PEDIATRICS Vol. 121 No. 3 March 2008, pp. e693-e704 (doi:10.1542/peds.2007-0820)
STATE-OF-THE-ART REVIEW ARTICLE |
Ethical, Legal, and Social Concerns About Expanded Newborn Screening: Fragile X Syndrome as a Prototype for Emerging Issues
a RTI International, Research Triangle Park, North Carolina
b FPG Child Development Institute
c Department of Social Medicine
d Department of Pediatrics, University of North Carolina, Chapel Hill, North Carolina
ABSTRACT
Technology will make it possible to screen for fragile X syndrome and other conditions that do not meet current guidelines for routine newborn screening. This possibility evokes at least 8 broad ethical, legal, and social concerns: (1) early identification of fragile X syndrome, an "untreatable" condition, could lead to heightened anxiety about parenting, oversensitivity to development, alterations in parenting, or disrupted bonding; (2) because fragile X syndrome screening should be voluntary, informed consent could overwhelm parents with information, significantly burden hospitals, and reduce participation in the core screening program; (3) screening will identify some children who are or appear to be phenotypically normal; (4) screening might identify children with other conditions not originally targeted for screening; (5) screening could overwhelm an already limited capacity for genetic counseling and comprehensive care; (6) screening for fragile X syndrome, especially if carrier status is disclosed, increases the likelihood of negative self-concept, societal stigmatization, and insurance or employment discrimination; (7) screening will suggest risk in extended family members, raising ethical and legal issues (because they never consented to screening) and creating a communication burden for parents or expanding the scope of physician responsibility; and (8) screening for fragile X syndrome could heighten discrepancies in how men and women experience genetic risk or decide about testing. To address these concerns we recommend a national newborn screening research network; the development of models for informed decision-making; materials and approaches for helping families understand genetic information and communicating it to others; a national forum to address carrier testing and the disclosure of secondary or incidental findings; and public engagement of scientists, policy makers, ethicists, practitioners, and other citizens to discuss the desired aims of newborn screening and the characteristics of a system needed to achieve those aims.
Key Words: newborn screening
Abbreviations: ACMG—American College of Medical Genetics • NBS—newborn screening • FXS—fragile X syndrome • FMRP—fragile X mental retardation protein • CF—cystic fibrosis • IDM—informed decision-making
In a recent report, the American College of Medical Genetics (ACMG) reviewed the state of newborn screening (NBS) in the United States, proposed a framework by which conditions could be evaluated to determine suitability for screening, and reported the results of expert ratings of 78 candidate conditions.1 A primary goal was to reduce cross-state discrepancies by providing a systematic way for states to evaluate conditions under consideration for screening.2,3 The ACMG recommended that all states screen for a core panel of 29 conditions and report 25 "secondary" conditions that would necessarily be identified when using methods such as tandem mass spectrometry.
Fragile X syndrome (FXS), the most common inherited form of intellectual disability, was not recommended for screening by the ACMG, primarily because of the lack of a reliable and cost-effective screening test and the absence of data on benefits that could accrue from screening. However, in the near future, an accurate and inexpensive test will likely be available. In anticipation of this imminent possibility, we have been planning an NBS study and considering issues such as how to provide adequate informed consent, whether to test for carriers, what outcomes should be measured, and the research designs that could answer questions about benefits of earlier identification.
The impetus for this project came from interviews with families that highlighted the challenges they experienced in getting a diagnosis of FXS. We published an article that described the experiences of 40 families,4 followed by a more extensive survey of 274 families.5 These and other studies6 have documented that although families often become concerned about development by 12 months of age, a diagnosis of developmental delay typically is not made until the child is nearly 2 years of age, and a diagnosis of FXS may not occur until the child is nearly 3 years old. Children miss the opportunity to participate in early intervention, and their parents often have additional children with FXS without knowledge of the reproductive risk. These parents report frustration with professionals and the health care system, strongly support voluntary NBS for FXS, and consider advantages of screening more likely than disadvantages.5,7
In subsequent publications, we have argued for expanding concepts of benefit beyond the requirement of an effective medical treatment.8–10 NBS for conditions such as FXS would (1) provide access to early psychosocial and therapeutic interventions, the value of which has already been demonstrated; (2) be supported by an existing national network of early intervention programs that most parents consider helpful; (3) provide information to families and allow for support to maximize positive family adaptation; (4) be consistent with research on family preferences for information; and (5) provide other societal benefits (eg, identifying the true prevalence of the condition, describing the full range of genotype and phenotypic expression [allowing for studies of early development] and stimulating research on earlier interventions).
In this article, we turn to concerns about NBS for FXS. Since NBS was first proposed for phenylketonuria >40 years ago, questions have been raised about possible harms.11,12 Several working groups have recommended guidelines to maximize the benefits of NBS and prevent harm.2,13–17 The authors of a recent commentary criticized the ACMG report for failing to attend to ethical, legal, and social ramifications of expanded screening and recommended that expanded screening be conducted within a national research paradigm.18 FXS is an excellent prototype for this discussion, because it raises many issues that inevitably will emerge as technology allows for a rapid expansion of screening.
