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Ross • MandatoRy veRsus voluntaRy Consent foR newboRn sCReening?

[ 299 ]Kennedy Institute of Ethics Journal Vol. 20, No. 4, 299–328 © 2011 by The Johns Hopkins University Press

Lainie Friedman Ross

Mandatory versus Voluntary Consent for Newborn Screening?

ABSTRACT. Virtually every infant in the United States undergoes a heel stick within the first week of life to test for a variety of metabolic, endocrine, and he-matological conditions as part of state-run universal newborn screening (NBS) programs. The history of this mandatory public health program is examined, as well as whether the policy was morally justifiable. Three changes in NBS practice necessitate a re-evaluation of the mandatory nature of NBS. First is the adop-tion of NBS for hemoglobinopathies in the 1980s that led to the identification of many sickle cell carriers and carriers of other hemoglobin variants. In all other contexts, carrier testing requires consent, and there is no moral rationale why NBS ought to be exceptional. Second is the application of tandem mass spectrometry (MS/MS) to NBS in the 1990s that led to the identification of many metabolic conditions and variants, some of which were not treatable and others of which had unknown clinical relevance. To the extent that the conditions do not need emergent diagnosis and treatment, there is less justification for mandatory screen-ing. Third, there is great interest in using residual blood spots for research, and the cornerstone of research ethics is the voluntary consent of the participant (or his or her proxy). These three changes support revising mandatory NBS with a tiered consent process to best balance respect for parental autonomy and the promotion of children’s health.

Virtually every infant in the United States (U.S.) undergoes a heel stick within the first week of life to test for a variety of metabolic, endo-crine, and hematological conditions as part of state-run universal

newborn screening (NBS) programs. In the U.S., NBS began in the 1960s for phenylketonuria (PKU), a metabolic condition that causes intellectual disability if left untreated. I review the history of how NBS came to be a mandatory public health program that did not require parental consent1

and examine whether the policy was morally justifiable. I then examine how three changes to NBS programs are prompting a re-evaluation of the

kennedy institute of ethiCs jouRnal • deCeMbeR 2010

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mandatory nature of NBS. The three changes are: (1) the implementation of hemoglobinopathy screening by hemoglobin electrophoresis; (2) the implementation of tandem mass spectrometry (MS/MS), a platform tech-nology that tests for many metabolic conditions using one sample; and (3) the increasing interest in research on residual blood spots collected for NBS. I argue that even in its original incarnation, mandatory NBS for PKU was not justified and that the three changes further support the need to revise state laws to require parental consent. A tiered approach to consent may best balance respect for parental autonomy and the promotion of children’s health.

HISTORY OF NEWBORN SCREENING: THE CASE OF PKU

The history of NBS begins with phenylketonuria (PKU). Phenylketonuria is a genetic condition that leads to intellectual disability if left untreated. In 1934, Asbjorn Folling discovered that exposing the urine of certain children with intellectual disability to ferric chloride resulted in a green color, which identifies the presence of phenylpyruvic acid—a metabolite found in those who lack the enzyme phenylalanine hydroxalase—in the urine (Folling 1934). In 1954, it was reported that diets low in phenylalanine could reverse the major biochemical abnormalities associated with PKU and therefore prevent intellectual disability (Bickel, Gerrard, and Hickmans 1953). In 1957, California initiated screening by testing the urine in infants’ diapers for phenylpyruvic acid (Centerwall 1957). There were obstacles to urine sample collection and testing by parents and physicians, and it was judged not to be a suitable test for population-wide screening by the Children’s Bureau (now known as the Maternal and Child Health Bureau) (National Research Council 1975, pp. 25–26). However, in 1961, Robert Guthrie developed both the bacterial inhibition assay (BIA), a blood-based method for PKU screening, and a method to collect and store a small amount of blood on filter paper (now known as the Guthrie card). These two discover-ies made wide-scale population screening both feasible and acceptable.

Although the frequency of PKU in the population was unknown, three factors coalesced to garner widespread interest and support for a program that promised to be able to screen, diagnose, and prevent at least one cause of intellectual disability. First, President Kennedy had a special interest in intellectual disabilities, partially due to his sister Rose. In October 1961, Kennedy established the President’s Panel on Mental Retardation, which submitted a report to the president one year later (President’s Panel on Mental Retardation 1962). Within two years, Kennedy signed Public Law


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88–164 and Public Law 88–156, which authorized the Secretary of Health, Education and Welfare to make grants to states for comprehensive plan-ning in mental retardation (Krause and President’s Committee 1986, p. 6). The involvement of the federal government was matched by the states “as governors and their administrators followed the lead of President Kennedy” (Krause and President’s Committee 1986, p. 2).

A second key factor was the growing strength of the National Associa-tion for Retarded Children (NARC), now known as the ARC (Association for Retarded Citizens). Founded in 1950, mainly by parents of children with intellectual disabilities “who felt neglected by professionals” (Swazey 1971, p. 895), it opened its headquarters in New York City in 1954. Later that year, President Eisenhower proclaimed the first National Retarded Children’s Week (Segal n.d.). By 1955, membership reached 29,000 with 412 local units and would reach 100,000 members in 1965 (Segal n.d.). NARC played a major role in the passage of federal legislation and also advocated for greater research funding by the federal government for intel-lectual disabilities. Between 1956 and 1961, identifiable federal support for mental retardation services and research increased from $14 million to $94 million (Segal n.d.).

Guthrie’s own early research received financial support from NARC. In 1961, he conducted a study to evaluate PKU at the Newark State School near Rochester, New York. Samples were collected of both urine and blood, and Guthrie found 23 cases of PKU in the blood samples, four more than had been discovered by urine testing (Guthrie 1961). NARC encouraged him to publish quickly, and the findings appeared as a letter to the editor in the Journal of the American Medical Association in October 1961. Fol-lowing publication of the findings, NARC released a statement emphasizing “the urgency of testing all newborns for metabolic disorders, including PKU” (National Research Council 1975, p. 27).

