Editorial Screening for Cystic Fibrosis Ethical and Social Issues Discovery of the cystic fibrosis (CF) (1-3) gene provides a long-awaited opportunity for clinical advance in the detection and management of the disease. At the same time, this opportunity presents researchers and clinicians, patients with CF and their families, and society more generally with a variety of complex social and ethical dilemmas. In particular, the issue of screening for CF needs to be addressed. CF is the most commonly inherited human disease. Among Caucasians of European ancestry, approximately 1:25are carriers of CF, i.e.,they have one normal and one abnormal CF gene. It is therefore estimated that about 10million people in North America are carriers of CF. The disease is characterized by chronic lung disease, which usually leads to the patient's death. Currently, the median survival for Canadian patients with CF is 24 yr (20 yr for females and 30 yr for males) (4). In addition, patients with CF suffer from pancreatic insufficiency and other less common manifestations such as meconium ileus, hepatobiliary abnormalities, diabetes mellitus, and musculoskeletal problems (5). Almost all males with CF are infertile; females who reach adulthood are fertile and may have normal pregnancies and children. At present, it is not possible to predict the prognosis of a particular patient, although it is likely that some CF mutations are associated with a milder clinical course (3, 6). In most of the large centers, many patients with CF are able to livea fairly normal life until adolescence. They attend regular schools and can enjoy normal childhood activitiessuitable for their age. However, these children must attend the CF clinic every 3 to 6 months; occasionally, they are hospitalized for respiratory infection. Most patients with CF use oral enzyme supplements with each meal; lacking these, they have increased bowel movements together with food maldigestion. As well, most patients with CF must take antibiotics and vitamins on a regular basis, and they require chest physiotherapy twice daily. As the disease
progresses, patients with CF havechronic cough; this presents growing interference with their daily activity. Later, respiratory impairment becomes predominant in the lives of patients with CF and, eventually, they die as a result of respiratory insufficiency. Parents of children with CF, and the families of these chronically ill children, have a number of serious responsibilities in relation to their care. The daily medication schedules are demanding; assistance with the required physiotherapy is time-consuming; the continuing possibility of imminent death for these patients poses serious psychologic concerns. Most parents and families can and do cope quite well with the hardships, although parental and family dysfunction does occur. Although such dysfunction may not be traceable directly to the burden of caring for a child with CF, such care inevitably adds stressto normal family interaction. With the recent introduction of lung transplantation for patients with CF, there is new optimism for the prognosis and treatment of those affected by the disease.Although long-term follow-up is not yet available, there is presently a greater than 700/0 short-term survival rate in experienced centers (7, 8). CF does not seem to recur in the lungs of those patients who have undergone transplantation. Studies show that the characteristic electrophysiologic abnormalities do . not develop in the transplanted lungs in the subsequent 2 yr (9). Although this is encouraging, lung transplantation is a relatively new procedure, limited to a small number of centers; further, it is a major operation, associated with pain and discomfort, and requires immunosuppressivetherapy for the rest of the patient's life. The incidence of obliterative bronchiolitis, infections such as HIV transmitted by the donor, or other longterm complications has not been determined yet. Because of the prevailing shortage of donors, lung transplantation is available to only a small number of those patients who could benefit from it. In the future, it is hoped that within-
creased experience, improved preservation methods, and better surgical techniques, lung transplantation could be available for many patients with CF. As a result, their prognoses and quality of life would be drastically altered. Further study of the CF gene may well lead to a better understanding of the functional nature of the biochemical defect here, and thus to specific pharmacologic treatment of CF; more distantly, such study may lead to development of CF gene therapy. In the Caucasian society, CF is the only recessive disorder sufficiently common to warrant general population screening. Currently, DNA analysis can identify a single mutation in the CF gene (AF s 0 8 ) , which is present in 70 to 75lflo of Caucasian carriers. Approximately 70 mutations (CF Genetic Analysis Consortium, unpublished data) that produce CF have now been identified. The identification of multiple, individual rare mutations rather than a small number of common mutations will make carrier testing more difficult. Although carrier testingof close relatives in families in which the disease has occurred is possible, and mass carrier screening programs may become possible in the near future, the inability to detect all carriers creates complexitiesfor the use of carrier screening at this time. Three justifications have been offered .in support of programs for CF screening: (1) prenatal diagnosis will provide information on which to base decisions concerning the continuation of a CF pregnancy; (2) neonatal screening will lead to early diagnosis and treatment, which will improve the well-being or prognosisof the patient; (3)carrier screening will provide information of value to the patients in making decisions regarding marriage and reproduction. Prior to implementation of any such CF screening programs, attention should be given to the social and ethical issues accompanying introduction of this activity (10-12). Until recently, prenatal diagnosis of CF was made from cells obtained by amniocentesis or by chorionic villous sampling (13). So far, most of the couples 457
