Genetic Testing and Screening: II. Newborn Genetic Screening
II. NEWBORN GENETIC SCREENING
Throughout the United States, and in many other countries around the world, newborns are tested within the first few days to weeks of life for a varying array of metabolic disorders. Until recently, newborns were typically screened for only a handful of disorders, but recent technological advances and new knowledge about genetics have led to pressure for greatly expanded screening. At first glance, newborn screening might seem unremarkable. Much of medical practice is devoted to the early detection of disease to allow the delivery of effective interventions, and new developments are often received enthusiastically. But newborn screening programs have several features that individually and collectively pose particular ethical challenges.
All U.S. states require that newborns be screened, either prior to discharge or, if delivered outside a healthcare facility, within the first two to three days of life (AAP). Maryland, Wyoming, and, for some but not all tests, Georgia and Massachusetts require that parents give their permission for screening, though many states do permit parents to refuse screening (generally for religious reasons). This option may be difficult to exercise in practice, however, since few states require that parents even be told that screening is occurring, much less that they have a right to refuse. Thus, one of more remarkable aspects of newborn screening is that parents are not even nominally part of the decision-making process for their new infants (AAP; Paul; Clayton).
Those who argue against either notifying parents or seeking their permission reason that all children should be screened, and it would thus be a waste of money and effort to talk with parents (Cunningham). Proponents of mandatory screening argue that most parents would agree to screening, but that they might be unduly worried if they knew about the test (Cunningham). They assert further that parents who refuse would be harming their own children. These arguments raise two separate issues: (1) the justifiability of excluding parents, and (2) the characteristics of newborn screening programs (and the disorders they seek).
The Role of Parents
The role of parents in making healthcare decisions for their infants is addressed elsewhere in this encyclopedia. In general, parents are presumed to have a role to play in such decisions, which can be overridden only to avert serious harm. But clinicians cannot decide not to talk with parents simply because they think it would take too much time, would make parents worry, or that it would be a waste of effort because parents usually agree to the clinician's recommendations anyway.
These principles suggest to the advocates of seeking parental permission that parents cannot justifiably be denied the opportunity to be informed about and participate in decisions about newborn screening. Most parents agree to screening, and informed parents are more likely to ensure that screening is performed, as well as to obtain any followup that may be required (Andrews). Even if parents refuse screening, it is unlikely that their children will come to harm, for the disorders sought in these programs are very rare.
Newborn Screening Programs
Universal newborn screening was first adopted for phenylketonuria (PKU), an inherited metabolic disorder that causes severe mental retardation unless treatment is started in the first few weeks of life (NAS). Children with this disease have few symptoms early on, but the metabolic abnormality can be detected in the first few days of life by testing either the urine or the blood. Thus, several factors converged to support the idea of early detection:
- The disease has a devastating outcome
- Treatment is highly effective in averting this outcome, but only if it is started early
- Affected children cannot be detected on the basis of symptoms in time to start effectivetreatment
- Screening reliably detects most affected children (NAS)
When clinicians were slow to adopt these tests in their clinical practice, in part because they were uncertain about the efficacy of treatment, advocates went to their legislators to get them to enact laws requiring PKU screening (AAP; Clayton; NAS).
In the two decades that followed the enactment of these initial laws, the diseases that were added to the testing panels generally had similar characteristics. Congenital hypothyroidism requires early treatment to prevent severe retardation, and it frequently is not detected clinically during the newborn period. The risk of overwhelming bacterial infection faced by young children with sickle-cell disease can be greatly reduced by giving prophylactic penicillin. Children with galactosemia are often critically ill by the time the condition is detected on the basis of their symptoms, an outcome that can be averted by using a formula that does not contain lactose (milk sugar). Typically, programs were expanded to these and other disorders in response to a combination of mounting medical evidence and political pressure by families and clinicians.
Pressure to expand the number of disorders being screened for expanded dramatically during the 1990s, largely as a result of the development of tandem mass spectrometry ("MS/MS") (AAP). This technology permits the detection of a large number of metabolic abnormalities on a single specimen of blood. Unfortunately, no treatment exists for many of the disorders detectable by MS/MS, which raises issues of whether to test for these abnormalities, and of what to tell families whose children may have one of the untreatable diseases.
Until recently, most state statutes focused on identifying affected children. Most state programs tried to ensure that these children were directed to appropriate sources of care, but few actually ensured the availability of needed medications and diets. Since children do not have universal access to healthcare, some children received no treatment, and some parents suffered job lock. Increasingly, states, practitioners, and clinicians have begun to work together to develop systems to ensure the delivery of care for these children (AAP), a laudable goal which is threatened by the increasing pressure to privatize newborn screening.