In 1962, the Children’s Bureau funded a pilot study involving more than 400,000 infants from 29 states that involved both blood samples collected before the infant was discharged from the hospital nursery and urine samples collected from a wet diaper when the infant was 3 weeks old. Both blood and urine phenylalanine were tested using the BIA. Unfortunately only 64 percent of infants provided both blood and urine samples, and there were numerous false negative urine tests. Although there were a significant number of false positive and a few false negative results, the BIA test on blood spots was judged to be sufficiently accurate for the Children’s Bureau to advocate for a national screening effort in 1964 (Reilly 1977, p. 44).


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The Public Health Services Committee of NARC, with Robert MacCready as chair, went “on record as recommending mandatory legislation for the screening of PKU” (National Research Council 1975, p. 27).

The third key factor was MacCready himself, the state laboratory direc-tor for Massachusetts. Although MacCready was assigned to collect samples from 10,000 infants for the Children’s Bureau pilot, he was determined to test all infants born in Massachusetts. The Massachusetts state labora-tory discovered 3 cases in the first 8,000 infants tested, and MacCready publicized these results widely. Within six months after testing began, every hospital in Massachusetts was participating (Koch 1997, p. 39). In fact, 165,000 of the 400,000 infants tested in the pilot study and 10 of the 39 infants identified with PKU were from Massachusetts.

Despite the fact that virtually every hospital in Massachusetts volun-tarily participated in PKU screening, MacCready lobbied for mandatory legislation in Massachusetts because he thought uptake was not growing fast enough (Koch 1997, p. 39). MacCready also was instrumental in encouraging NARC to support mandatory legislation (Koch 1997, p. 40). In 1964, NARC drew upon the Massachusetts statute for model language for mandatory PKU testing. Although the statute’s language was not ad-opted uniformly, 43 states had passed similar legislation by 1968 (National Research Council, 1975, p. 48). Today, 48 states have mandatory NBS programs, although in most states, some or all parents may opt out.

OPPOSITION TO MANDATORY PKU SCREENING

Not everyone supported mandatory screening. The most vocal opposi-tion came from organized medicine. Diane Paul (1999, p. 209) notes that the two main objections were whether there were enough data to justify such a program and concerns about the government’s dictating medical care. She argues that the issue of mandated screening was not initially an important objection because the issue of seeking consent for most medi-cal interventions would not become commonplace until the 1970s (Paul 1999, p. 209).

The debate within the American Academy of Pediatrics (AAP) in the 1960s supports her hypothesis. The AAP Committee on Fetus and New-born (1965) published a statement in Pediatrics in 1965 that supported universal screening for PKU and mellituria (now known as galactosemia) but did not mention the issue of whether screening should be mandatory or should require voluntary consent. It considered but rejected screening for a variety of other conditions because the committee did not believe


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that they were ready for application to all newborns. In the same issue of Pediatrics, the AAP Committee on the Handicapped Child (1965) argued that more research on PKU, and not universal screening, was in order. The committee agreed “that children with PKU can be helped if the problem is detected early enough and adequate treatment is begun promptly and maintained adequately,” however, it argued that much more data must be collected before one can make definitive statements about the precise value of diet, who should be placed on the diet, and the duration of therapy (AAP Committee on the Handicapped Child 1965, p. 503). In 1966, an ad hoc committee of scientists and representatives of the AAP Committee on Nutrition, the Committee on Fetus an Newborn, and the Committee on the Handicapped Child produced a joint statement that cautioned: “Failure to achieve expected health benefits as a result of premature and injudicious legislation may do irreparable harm to the orderly development of mass screening techniques for the early identification of disease and undermine public support of further research” (AAP 1967, p. 623). The joint statement concluded: “The American Academy of Pediatrics favors neither the extension of current compulsory legislation nor passage of new legislation for the compulsory testing of newborn infants for the presence of congenital metabolic disease” (AAP 1967, p. 624). The AAP’s position was endorsed by the American Medical Association, practitioners, and some scientists (Paul 1994, p. 324).

Part of the early objection by health care providers to PKU screening was the unorthodox way in which Guthrie had published his data. For expedience, NARC had encouraged Guthrie to publish the results of the field trial as a letter to the editor. A peer-reviewed full-length manuscript did not appear in print until two years later (Guthrie and Susi 1963). There were also concerns that the diet had never been tested in a randomized clinical trial (Nitowsky 1973) and that the claims of benefit made such a trial appear to be unethical (Holtzman 1977). However, “in the face of the parents’ claim that screening could prevent mental retardation that caused suffering and cost the government a great deal, the medical opposition apparently had little impact on legislators” (National Research Council 1975, p. 46).

Criticisms of newborn screening became linked to the issue of consent in the 1970s (Paul 1999, p. 209). In 1973, the state of Maryland estab-lished a Commission on Hereditary Disorders with a majority of consumer members (Holtzman 1980, p. 250), which established a written parental consent provision for NBS in 1976. Interestingly the Maryland chapter of


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the AAP “asked the Commission to modify its requirements for written parental informed consent for neonatal screening because it feared that informed consent would be extended to other routine procedures and also that many parents would refuse to allow their infants to be screened” (Holtzman 1980, p. 253).

To evaluate the Maryland chapter’s concern, researchers at Johns Hop-kins University conducted a study in 1978 of all 39 Maryland hospitals with active obstetrical units. They contacted hospital administrators, di-rectors of nursing, and maternal child health service chiefs to evaluate the awareness of the PKU parental consent regulation. They found that only 69 percent of chiefs of pediatrics and 53 percent of nursing administrators were aware of the regulation; fewer chiefs of obstetrics (30 percent) and hospital administrators (29 percent) were aware. The majority of providers (238 of 367 (65 percent)) opposed the requirement of voluntary consent, although the vast majority supported informing the parent that the PKU test would be done. The one exception was floor nurses (who were responsible for the provision of information to the patients). Only 35 percent of floor nurses supported seeking parental consent, and approximately 67 percent of those who did not support it also did not even support an educational requirement (Faden et al. 1982).

