Published online July 1, 2008
PEDIATRICS Vol. 122 No. 1 July 2008, pp. 192-197 (doi:10.1542/peds.2007-3027)
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HISTORICAL ARTICLE

Adverse Medical Outcomes of Early Newborn Screening Programs for Phenylketonuria

Jeffrey P. Brosco, MD, PhD, Lee M. Sanders, MD, MPH, Michael I. Seider, BGS and Angela C. Dunn, BA

Department of Pediatrics, Miller School of Medicine, University of Miami, Miami, Florida

ABSTRACT

OBJECTIVE. Despite the success of current newborn screening programs, some critics have argued that in the 1960s hundreds of children with false-positive results for phenylketonuria suffered death or disability from treatment with restrictive diets. Medically adverse outcomes after false-positive results may be a reason to be cautious when expanding current newborn screening programs. We sought to determine if newborn screening programs for phenylketonuria before 1980 led to adverse medical outcomes in children with false-positive results.

PATIENTS AND METHODS. We examined the history of newborn screening programs for phenylketonuria in the United States. We reviewed the historical scholarship, conducted a systematic search for medical adverse outcomes, and interviewed key participants in the history of newborn screening programs.

RESULTS. We found no population-based studies of early screening programs for phenylketonuria. One author reported 2 infants treated with restrictive diets after false-positive results for phenylketonuria who were developmentally delayed, and there is unpublished evidence of 4 additional cases of inappropriate treatment, although adverse outcomes were not documented. There were also 4 published reports of adverse medical outcomes after treating children with phenylketonuria variants, as screening for phenylketonuria revealed infants with intermediate or transiently high levels of phenylalanine.

CONCLUSIONS. We found little evidence of death or disability that resulted from the inappropriate treatment of well children who were falsely identified by early newborn screening programs. Because the first decade of newborn screening typically reveals diagnostic and therapeutic complexity, systematic follow-up of screened populations and rapid dissemination of results may reduce morbidity/mortality rates.

Key Words: adverse outcomes • history • newborn screening • phenylketonuria

Abbreviations: NBS—newborn screening • PKU—phenylketonuria • ID—intellectual disability

Universal newborn screening (NBS) for phenylketonuria (PKU) is typically described as one of the most successful public health programs in the history of modern medicine. Since their introduction in the early 1960s, state programs to identify and treat infants with PKU have prevented intellectual disability (ID) (formerly "mental retardation") in thousands of children.1,2 Although the benefits of PKU screening programs now seem to outweigh their costs,3 some critics have argued that the early history of NBS included widespread harm, particularly from inappropriate dietary restriction in infants with false-positive screening results for PKU.4 Pediatrician Norm Fost, in particular, has alleged that hundreds of infants were harmed by restrictive diets after false-positive test results for PKU.5,6 Because advances in science and technology offer the opportunity to expand universal NBS programs to include many new conditions,7 such criticism requires careful consideration: are we poised to repeat alleged mistakes of the past?

In earlier work, we reported that analysis of the first 6 major NBS programs introduced in the United States reveals scant evidence that medical treatment of infants with false-positive results led to substantial morbidity or mortality. To reach this conclusion, we reviewed all available estimates of disease-specific outcomes before and after the introduction of universal NBS for each of the following conditions: congenital hypothyroidism, PKU, congenital adrenal hyperplasia, galactosemia, sickle cell disease, and maple syrup urine disease.8 However, we did discover much more complexity in the early screening and treatment programs for PKU than is usually portrayed in historical descriptions of the program.9 In this present research, we extend our preliminary findings on PKU programs with archival research, oral-history interviews, and an extended search of the published literature to determine if there is evidence of widespread harms from early universal NBS programs for PKU.

METHODS

Literature Search
Our general approach has been described previously8 (see Appendix). Briefly, we searched medical textbooks, historical articles and books, relevant Web sites, and medical and social science electronic databases. For each identified article we searched the reference list to identify new sources and continued this "organic" approach until all sources were obtained. We also searched the electronic databases by author name once we identified key figures for each condition. In this study, we applied similar strategies to references suggested by oral-history interviewees. We also consulted with historians and other scholars in the field to identify any other missed sources. We restricted our search to publications in the English literature. Although this study focuses on the United States, we included all reports from Canada, Australia, New Zealand, and the United Kingdom.


