Prenatal screening for cystic fibrosis: Where are we now?
2002; Elsevier BV; Volume: 141; Issue: 6 Linguagem: Inglês
10.1067/mpd.2002.127666
ISSN1097-6833
AutoresPhilip M. Farrell, Norman Fost,
Tópico(s)Tracheal and airway disorders
ResumoSee related article, p 804.Cystic fibrosis (CF) has been regarded by the Centers for Disease Control and Prevention (CDC) as a “paradigm for public health genetics policy development.”1Centers for Disease Control and Prevention Newborn screening for cystic fibrosis: a paradigm for public health genetics policy development.MMWR Morb Mortal Wkly Rep. 1997; 46: RR-16Google Scholar This conclusion was based on a multidisciplinary analysis of newborn screening for CF, but prenatal tests are equally important in the current health policy sphere. Consequently, both targeted populations, ie, pregnant women and newborns, deserve commentary. This is the first in a series of articles that will focus on CF screening because of timely scientific medical, ethical, and policy issues that have intensified recently.In the fall of 2001, the American College of Obstetrics and Gynecology (ACOG) recommended “offering CF screening to individuals with a family history of CF, reproductive partners of persons who have CF, couples in whom one or both partners are Caucasian and are planning a pregnancy or seeking prenatal care” and that “screening should be made available to couples in other racial and ethnic groups who are of lower risk and in whom the test may be less sensitive.”2American College of Obstetricians and Gynecologists, American College of Medical Genetics Preconception and prenatal carrier screening for cystic fibrosis.in: 2001: 1-33Google Scholar This followed the published3Grody WW Cutting GR Klinger KW Richards CS Watson MS Desnick RJ Laboratory standards and guidelines for population-based cystic fibrosis carrier screening.Genet Med. 2001; 3: 149-153Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar “laboratory standards and guidelines for population-based cystic fibrosis carrier screening,” which uses a 25 cystic fibrosis transmembrane conductance regulator (CFTR) mutation panel recommended by the American College of Medical Genetics (ACMG), after an earlier (1997) recommendation from a National Institutes of Health (NIH) Consensus Conference.4Consensus Development Conference Statement NIH Genetic testing for cystic fibrosis, April 14-16, 1997.Arch Intern Med. 1999; 159: 1529-1539Crossref PubMed Scopus (132) Google Scholar For a variety of reasons, the NIH “consensus” report had very little impact on, and limited credibility with, the medical-scientific community. On the other hand, it is likely that ACMG and ACOG recommendations will influence the practice of obstetrical care. For instance, Kaiser-Permanente is considering system-wide implementation that follows the lead of the Northern California Permanente Medical Group where prenatal CF screening has been routinely offered to white couples for 2 years. Other groups implemented testing almost immediately after ACOG distributed a packet of guidelines and educational documents to its members during the fall of 2001.Medical and scientific issuesCF is a life-threatening, autosomal recessive disease that results from a chloride channel defect that is attributable to mutations in the CFTR gene. Approximately 1000 mutations have been discovered since 1989 when collaborating investigators from Toronto and Michigan described the most common CFTR allele, known as ΔF508.5Karem B-S Rommens JM Buchanan JA Markiewicz D Cox TK Chakravarti A et al.Identification of the cystic fibrosis gene: genetic analysis.Science. 1989; 245: 1073-1080Crossref PubMed Scopus (3161) Google Scholar The incidence of CF varies depending on region, ancestry, and CFTR allele prevalence in reproducing populations. In the United States, the most accurate data available6Kosorok MR Wei W-H Farrell PM The incidence of cystic fibrosis.Stat Med. 1996; 15: 449-462Crossref PubMed Scopus (116) Google Scholar reveal that the incidence is one CF homozygote or compound heterozygote patient for every 3500 live births, reflecting a predicted CF-heterozygote frequency of 1 in 30; this approximates the mean CF carrier frequency actually determined (1 in 31; 95% CI = 1 in 24 to 1 in 43) in the Wisconsin newborn population (reflecting actively reproducing adults7Gregg RG Wilfond BS Farrell PM Laxova A Hassemer D Mischler EH Application of DNA analysis in a population-screening program for neonatal diagnosis of cystic fibrosis (CF): comparison of screening protocols.Am J Hum Genet. 