458
seeking prenatal diagnosis are those who have already produced an affected child with CF or know of one in their family. Such couples will have some good basic knowledge and understanding ofthe disease. Furthermore, they may appreciate the difficulties they will face in their attempt to cope with a child who has chronic illness. Therefore, it would be interesting to know what the attitude of such couples towards prenatal diagnosis of CF might be. A study by Evers-Kiebooms and coworkers (14) demonstrates the major impact the birth of a CF child could have on parents' future reproductive plans. In families followed for at least 5 yr, a pregnancy subsequent to the birth of a CF child occurred in 35070 of the couples. Again, once the decision for pregnancy was made, the attitude of parents of a child with CF may change. In our institution, from 1986, when prenatal diagnosis based on restriction fragment length polymorphism (RFLP) analysis for CF was available, we followed 31 pregnancies in families in which one child with CF had already been born. Ten families did not agree to be referred for genetic counseling; three of them gave birth to CF babies. Three more families refused to proceed for amniocentesis. Of the eight pregnancies where the fetus was diagnosed as affected with CF, three (37.5 0J0) women decided to continue the pregnancy. It seems that in these cases, a relatively high percentage of women who decided to avoid prenatal diagnosis or to continue the pregnancy with an affected fetus is associated with the fact of having a child with CF. In the case of prenatal detection of CF, and the choices to be made in that regard, a distinction should be made between CF and other diseases that result in a severelyhandicapped child with short life expectancy and very poor quality of life (e.g., anencephaly, Tay-Sachs). There is a difference between having a child who is severely affected, with no chance of even a minimal time of normal life, and having a child with years of near normalcy, and the growing possibility of definitive therapy. For some parents, this difference will be expressed in their choice of termination of pregnancy in the one case and continuation of pregnancy in the other (15-17). Indeed, as the possibility of improved therapy for the child with CF is realized, will there be sufficient reasons to justify an elective termination of a CF pregnancy? It might be argued that the "right" to have a normal child overrides all other values in reproduction such
EDITORIAL
that reproduction of normal children becomes the standard practice (18). Although identification of the "abnormal" might be relatively easy in that circumstance, what will the standard for "abnormal" that involves termination of pregnancy be? Society has no one ethical standard here; individuals and their physicians must thus set their own ethical criteria for such decision making. As assisting in the decision-making process, physicians must provide individual couples with all available scientific information. As survival among patients with CF improves, more individuals in society will carry the CF gene, even as all children of patients with CF will carry the CF mutation. It might be seen as more cost effective to terminate any CF pregnancy rather than treat the child with CF for years while awaiting the possibility of lung transplantation. Any savings thus realized could be used to provide health care assistance for other patients with CF or other disease. Further to this view, insurance companies or health authorities might decide in favor of policies that encourage abortion in this circumstance, i.e., on grounds of economic/public health factors. In that case, the health care system or the insurance company might refuse coverage for children with CF born to identified carriers who had decided to give birth to an affected child. Those in opposition to this view, whether on religious or conscientious grounds, might then refuse prenatal diagnosis altogether. Although these are only theoretical concerns at present, guidelines projective of individual choice in this matter should be developed before any prenatal screening program is put in place. Neonatal screening has been used to diagnose before the onset of overt symptoms. Serum levels of immunoreactive trypsinogen are elevated in virtually every child with CF (19). This assay has been performed on dried blood spot samples; it has been shown to have high sensitivity and specificity and is currently employed for wide-scale screening in various parts of the world (19, 20). Presumably, such testing is justifiable in terms of the possibility that early diagnosis and treatment, prior to the onset of clinical disease, will significantly improve the long-term outcome for the patient. However, it is not clear that neonatal testing for CF does affect the long-term outcome. Whereas early introduction of treatment for hypothyroidism or phenylketonuria may lead to normal health for
the affected child, all patients with CF will ultimately develop progressive pulmonary disease, despite currently available treatment. Given the relatively long life span of patients with CF, any proof of the medical benefit of CF neonatal screening will be difficult. Because a large patient population and years of follow-up will be required, it may take at least another decade before results of neonatal screening programs of this kind will be available for proper analysis. Meanwhile, a largescale study is being conducted in the United States in order to answer these and other questions (21).Until the information can be obtained it is suggested that no mass neonatal screening for CF be implemented, even if a valid and reliable test is available (22). There are potential benefits of early diagnosis of CF. Early diagnosis may avoid the time period between the onset of symptoms and the diagnosis, which is one of stress and emotional strain (23). In addition to the possible benefit to the child in question, a neonatal screening program for CF would have benefit for the child's parents insofar as obtaining knowledge of