FXS OVERVIEW
FXS is a single-gene disorder on the X chromosome. The code for the FMR-1 gene contains a limited number of repetitions of cytosine and guanine that occur in CGG triplets. Typically, this triplet occurs between 5 and 50 times. However, some people have an expanded number that results in either premutation carrier status (50–200 repeats) or full mutation (affected) FXS status (>200 repeats). Both males (XY) and females (XX) can be premutation carriers or have the disorder. Carrier fathers can only transmit the gene to their daughters. All daughters of carrier fathers inherit the gene, but always as carriers. Female carriers typically have 1 normal X chromosome and, thus, a 50% chance of transmitting the fragile X gene to any of their children. The gene can be transmitted in the premutation carrier state, or it may expand into the full mutation. The chances of expansion to the full mutation increase with successive generations. CGG repeats of >200 usually result in methylation of the FMR-1 gene, which "silences" the gene and affects production of the fragile X mental retardation protein (FMRP).
FMRP plays an important role in brain activity depending on synaptic function, maturation, and plasticity. When expression of FMRP is reduced, abnormal morphology of cortical dendritic processes is observed, which suggests that FMRP is involved in synapse maturation and elimination.19 Recent research has suggested that abnormal metabotropic glutamate receptor signaling may play a critical role in phenotypic expression.20 If these theories are true, treatments to benefit children with FXS should be more effective if provided as early as possible.
Males typically exhibit moderate-to-severe intellectual disability.21 Females as a group are more mildly affected than males, primarily because of X inactivation and cellular mosaicism.22 Social and behavioral difficulties are prevalent in males23 and, despite relatively more intact neurocognitive functioning, in females as well. Autistic spectrum behaviors are frequently seen, including hand flapping, poor eye contact, and social anxiety, and as many as 25% to 35% of affected males meet the diagnostic criteria for autism.24 Affected males have been described as impulsive, hyperactive, inattentive, and hypersensitive to a variety of sensory stimuli, and affected females have been described as shy and socially anxious.25 Some affected males exhibit self-injurious behavior,26 and many have difficulty regulating arousal,27 which often results in irritability, temper tantrums, and problems with transitions.
Premutation carriers may also be affected. Female carriers have a higher risk of premature ovarian failure.28 Carrier males older than 50 years are at increased risk for fragile X–associated tremor/ataxia syndrome, a neurodevelopmental disease that involves tremor, ataxia, dementia, and parkinsonism.29 Carrier females are also at risk for fragile X–associated tremor/ataxia syndrome but at a lower rate.30
ETHICAL, LEGAL, AND SOCIAL CONCERNS ABOUT NBS FOR FXS
FXS affects both the child and his or her family. Although screening would identify newborns for whom there is no direct medical benefit it is widely endorsed by parents of affected children, because it could prevent the "diagnostic odyssey" that most experience, allow access to early intervention during a time of critical brain development, and provide them with important information about reproductive risk.7 However, despite potential benefits, several aspects of FXS suggest that NBS could have negative consequences. In the remainder of this article we describe and discuss 8 ethical, legal, and social concerns and conclude with 5 recommendations for how these concerns could be addressed.
Early Identification of This "Untreatable" Condition Could Lead to Heightened Anxiety About Parenting, Oversensitivity to Development, Alterations in Parenting, or Disrupted Bonding
Social scientists, bioethicists, and health care providers have expressed concern that screening newborns for medically untreatable conditions or susceptibility could have a negative impact on parenting. Increased parental anxiety, stress, and "vulnerable-child syndrome" (in which parents are overprotective of the child in the absence of symptoms) have been mentioned as potential harms when screening for conditions such as cystic fibrosis (CF),31 Duchenne muscular dystrophy,32,33 and type 1 diabetes mellitus.34 Review of studies on CF35 concluded that parents may experience heightened anxiety in the period between receiving a positive screening result and the confirmatory diagnosis. One study of NBS for type 1 diabetes found an absence of maternal stress 4 to 5 months after risk notification,36 but others have indicated that maternal response is highly variable, with some mothers being more vulnerable to depressive symptoms or anxiety as a result of notification.32,37
Overall, there is scant information on the relative weight of harms and benefits related to parenting as a consequence of NBS.32 Stress and disruption are normal responses to the identification of most conditions,38 and there is little evidence that early screening for untreatable diseases causes any greater distress than diagnosis by other methods.12 Because parents also experience heightened anxiety by not knowing what is causing the child's problematic behaviors and delayed development, early diagnosis could reduce the anxiety and worry that families would experience if they had to undergo a prolonged diagnostic odyssey.
There is little information about how parents might react to a newborn diagnosis of FXS. A survey of parents of children with FXS7 asked if they thought that receiving a diagnosis at birth would have affected bonding. The majority (60.2%) believed there would be no effect, explaining that the child is their child no matter what and would be loved the same as any other child. A small number of the respondents (9.3%) thought that knowing the diagnosis would make bonding easier, because it would help them gain a better understanding of the child or cause them to spend more time with the child. The 10% who believed bonding would be more difficult wrote that new parents would worry about how to manage a child with FXS and the additional family demands or that the diagnosis could engender negative emotions that might affect bonding. Parents indicated that screening would result in more positive outcomes than negative outcomes, but some voiced concern that it might lead to increased stress and worry about the child.