The study also found that the costs involved in compliance were low. Two-thirds of nurses stated that obtaining consent or refusal took one to five minutes. In a one year period, 27 of 50,000 mothers refused (0.05%), which the authors point out is “100 times less than the chance of missing a PKU infant because of a false negative test result” (Faden et al. 1982, p. 1351). The researchers located seven of those who refused, and their reasons indicated a poor understanding of the screening. Two women did not speak English, although one consented to screening in her private pediatrician’s office after it was explained in her native language, and one of the others who refused initially also had screening done in her private pediatrician’s office (Faden et al. 1982). The researchers also did a study to compare knowledge when mothers were given a standard disclosure versus when they gave consent. They found that the knowledge score was significantly higher after giving consent (Holtzman et al. 1983). Thus their studies contradicted the three main arguments against voluntary consent: (1) screening is in the child’s best interest and parental consent would reduce uptake; (2) consent is too complex and costly; and (3) consent would be perfunctory. The data were presented to the Commission which concluded that the data eliminated the major moral and policy objections to the


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parental consent regulation. The Commission chose to continue with the parental consent requirements (Faden et al. 1982).

In an accompanying article, Ruth Faden, Neil Holtzman, and Judith Chwalow (1982) commented on their findings. They acknowledged that their data showed that the consent requirement had achieved meaningful parental choice and that the costs of implementation were small. However, they argued that “it does not necessarily follow from the empirical results of our evaluation study that parental consent and refusal requirements ought to be public policy for PKU screening” (Faden, Holtzman, and Chwalow 1982, p. 1396). They argued that the primary function of a parental con-sent requirement is to protect the welfare of children, and not to respect the autonomy of the proxy (Faden, Holtzman, and Chwalow 1982, p. 1397). They also argued that the harm principle effectively overrides any parental right to refuse PKU screening rooted in a principle of parental autonomy. Of note, Faden, Holtzman, and Chwalow only wanted screening to be mandatory for conditions in which the benefits greatly outweighed the harms. In cases of more ambiguous benefit to the child, they conceded that parents should have the right to decide. In all cases, however, they argued that there was an obligation to inform parents about NBS (Faden, Holtzman, and Chwalow 1982).

George Annas (1982, p. 1401) published a commentary in which he stated that Faden and colleagues make “two fundamental mistakes.” First, he argued that their data supported voluntary screening for PKU screen-ing with minimal risk of missing an affected infant. At the observed rate, it would take 500 years before one case was missed because of parental refusal (Annas 1982, p. 1402). In fact, a study from 1979 calculated the percentage of newborns screened from 12 states and found that the two states with the highest percentage of newborns screened were Maryland, which has a voluntary program, and New Hampshire, which allows parents to refuse screening for any reason (Sepe, Levy, and Mount 1979). Second, Annas questioned whether the state can properly mandate screening for diseases that the children almost certainly do not have. He argued that the question was not whether “parents have the right to consign their child to a state of irreversible mental retardation?” as Faden and colleagues suggested, but rather the question was: “Is mandatory screening for PKU a legitimate exercise of the state’s public health powers?” (Annas 1982, p. 1402). Annas agreed that infants should be screened for PKU, but the data showed that mandatory screening was not necessary. Rather, Annas argued that there were moral reasons why a parent may refuse based on religious belief or


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on their own assessment of risks and benefits. For example, parents are more likely to receive a false positive result than a true positive, and data from the time found that over one-third of parents expressed heightened concern about the health of their infant because of repeat testing (Sorenson et al. 1984). Annas predicted that this would become a bigger problem as programs began to screen for more and more conditions, a prediction that turned out to be prescient (Tarini, Christakis, and Welch 2006; Waisbren et al. 2003).

The debate about informed consent for NBS has gained momentum in the last two decades. The main argument in support of voluntary consent is based on the great deference American society gives to individual decision making about health care matters (Andrews 1985a, p. 5), and in the realm of pediatrics, the deference given to parents about how they raise their children (Buchanan and Brock 1989; Goldstein, Freud, and Solnit 1979; Ross 1998). Parents are presumed decision makers for their children, and they are given great leeway in deference to family privacy and autonomy. Those who support parental autonomy and the right to refuse NBS con-cede that screening for conditions like PKU is clearly in a child’s medical best interest. However, even if a failure to consent is morally problematic, overriding parental authority is very difficult to justify when the likelihood of a bad outcome is quite remote (Newson 2006). Rather, the threshold for state intervention is not whether a parent’s action is less than ideal, but whether a parent’s decision is so bad as to be described as abusive or neglectful (Buchanan and Brock 1989; Clayton 1992; Goldstein, Freud, and Solnit 1979; Ross 1998). Given that the likelihood of a true positive screen is quite low, parental refusal does not fall below this threshold.

Another argument in support of voluntary consent is that it necessitates that health care providers educate parents in order that they can make an informed decision. Parental understanding about the meaning of positive results will promote compliance with further testing and follow-up, when necessary (Clarke 1997). It may also help reduce the anxiety that may result from an initial positive screen because parents will be told up-front that a positive screen is more likely to be a false positive than a true positive (Tarini, Christakis, and Welch 2006). In fact, the literature on parental reactions to false positives shows that it is not always benign. Data show that many parents do not understand a false positive test result (Sorenson et al. 1984; Tluczek et al. 1992; Waisbren et al. 2003), even if it is accom-panied by counseling (Mischler et al. 1998). For example, in the Wisconsin NBS Cystic Fibrosis (CF) study, approximately 5 percent of parents whose


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infants had false-positive results still believed their children might have CF when questioned a year later (Tluczek et al. 1992). This is not to deny the benefit of diagnosing a true positive by newborn screening, particularly if effective treatment exists, but only to acknowledge the possible harms, especially since false positives are much more common than true positives (Grob 2006).