The Problem of False Positives
Screening tests are assessed according to their sensitivity (the percentage of affected individuals detected) and their specificity (the percentage of unaffected individuals who are correctly excluded from further testing). The actual number of people who receive inaccurate initial screening results depends in large part on the frequency of the disease in the population. The more common the disease, the more likely it is that a person who receives a positive (abnormal) test result will actually be affected. (The rhetoric of screening and testing is confusing in that "positive" test results almost always mean that something is wrong.) As the disease becomes less frequent, the proportion of initial results that turn out to be "false positives" increases. Suppose a disease has an incidence of 1 in 10,000 and a population of 100,000 people is tested with a screening test that has a sensitivity of 90 percent (so that 9 out of 10 affected people will test positive) and a specificity of 99 percent (so that 99 out of 100 unaffected people will test negative). The results overall would be as follows:
|Test positive||Test negative|
|Affected||9 "true positive"||1 "false negative"|
|Unaffected||999 "false positive"||98,991 "true negative"|
Put another way, for every person who was truly affected (and tested positive), 100 people who did not have the disease would also (falsely) test positive. In addition, nine people who did have the disease would test negative. While most people who get false positive test results are ultimately reassured by further testing, some may continue to be worried. Affected children who are missed in these programs may face substantial delays in diagnosis if clinicians reason that the child could not have the disorder because it would have been identified in the newborn period.
The disorders sought in newborn screening programs typically are quite rare, usually having frequencies in the 1-in-5,000 to 1-in-15,000 range. Some of the diseases that are being added being to newborn screening panels are as rare as 1 in 100,000. Without denying the benefits that can come to affected children who are detected in these programs, it is important to acknowledge the possible harms that may befall the many children who inevitably receive falsely abnormal results. The newborn period is a particularly vulnerable time. Parents are just beginning to know and bond with their infants. Bad news, even if incorrect, can interfere with the formation of this central relationship and lead parents to view their new infants as medically fragile. One study revealed that almost 10 percent of parents whose infants received initial false-positive screening results for cystic fibrosis were still worried a year later that their children were affected or otherwise sickly.
Thus, the trend has been to increase the disorders for which newborns are screened, including some for which the benefits of early invention are unclear or may be absent, all the while causing a growing number of infants to receive false-positive test results, which will cause some of them harm.
The Implications of These Disorders
Most of the disorders sought by newborn screening are inherited, usually as autosomal recessive disorders. If parents have a child with one of these diseases, they have a one in four chance in each subsequent pregnancy of having another affected child. Children with such a disease can have affected children themselves if they have children with partners who have one or two copies of the same mutated gene. Some screening protocols, such as those for sickle-cell disease and cystic fibrosis, also detect carriers (children who have a single copy of a mutated gene). While these children do not have the disease, the presence of a mutated gene signals an increased risk of having a truly affected child, both for them and for their parents. From an ethical perspective, it seems obvious that parents should be told about all of these implications, but this sort of communication often does not occur.
One of the more difficult ethical questions is whether parents should be encouraged to alter their future reproductive plans in order to decrease the costs of disease to society.
The general consensus is that decisions about having children are to be made by the prospective parents according to their own values, and that genetic counseling is to be nondirective (Andrews, Fullerton, Holtzman, et al.).
Another complex issue is whether decreasing the number of affected children born, whether as a result of state intervention or even of independent decisions by prospective parents, should be seen as an additional goal or benefit of newborn screening. Some governmental officials have made this argument, even calculating the decreased healthcare expenditures that follow from the birth of fewer affected children in their efforts to calculate the cost efficacy of newborn screening (Cunningham). Others, including advocates of disability rights and opponents of prenatal diagnosis, find these arguments distasteful and potentially coercive (Asch).
Untreated women with PKU are profoundly retarded and rarely have children. As a result of the successful implementation of newborn screening and treatment for PKU, however, many affected females are now in their reproductive years, have intelligence in the normal range, and can and do become pregnant. Unless these women adhere to the highly restrictive and burdensome PKU diet prior to conception and throughout their pregnancy, their children will be born with severe brain injury.
These children typically do not have PKU themselves because their fathers are not likely to be carriers since those mutations are not common. The injuries they suffer during pregnancy result instead from the high levels of phenylalanine that exist in their mothers' blood when they eat a normal diet, levels which are particularly toxic to the developing brain. The irony then is that improving the lives of women with PKU creates a high level of risk to the children they may bear. Clearly, these women need to be educated about the importance of adhering to the proper diet prior to and during pregnancy. The ethical dilemma is whether it is ever appropriate, and if so, how, to bring pressure to bear to lead these women to either follow this onerous diet or avoid childbearing altogether (Robertson and Schulman).