Because Screening for FXS Should Be Voluntary, the Consent Process Could Overwhelm Parents With Information, Significantly Burden Hospitals, and Reduce Participation in the Core NBS Program
Screening for conditions that do not meet current NBS criteria and for which risks and benefits are debated should be performed in the context of voluntary research programs with informed consent.18,33 Instituting a consent process brings up issues that will need attention to prevent undue burdens on parents, medical providers, and states12,39 because routine NBS in the United States is typically performed without consent. Although most states allow parents to decline screening for religious reasons, and a few allow it for any reason, only 8 states have notice procedures and only 2 (Wyoming and Maryland) require explicit parent permission for screening. Concerns have been raised about the lack of active consent processes in NBS,40,41 but most professional organizations, clinicians, and researchers agree that the "opt-out" model is appropriate given the nature of the conditions for which we currently screen. In states with informed consent requirements, very few parents decline screening, and even pilot screening programs have often reported participation of >90%.42
Moving to a consent model for conditions such as FXS raises a number of challenges, including how to adequately describe a potentially unfamiliar condition, the screening and testing process, and potential consequences of either accepting or declining screening and testing.43 Screening will require materials that explain FXS and the secondary conditions that may be identified, potential risks and benefits, the screening process itself, and possible ramifications of a positive diagnosis. The process must also address confidentiality and privacy concerns that may arise from the medical information gathered in screening and its possible disclosure and from the storage and use of the blood sample. The consent process must provide sufficient detail to permit informed decision-making (IDM) and the opportunity to discuss the screening study. Assessments of state NBS brochures have shown that much work is needed to develop user-friendly informational materials that are comprehensible to individuals with limited scientific knowledge or literacy skills.44
Although some NBS information is available prenatally, it is typically provided during the hospital stay; consequently, most parents have only a vague recollection of the nature and content of that information.45 Studies have indicated that parents want more information about screening, preferably during the prenatal period.45–48 Although it would be ideal to provide information about screening for FXS in prenatal settings, it may be difficult to obtain consent then. Whether prenatally or in the hospital, a face-to-face process is best, given the complexities of genetic screening and follow-up. However, this more extensive consent process is likely to be burdensome for health care providers, families, and researchers.
A final concern is that seeking consent for conditions such as FXS could influence how parents think about the desirability of screening in general and about whether genetic information should be entered into research and medical charts or disclosed to others. Some are worried that this broader awareness could threaten children's health and state NBS programs by causing some parents to question or decline screening for core conditions, although no data exist to support this assertion.
Screening for FXS Will Identify Some Children With the Full Mutation Who Are or Appear to Be Phenotypically Normal
Most males identified with the full mutation FXS have a moderate-to-severe intellectual disability. However, several case studies have reported "high-functioning" males with intellectual ability in the mild or borderline range.49–52 Thus far these findings have been explained as relatively infrequent events (possibly 
20% of the population with FXS) that result from mosaicism or a partially methylated full mutation.49,53,54 However, one third to one half of all females with the full mutation FXS will have normal intellectual function54 as a result of cellular mosaicism and X inactivation.22
It is likely that most males with the full mutation and mild or borderline levels of intellectual functioning and most females with the full mutation and borderline or normal intellectual function have never been diagnosed with FXS. Thus, NBS would potentially identify a significant number of males and females with the full mutation who would never otherwise have been detected, some of whom may not have symptoms (ie, they have the FXS genotype but do not express the classic phenotype). Authors of some reports have expressed concern that identifying such children could have a negative impact on parenting and increase parental anxiety or lead to a state of hypervigilance in which parents are overprotective of the child in the absence of symptoms.15
Screening for FXS Could Identify Children With Other Conditions Not Originally Targeted for Screening
Genetic testing increasingly carries the possibility of results that are incidental to the purpose of the test but that would need to be revealed. The ACMG listed 25 such "secondary conditions" that do not meet the current criteria for NBS but are necessarily identified when screening for the recommended conditions.1 For example, benign hyperphenylalaninemia is distinguished from phenylketonuria, but practitioners differ on the cutoff point for phenylketonuria. In the case of short-chain acyl-coenzyme A dehydrogenase deficiency, many children who are identified through NBS may never have symptoms.1,55 Depending on the test used for FXS, secondary conditions related to the X chromosome could be detected, including Klinefelter syndrome, Turner syndrome, or triple X syndrome. These syndromes typically have a range of phenotypic features, many of which (except for females with Turner syndrome, who have heart disease or kidney conditions) would be considered either mild or not clinically relevant and only become apparent later in childhood or adulthood, if ever. Also, screening for FXS would identify girls with a wide range of phenotypic expression, including some who have few if any clinical features. Thus, FXS screening could identify a large number of infants with uncertain phenotypic futures. Issues raised by a diagnosis of a condition with mild or no symptoms are particularly acute when the possible phenotype is behavioral or emotional, because families and practitioners are likely to look for and worry about (and at times, find) symptoms in the absence of clinical results.