1993; 52: 616-626PubMed Google Scholar), as well as in the pregnant population of Northern California (1/27-1/34) studied in 1991 and 1992 by Witt et al.8Witt DR Schaefer C Hallam P Wi S Blumberg B Fishbach A et al.Cystic fibrosis heterozygote screening in 5161 pregnant women.Am J Hum Genet. 1996; 58: 823-835PubMed Google Scholar In the nonwhite US population, the incidence has been calculated6Kosorok MR Wei W-H Farrell PM The incidence of cystic fibrosis.Stat Med. 1996; 15: 449-462Crossref PubMed Scopus (116) Google Scholar at 1:12,163; this corresponds to a CF heterozygote prevalence of 1 in 56, assuming Hardy-Weinberg equilibrium. Compared with African Americans (estimated at 1 in 653Grody WW Cutting GR Klinger KW Richards CS Watson MS Desnick RJ Laboratory standards and guidelines for population-based cystic fibrosis carrier screening.Genet Med. 2001; 3: 149-153Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar) and Hispanic Americans (estimated at 1 in 463Grody WW Cutting GR Klinger KW Richards CS Watson MS Desnick RJ Laboratory standards and guidelines for population-based cystic fibrosis carrier screening.Genet Med. 2001; 3: 149-153Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar), there is less certainty about the CF heterozygote prevalence in Asian American populations.3Grody WW Cutting GR Klinger KW Richards CS Watson MS Desnick RJ Laboratory standards and guidelines for population-based cystic fibrosis carrier screening.Genet Med. 2001; 3: 149-153Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar, 6Kosorok MR Wei W-H Farrell PM The incidence of cystic fibrosis.Stat Med. 1996; 15: 449-462Crossref PubMed Scopus (116) Google Scholar Undoubtedly, the common misunderstanding that CF is a “Caucasian disease” leads to underdiagnosis and under-reporting 6Kosorok MR Wei W-H Farrell PM The incidence of cystic fibrosis.Stat Med. 1996; 15: 449-462Crossref PubMed Scopus (116) Google Scholar in nonwhite patients, ie, a bias in ascertainment, and the CF incidence is probably higher in African Americans and Hispanic populations of the United States. In addition to ethnicity-associated variations in CF incidence, CFTR mutation profiles are closely related to ancestry.9Bobadilla JL Macek Jr, M Fine JP Farrell PM Cystic fibrosis: a worldwide analysis for CFTR mutations—correlation with incidence data and application to screening.Human Mutat. 2002; 19: 575-606Crossref PubMed Scopus (783) Google ScholarCF causes pathology in many organs where CFTR expression and chloride transport are important. Sweat gland epithelial cells are altered functionally, but not histologically; their failure to reabsorb electrolytes serves as the diagnostic test for CF and places patients at risk for hypoelectrolytemia and death in hot weather. Second, pancreatic ductal obstruction occurs in utero and results in pancreatic insufficiency with subsequent malabsorption and potential malnutrition in about 85% of patients older than 1 year. The third characteristic feature of CF, airways obstruction with dehydrated secretions, leads at a variable age to chronic obstructive pulmonary disease and recurrent respiratory infections with unusual pathogens such as Pseudomonas aeruginosa. Ultimately, lung disease determines the prognosis for most patients.10Wood RE Prognosis.in: Cystic fibrosis. : Thieme-Stratton, Inc, New York1984: 434-460Google Scholar On the other hand, some key organs and physiologic functions are not altered by CFTR mutations, such as the central nervous system and musculoskeletal system. This distinguishes CF from other hereditary disorders included in prenatal screening programs, such as Tay-Sachs disease, 11Kaback M Lim-Steele J Dabholkar D Brown D Levy N Zeiger K Tay-Sachs disease—carrier screening, prenatal diagnosis, and the molecular era: an international perspective, 1970 to 1993.JAMA. 1993; 270: 2307-2315Crossref PubMed Scopus (220) Google Scholar in which progressive neurologic lesions severely limit the quality of life. When placed in a health policy perspective, the sparing of those organs may be as important for children as the organs affected when one considers that there is very good treatment (essentially preventive) for the loss of electrolytes in sweat and for the malabsorption and malnutrition, while the lung is functionally and histologically normal at birth and also a prime candidate for eventual development of curative therapy. 