Newborn Screening Samples as DNA Databanks
Birth is the only time of life when the government collects blood from virtually everyone. Some states discard these samples within a few months after birth, while others retain them indefinitely. In the past it was not possible to extract much information from these samples because most metabolites deteriorate quickly, but recent advances, particularly in DNA testing, have created new possibilities. Newborn samples can be used for DNA identification, for further investigation when a child subsequently becomes sick, or for research, for which they may be particularly attractive as a true population sample. However, all these uses are secondary to the purpose for which they were initially collected—to detect children with diseases that urgently require treatment.
The appropriateness of using these samples for these other purposes raises many of the questions that attend any use of stored tissue samples for research, including: (1) whether it is necessary to ask the donor (or in this case the parent) for permission; (2) when, if ever, it is appropriate to inform individuals of their personal results; and (3) what sort of review needs to occur before these samples can be used. The fact that these samples are typically obtained without parental knowledge or permission makes these issues that much more urgent, particularly in a society that is so deeply concerned about issues of genetic privacy. It would be rather ironic if a system of universal DNA identification were developed as a by-product of newborn screening rather than as a result of an explicit policy decision.
The particular ethical issues posed by newborn screening arise because these programs are required and run by the government, typically do not involve parents in decision making, often implicate reproductive decision making, and can provide samples for a growing number of secondary uses. These unique factors suggest that parents should have a greater role to play in these programs, and that these programs should remain narrowly focused on detecting diseases for which treatment is urgently needed to avert serious sequelae.
ellen wright clayton
SEE ALSO: Cloning: Reproductive; Disability; Embryo and Fetus; Eugenics; Eugenics and Religious Law; Genetic Counseling, Ethical Issues in; Genetic Counseling, Practice of; Genetic Discrimination; Genetics and Human Self-Understanding; Infants; Informed Consent; Maternal-Fetal Relationship; Mistakes, Medical; Moral Status; Reproductive Technologies;Value and Valuation; and other Genetic Testing and Screening subentries
American Academy of Pediatrics (AAP), Newborn Screening Task Force. 2000. "Serving the Family From Birth to the Medical Home, Newborn Screening: A Blueprint for the Future, A Call for a National Agenda on State Newborn Screening Programs." Pediatrics 106 (suppl.): 383–427.
Andrews, Lori B. 1985. "New Legal Approaches to Newborn Screening and the Rationale behind the Recommendations for Quality Assurance in Newborn Screening." In Legal Liability and Quality Assurance in Newborn Screening, ed. Lori B. Andrews. Chicago: American Bar Foundation.
Andrews Lori B.; Fullerton, Jane E.; Hotlzman, Neil A., et al., eds. 1994. Assessing Genetic Risks: Implications for Health and Science Policy. Washington, D.C.: National Academy Press.
Asch, A. 1989. "Reproductive Technology and Disability." In Reproductive Laws for the 1990s, ed. S. Cohen and N. Taub. Clifton, NJ: Humana Press.
Clayton, Ellen W. 1992. "Screening and Treatment of Newborns." Houston Law Review 29(1): 85–148.
Cunningham, George. 1990. "Balancing the Individual's Rights to Privacy against the Need for Information to Protect and Advance Public Health." In Genetic Screening: From Newborns to DNA Typing, ed. Bartha M. Knoppers and Claude M. Laberge. Amsterdam: Excerpta Medica.
Faden, Ruth; Chwalow, A. J.; Holtzman, Neil A.; et al. 1982. "A Survey to Evaluate Parental Consent as Public Policy for Neonatal Screening." American Journal of Public Health 72: 1347–52.
Hannon, W. Harry, and Grosse, Scott D. 2001. "Using Tandem Mass Spectrometry for Metabolic Disease Screening Among Newborns." Morbidity and Mortality Weekly Report 50(RR03): 1–22.
National Research Council, Committee for the Study of Inborn Errors of Metabolism. 1975. Genetic Screening: Programs, Principles, and Research. Washington, D.C.: National Academy Press.
"Newborn Screening for Sickle Cell Disease and Other Hemoglobinopathies." 1989. Pediatrics 83(5/2): 813–914
Paul, D. 1999. "Contesting Consent: The Challenge to Compulsory Neonatal Screening for PKU." Perspectives in Biology and Medicine 42: 207–219.
Robertson, J. A., and Schulman, J. D. 1987. "Pregnancy and Prenatal Harm to Offspring: The Case of Mothers with PKU." Hastings Center Report 17(4): 23–33.
Tluczek A.; Mischler, E. H.; Farrell, P. M.; et al. (1992). "Parents' Knowledge of Neonatal Screening and Response to False-Positive Cystic Fibrosis Testing." Journal of Developmental Behavioral Pediatrics. 13(3): 181–186.
Waisbren S.E., Hanley, W; and Levy, H. L.; et al. 2000. "Outcome at Age 4 Years in Offspring of Women with Maternal Phenylketonuria: the Maternal PKU Collaborative Study." Journal of the American Medical Association 283(6): 756–762.