a positive screen was initially set low. Consequently, the test re- sulted in an initial false positive rate of 90 percent.24 These issues had not
been worked out by the time screening was implemented, and the push for testing might have backfi red if detection, diagnosis, or treatment had failed to fulfi ll the promise of preventing mental retardation. The origin of PKU screening also offered a lesson about the power of advocacy: “The public, including patient advocacy organizations, has more political power than the medical community, and may impose testing without an evidence base.”25 Critics concluded that in the future, scientifi c uncertainties should
be worked out fi rst and public health offi cials should develop a healthcare infrastructure for treatment before investing in newborn screening.26 PKU
screening had worked because the pieces had fallen into place eventually, but the initial programs, according to observers in the next generations, had been built on hope, luck, and activism rather than a solid scientifi c base.
The professional caution narrative dominated a series of authoritative reports issuing guidelines for implementing genetic screening after the highly anticipated decoding of the human genome. Each report drew cau- tious lessons from the implementation of PKU screening. For example, a 1975 report from the National Academy of Sciences, Genetic Screening:
Principles, Practice, and Research, dissected in three chapters what was
neglected in the implementation of PKU screening and drew lessons for the introduction of additional genetic screens.27 The committee charac-
terized the adoption of mandatory PKU screening as “fragmented, uned- ucated, and hurried decision- making”28 and observed with hindsight: “It
is clear that those involved in [PKU] screening in the early days did not anticipate many problems and failed to see the necessity of document- ing their successes.”29 The message was that a more measured, scientifi -
cally supported approach with adequate quality control, and buy- in from health professionals was preferable.
In 1994, the Institute of Medicine (IOM) report, Assessing Genetic
wisdom from newborn screening for sickle cell disease in African Ameri- cans, which revealed similar issues as PKU screening. Screening for sickle cell disease failed to distinguish between carriers and full- blown cases of the disease. Knowing one’s carrier status had few medical benefi ts but led to stigmatization and discrimination. Some in the African- American com- munity perceived the screening as a targeted form of genocide since car- riers were warned against reproducing. This impression was further per- petuated by the fact that some states targeted “high- risk” ethnic groups rather than screening the entire population. Screening also started in the early 1970s but only in 1986 did a randomized clinical trial establish that penicillin prophylaxis reduces infant and childhood mortality for sickle cell disease. The IOM committee found that since 1975 “various diseases had been added to newborn screening programs without careful assess- ment of benefi ts and risks.”30
In 1998, the Task Force on Genetic Testing, an advisory group report- ing to the NIH’s National Human Genome Research Institute, issued a report titled Promoting Safe and Effective Genetic Testing in the United
States. In a lengthy appendix about the history of PKU, the report stated:
“The history of PKU shows that it is easy to exaggerate the ease and effi - cacy of treatment and to understate the costs. . . . Once the idea of new- born screening became established, the program could be rapidly routin-