12Mall M Wissner A Gonska T Calenborn D Kuehn J Brandis M et al.Inhibition of amiloride-sensitive epithelial Na(+) absorption by extracellular nucleotides in human normal and cyctic fibrosis airways.Am J Respir Cell Mol Biol. 2000; 23: 755-761Crossref PubMed Scopus (93) Google Scholar Indeed, as Crozier optimistically stated, 13Crozier DN Cystic fibrosis: A not-so-fatal disease.Pediatr Clin North Am. 1974; 21: 935-950Crossref PubMed Scopus (57) Google Scholar CF is “a not-so-fatal disease” anymore.The survival of CF patients has been increasing during the past 4 decades. The most useful expression of mortality information has been provided by the US Cystic Fibrosis Foundation (CFF). Results of survival analysis are published annually by using data stored in the CFF Registry for patients born between 1926 and the year before publication. 14Cystic Fibrosis Foundation Cystic Fibrosis Foundation Patient Registry Annual Data Report, 2000. : Cystic Fibrosis Foundation, Bethesda (MD)2000Google Scholar The report distributed in September 2001 included 22,301 patients ranging in age from 1 month to 74 years and showed a medial survival of 32.2 years; ~40% of patients are older than 18 years. It should be emphasized that the CFF-registered patients reflect the diagnostic and therapeutic modes of the past several decades, and the majority of older patients did not have access as children to recent advances in nutritional (eg, high potency pancreatic enzyme supplements) andrespiratory (eg, aerosolized deoxyribonuclease and tobramycin) care. In contrast, patients diagnosed early through newborn screening show a relatively flat survival curve, 15Mérelle ME Schouten JP Gerritsen J Dankert-Roelse JE Influence of neonatal screening and centralized treatment of long-term clinical outcome and survival of CF patients.Eur Respir J. 2001; 18: 306-315Crossref PubMed Scopus (109) Google Scholar leading to longevity estimates exceeding 50 years.Although many factors contribute to lowering the morbidity and mortality of CF patients, it has become clear during the past decade that age of diagnosis, sex, genotype, pancreatic functional status, socioeconomic status, and respiratory flora are especially significant. Diagnosis early in infancy because of a positive family history or newborn screening, ie, presymptomatic identification, improves nutritional outcomes and may also be associated with less severe lung disease, 1Centers for Disease Control and Prevention Newborn screening for cystic fibrosis: a paradigm for public health genetics policy development.MMWR Morb Mortal Wkly Rep. 1997; 46: RR-16Google Scholar as will be described fully in the second commentary. Sex has been considered a prognostic factor, particularly since females show relatively shorter survival, although they also experience greater delays in diagnosis. 16Lai H-C Kosorok MR Laxova A Makholm LM Farrell PM Delayed diagnosis of US females with cystic fibrosis.Am J Epidemiol. 2002; 158: 165-173Crossref Scopus (58) Google Scholar CF patients with pancreatic sufficiency are typically spared from malnutrition and have a significantly better prognosis. 10Wood RE Prognosis.in: Cystic fibrosis. : Thieme-Stratton, Inc, New York1984: 434-460Google Scholar The CF genotype of patients reliably, but not infallibly, predicts the phenotype with respect to pancreatic functional status. With more than 1000 CFTR alleles, however, it has been difficult to obtain sufficient epidemiologic data for a comprehensive categorization/prognostication system beyond the I through V classification method 17Welsh MJ Tsui L Boat TC Beaudet AL The metabolic and molecular bases of inherited disease.in: 17th ed. Cystic fibrosis. : McGraw-Hill, New York1995: 3799-3876Google Scholar that organizes CF mutations by severity of molecular defects and clinical effects. In addition, most CF mutations seem to be “private,” ie, occurring in only one patient or family, and their effects are largely based on anecdotal observations. Unquestionably, many CFTR alleles relate closely to ancestry. For instance, 3120 + 1G → A is associated with African American CF patients, and R75X with Hispanics. 9Bobadilla JL Macek Jr, M Fine JP Farrell PM Cystic fibrosis: a worldwide analysis for CFTR mutations—correlation with incidence data and application to screening.Human Mutat. 