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  		APPENDIX LITERATURE SEARCH

 
Oral-History Interviews
We conducted semistructured interviews designed to elicit information on adverse medical outcomes of NBS programs, with particular focus on PKU. Subjects were chosen because of their involvement in early NBS programs in the United States or Canada, and each subject was asked to suggest other persons to be interviewed. Potential subjects were contacted by e-mail with a standard letter and asked to participate. Subjects were offered telephone or in-person interviews, and one of the authors conducted each interview. Dr Brosco trained Mr Seider and Ms Dunn on techniques of oral interviewing, and all 3 used a standard set of questions to guide the interviews.

Interviewers asked the subject broadly about his or her involvement in early NBS programs and about the risks and benefits of early programs, including accuracy of diagnosis and safety and efficacy of treatment. If false-positive results were not mentioned by the subject, the interviewer asked probing questions, particularly about adverse outcomes of false-positive results. Typical questions included: "In the early years of NBS for metabolic disorders (particularly phenylketonuria), did you have any experience with children with false-positive results who had medically adverse outcomes?" "Did you hear of any such cases?" "Do you know of any evidence that children with false-positive results had medically adverse outcomes [publications, medical charts, other documents]?"

Informed consent was obtained for all interviews, including permission to audiotape the interview. Transcriptions of key portions of each interview were completed, and results were shared with interview subjects to verify accuracy. This portion of our research was approved by the University of Miami Human Subjects Research Office.

RESULTS

By 1966, 27 states in the United States had NBS programs for PKU and ~1 million infants had been tested.10 We discovered no evidence of attempts to formally or informally follow-up children with false-positive results in the early years of NBS programs for PKU. More generally, we discovered no systematic analyses of PKU NBS programs in the United States before 1980 that followed either false-positive or true-positive results at a population level. Great Britain11 and some other European nations have maintained PKU registries since the 1960s, but these data repositories did not include information on infants who were falsely identified as having PKU.

In 1966, Rouse12 described 2 children who were admitted to the pediatric hospital at the University of Texas (Galveston, TX) for failure to thrive. Both children had initial results suggesting PKU but no follow-up testing to confirm the diagnosis; it is not clear from Rouse's report if the confusion began with results from a state NBS program. Texas implemented a pilot PKU program in 1964, and statewide screening became law in 1965.13 After several months of receiving formulas low in phenylalanine, both infants developed the known effects of restricting this essential amino acid: they became listless, had poor gain weight, and developed severe eczematous rashes. Their symptoms resolved within days of starting a whole-milk formula, but both infants continued to demonstrate developmental delay at the time of publication. Rouse concluded that "these cases reflect the fallacy of institution of phenylalanine restriction before a definitive diagnosis of phenylketonuria is established."12

There have been no other published cases of children with false-positive results who were inappropriately treated for PKU. At the American Pediatric Society's annual meeting in 1965, Schneider and Garrard14 presented the case of a child with "persistent hyperphenylalaninemia" who was apparently treated with a low-phenylalanine diet, but no details are available on the child's outcome.14–16 In 1970, Hanley15 reported a personal communication with W.A. Cochrane regarding an infant who was inappropriately treated for PKU, but the outcome of this infant was not described. Our oral-history interviews did confirm that at least 2 other children were started on restrictive diets without appropriate confirmatory tests, but no one had direct experience with children who suffered serious long-term outcomes after inappropriate treatment (Table 1).


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  		TABLE 1 Results of Oral-History Interviews

 
There were many case reports of infants who received overly stringent treatment for PKU in the 1950s and 1960s. In all of these cases, the authors monitored phenylalanine serum levels and believed that the infants did have an abnormality in the metabolic pathway for phenylalanine. Moncrieff and Wilkinson,22 for example, reported in 1961 the case of an infant at Great Ormond Street Hospital (London, United Kingdom). The child had indeterminate screening-test results and was treated for PKU because of high serum levels of phenylalanine, which normalized with a restricted diet. However, the infant continued to have poor growth, restlessness, and a skin rash despite weeks of close follow-up that included adjustments to the diet and careful attention to serum and urine test results. All symptoms resolved when "half-cream dried milk" was begun, and over the next few months the child thrived and maintained normal serum levels of phenylalanine despite the lack of a restrictive diet. Her developmental quotient was reported as 103 at 14 months of age. Other clinicians reported cases of children with PKU who suffered adverse medical consequences during treatment with dietary restriction: seizures17,18; bone changes19,20; hypoglycemia21; failure to thrive22; rash23; megaloblastic anemia24; and death.25 In 1962, Wilson and Clayton23 also noted secondhand reports of deaths of children who had been treated for PKU: "From contacts with other pediatricians it has become apparent that...in some instances there has been a fatal outcome." We identified no case reports after 1970 of adverse medical events that resulted from treatment of PKU, although Bickel26 noted that at least 2 children with PKU who were "seriously" overtreated for months both ended up with IQs of >100.