EXPANSION OF NBS: THE CASE OF HEMOGLOBINOPATHY SCREENING

The expansion of NBS in the three decades following the passage of PKU legislation in Massachusetts was both fast and slow. Adoption of PKU testing was quick: Within five years, PKU screening was being per-formed universally in 43 states. But the number of conditions that were added to state screening panels rose slowly. One reason was that each condition added required a new technology with the result that most states were screening for fewer than eight conditions in 1985 (Andrews 1985b). However, in 1986, Gaston and colleagues published a clinical trial that showed that penicillin prophylaxis reduced morbidity and mortality in infants with sickle cell disease(Gaston et al. 1986). A National Institutes of Health (NIH) Consensus Panel was quickly convened and recommended routine hemoglobinopathy NBS (NIH 1987).2

Hemoglobinopathy screening challenged the status quo because it in-cidentally discovered those who are heterozygote carriers of sickle cell, commonly known as sickle cell trait. Like PKU, sickle cell disease is an autosomal recessive condition, meaning that one must inherit one abnormal gene from each parent. The parents are heterozygote carriers for the condi-tion but do not have any of the symptoms and may not even be aware that they are carriers. This is particularly true when a condition is very rare, like PKU, in which 1 in 60 white Americans are carriers, and the disease occurs in 1 in 15,000 white Americans and even less frequently in other ethnicities. In contrast, 1 in 10 African Americans are carriers of sickle cell, and the disease occurs in 1 in 400 individuals of African ancestry and less commonly in those of other geographical ancestry.

A test to identify sickle hemoglobin called the Sickledex was developed in the 1968 and was used for population screening of adults for carrier identification (Nalbandian et al. 1971). The Sickledex test was problematic in several ways: (1) it did not distinguish between carriers of the trait and the disease itself; (2) it only identified individuals with hemoglobin S but not other hemoglobin variants that may be responsible for sickle cell disease variants; and (3) false positives occurred in persons with a high quantity


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of fetal hemoglobin. The population screening program was a political disaster leading some African Americans to call it a genocidal program (Wailoo 2001). Although a few states screened for hemoglobinopathies in NBS panels in the 1970s and 1980s, the problems with the test, the lack of effective treatments to prevent or reduce morbidity from the disease, and the political controversies that surrounded the population screening programs of the 1970s prevented more widespread uptake. But this changed with the 1986 publication by Gaston and colleagues. By 1994, 42 states were screening for sickle cell and other hemoglobin variants (Andrews et al. 1994, p. 42).

Hemoglobinopathy screening identifies genetic carriers of sickle cell hemoglobin and many other hemoglobin variants. In general, carriers are healthy, and genetic identification of carriers is mainly done to inform reproductive choices. There is widespread agreement that carrier genetic testing should be voluntary and should require the informed consent of the individual to be tested (Andrews et al. 1994, p. 101). Given the mandatory nature of newborn screening, one must decide how to handle the incidental discovery of sickle cell trait. A May 1989 issue of the journal Pediatrics found that each state had its own policy and practice—with some states disclosing and others not. In 1994, the Institute of Medicine (IOM) issued a report stating that carrier information belongs to the child and that the parents, as the child’s surrogates, should be informed and should give pa-rental consent before testing is done (Andrews et al. 1994, p. 6).

The question of disclosure appeared to be resolved with the 1994 IOM report. Whereas the AAP Committee on Genetics (1992) made no mention of the controversy about voluntary or mandatory newborn screening in its 1992 statement, in its 1996 newborn screening fact sheets, the Committee concluded:

Although no clear consensus of the committee was forthcoming regarding informed consent for newborn screening, a strong recommendation was made that informed consent be an integral part of newborn screening, including disclosure of the benefits and risks of the tests and treatments, and that in-formation unrelated to the health of the individual (e.g., carrier status and paternity) may be disclosed. (AAP Committee on Genetics 1996, p. 473).

However, the Committee was divided about obtaining consent for “estab-lished tests in which patients would clearly benefit from early diagnosis and treatment (e.g., phenylketonuria [PKU] and congenital hypothyroidism).” (AAP Committee on Genetics 1996, p. 473). Some members argued that state departments of health should mandate the offering of such testing,


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whereas others argued that the testing itself should be universally mandated. However, all agreed that informed consent would benefit parents by serv-ing as an education tool (AAP Committee on Genetics 1996, 473–74). In 2001, the AAP Committee on Bioethics, also argued in favor of parental consent for newborn screening. Like the IOM report, it also concluded that “carrier status results that are obtained incidentally should be conveyed to parents who have undergone previous counseling and have given consent” (AAP Committee on Bioethics 2001, p. 1453).

Today, hemoglobinopathy screening is part of all state NBS programs in the U.S., and many hemoglobinopathy carriers are identified. Carriers are also detected in many CF NBS programs. If gene chips become rou-tine in NBS, many more carriers and affected children will be identified. Given the general consensus that elective carrier testing of children is not appropriate (AAP Committee on Bioethics 2001; ASHG/ACMG 1995; Andrews et al.1994; Working Party of the Clinical Genetics Society (UK) 1994), mandatory identification of carrier status, even if unintentional, is morally problematic. The need for consent is further heightened because the identification of a child as a carrier affirms that at least one parent is a carrier, a parent who may have elected not to undergo elective prenatal or preconception screening. Thus, the incidental identification of genetic carriers in NBS means that some adults are being told about their carrier status, despite their prior informed refusal to be tested. This gives further support to the elimination of mandatory screening and to required parental education and consent.