their risk for future ~reg nancies is concerned. There is no controversy about this benefit. However, screening for this purpose would be costly, and potential harmful side effects of early identification must also be considered. Little is known about the effect of diagnosing a chronic, fatal disease such as CF insofar as parental reactions towards this child are concerned. Parental distress, anxiety, guilt feelings, and fears of losing their child with CF have been reported (24, 25). Others have reported psychologic problems in many families where an infant has had a false positive diagnosis for phenylketonuria or hypothyroidism (26, 27). The implications of false results must thus be considered. Theoretically, the specificity and sensitivity of the DNA testing for the presence of the CF mutation is 100%. However, false results may arise from laboratory errors. False negative results may also be the results of failure to identify all the CF mutations. False negative results may induce a false sense of security so that the disease is not suspected when the child subsequently develops symptoms of CF. This could delay proper diagnosis and thus lead to delay in treatment of the patient, with potentially deleterious consequences. The cloning of the CF gene, and identification of the most common mutation
EDITORIAL
(~F508' present in 70 to 750/0 of Caucasian carriers) (3) has important implications for the identification of carriers of the mutant CF gene in the general population. The American Society of Human Genetics has commented: "It will be appropriate to begin large-scale population screening in the foreseeable future, once the test detects a larger proportion of CF carriers and more information is available regarding the issues surrounding the screening process" (28). Because of the large number of different mutations in the remaining CF population, it is presently impossible to screen our population to detect 95 to 100% of the carriers (29). Nonetheless, it has been suggested that mass population screening for CF be initiated immediately (30-32). Some commercial companies have already designed kits for rapid detection of the major CF mutation. Such screening programs would involve simple blood sampling, which will be sent to the laboratory for testing. Unlike contagious diseases (in which undiagnosed individuals may endanger the health of others), there is currently no public health justification for mandatory screening for genetic disease. Further, such screening is not comparable to the situation in which parents ask their doctor for advice regarding their child's disease. Genetic carrier screening is done by a third party on those individuals more likely to have this status; those individuals actually found to be carriers are then warned of the effects of the disease, and advised of the action they can take in response to such information. Such intervention has the potential to both help and harm. Should the individual test positive for the heterozygote state, it may raise feelings of guilt, fear, unwillingness to have children, or rejection by members of the society. Given these concerns, a well-developed educational program should be in place prior to initiation of any such screening program. Such a program would acquaint the public with the nature of the disease and the implications of termination of pregnancy in its regard. Education with regard to any CF screening program must target the whole community as misbelief, prejudice, and misconceptions should be eliminated and prevented. Lacking such education, there may be serious family and emotional pressure to undergo testing; there may be real or apparent rejection of those individuals who test positive for the disease, even if only as heterozygous. Some of the potential hazards of carrier screening for
459
CF in the absence of extensive and continuous education can be seen in the results of the sickle cell anemia screening program recently offered in Massachusetts (33). In this program, proactive and ongoing educational efforts were not carried out. The consequences of that were that individuals who were heterozygous for sickle cell anemia lost their jobs, and, in others, symptoms of heart disease or acute appendicitis were misinterpreted. Among the issues to be discussed in providing a screening program: the possibility of false results, risks in exercising reproductive options, confidentiality of test results, individual and family privacy, noncoercion with regard to testing, and the like. Further, in consideration of the psychologic, social, and ethical impact of initiation and implementation of such screening programs, several series of guidelines have already appeared in documents prepared by the U.S. Presidential Commission for the Study of Ethical Problems in Medicine and Behaviorial Research, and reports from The Genetics Research Group from the Hastings Center (34-36). These documents emphasize the following concerns: 1. The goals to be served by such screening, and thus the target population for such screening should be welldefined. Screening programs of this kind cannot be justified on such general grounds as "a genetically healthy society." 2. So as to minimize error rates, screening should be undertaken only when stringent quality control laboratory analysis is available. 3. Limits for false-positive and falsenegative results should be clearly delineated. The number of individuals with negative results who will be carriers of CF may still be quite high. 4. The confidentiality of the information obtained by the screening should be recognized, and the health authorities should protect the information as well as relevant data banks from illegal access. There is a need to define the use of information gained from such screening, as well as the circumstances in which such information will be released (e.g., adoption). Guidelines for disclosure of incidental findings such as nonpaternity must be developed. 5. Well-formulated procedures to protect the rights of privacy of individuals and their families should be set out well in advance. 6. Any participation in such a screening program must be voluntary.