In some of these cases reports of infants receiving "overtreatment" for PKU, it is not clear whether the infants had "classic" PKU, metabolic variants, or transient elevations of phenylalanine. As universal NBS programs identified large numbers of infants with PKU in the 1960s, PKU specialists began to unravel the complexities of phenylalanine metabolism.9,16,27–29 Some infants with high levels with high serum phenylalanine levels (>20 mg/dL) responded well to treatment with dietary restriction and were considered to have classic PKU. However, many infants had transiently elevated phenylalanine levels, especially those infants born at low birth weight, and they did not seem to require treatment, at least not once their phenylalanine levels normalized (<4 mg/dL). Other infants had persistently "intermediate" levels of phenylalanine (4–20 mg/dL), and it was unclear whether such infants needed treatment, because the long-term outcome for such levels of phenylalanine was unknown.20,30 In total, we identified 4 published cases of infants who apparently did not have classic PKU, were treated with a low-phenylalanine diet, and had adverse medical outcomes (Table 2).


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  		TABLE 2 Published Case Reports of Adverse Outcomes After Treatment of Children Identified With Transient or Intermittent Hyperphenylalaninemia

 
The decision to treat for PKU was complicated by reports that at least some individuals with levels of phenylalanine at >20 mg/dL did not develop ID, and PKU experts understood that a restrictive diet was not without risks.31,32 Critics of PKU NBS in the 1960s also pointed out that some infants with classic PKU received appropriate treatment but still developed ID.20,32 Indeed, treating clinicians reported considerable difficulty in balancing the nutritional needs of the growing infant with the need to keep phenylalanine levels low. There was little agreement on how low to keep phenylalanine levels, how to ensure sufficient protein intake, and whether some unknown but critical nutritional component was missing from phenylalanine-restricted diets.33 As late as 1970 Hanley et al15 reported ongoing problems with malnutrition in patients with classic PKU and less-than-perfect outcomes: 19% (6 of 32) of children treated for PKU before 6 months of age had IQs of <75 by the age of 5 years.

Despite these concerns regarding early NBS programs for PKU, in 1965 the American Academy of Pediatrics Committee on Fetus and Newborn34 recommended screening all newborns for PKU. That same year the American Academy of Pediatrics Committee on the Handicapped Child33 was also supportive of PKU screening programs, although it cautioned that clinicians must avoid "unrealistic expectations" given the many areas of confusion in PKU diagnosis and treatment. In 1966, the National Association for Retarded Children35 sponsored a consensus conference on PKU treatment, and the US Children's Bureau36 helped organize a similar conference a few months later. Both groups of experts concluded that overall PKU screening and treatment programs were beneficial and should be continued. All agreed that more research was needed, and in 1967 Koch and colleagues37 began a 20-year PKU collaborative study sponsored by the United States Children's Bureau (USCB). Despite calls for an untreated control group, most PKU experts believed that dietary restriction was beneficial and that, therefore, it was not ethical to perform a controlled trial.36,38 Thus, the PKU collaborative study compared different treatment strategies and did not have an untreated control group. The authors concluded that their data strongly supported the importance of early initiation and long-term maintenance of a low-phenylalanine diet.37

DISCUSSION

In the early history of universal NBS for PKU, there is no evidence of substantial numbers of children with false-positive results who had medically adverse outcomes. Publication bias against reporting adverse outcomes is an unlikely explanation for our results, because many authors and journals freely reported difficulty with treating children who were believed to have PKU. However, there are no population-based data available on NBS programs such as PKU in the United States, so we cannot exclude the possibility that medically adverse outcomes occurred but were not reported.

The early years of NBS for PKU was an exciting time, when physicians, political leaders, and the general public believed that applying scientific interventions would eliminate or at least greatly reduce the morbidity of ID.8,39 However, a close examination also reveals that experts in PKU confronted many problems in the first decade of NBS programs. Diagnostic criteria for PKU were neither clear nor universally shared, and quality standards for laboratory testing on newborn blood samples were not well established. As a result, there was great geographic variation in the rates of false-positive and false-negative results. It was also not clear in states with NBS programs that every infant was being tested and receiving appropriate treatment. More generally, treatment was complex, clinical phenotypes did not always match laboratory results, and fundamental questions such as the precise cause of ID in classic PKU still had not been answered.