These issues are similar to those that arise in the context of false-positive screening results.18,43 Most studies indicate that a minority of mothers experience increased stress and anxiety; think less of their own health; are more worried about their child's future; and continue to think the child is prone to illness or has symptoms of the condition.35,56–59 One study explored these issues by interviewing 14 families of children with Turner or Klinefelter syndrome.60 Most families were in favor of NBS, but families of a child with milder symptoms were more ambivalent. Their ambivalence stemmed from the feeling that early identification would result in no medical benefit and could even be harmful. Some families reported that receiving the diagnosis earlier would have caused unnecessary worry and emotionally draining searches for treatments. Several families suggested screening as part of routine well-infant checks rather than at birth. Families of children with more severe symptoms felt differently. They reported relief at receiving the diagnosis that put a name to symptoms and provided access to information and care.
Issues raised by NBS are particularly acute for triple X syndrome. Families of a daughter diagnosed with triple X syndrome at birth are likely to look for information about the condition and may get misleading information from the Internet or medical practitioners about the syndrome being associated with mental retardation or severe behavioral and learning disabilities. This may cause them to worry needlessly about a condition for which symptoms are likely to never present.
As medical practitioners or state programs increase their use of genetic testing, they inevitably will detect genetic or chromosomal anomalies that may be unrelated medically to the condition for which the original test was conducted.61 Do individuals want to know this information? It is likely that the desirability of disclosing incidental findings will vary as a function of both their clinical significance and individual perceptions of risk and views about the value of genetic information. Such incidental or secondary findings could label individuals as having a genetic diagnosis that becomes part of their medical chart, but there is no clear understanding of whether the individual is at medical risk because there may be little or conflicting literature. This peculiar feature of genetic testing requires much additional analysis.
Families' Needs for Information and Support Could Overwhelm an Already Limited Capacity for Genetic Counseling and Comprehensive Care
FXS has a complex inheritance pattern with implications for both parents and extended kin. Parents of children with positive screen results will need information about the need for definitive diagnostic testing, what the testing might disclose, and the odds that their child has FXS. Parents of infants with confirmed FXS or carrier status will need more in-depth information on the type of mutation identified; prognosis for their child; potential future medical, developmental, and behavioral problems; recommendations and referral for early intervention services; the risk of recurrence in future children; and advice regarding testing of other family members and sharing of information with distant relatives. Providing accurate and balanced information for any genetic condition is challenging, but the need will increase greatly with NBS for FXS and will be further complicated if X chromosome variations or FXS carriers are detected.
The most common model for counseling in the United States is a team of genetic counselors (Master's level) and clinical geneticists (physicians with specialty training in genetics).62 There are 2000 board-certified genetic counselors in the United States (www.abgc.net), which is 1 per 200000 people.63 There are 1000 board-certified medical (physician) clinical geneticists (www.abmg.org/stats-allyears.htm). Only 34% of genetic counselors are in pediatrics (www.nsgc.org/career/pss_index.cfm). Similar data are not available for medical geneticists, but one may roughly estimate that 75% of them work in pediatrics. On the basis of current incidence figures and assuming 100% sensitivity of testing methods, the number of estimated births per year with the full or premutation FXS plus those with X chromosome variations is 22500, which represents 19 infants per clinical geneticist or genetic counselor. Many clinical genetic centers already have long waiting times that range from a few weeks to several months. Adding conditions such as FXS will quickly overwhelm the supply of available genetic professionals.64 Thus, there is a critical need for new techniques to provide understandable yet comprehensive information for families about FXS and any other condition for which screening is offered.
One suggestion is that primary care physicians provide genetic counseling,65 but studies have shown that primary care providers are not well trained in genetics.63,66 Primary care providers will need to be familiar with basic information about these conditions because they are often the first contact for families after a positive NBS result and are critical for providing a medical home for infants and children with special needs.67 However, the expectation that they will be able to provide in-depth information about these disorders to families in addition to genetic counseling is unrealistic.
Genetic information is sometimes provided by nurses and other health professionals with experience or training in specific areas such as cancer genetics. There have been attempts to increase the number of professionals who are "credentialed" to deliver genetic information to patients about specific disorders through issuance of certificates based on continuing education credits and case logs without oversight of professional genetic societies.68 Lack of standardized training through such credentialing programs has the potential for communicating inaccurate information. Even if adequate training could be given to non–genetic health professionals for a specific condition such as FXS, as NBS expands the attempt to train non–board-certified genetic counselors about each new condition will be overwhelming and impractical. A more practical solution is to increase the number of trained, board-certified genetic counselors.
Another concern is how to pay for services required by screening. Charges for screening vary widely among states (www2.uthscsa.edu/nnsis/menu.cfm). Six states have no fees, and 45 charge fees that range from $10.50 to $139.33. Use of fees also varies among states. Eleven states use fees to support the laboratory component of screening only. Other states use the fees to cover program administration and follow-up, treatment, education, and specialty formulas. In only 6 states do fees cover genetic counseling.
Resources to pay for genetic counseling services for families of infants identified through NBS will need to be found. Although physician geneticists can bill for their services, not all third-party payers cover genetic counseling, and not all children are insured. Medicaid reimbursement for genetic services in most states is poor.