2002; 19: 575-606Crossref PubMed Scopus (783) Google ScholarBecause new methods of analytic molecular genetics allow commercial laboratories to detect CFTR alleles that occur in minority populations, it is somewhat surprising that ACMG/ ACOG limited its recommendation to a 25 CF mutation panel that deliberately excludes CFTR alleles in “minority” ethnic groups of the United States. Indeed, the field of genetic analysis is evolving rapidly, concurrent with the Human Genome Project, and commercial testing for 86 mutations is already becoming routine. DNA samples as small as 5 ng can now be used for CF multimutation analysis. These tests range in cost from $50 to $285 for CFTR gene scanning (potentially allowing most of the 1000 mutations to be detected through a commercially available method) to <$1 for ΔF508 detection. 18Le Maréchal C Audrézet MP Quére I Raguénes O Langonné Férec C Complete and rapid scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by denaturing high-performance liquid chromatography (D-HPLC): major implications for genetic counseling.Hum Genet. 2001; 108: 290-298Crossref PubMed Scopus (112) Google ScholarEthical and policy issuesIt is now technically feasible to screen large populations for CF carrier status in primary care and obstetric practices. 8Witt DR Schaefer C Hallam P Wi S Blumberg B Fishbach A et al.Cystic fibrosis heterozygote screening in 5161 pregnant women.Am J Hum Genet. 1996; 58: 823-835PubMed Google Scholar, 19Doherty RA Palomaki GE Kloza EM Erickson JL Haddow JE Couple-based prenatal screening for cystic fibrosis in primary care settings.Prenat Diagn. 1996; 16: 397-404Crossref PubMed Scopus (32) Google Scholar The central question is whether screening can or will be implemented in a way that is consistent with widely supported ethical principles, particularly respecting the importance of voluntary informed consent. In other words, “Are we ready?” 20Grody WW Desnick RJ Cystic fibrosis population carrier screening: here at last—are we ready?.Genet Med. 2001; 3: 87-90Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar Virtually all statements about the basic ethical principles that should guide genetic testing emphasize the critical importance of informed consent. 21President's Commission for the Study of Ethical Problems in Medicine and Biomedical Research Screening and counseling for genetic conditions. : US Government Printing Office, Washington (DC)1983Google Scholar, 22National Institutes of Health Workshop on population screening for the cystic fibrosis gene.N Engl J Med. 1990; 323: 70-71PubMed Google Scholar, 23Andrews LB Fullarton JE Holtzman NA Motulsky AG Assessing genetic risks: implications for health and social policy. : National Academy Press, Washington (DC)1994Google Scholar The ACOG emphasis is typical: “Genetic screening must always be voluntary and always requires informed consent,” and “whether to have carrier screening for CF is a personal decision and not a clinical decision or a routine medical test.” 2American College of Obstetricians and Gynecologists, American College of Medical Genetics Preconception and prenatal carrier screening for cystic fibrosis.in: 2001: 1-33Google ScholarAlmost as common as the restatement of the underlying principle is the observation that obtaining truly informed consent for this test is difficult in the setting of a busy office practice. The ACOG guidelines concede that printed patient information “is not intended to substitute for a discussion of CF carrier screening between the patient and the support staff or provider,” and suggest that “ideally this information may be provided by trained support staff.” It is unclear whether each obstetric office will be able to afford sufficient support staff who are trained to educate every patient. A British study suggests that a 0.5 full-time equivalent midwife that spends 11 minutes per patient could serve a practice with 5000 deliveries per year, 24Cuckle HS Richardson GA Sheldon TA Quirke TA Cost effectiveness of antenatal screening for cystic fibrosis.BMJ. 1995; 311: 1460-1464Crossref PubMed Scopus (48) Google Scholar but trained genetic counselors believe that an hour or more is needed to educate an uninformed layperson to the point where she can make a truly informed choice. 25Modaff M Biesecker B Personal communication.January, 2002Google ScholarPrinted information has been shown to be effective in conveying information regarding CF, but such materials may be less effective for those with lower educational background. 