7. Genetic counseling should be offered to all individuals prior to their participation in such screening programs. Couples found to be 1:4 risk will require additional counseling of this kind. Such counseling should be non-directive and should aid the couple to make reproductive decisions consistent with their own beliefs. 8. Comprehensive educational programs must be designed and ready for implementation prior to commencement of such screening programs. Community leaders and organizations representing the population to be screened (the CF Foundation) should play an integral part in population-education program planning. Such programs must include access to physicians who can inform patients of their risk for genetic disease and the availability of screening tests. 9. The long-term outcome of any such screening program must be monitored; the program must be evaluated on a regular basis. The high number of CF carriers (5% of the Caucasian population, or about 10 million people in North America) poses a particular problem in terms of any health expenditures budget; a CF carrier screening program would be one more competitor in a field already strained to accommodate present needs. In addition, the potential demand for millions of tests in a short period of time, with the related need for follow-up diagnostic studies and counseling, will have grave impact on a system that is currently unprepared with regard to an ethical framework and in its ability to provide the general population with a high standard of service. As new knowledge of CF is developed, screening programs for detection of carrier and affected status will be proposed. Such proposals must be considered within a well-defined social and ethical framework. Among the questions arising in such considerations: (1) How will the health care system, and society more generally, respond to identification of massive numbers of heterozygotes? (2) Will elective abortion of an affected fetus be justified, given anticipated developments in extension of life span and improved quality of life for patients with CF? (3) What consequences will there be for those heterozygous carriers whose testing provides false negative results? What planning is required for such outcomes? Acknowledgment
The writers thank Drs. H. O'Brodovich,
460
EDITORIAL
H. Levison, B. Kerem, and L.C. Tsui for their constructive criticism of the manuscript, Mrs. C. Shuman, L. Green, and S. Carpenter for the information regarding pregnancies in CF families, and J. Chay for secretarial assistance. EITAN KEREM, M.D. ABBYANN LYNCH, PH.D.
Division of Chest Medicine and Department of Bioethies The Hospital for Siek Children Toronto, Ontario, Canada References 1. Rommens JM, Iannuzzi MC, Kerem B, et a/. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 1989; 245: 1059-65. 2. Riordan JR, Rommens JM, Kerem B, et a/. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989; 245:1066-73. 3. Kerem B, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosis gene: genetic analysis. Science 1989; 245:1073-80. 4. Canadian Cystic Fibrosis Foundation. Report of the Canadian Cystic Fibrosis Patient and Data Registry, 1988. 5. Boat TF, WelshMJ, Beaudet AL. Cystic fibrosis. In: Scriver CR, Beaudet AL, Sly WS, Valle 0, eds. The metabolic basis of inherited disease. 6th ed. New York: MacGraw-Hill, 1989; 2649-80. 6. Kerem E, Corey M, Kerem B, et al. The relationship between genotype and phenotype in cystic fibrosis: analysis of the most common mutation (~F508)' N Engl J Med 1990; 323:1517-22. 7. Geddes OM, Hodson ME. The role of heart and lung transplantation in the treatment of cystic fibrosis. J R Soc Med 1989 82(Suppl 16:49-53). 8. Scott J, Higgenbottam T, Hutter J, eta/. Heart lung transplantation for cysticfibrosis. Lancet 1988; 2:192-4. 9. Alton EWFW, Batten JC, Hodson M, Wallwork J, Biggenbottam T, Geddes OM. Absence of