Public health benefits and improved outcomes through NBS programs will only be realized if there are adequate resources for long-term follow-up care and management.2,18,69 For FXS, this includes pediatric developmental specialists; early intervention programs; speech, physical, and occupational therapists; and mental health professionals. Pediatric endocrinologists will frequently be needed for children with X chromosome variations.
Although many states provide some financial support for genetic programs, funding has not kept pace with expansion of NBS and is inconsistent across states. Additions to NBS are often unfunded mandates by state legislatures. If there is to be benefit to infants and their families from early detection of such conditions, it will be through the follow-up programs provided, including genetic counseling, medical evaluations, treatment and management, early intervention programs, and educational resources.
Screening for FXS, Especially if Carrier Status Is Disclosed, Increases the Likelihood of Harm, Including Negative Self-concept, Societal Stigmatization, and Insurance or Employment Discrimination
Although the potential for psychosocial harms and discrimination exist whenever FXS is diagnosed, NBS would increase the number of identified individuals at risk and the length of time that genetic information is known. Screening would identify individuals who might never be diagnosed in childhood or their lifetime as having FXS or being a carrier, thus intensifying the category of the "presymptomatic individual."70 Parents of identified infants would be faced with the decision of when to reveal carrier status to their children and worried about how that information could negatively impact their children's self-concept or affect how others might treat them, including insurance providers.
Current consensus generally opposes screening for carrier status and late-onset disorders.2,16 One concern about disclosing this information is the possible psychosocial harm to the child, including anxiety, negative self-concept, and impact on decisions related to marriage, reproduction, and career.16,71,72 There are also concerns that early identification could cause stigmatization and legal discrimination of individuals who are asymptomatic yet labeled as having a genetic disorder70 and that screening children for carrier status or adult-onset disorders takes away their right to decide for themselves when they are older73 and is not in the best interests of the child.74 These issues relate to the overall tension between children's future autonomy and parents' right to know information about their child's health status.
Surveys of parents with children with FXS have shown that most would want to know if their child had FXS or was a carrier at birth7 but also that parents are concerned about providing the right kind of guidance to their children relative to their carrier status75 and about choosing the right time to disclose this information.76 Studies of carrier females have indicated that they experience some negative emotions initially when finding out their status and continue to have some concern about how it could affect marriage and motherhood.77,78 There is some concern among families of children with FXS that identification will lead to discrimination. Approximately one third of the families in 1 study responded that they had been discriminated against because of the FXS diagnosis, and more than half said that the source of discrimination had been a health insurance provider.79 In a larger, more recent study,7 11% of the sample reported that their insurance coverage changed as a result of the FXS diagnosis. Most of the problems were with insurance companies turning down their applications, canceling coverage, or not covering therapies for the affected child. One mother was denied obstetric and gynecologic services when she revealed her carrier status. Other families noted that they had to fight to keep coverage or decided not to disclose the diagnosis to the insurance company. National legislation prohibiting insurance or employment discrimination is currently under consideration in the US Congress and would help alleviate such concerns.
Screening for FXS Would Implicate or Suggest Risk in Extended Family Members, Raising Ethical and Legal Issues (Because They Never Consented to the Initial Screening) and Creating a Communication Burden for Parents or Expanding the Scope of Physician Responsibility
Almost all disorders now included in NBS are autosomal recessive conditions. Although diagnosis of a newborn with these conditions has possible implications for relatives of carrier parents, the likelihood of these relatives bearing children with the same condition is far less than with FXS, which has significant reproductive ramifications for both close and distant kin. When FXS is diagnosed, relatives who may never have wished to know their genetic status are implicated as potential carriers, and their ancestors and offspring are identified as possibly having or carrying FXS.80 Repercussions may be felt across extended kin networks, raising a number of concerns.
First, families whose newborns are diagnosed become involved in "genealogical ethics,"70 a moral decision-making process of whom in the extended family to tell, what genetic information to reveal, when to disclose, and who should do the telling. These patterns of disclosure or nondisclosure have significant consequences for relatives' identities, health, reproductive decisions, and well-being, and the telling itself has the power to alter family relationships.81 Given that the "duty to inform" typically lies with the identified family and not a health care professional, the parent becomes the bearer of the news that FXS may reside in the family lineage. A survey of parents of children with FXS revealed that of the parents who were the first in their extended families to learn of FXS, 91% had to tell others in the family, a duty largely conducted by women. More than one third of them rated this experience as somewhat stressful, and another third rated it as very stressful.5 A majority of the parents described dilemmas in disclosing information about FXS to relatives, the most common being relatives' denial. Extended kin did not want to know, became defensive, were reluctant to accept the diagnosis, could not deal with it, could not believe there was something wrong in the family, or were angry at being informed. In some cases, disclosing the information created or intensified rifts in family relationships and sometimes resulted in relatives refusing to speak to the carrier who told them. Relatives began to wonder whether they or their children inherited the gene, and guilt was often felt by those who learned they had passed on the fragile X gene. Many parents described patterns of "selective telling" or differential disclosure, assessing the likely reaction of a particular relative before deciding whether to divulge genetic information. Parents' responses also indicated a lessened sense of obligation to inform relatives who were perceived as biologically or geographically distant.6 Some parents indicated that it was difficult to explain the genetics of the syndrome and the patterns of inheritance. Another study also indicated that many parents were not sure about the inheritance patterns or risk of a particular relative having the fragile X gene and were not conveying accurate risk information to extended kin.82
Families' selective disclosure, refusal to tell certain relatives, and possible miscommunication of risk raise ethical issues for professionals about the duty to inform.83 In most cases, privacy concerns and patient rights preclude professionals from informing the patient's relatives of risk without the explicit consent of the patient. Although they may help the patient to identify at-risk relatives and give them written information to pass on, there is little follow-up on what gets communicated to whom. These issues of disclosure and duty to inform are not exclusive to NBS, because they occur whenever FXS or other conditions are discovered,84 but with its potential to identify carriers, screening for FXS broadens the number of individuals identified as at risk and increases the duty to inform, either of parents or of genetic professionals.