Uncertainty about PKU diagnosis and treatment persisted through the early 1970s, in part because there was no systematic, collaborative review of screening and treatment results from NBS programs in the United States. In some ways, this is not surprising. Compared with northern European nations, the United States has historically not developed large-scale databases to track health. This is partly because of the highly decentralized nature of the US health care system and also because physicians have long resisted federal or state involvement in health care. As late as 1974, only 18% of primary care physicians in the United States agreed that the government should maintain a PKU registry.40 Although there have been some notable recent examples in the United States of coordinating data from NBS programs, the future for expanded NBS programs remains uncertain.41

To review the early history of NBS for PKU is to revisit how physicians and scientists struggled with the complexity of what was initially considered a simple genetic disorder. Today we understand the term PKU to mean a specific condition that is characterized by hyperphenylalaninemia and cognitive deficits that responds to phenylalanine restriction. Classic PKU results from a near-complete absence of active phenylalanine hydroxylase, an enzyme that with oxygen and the biological cofactor tetrahydrobiopterin is responsible for catalyzing the conversion of L-phenylalanine to L-tyrosine. The phenotype of PKU typically results from 1 of >400 possible mutations on chromosome 10 that codes for phenylalanine hydroxylase. Many PKU variants have been identified: each defect in the phenylalanine metabolic pathway leads to its own clinical and biochemical phenotype.29,42

As the complexity of PKU diagnosis and treatment emerged in the 1960s, researchers and physicians confronted an ethical dilemma. Although there were many substantial questions about treatment, few experts32,43 felt that potentially beneficial treatment could be withheld, and no placebo-controlled clinical trials of PKU dietary treatment from birth were ever conducted. This problem for PKU researchers is relevant to current policy debates regarding the expansion of NBS today. Given the extremely low incidence of each individual PKU variant, the complexity of disorders of phenylalanine metabolism could not have been discovered without the implementation of widespread NBS programs. This is likely to be true for most conditions being considered for screening today. Gaucher disease is a recent example among many for which the natural history and its variability are incompletely understood.44,45

The implication of this part of the PKU story is that similar ethical dilemmas will arise if we strictly adhere to Wilson and Jungner's46 "effective, available treatment" as an essential criterion for including conditions in an expanded NBS program. Once treatment is available, it is difficult to withhold. However, with little understanding of the natural history of disease variants, it is difficult to judge whether the benefits outweigh the risks of treatment, especially when treatment may have a high morbidity rate, such as bone marrow transplants. The PKU precedent suggests that there is value in broad NBS programs that systematically follow all identified children, including those with false-positive results, and document both medical and psychosocial outcomes.

A final lesson from the history of PKU NBS programs comes from Joseph Cooper, a political scientist at Howard University who attended the US Children's Bureau consensus conference in 1965 and became a persistent critic of NBS programs. As Cooper listened to the debate among the world's experts in PKU and heard disagreement on nearly every basic point, he asked whether we had lost sight of the larger problems facing the United States, and children in particular. He noted high rates of poverty, limited access to health care, and an unpopular war and then wondered why we have mandatory state laws to identify rare disorders that we do not completely understand.47 Given persistent problems with poverty and access to health care in the United States, Cooper's words remind us that judging the value of any NBS program must be done in the context of broader issues that affect child health.

ACKNOWLEDGMENTS

This work was supported by Robert Wood Johnson Foundation General Scholar Program grant 033954 (to Dr Brosco) and Department of Health and Human Services/Health Resources and Services Administration/Maternal and Child Health Bureau Advisory Committee on Heritable Disorders and Genetic Diseases in Newborns and Children subcontract 06-C210-01 (to Dr Brosco).

We thank Lee Worley, R. Rodney Howell, Diane Paul, and Chris Feudtner for assistance with the manuscript. We also thank the scientists and physicians involved in the early history of newborn screening and treatment for PKU who were so gracious and willing to participate in our efforts to conduct this research.

FOOTNOTES

Accepted Nov 1, 2007.

Address correspondence to Jeffrey P. Brosco, MD, PhD, University of Miami, Miller School of Medicine, Department of Pediatrics, PO Box 016820, Miami FL 33101. E-mail: jbrosco{at}miami.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.

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