electrochemical defect of cystic fibrosis in transplanted lung. Lancet 1987; 1:1026. 10. Arnold A, Mosely R. Ethical issues arising from medical genetics. J Med Ethics 1976;2:12-7. II. Seller MJ. Ethical aspects of genetic counselling. J Med Ethics 1982; 8:185-8. 12. West R. Ethical aspects of genetic disease and genetic counselling. J Med Ethics 1988; 14:194-7. 13. Beaudet AL, Feldman GL, Fernback SO, Buffone GJ, O'Brien WE. Linkage disequilibrium, cystic fibrosis, and genetic counselling. Am J Hum Genet 1989; 44:319-26. 14. Evers-Keibooms G, Benyer L, Cassiman JJ, van-den Berghe H. Family planning decisions after the birth of a cystic fibrosis child. The impact of prenatal diagnosis. Scand J Gastroenterol Suppl 1988; 143:38-46. 15. Faden RR, ChwalowAJ, Quaid K, et al. Prenatal screening and pregnant women's attitudes toward abortion of defective fetuses. Am J Public Health 1987; 77:288. 16. Beck JR, Jordan AG, Meier FA. Modern prenatal diagnosis: the ethical dimension. Lancet 1983; 1:303. 17. Johnson SR, Elkins TE. Ethical issues in prenatal diagnosis. Clin Obstet Gynecol 1988; 32:408-17. 18. Ramsey P. Screening: an ethicist's view. In: Hunt R, Arras J, eds. Ethical issuesin modern medicine. Palo Alto, CA: Mayfield Publishing Company, 1977. 19. Heeley AF, HeeleyME, King ON et a/. Screening for cystic fibrosis by dried spot trypsin assay. Arch Dis Child 1982; 57:18-21. 20. Wilcken B, Brown ARD, Urwin R, et al. Cystic fibrosis screening by dried blood spot trypsin assay: Results in 75000newborn infants. J Pediatr 1983; 102:383-7. 21. Mischlen E, Farrel P, Bruns T, et a/. Wisconsin experience with newborn screening for cystic fibrosis: no conclusion yet! Pediatr Pulmonol1988; 2(Suppl); 43-5. 22. Ad Hoc Committee Task Force on Neonatal Screening, Cystic Fibrosis Foundation. Neonatal screening for cystic fibrosis (position paper). Pediatrics 1983; 72:41-5.
23. Accurso F, Helton J, Hammond K, Abman S. Newborn screening for cystic fibrosis. Pediatr Pulmonol 1988; 2(Suppl); 41-2. 24. Fischer-fay A, Goldberg S, Simmons R, et a/. Does a chronic illness affect the mother-child relationship? Pediatr Pulmonol 1987; I(Suppl):143. 25. SvegerT, Thelin T. Four-year-oldchildren with alpha-t-Al' deficiency: clinical follow-up and Jarental attitudes towards neonatal screening. Acta Pediatr Scand 1981; 70:171-7. 26. Rotenbery MB, Sills EM. Iatrogenesis: The PKU anxiety syndrome. J Am Acad Child Psychiatry 1968; 7:689. 27. Bodegard G, Fyro K, Carsson A. Psychological reactions in 102 families with a newborn who has a falsely negative screening test for congenital hypothyroidism. Acta Pediatr Scand 1983; 304:1-21. 28. Caskey CT, Kaback MM, Beaudet AL, et a/. The American Society for Genetics statement on cystic fibrosis screening. Am J Hum Genet 1990; 45:393. 29. Statement from the NIH Workshop on population screening for the cystic fibrosis gene. Am J Hum Genet (In Press). 30. Goodfellow PN. Steady steps lead to the gene. Nature 1989; 341:102-3. 31. McIntosh I, Lorenzo M-L, Brock DJH. Frequency of ~F508 mutation on cystic fibrosis chromosomes in UK. Lancet 1989; 2:1404. 32. Vassart G, Cochaux P, Abramowicz M. CF screening. Nature 1990; 33:586. 33. Beutler E, Boggs DR, Heller P, Maurer A, Motulsky AG, Sheehy TW. Hazards of indiscriminatory screening for sickling.N Engl J Med 1971; 285:1485-6. 34. Lappe M, Gustafson JM, Roblin R. E;thical and social issues in screening for genetic disease. N Engl J Med 1972; 286:1129-32. 35. Powledge TM, Fletcher J. Guidelines for the ethical, social and legal issues in prenatal diagnosis. N Engl J Med 1979; 300:168-72. 36. President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Screening and counseling for genetic conditions. Washington, DC: U.S. Government Printing Office, 1983; 41-104.