Screening for FXS Could Heighten Discrepancies in How Men and Women Experience and Respond to Genetic Risk or Decide About Testing
FXS poses different biological and social issues for males and females. Although females are generally less affected by the symptoms associated with FXS, they are more directly affected by NBS and the ramifications of a diagnosis. There are a number of gendered aspects to FXS, including the "gendering of responsibility."85 How might these aspects be amplified by NBS?
First, studies of prenatal decision-making have indicated that men are more likely to be "bystanders" in this process and that women bear the major responsibility for assessing genetic and testing risks, making sense of ambiguous information, and deciding whether to test.86,87 It is likely that this pattern would be similar for NBS decisions. Studies have also shown that women are typically the "keepers" and key communicators of genetic information,88,89 taking on responsibility for disclosing genetic information to others and often bearing the brunt of the stress and burdens that it can cause.85,89 Women are also more likely to go for testing themselves. A study of family communication about FXS revealed that in extended families, when there was a question of whether the husband or wife carried the FXS gene, it was the woman who would undergo confirmatory testing so that she could either "rule out" her husband or be ruled out herself.82
The inheritance patterns and differential manifestations of FXS in males and females lead to gendered patterns of response. Men may feel guilt at passing the gene in its carrier state to their daughters and then to their grandchildren, but women are more directly implicated because only they can directly pass on the full mutation. Although negative emotions may lessen or disappear in time, many mothers continue to deal with the knowledge that they carried the gene that resulted in their child's problems. NBS could exacerbate these feelings, extending them to the vulnerable first months of mother-child bonding. Reproductive decisions may also be more difficult for female carriers than for male carriers because only women risk having a child with the full mutation. This gender difference may impact children who are carriers and perhaps lead young men and women to make different marriage and reproductive choices. Women carriers bear much of the responsibility for future reproductive decisions and are the bodies on which assisted reproductive technologies are practiced.
FUTURE DIRECTIONS
Technologic advances will surely make possible inexpensive and accurate screening for children with conditions such as FXS. When this eventuality occurs, advocacy groups will inevitably pressure states to include these conditions in state NBS programs. Health departments will need to decide whether a condition such as FXS is sufficiently consistent with state policy to include it as a part of the routine (usually mandated) NBS program. The lack of efficacy data makes it unlikely that screening for FXS will be mandatory. Offering screening on a voluntary basis is more likely, but the burdens associated with helping families make informed decisions about screening and other complex issues described in this article will make it difficult for states to offer screening even on a voluntary basis.
Our original intent with this review was to delineate a set of objections to NBS for FXS and review evidence regarding the validity of each. We entered with the assumption that scant evidence of harm would be found and that we would be able to reinforce our earlier argument that "in the absence of data indicating harm as a result of newborn screening, a significant expansion of newborn screening is warranted."9(p 1891) We now realize that this approach was based on an erroneous assumption that the literature would provide more definitive answers. In fact, the complicated issues surrounding FXS screening, interfaced with the complex and varied nature of public health screening and follow-up, has led us to a very straightforward conclusion: Each of the concerns about NBS for FXS is valid. Although we do not have sufficient data to estimate the magnitude of any of them, each rises to a level of significance that must be addressed so that decisions about expanded screening maximize the potential for benefit and minimize risk or harm.
Despite our previous arguments for the many benefits that could accrue from NBS for FXS,8–10 we do not believe that states currently have the capacity to implement NBS for FXS or similar conditions in ways that maximize benefit and minimize harm. Five major initiatives are urgently needed to address these ethical, legal, and social issues.