EXPANSION OF NBS: THE CASE OF TANDEM MASS SPECTROMETRY (MS/MS)

Mass spectrometry was developed more than 100 years ago, but the use of mass spectrometers in series (tandem) has only been applied to NBS since the early 1990s (Millington et al. 1990). Tandem mass spectrometry (MS/MS) is a platform technology that allows for multiplex testing for many metabolic conditions using one sample. Whereas expansion of NBS initially entailed a new test for each condition added, MS/MS can detect dozens of conditions simultaneously. In 1994, IOM considered the development and implementation of platform technologies in NBS panels. It concluded that newborns should not “be screened using multiplex testing for many disorders at one time unless all of the disorders meet the principles described . . . .” (Andrews et al. 1994, p. 5). These principles included: (1) benefit to the newborn, (2) a confirmatory system in place, and (3) availability of treatment and follow-up (Andrews et al., 1994).


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In 2002, the Maternal and Child Health Board of the Health Resources and Services Administration (HRSA) funded the American College of Medical Genetics (ACMG) to evaluate 84 conditions for possible inclusion in a uniform screening panel. The ACMG developed and implemented a non-validated survey instrument to determine whether a condition should be included in the uniform panel (Botkin et al. 2006). The vast majority of the conditions being evaluated were identifiable by MS/MS, in part because the ACMG instrument gave significant weight to multiplex test-ing methodologies. In its report, “Newborn Screening: Toward a Uniform Screening Panel and System,” the ACMG recommended the inclusion of 29 primary or core conditions and 25 secondary conditions. Most of the secondary conditions were identified through MS/MS as part of the dif-ferential of the 29 core conditions, but did not themselves meet enough of the ACMG’s other criteria, such as whether there was an at least partly effective therapy or whether diagnosis provided benefits to the child or family (ACMG/HRSA 2005). In 2005, the Department of Health and Hu-man Services Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children voiced its support for the uniform panel. Although there are serious criticisms regarding the ACMG methodology, the endorse-ment by the Advisory Committee before the report was complete, and the overlap in membership between the authors of the ACMG report and the Advisory Committee (Botkin et al. 2006; Natowicz 2005), contributed to all states having now adopted or being in the process of adopting the uniform panel. Twenty of the 29 core conditions can be identified by MS/MS. The three hemoglobinopathies can be detected by high pressure liquid chromatography or bioelectric focusing although some work is being done to be able to use MS/MS for these conditions as well. Only six of the core conditions require unique testing methods: congenital hypothyroidism, biotinidase deficiency, congenital adrenal hyperplasia, galactosemia, CF, and hearing loss. Of the 25 secondary conditions, all but two are detect-able using multiplex platforms, and these two are included because they are part of the differential diagnosis of galactosemia (President’s Council on Bioethics 2008, p. 41).

The widespread adoption of the uniform panel represents a paradigm shift in NBS. Traditionally, the justification for using the state’s public health powers to mandate screening depended on meeting the Wilson and Jungner criteria, which include such requirements as the condition should be an important health problem, the natural history of the condition should be well understood, and there should be a suitable test acceptable to the


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population, as well as an accepted treatment and an agreed upon policy on whom to treat as patients (Wilson and Jungner 1968). The expansion of NBS to include conditions identified by MS/MS for which the effectiveness of treatment, the need for treatment, and/or the duration of treatment are unknown represents a shift in focus from public health emergencies to the provision of a public health service (Grosse et al. 2006).

The paradigm shift has not gone unnoticed by public health and parent advocates, who now argue that the Wilson and Jungner criteria are obsolete (Howell 2006; Bailey et al. 2006). Duane Alexander and Peter Van Dyck (2006), of NIH and HRSA respectively, support expanded screening, even if the Wilson and Jungner criteria are not met, in order to identify infants for whom new interventions can be tested. Their position reiterates the ACMG/HRSA report, which states: “Multiplex testing and the identifica-tion of conditions falling outside of the uniform screening panel provides the opportunity for such conditions to be included in research protocols” (ACMG/HRSA 2005, p. 20). However, numerous professional organiza-tions reject this justification. For example, Virginia Moyer and colleagues (2008, p. 34) writing on behalf of the United States Preventive Services Task Force have argued that it is not ethically justifiable to mandate screening “in order to recruit research subjects.”

Advocates of expansion also argue for a broader definition of benefit including (1) avoiding the diagnostic odyssey and (2) benefit to the family for reproductive and other planning purposes. They also argue that the small incremental costs of additional tests performed through MS/MS al-low for even broader understanding of benefit. Alexander and Van Dyck (2006, p. S352) maintain that the dogma “that it is appropriate to screen only for conditions for which effective treatment already exists . . . fails to consider other benefits of diagnosis in the newborn period and dooms us to continued ignorance . . . .”

The problem with this position is that the broader definition of benefit fails to acknowledge that a broader definition of harms also may result from expanded screening, including (1) the therapeutic odyssey as families attempt to find ‘treatments” outside of the traditional medical arena; (2) the psychosocial and emotional harms from the increased number of false positives; and (3) the therapeutic harms that may result from treating a child who may never develop symptoms. The argument that adding tests using MS/MS is a minimal addition fails to view newborn screening as a system that includes the following elements: education, screening, follow up, diagnosis, treatment, and evaluation (President’s Council on Bioethics


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2008, p. 7). It also fails to take into account the opportunity costs (Baily and Murray 2008).

In addition, there are risks of overdiagnosis and overtreatment. This issue is not unique to MS/MS. In the 1970s, children were identified with histidinemia and were placed on restrictive diets until researchers showed that the condition was often a normal variant (Levy 2003). But the risk of overdiagnosis increases dramatically when MS/MS is used because MS/MS permits very rapid and very accurate measurement of many different types of metabolites that can be analyzed individually and in ratios with other metabolites leading to novel patterns or metabolic profiles of unknown significance. For example, within the first few years of the adoption of MS/MS, the state of Wisconsin identified over two dozen Hmong children with 2-methylbutyrl-CoA Dehydrogenase Deficiency (2-MBAD), a condition that rarely had been diagnosed previously. These children were placed on restrictive diets, although it is now believed that the disorder identified is a normal variant (van Calcar et al. 2007).