progresses, patients with CF havechronic cough; this presents growing interference with their daily activity. Later, respiratory impairment becomes predominant in the lives of patients with CF and, eventually, they die as a result of respiratory insufficiency. Parents of children with CF, and the families of these chronically ill children, have a number of serious responsibilities in relation to their care. The daily medication schedules are demanding; assistance with the required physiotherapy is time-consuming; the continuing possibility of imminent death for these patients poses serious psychologic concerns. Most parents and families can and do cope quite well with the hardships, although parental and family dysfunction does occur. Although such dysfunction may not be traceable directly to the burden of caring for a child with CF, such care inevitably adds stressto normal family interaction. With the recent introduction of lung transplantation for patients with CF, there is new optimism for the prognosis and treatment of those affected by the disease.Although long-term follow-up is not yet available, there is presently a greater than 700/0 short-term survival rate in experienced centers (7, 8). CF does not seem to recur in the lungs of those patients who have undergone transplantation. Studies show that the characteristic electrophysiologic abnormalities do . not develop in the transplanted lungs in the subsequent 2 yr (9). Although this is encouraging, lung transplantation is a relatively new procedure, limited to a small number of centers; further, it is a major operation, associated with pain and discomfort, and requires immunosuppressivetherapy for the rest of the patient's life. The incidence of obliterative bronchiolitis, infections such as HIV transmitted by the donor, or other longterm complications has not been determined yet. Because of the prevailing shortage of donors, lung transplantation is available to only a small number of those patients who could benefit from it. In the future, it is hoped that within-
creased experience, improved preservation methods, and better surgical techniques, lung transplantation could be available for many patients with CF. As a result, their prognoses and quality of life would be drastically altered. Further study of the CF gene may well lead to a better understanding of the functional nature of the biochemical defect here, and thus to specific pharmacologic treatment of CF; more distantly, such study may lead to development of CF gene therapy. In the Caucasian society, CF is the only recessive disorder sufficiently common to warrant general population screening. Currently, DNA analysis can identify a single mutation in the CF gene (AF s 0 8 ) , which is present in 70 to 75lflo of Caucasian carriers. Approximately 70 mutations (CF Genetic Analysis Consortium, unpublished data) that produce CF have now been identified. The identification of multiple, individual rare mutations rather than a small number of common mutations will make carrier testing more difficult. Although carrier testingof close relatives in families in which the disease has occurred is possible, and mass carrier screening programs may become possible in the near future, the inability to detect all carriers creates complexitiesfor the use of carrier screening at this time. Three justifications have been offered .in support of programs for CF screening: (1) prenatal diagnosis will provide information on which to base decisions concerning the continuation of a CF pregnancy; (2) neonatal screening will lead to early diagnosis and treatment, which will improve the well-being or prognosisof the patient; (3)carrier screening will provide information of value to the patients in making decisions regarding marriage and reproduction. Prior to implementation of any such CF screening programs, attention should be given to the social and ethical issues accompanying introduction of this activity (10-12). Until recently, prenatal diagnosis of CF was made from cells obtained by amniocentesis or by chorionic villous sampling (13). So far, most of the couples 457
458
seeking prenatal diagnosis are those who have already produced an affected child with CF or know of one in their family. Such couples will have some good basic knowledge and understanding ofthe disease. Furthermore, they may appreciate the difficulties they will face in their attempt to cope with a child who has chronic illness. Therefore, it would be interesting to know what the attitude of such couples towards prenatal diagnosis of CF might be. A study by Evers-Kiebooms and coworkers (14) demonstrates the major impact the birth of a CF child could have on parents' future reproductive plans. In families followed for at least 5 yr, a pregnancy subsequent to the birth of a CF child occurred in 35070 of the couples. Again, once the decision for pregnancy was made, the attitude of parents of a child with CF may change. In our institution, from 1986, when prenatal diagnosis based on restriction fragment length polymorphism (RFLP) analysis for CF was available, we followed 31 pregnancies in families in which one child with CF had already been born. Ten families did not agree to be referred for genetic counseling; three of them gave birth to CF babies. Three more families refused to proceed for amniocentesis. Of the eight pregnancies where the fetus was diagnosed as affected with CF, three (37.5 0J0) women decided to continue the pregnancy. It seems that in these cases, a relatively high percentage of women who decided to avoid prenatal diagnosis or to continue the pregnancy with an affected fetus is associated with the fact of having a child with CF. In the case of prenatal detection of CF, and the choices to be made in that regard, a distinction should be made between CF and other diseases that result in a severelyhandicapped child with short life expectancy and very poor quality of life (e.g., anencephaly, Tay-Sachs). There is a difference between having a child who is severely affected, with no chance of even a minimal time of normal life, and having a child with years of near normalcy, and the growing possibility of definitive therapy. For some parents, this difference will be expressed in their choice of termination of pregnancy in the one case and continuation of pregnancy in the other (15-17). Indeed, as the possibility of improved therapy for the child with CF is realized, will there be sufficient reasons to justify an elective termination of a CF pregnancy? It might be argued that the "right" to have a normal child overrides all other values in reproduction such