Establish a National NBS Research Network
There is a critical need for research to document the benefits and costs of expanded screening. As new treatments are discovered, there will be a need for research that documents treatment efficacy. Because most conditions likely to be proposed for expanded screening will be rare, it will be difficult, if not impossible, for researchers to conduct large-scale clinical trials to evaluate the consequences of screening for and/or treating each condition. To maximize return on investment and minimize the potential piecemeal nature of individual projects, research on NBS should be conducted within the context of a national effort.90,91 A network of collaborative research sites supported by a scientific advisory board and a coordinating center would be a valuable national resource to aid in the rapid scale-up and implementation of research that cuts across multiple conditions and addresses a wide range of issues. Studies supported by a collaborative network could:
- determine the willingness of a diverse public to participate in screening for newly proposed conditions, reactions of parents to information learned from screening, and factors associated with variations in participation rates;
- demonstrate cost-effective methods for providing understandable information to families and informed consent processes;
- test the validity of new high-throughput laboratory methods for screening;
- provide better estimates about the incidence and effects of particular conditions, which would afford new opportunities for population-based studies of the prevalence of genetic anomalies and the range of phenotypic expression;
- allow for rapid scale-up of clinical trials for testing the efficacy of new treatments, especially for low-incidence conditions;
- determine effective models for family support and the care and management of children with rare conditions identified through NBS;
- assess the array of potential costs and benefits of screening for children, families, and society and how they may vary according to ethnicity or income;
- describe the earliest developmental patterns of specified conditions and the onset of primary and secondary neurologic, physical, or behavior features;
- test the efficacy of genetic counseling models and early psychosocial or biomedical interventions for children and families of diverse backgrounds; and
- identify ethical, legal, and social issues and evaluate strategies for ensuring that the disclosure of genetic information benefits rather than harms individuals and that such information is used in a socially and ethically responsible way.
A critical task of this network would be to determine research designs that could answer the question of whether earlier identification is better than later identification. The Wisconsin CF study randomly assigned children and families to early versus late disclosure of CF, but ethical and legal concerns now make such a design more difficult to implement.92 Alternative designs (such as simultaneous community-based screening of all 1- and 2-year-olds) will need to be considered.
Develop and Evaluate Models for IDM
Expanded screening, with which parents could learn about genetic variations with no medical treatment, uncertain outcomes, or carrier status, could lead to a new context in which a "second-tier" screening is offered on a voluntary basis. This possibility evokes concerns about the ability of the public health system to provide information that is sufficient for families to make an informed decision about screening, particularly because research has documented that parents are not well-informed about even routine NBS.45 In addition, the complexities that parents face when deciding whether to accept screening for a condition such as FXS suggest that current models of informed consent may not be sufficient. For example, a recent study revealed that a majority of families who consented to NBS for CF did not remember that NBS could detect carriers.47
A broad and comprehensive approach is needed to ensure that families' decisions about screening are informed and their personal values and preferences are supported in the process. One such model is IDM, "the process that patients go through to make a decision about engaging in a medical or health-related procedure or activity considering benefits, harms, risks, health improvements, the match between these properties and personal values and preferences, and understanding the uncertainty and limitations of the procedures." The IDM model reflects current movements that endorse shared decision-making, with physicians, patients, and families working in partnership.93,94
Applying IDM in the context of NBS would likely involve a combination of written or other visual materials, multiple opportunities for discussion during the prenatal period, and a tiered consent process. Expectant mothers could be offered written or Web-based materials that provide information on the condition and the screening program.45,95 In the postpartum unit they can be provided consent materials in a variety of media and given an opportunity to discuss the screening with a staff or research team member before deciding to participate. Parents will need time to deliberate and ask questions.
A central tenet of IDM is that parents make decisions that are consistent with their personal values. Concerns about expanded screening may be magnified for those in lower-economic, minority, or immigrant groups who have decreased access to health care in general and may be less likely to have access to adequate genetic counseling and medical practitioners with knowledge of the conditions. These access issues may be exacerbated by variations across states in their NBS education and implementation programs.96,97 There has been relatively little attention to economic, geographic, ethnic, and cultural differences in how NBS results are interpreted and have an impact. For genetic testing in general, research has shown that Hispanic and black families have more concerns about the negative consequences of genetic testing.98–101 These issues require additional research on the effect of cultural, ethnic, and economic differences in the interpretation, impact, and use of genetic information and in the materials and processes used to help families make decisions about whether and how to participate in expanded NBS for conditions such as FXS.
Develop Materials and Approaches to Help Families Understand Complex Genetic Information and Ways to Communicate That Information to Extended Family Members
Deciding whether to participate in expanded NBS requires basic information that will help families make this decision and, we would hope, better prepare them if their children screen positive and require confirmatory testing. However, for families of children with a definitive diagnosis, the need for timely and comprehensible information is critical. As a result of NBS, they will learn that their child has a genetic or chromosomal abnormality. However, this disclosure is only the beginning of what will likely become a lifelong search for relevant information about their child's condition, new research, and treatments or services that have the potential to aid them in helping their child. In a recent review we found that information was consistently rated as the highest need by families of children with disabilities.102 Parents from a wide range of countries, ethnicities, and age groups viewed the need for information as paramount. Information enables families to be and feel more effective as advocates and parents, building confidence through IDM103,104 and changing the ways in which they engage with the medical and research communities.105,106
Three considerations are important in developing the information component of an NBS system. First, the system should build on the ways in which families typically access information, maximizing both ease of access and breadth of coverage. Second, the way information is shared may be just as important as the content of the information itself. Information presented in a didactic, directive, or authoritarian way is not likely to be received as well as information that is shared in the context of a partnership. Third, an ultimate goal should not be to simply provide information but to enable and empower parents to find and evaluate the usefulness of information themselves.