Platform technologies that allow for testing of multiple conditions will only grow with time. Recently, the National Institutes of Child Health and Development instituted a new research initiative on NBS. One goal is the development of systematic methods to identify additional conditions ap-propriate for newborn screening (Alexander and Hanson 2006).

One way to address the variability in conditions that are identified by NBS is to consider a two-tiered consent process for NBS. The Massachu-setts Department of Public Health successfully used a two-tiered approach for a decade beginning in 1999 when it included 10 core conditions in their NBS panel including medium chain acyl CoA dehydrogenase defi-ciency (MCAD), which was identified by MS/MS. CF and 19 additional conditions identified by MS/MS were offered as an optional program for no additional fee. Although the core panel was mandatory, parents were asked to give written permission to the pilot screening and more than 97 percent did (Pass et al. 2003). In February 2009, Massachusetts decided to incorporate these conditions into the standard newborn screening on the grounds that there were sufficient benefits to screening and the pilot had given them the experience to maximize benefits and minimize harms (New England Newborn Screening Program n.d.).

The uptake of 97 percent for a pilot newborn screening program is quite high, although slightly lower than the >99% uptake for nonexperimental newborn screening in Maryland. In other pilot studies and research projects in the newborn period, uptake is usually more than 90 percent (Clarke


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1997; Ross 2003). When California introduced MS/MS under a research protocol, 90 percent of those offered the screening agreed to participate. However, only 52 percent of parents were offered screening because of the cost and time involved (Feuchtbaum et al. 2006).

Given such high uptake rates, one must ask what the problem is with seeking voluntary consent for both those conditions that meet the Wilson and Jungner criteria and for those that do not. One problem would be the failure to be offered the testing as occurred with California’s introduction of MS/MS under a research protocol. This problem can be solved by man-dating the offering of such screening rather than mandating the screening itself; that is, by requiring that health care providers offer the test and giving the patient the opportunity to make an informed decision. The “manda-tory offer policy” was quite effective for maternal serum alpha fetoprotein (MSAFP) in the prenatal setting in California from 1986 to 1995 (Cun-ningham and Tompkinson 1999), and such a policy could be modified for NBS.3 In reality, many of today’s mandatory NBS programs are not truly mandatory because they permit parents to opt out, as such they might be better described as mandatory offer programs. However, these programs are not truly “mandatory offer programs” because health care providers frequently fail to offer the test and merely inform the parents that testing is to be done and proceed unless the parents actively refuse.

Properly performed a “mandatory offer program” is similar to an opt-out parental consent process, which has precedence in pediatrics in the way immunization delivery occurs. In both cases, the health care providers seek parental permission, although testing (or vaccinating) is expected to occur unless the parents actively refuse. To properly implement a mandatory offer program or an opt-out parental consent process requires that health care providers give parents more information than they currently do about the purpose of the heel stick and the benefits and limitations of screening.

A problem with the opt-out parental consent process described above is that it fails to distinguish between those conditions that have a highly favorable benefit:risk ratio and those that do not. Although parents may refuse some vaccines and accept others, parents who refuse state-sponsored NBS currently only have the option of refusing screening for all conditions. It would be in the best interest of infants if NBS programs distinguished between those conditions that, if identified, would be characterized as public health emergencies—e.g., PKU—and other conditions. Although opt-out parental consent may be morally justifiable for conditions with a highly favorable benefit:risk ratio, a more robust (opt-in) parental consent


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process is more justifiable when the benefit:risk ratio is less clear cut. Thus one could imagine a tiered approach with opt-out procedures for those conditions that meet the Wilson and Jungner criteria and an opt-in or more formal consent process for those conditions that do not.

A tiered approach has been supported by the Task Force on Genetic Screening (Holtzman and Watson 1997), the Newborn Screening Task Force (2000), and the President’s Council on Bioethics (2008). The main benefit of the tiered approach is its acknowledgment that the clinical ben-efits provided by screening vary between conditions and that screening that provides great benefit to the child should be highly encouraged whereas greater parental discretion should be given to screening for conditions of lesser evidence-based value. The Task Force on Genetic Screening and the Newborn Screening Task Force suggested two tiers, with waived written consent for tier one and written informed consent for tier two. Likewise, the President’s Council on Bioethics discussed mandatory screening for tier one and voluntary screening with informed consent for tier two. The proposal presented here is slightly different, arguing for consent for both tiers, with more directive education and counseling with respect to deci-sion making for conditions included in tier one and wider support for parental discretion for conditions included in tier two. The main benefit of this proposal is that requiring consent for both tiers is more consistent with all other medical decisions made for children and shows respect for parental decision-making authority.

The main objections to a tiered process are not moral but pragmatic. First, a tiered approach would have to be reviewed frequently and revised according to changing knowledge that influences which conditions meet the Wilson and Jungner criteria. In August 2008, physicians involved in research on severe combined immunodeficiency syndrome (SCID) recom-mended its inclusion in the uniform panel. The data were reviewed by the Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children (2009) and were told that SCID was not ready for inclusion in the uniform panel. However, in January 2010, the Advisory Committee recommended its inclusion after Dr. Jennifer Puck and colleagues presented additional data to show its efficacy (Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children Committee 2010). Other conditions also are being proposed and reviewed. To the extent that a tiered approach would be incorporated into state legislation, as is current practice for state newborn screening panels, it will require legislative revisions on a frequent basis. This will demand much time and political investment,


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and it will be important that the recommendations be focused on best evidence and not self interest. Data from Diane Paul (2008), a historian who has studied newborn screening advocacy for the past four decades, are not reassuring as she shows how advocates have become more focused on promoting conditions based on self interest rather than on promoting the public good.