EDITORIAL
that reproduction of normal children becomes the standard practice (18). Although identification of the "abnormal" might be relatively easy in that circumstance, what will the standard for "abnormal" that involves termination of pregnancy be? Society has no one ethical standard here; individuals and their physicians must thus set their own ethical criteria for such decision making. As assisting in the decision-making process, physicians must provide individual couples with all available scientific information. As survival among patients with CF improves, more individuals in society will carry the CF gene, even as all children of patients with CF will carry the CF mutation. It might be seen as more cost effective to terminate any CF pregnancy rather than treat the child with CF for years while awaiting the possibility of lung transplantation. Any savings thus realized could be used to provide health care assistance for other patients with CF or other disease. Further to this view, insurance companies or health authorities might decide in favor of policies that encourage abortion in this circumstance, i.e., on grounds of economic/public health factors. In that case, the health care system or the insurance company might refuse coverage for children with CF born to identified carriers who had decided to give birth to an affected child. Those in opposition to this view, whether on religious or conscientious grounds, might then refuse prenatal diagnosis altogether. Although these are only theoretical concerns at present, guidelines projective of individual choice in this matter should be developed before any prenatal screening program is put in place. Neonatal screening has been used to diagnose before the onset of overt symptoms. Serum levels of immunoreactive trypsinogen are elevated in virtually every child with CF (19). This assay has been performed on dried blood spot samples; it has been shown to have high sensitivity and specificity and is currently employed for wide-scale screening in various parts of the world (19, 20). Presumably, such testing is justifiable in terms of the possibility that early diagnosis and treatment, prior to the onset of clinical disease, will significantly improve the long-term outcome for the patient. However, it is not clear that neonatal testing for CF does affect the long-term outcome. Whereas early introduction of treatment for hypothyroidism or phenylketonuria may lead to normal health for
the affected child, all patients with CF will ultimately develop progressive pulmonary disease, despite currently available treatment. Given the relatively long life span of patients with CF, any proof of the medical benefit of CF neonatal screening will be difficult. Because a large patient population and years of follow-up will be required, it may take at least another decade before results of neonatal screening programs of this kind will be available for proper analysis. Meanwhile, a largescale study is being conducted in the United States in order to answer these and other questions (21).Until the information can be obtained it is suggested that no mass neonatal screening for CF be implemented, even if a valid and reliable test is available (22). There are potential benefits of early diagnosis of CF. Early diagnosis may avoid the time period between the onset of symptoms and the diagnosis, which is one of stress and emotional strain (23). In addition to the possible benefit to the child in question, a neonatal screening program for CF would have benefit for the child's parents insofar as obtaining knowledge of their risk for future ~reg nancies is concerned. There is no controversy about this benefit. However, screening for this purpose would be costly, and potential harmful side effects of early identification must also be considered. Little is known about the effect of diagnosing a chronic, fatal disease such as CF insofar as parental reactions towards this child are concerned. Parental distress, anxiety, guilt feelings, and fears of losing their child with CF have been reported (24, 25). Others have reported psychologic problems in many families where an infant has had a false positive diagnosis for phenylketonuria or hypothyroidism (26, 27). The implications of false results must thus be considered. Theoretically, the specificity and sensitivity of the DNA testing for the presence of the CF mutation is 100%. However, false results may arise from laboratory errors. False negative results may also be the results of failure to identify all the CF mutations. False negative results may induce a false sense of security so that the disease is not suspected when the child subsequently develops symptoms of CF. This could delay proper diagnosis and thus lead to delay in treatment of the patient, with potentially deleterious consequences. The cloning of the CF gene, and identification of the most common mutation
EDITORIAL
(~F508' present in 70 to 750/0 of Caucasian carriers) (3) has important implications for the identification of carriers of the mutant CF gene in the general population. The American Society of Human Genetics has commented: "It will be appropriate to begin large-scale population screening in the foreseeable future, once the test detects a larger proportion of CF carriers and more information is available regarding the issues surrounding the screening process" (28). Because of the large number of different mutations in the remaining CF population, it is presently impossible to screen our population to detect 95 to 100% of the carriers (29). Nonetheless, it has been suggested that mass population screening for CF be initiated immediately (30-32). Some commercial companies have already designed kits for rapid detection of the major CF mutation. Such screening programs would involve simple blood sampling, which will be sent to the laboratory for testing. Unlike contagious diseases (in which undiagnosed individuals may endanger the health of others), there is currently no public health justification for mandatory screening for genetic disease. Further, such