The ways in which parents of young children typically access information vary according to the topic and the educational level of parents.107 Traditionally, the child's pediatrician or family practice physician has been a trusted source for information, followed by the child's teacher, caregiver, or early intervention specialist. However, many genetic and chromosomal conditions are rare; thus, many clinicians may have had little if any exposure to a particular condition. Parents report considerable frustration when professionals whom they consider to be specialists have little knowledge about their own child's condition, and recent research has shown that a substantial proportion of pediatricians and family physicians reported that they did not feel competent to discuss the findings for conditions routinely included in NBS.66 This issue will be compounded as the number of conditions for which we screen expands, because most will be rare. The Internet has dramatically changed how parents seek information and what they know about their child. One study105 that followed up with parents after visits to a pediatric genetic clinic revealed a high rate of Internet use. Parents searched for information about their child's condition and possible treatments, e-mailed other parents, and linked with advocacy groups. In fact, because of their efforts, many parents reported that they were more knowledgeable about their child's condition than many professionals. However, Internet access is not universally available, many people are not fluent in using the Internet, and much variability is evident in the accuracy of information across Internet sites.
A major effort is needed to enhance the general health and genetic literacy of the American public.108 As new conditions are added to NBS, accessible, comprehensive, and comprehensible information about those conditions will be needed in multiple formats. Models for this exist,109 but alternatives need to be developed and tested, and guides need to be developed to help evaluate the accuracy and usefulness of conflicting information from multiple sources.
There is also a need for more research on what actually happens as families communicate genetic information so that more effective strategies can be developed to help them understand the information and communicate concerns.81,110 In terms of practice, there is a need for expanding resources available to families for communicating complex genetic information and dealing with the consequences of disclosure and, perhaps, a need for new models of genetic counseling in the context of NBS for conditions such as FXS. Relevant to practice is genetic counseling for parents that can assist them in deciding what and when to disclose the information to their children76 and comprehensive genetic counseling services for children, adolescents, and their families throughout developmental stages.111
Convene a National Forum to Address Carrier Testing and the Disclosure of Secondary or Incidental Findings
Major professional organizations, including the American Academy of Pediatrics, generally oppose carrier testing for infants, arguing that screening should only be performed to benefit the infant and that no benefit is conferred on carrier infants.2,16 However, carrier status already is being disclosed in many states for both sickle cell disease and CF. A national forum is urgently needed to reconsider issues of carrier testing and the disclosure of secondary or incidental findings because such information is inevitable in an era of expanded technologic capacity.
In addition, the issue of secondary or incidental conditions in NBS requires a concentrated and targeted research agenda, given the lack of data about the actual resultant harms to children and their families of early identification of carrier status or late-onset disorders.71,112 Studies are needed that include further examination into the ways in which practitioners understand secondary conditions, distinguish them from primary conditions, and explain them to patients. Improving education about NBS is also an important aspect of reducing stress and anxiety that result from false-positive results and the disclosure of secondary or incidental findings.45,58
Engage Scientists, Policy Makers, Ethicists, Practitioners, and Other Citizens in a Discussion of the Desired Aims of NBS and the Characteristics of a System Needed to Achieve Those Aims
Why screen infants for any condition? As Grosse et al113 have suggested, screening typically has been based on a model of "public health emergency" (screening so that immediate action can be taken to prevent irreversible harm). Their suggestion that we are moving to a model of "public health service" (screening as a service to families and infants, justified by broader but possibly more moderate benefits) fundamentally changes the answer to the questions of why we screen and what might constitute acceptable "moderate benefits." Historically, this question has been answered by the public health community. However, as suggested in a recent review,115 low levels of genetic literacy combined with public ambivalence and perhaps skepticism about the value of genetic information116 call for a broader effort in which the public health community engages with the public in a discussion about whether and how to proceed with expanded NBS.
CONCLUSIONS
A recent survey of service providers in England during the first phase of newborn hearing screening made clear the need to address issues at a systems level, attending to such factors as interagency coordination, funding, and the political context in which screening exists.117 In 2000, the American Academy of Pediatrics published a set of recommendations for how pediatricians, state agencies, federal agencies, and other groups need to coordinate efforts and address barriers to a comprehensive and supportive national NBS system.2 In the ensuing years, much progress has been made and a number of activities are now underway.67 However, issues such as the possible expansion of screening to "untreatable" conditions and the disclosure of information such as carrier status (as in the case of FXS) will not be solved by systems-level reform alone. These issues require careful study and a more intense focus on the processes and materials that enable parents to make informed decisions about expanded NBS and to become "genetic citizens" who engage in public debates and help forge policy and research agendas.118,119
ACKNOWLEDGMENTS
Preparation of this article was supported by grants from the Ethical, Legal, and Social Implications Research Program, National Human Genome Research Institute (grant P20-HG003387), and the National Institute for Child Health and Human Development (grant R21-HD043616).
FOOTNOTES
Accepted Jul 16, 2007.
Address correspondence to Donald B. Bailey, Jr, PhD, RTI International, 3040 Cornwallis Rd, Research Triangle Park, NC 27709-2194. E-mail: dbailey{at}rti.org
The authors have indicated they have no financial relationships relevant to this article to disclose.
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