A second problem with tiered consent is that some conditions identified by MS/MS, specifically PKU and MCAD, meet the Wilson and Jungner criteria while others do not. However, if a parent consents to screening for the first-tier conditions and MS/MS is performed, all of the conditions identified by MS/MS, many of which belong in the second tier, are identi-fied. To respect parental choice, state labs would have to blind themselves to data already obtained or at least not report data for which consent was not obtained. This is complicated but it is feasible. For several years in the past decade, Massachusetts provided newborn screening MS/MS labora-tory functions for several states that only tested a few conditions identified by MS/MS. Most MS/MS data from Rhode Island and New Hampshire were not reviewed or reported until these states added all of the conditions identified by the uniform panel to their state panel (Comeau et al. 2004). But blinding does raise questions of responsibility for nondisclosure by state personnel if and when a positive result is obtained. In addition, the likelihood of reporting error is increased when some parents request full disclosure and others request restricted data reporting.

A third problem is the amount of education about NBS that health care providers would need in order to explain why some conditions achieve tier-one status and others do not. Although no one would expect the providers to be able to give a condition-by-condition explanation for those that either meet or do not meet the Wilson and Jungner criteria, they would need to provide a solid explanation of why some conditions are more encouraged than others, and why the list is constantly evolving.

Despite these difficulties, a tiered consent process would help to address the challenge that MS/MS raises for the mandatory screening program through its introduction of conditions for which the benefit:risk ratio is more ambiguous. Whether one supports a mandatory/voluntary tiered consent process like that proposed by the President’s Bioethics Council or the opt-out directive approach for tier one and the opt-in discretionary approach for tier two that is favored in this manuscript, parental informed consent will be necessary for at least some conditions.


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THE CONTROVERSY EXPANDS TO THE STORAGE OF THE GUTHRIE CARDS

The potential use of residual blood spots for research was realized early in the history of NBS. In 1975 the National Research Council wrote:

In some programs, almost countless dried blood spots are stored away against the day when additional tests could be done. That such tests might be done would, of course, be unknown to the person from whom the blood was taken. This raises certain legal questions with regard to the ownership of such samples, the consent needed for running tests on them, and the disposition of information. (National Research Council 1975, p. 106)

This concern was prescient. Newborn blood spots have been used through-out the past three decades for de-identified population research on envi-ronmental exposures, infectious diseases, and genetics (Chaudhuri et al. 2009; Coffee et al. 2009; Hoff et al. 1988). In the development of MS/MS, NBS programs supplied researchers with cards from children who were diagnosed with particular rare metabolic conditions (Chace et al. 1993; 1995).

Parental concern about the use of residual blood spots for research is more recent however. Twila Brase, President of Citizens’ Council on Health Care (founded in 1988) writes that what researchers claim as a “national resource” fails to acknowledge that the DNA-rich blood spots are personal genetic property, not the property of state governments and genetic research-ers (Citizen’s Council on Health Care 2009b). Recently, parents in Texas and Minnesota have gone to court arguing that blood spots should not be kept for research purposes because the parents did not consent.

On 11 March 2009, nine families sued the Minnesota Department of Health and the State of Minnesota under Chapter 13 of the Minnesota Government Data Practices Act. The families argued that the Minnesota Department of Health violated the 2006 state genetic privacy law by its col-lection, storage, use, and dissemination of newborn blood and baby DNA. The lawsuit against the Minnesota Department of Health and the State of Minnesota was dismissed by the judge on 3 December 2009 (Citizen’s Council on Health Care 2009a).

On 18 March 2009, the Texas Civil Rights Project (2009) filed a lawsuit against the Texas Department of State Health Services (TDSHS) on behalf of five families claiming that the Department “ unlawfully and deceptively collected blood samples from their children at time of birth and stored those samples indefinitely for undisclosed research purposes, without plaintiffs’ knowledge or consent.” On 22 December 2009, under a federal lawsuit


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settlement, the TDSHS agreed to destroy an estimated 5.3 million blood samples legally collected from newborns before 27 May 2009 but kept without parental consent (Citizens’ Council on Health Care 2009c). After the settlement, the TDSHS released nine years worth of e-mails and internal documents that showed that it had transferred “hundreds of infant blood spots to an Armed Forces lab to build a national and, someday, interna-tional mitochondrial DNA (mtDNA) registry” (Ramshaw 2010). Hence the decision to settle before discovery may have been less transparent than initially thought.

Although the lawsuits sought blanket prohibitions against research using NBS blood spots without consent, that approach may not be ideal. Although research on blood spots that can be linked to a particular child clearly should require informed consent and approval by an institutional review board (IRB), an opt-out process of informing parents that the left-over samples may be used for population research may be sufficient for research that uses only de-identified samples. It may even be appropriate to insist that such research be restricted to research on conditions that are relevant to infants. Although one may want review by an IRB (or some other oversight committee) to ensure that the samples are truly unlinked and that the research is meant to promote pediatric health care, IRB review may not be legally required under human subjects protection regulation in the United States. According to the Office for Human Subjects Protection (OHRP), research with coded samples in which the link has been destroyed is not “human subjects research” because there is no intervention with liv-ing individuals and is not subject to the regulations (OHRP 2008; Maschke 2009, pp. 240–41).

When the research uses identifiable samples, the consensus has been to require consent. However, recently, some ethicists and policymakers have argued for waiving parental consent even when identifiable residual blood spots are used (Botkin 2009; Tarini et al. 2008). Beth Tarini and colleagues (2008, p. 23) argue in favor of waiving informed consent for population-based NBS research because the risks are minimal and the waiver “facilitates the development of flexible strategies for informing and educating parents about NBS research that reflect the logistics of population-based NBS screening.” The main justification is that requiring consent would create incentives for the implementation of inadequately evaluated NBS tests as currently occurs today (Tarini et al. 2008). Jeffrey Botkin also argues in favor of waiving consent in NBS research in order to strengthen the evidence base for NBS. He proposes that a state that adds a condition to its newborn


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screening panel may decide to retrospectively identify children who were born five years earlier to compare and contrast that group with a screened group to determine whether screening favorably influences outcome and how great the benefit really is (Botkin 2009).