screening is not comparable to the situation in which parents ask their doctor for advice regarding their child's disease. Genetic carrier screening is done by a third party on those individuals more likely to have this status; those individuals actually found to be carriers are then warned of the effects of the disease, and advised of the action they can take in response to such information. Such intervention has the potential to both help and harm. Should the individual test positive for the heterozygote state, it may raise feelings of guilt, fear, unwillingness to have children, or rejection by members of the society. Given these concerns, a well-developed educational program should be in place prior to initiation of any such screening program. Such a program would acquaint the public with the nature of the disease and the implications of termination of pregnancy in its regard. Education with regard to any CF screening program must target the whole community as misbelief, prejudice, and misconceptions should be eliminated and prevented. Lacking such education, there may be serious family and emotional pressure to undergo testing; there may be real or apparent rejection of those individuals who test positive for the disease, even if only as heterozygous. Some of the potential hazards of carrier screening for
459
CF in the absence of extensive and continuous education can be seen in the results of the sickle cell anemia screening program recently offered in Massachusetts (33). In this program, proactive and ongoing educational efforts were not carried out. The consequences of that were that individuals who were heterozygous for sickle cell anemia lost their jobs, and, in others, symptoms of heart disease or acute appendicitis were misinterpreted. Among the issues to be discussed in providing a screening program: the possibility of false results, risks in exercising reproductive options, confidentiality of test results, individual and family privacy, noncoercion with regard to testing, and the like. Further, in consideration of the psychologic, social, and ethical impact of initiation and implementation of such screening programs, several series of guidelines have already appeared in documents prepared by the U.S. Presidential Commission for the Study of Ethical Problems in Medicine and Behaviorial Research, and reports from The Genetics Research Group from the Hastings Center (34-36). These documents emphasize the following concerns: 1. The goals to be served by such screening, and thus the target population for such screening should be welldefined. Screening programs of this kind cannot be justified on such general grounds as "a genetically healthy society." 2. So as to minimize error rates, screening should be undertaken only when stringent quality control laboratory analysis is available. 3. Limits for false-positive and falsenegative results should be clearly delineated. The number of individuals with negative results who will be carriers of CF may still be quite high. 4. The confidentiality of the information obtained by the screening should be recognized, and the health authorities should protect the information as well as relevant data banks from illegal access. There is a need to define the use of information gained from such screening, as well as the circumstances in which such information will be released (e.g., adoption). Guidelines for disclosure of incidental findings such as nonpaternity must be developed. 5. Well-formulated procedures to protect the rights of privacy of individuals and their families should be set out well in advance. 6. Any participation in such a screening program must be voluntary.
7. Genetic counseling should be offered to all individuals prior to their participation in such screening programs. Couples found to be 1:4 risk will require additional counseling of this kind. Such counseling should be non-directive and should aid the couple to make reproductive decisions consistent with their own beliefs. 8. Comprehensive educational programs must be designed and ready for implementation prior to commencement of such screening programs. Community leaders and organizations representing the population to be screened (the CF Foundation) should play an integral part in population-education program planning. Such programs must include access to physicians who can inform patients of their risk for genetic disease and the availability of screening tests. 9. The long-term outcome of any such screening program must be monitored; the program must be evaluated on a regular basis. The high number of CF carriers (5% of the Caucasian population, or about 10 million people in North America) poses a particular problem in terms of any health expenditures budget; a CF carrier screening program would be one more competitor in a field already strained to accommodate present needs. In addition, the potential demand for millions of tests in a short period of time, with the related need for follow-up diagnostic studies and counseling, will have grave impact on a system that is currently unprepared with regard to an ethical framework and in its ability to provide the general population with a high standard of service. As new knowledge of CF is developed, screening programs for detection of carrier and affected status will be proposed. Such proposals must be considered within a well-defined social and ethical framework. Among the questions arising in such considerations: (1) How will the health care system, and society more generally, respond to identification of massive numbers of heterozygotes? (2) Will elective abortion of an affected fetus be justified, given anticipated developments in extension of life span and improved quality of life for patients with CF? (3) What consequences will there be for those heterozygous carriers whose testing provides false negative results? What planning is required for such outcomes? Acknowledgment
The writers thank Drs. H. O'Brodovich,
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EDITORIAL
H. Levison, B. Kerem, and L.C. Tsui for their constructive criticism of the manuscript, Mrs. C. Shuman, L. Green, and S. Carpenter for the information regarding pregnancies in CF families, and J. Chay for secretarial assistance. EITAN KEREM, M.D. ABBYANN LYNCH, PH.D.
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