Tarini and her colleagues and Botkin miss the point. To require and obtain informed consent for research on NBS blood spots would simplify follow up contact in both of these studies. Only if health care providers explain both the purpose of newborn screening for the child and the reason the residuals are used for research will high trust and high participation ensue. Although the authors describe research that can be done using NBS blood spots that may improve the care of children, they fail to explain why the state is in a better position than a child’s parents to judge whether par-ticipation in research is in a child’s best interest. In fact, when asked, most parents are more than willing to have their infants’ residual blood spots used for research (Neidich et al. 2008; Tarini 2008). Thus implementing a consent process for NBS that includes research will allow research to proceed without the threat of future additional lawsuits that may lead to the destruction of the residual blood spots. If a tiered consent approach to NBS is adopted, permission for the storage and use of residual blood spot samples for research could be approached as a third tier. To the ex-tent that researchers one might want permission to follow some children longitudinally and to collect environmental, psychosocial, nutritional, and medical data, like the National Children’s Study aims to do (Hirschfeld et al. 2010), several tiers of consent for different degrees of research engage-ment may be necessary.

WHERE IS THE DEBATE TODAY?

NBS programs traditionally are situated within public health depart-ments, in part because the infrastructure is well suited to handle large numbers of blood samples efficiently and accurately. But given the nature of the conditions, NBS could be provided as a clinical service. When pro-vided as a public health service, Grosse and colleagues (2006) argue that the service should be made on the basis of evidence of benefit, risk, and cost and with full consideration of public resources and priorities. The proposals to expand newborn screening beyond the historical rationale of preventing devastating harm to affected infants by providing immediate treatment and extend it to conditions in which the benefits are less dramatic or immediate challenge the public health rationale.


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This is not to suggest that newborn screening should move out of state-run laboratories. As Ellen Wright Clayton (1999, p. 112) explains:

There are good reasons to keep screening for PKU in state-run laboratories. The programs are well-established, the testing protocols are well developed and of high quality, and affected children are almost always detected and brought in for care. Decentralizing and moving these tests into the private sec-tor likely would be more costly and less efficient than current programs.

Currently, the role of primary care physicians in newborn screening is minimal. This may be due in part to the mandatory nature of newborn screening and because it is coordinated through public health departments. The result is that pediatricians know very little about what conditions are included in NBS panels and the methodologies used to detect them (Gen-naccaro, Waisbren, and Marsden 2005; Kim, Lloyd-Puryear, and Tonniges et al. 2003; Thompson et al. 2005; Stark, Lang, and Ross 2010). This is problematic because they are ill-prepared to explain the likelihood of disease after a patient receives a positive result, and they often know very little about the condition for which the patient needs to undergo further work-up. Although there have been many calls for obstetricians to take an active role in educating pregnant women about newborn screening (ACOG 2007), the data show that their knowledge about NBS is even less than pediatricians (Hasegawa, Au, and Matsumoto, 2005) and that they frequently fail to raise the topic during prenatal care (Faulkner et al. 2006; Lang et al. 2009). Both the lack of knowledge by pediatricians and obste-tricians and the inconsistent disclosure requirements converge to generate poor parental knowledge (Boyd et al. 2005; Lang et al. 2009) even though most programs believe that parents should be informed.

The changes in NBS over the past four decades provide an “opportunity to modify the model developed four decades ago for PKU. In particular, questions of voluntary screening and informed decision-making need to be reopened” (Grosse et al. 2006, p. 927), and primary care physicians need to take a more proactive role. Current state policies do not require that parents be informed about the testing (General Accounting Office 2003 ; Kemper, Fant, and Clark 2005). However, as Clayton (1999, p. 113) com-ments, “the absence of requirements for disclosure and parental permission is all the more striking in light of the clear demonstration that talking with parents is easily accomplished and that few parents oppose testing.” Even without legislative changes, clinical practice ought to go beyond legislative thresholds for both moral reasons (respect for parental decision making regarding their child’s health) and pragmatic reasons (unless parents un-


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derstand why NBS was done, they may not properly respond when they are called regarding an abnormal screen).

In this manuscript, I have argued that as public health screening merges with clinical practice and medical research in state NBS programs, the practice of seeking parental consent can no longer be viewed as optional. A tiered approach incorporating an opt-out process for conditions with a high benefit:risk ratio, an opt-in process for conditions with a more ambigu-ous benefit:risk ratio, and additional tiers for permission for residual blood spot storage and research may provide the best way to balance respect for parental autonomy and the promotion of children’s health.

I thank Jim Childress for inviting me to speak about consent in newborn screening in the context of a lecture series on Liberty and Coercion in Public Health, sponsored by the University of Virginia’s Institute for Practical Ethics and Public Life, and special thanks to Ben Wilfond and Ellen Clayton for serious conversations about this manuscript.

NOTES

1. In the pediatric literature, there has been a shift to refer to parental agreement to treatment as “parental permission” rather than “parental consent” on the grounds that one cannot consent for another (AAP, Committee on Bioethics 1995). Given the focus of this manuscript regarding whether newborn screen-ing should be mandatory or whether it should required voluntary consent, I use the phrase “parental consent.”

2. It is important to realize that the evidence used to justify NBS for hemoglobin-opathies was not based on evidence collected from a NBS research protocol. The study by Gaston and colleagues enrolled children who had been clinically diagnosed with sickle cell disease. This at least partly explains why the issue of carrier identification was not addressed by the Consensus Panel. I thank Ben Wilfond for pointing out this issue.

3. Some would advise caution with the MSAFP approach of mandatory offering, arguing that the mandatory offer became a de facto mandatory program be-cause the discussion was often “sandwiched between discussion of other blood tests which are routine, but not presented as voluntary” (Press and Browner 1997, p. 983). Nevertheless, these same authors did find that some women were able to say no (Press and Browner, 1998). If anything, the concerns these authors raise would argue for voluntary screening for all conditions and not for a two-prong mandatory/voluntary approach as discussed in the following paragraphs. I thank Ellen Wright Clayton for pointing out this issue.


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