26Clayton EW Hannig PI Pfotenhauer JP Parker RA Campbell 3rd, PW Phillips JA Teaching about cystic fibrosis carrier screening by using written and video information.Am J Hum Genet. 1995; 57: 171-181PubMed Google Scholar Even among college graduates, 5% to 10% maynot understand essential information, which could result in important procreative decisions being based on misinformation. The durability of this understanding is uncertain, with 20% to 33% of patients not understanding their results 3 months after testing. 27Bekker H Modell M Denniss G Silver A Mathew C Bobrow M et al.Uptake of cystic fibrosis testing in primary care: supply push or demand pull?.BMJ. 1993; 306: 1584-1586Crossref PubMed Scopus (159) Google Scholar In other studies, confusion among carriers has exceeded 50%. 28Mischler EH Wilfond BS Fost N Laxova A Reiser C Sauer CM et al.Cystic fibrosis newborn screening: impact on reproductive behavior and implications for genetic counseling.Pediatrics. 1998; 102: 44-52Crossref PubMed Scopus (117) Google Scholar, 29Grody WW Dunkel-Schetter C Tatsugawa ZH PCR-based screening for cystic fibrosis carrier mutations in an ethnically diverse pregnant population.Am J Hum Genet. 1997; 60: 935-947PubMed Google Scholar, 30Watson EK Mayall ES Lamb J Chapple J Williamson R Psychological and social consequences of community carrier screening programme for cystic fibrosis.Lancet. 1992; 340: 217-220Abstract PubMed Scopus (81) Google Scholar, 31Lippman-Hand A Fraser FC Genetic counseling: provision and reception of information.Am J Med Genet. 1979; 3: 113-127Crossref PubMed Scopus (95) Google Scholar Even a small incidence of adverse effects could affect many families if large numbers of persons are screened.One part of an informed choice involves an understanding of common or likely risks. The ACOG printed information for patients 32The American College of Obstetricians and Gynecologists Cystic fibrosis carrier testing: the decision is yours.2001Google Scholar curiously omits any discussion of the well-known risks of genetic screening, such as insurance and employment discrimination 33Billings PR Kohn NA de Cuevas M Beckwith J Alper JS Natowicz MR Discrimination as a consequence of genetic testing.Am J Hum Genet. 1992; 50: 476-482PubMed Google Scholar, 34Alper JS Geller LN Barash CI Billings PR Laden V Natowicz MR Genetic discrimination and screening for hemochromatosis.J Public Health Policy. 1994; 15: 3345-3358Crossref Scopus (59) Google Scholar, 35Natowicz MR Alper JK Alper JS Genetic discrimination and the law.Am J Hum Genet. 1992; 50: 465-475PubMed Google Scholar or the possibility of uncovering mispaternity. Failure to recognize mispaternity may result in an erroneous assessment of the probability of having an affected child, as well as the potential emotional calamity of bringing an illicit relationship to light. The incidence of mispaternity in prenatal carrier studies has been reported as at least 1% to 3%. 36Livingstone J Axton RA Gilfillan A Mennie M Compton M Liston WA et al.Antenatal screening for cystic fibrosis: a trail of the couple model.BMJ. 1994; 308: 1459-1462Crossref PubMed Scopus (65) Google Scholar Another basic element of informed consent is that it should be free and uncoerced. Some studies suggest that patients' decisions to be tested can be heavily influenced by the behavior of professionals. Interest in CF testing has been very low in nonpregnant populations, 27Bekker H Modell M Denniss G Silver A Mathew C Bobrow M et al.Uptake of cystic fibrosis testing in primary care: supply push or demand pull?.BMJ. 1993; 306: 1584-1586Crossref PubMed Scopus (159) Google Scholar, 37Clayton EW Hannig VI Pfotenhauer JP Parker RA Campbell 3rd, PW Phillips 3rd, JA Lack of interest by nonpregnant couples in population-based cystic fibrosis carrier screening.Am J Hum Genet. 1996; 58: 617-627PubMed Google Scholar but is typically as high as 80% among pregnant women and their partners, 36Livingstone J Axton RA Gilfillan A Mennie M Compton M Liston WA et al.Antenatal screening for cystic fibrosis: a trail of the couple model.BMJ. 1994; 308: 1459-1462Crossref PubMed Scopus (65) Google Scholar particularly if the offer is made directly by an interested health professional. 27Bekker H Modell M Denniss G Silver A Mathew C Bobrow M et al.Uptake of cystic fibrosis testing in primary care: supply push or demand pull?.BMJ. 1993; 306: 1584-1586Crossref PubMed Scopus (159) Google Scholar, 38Watson EK Mayall E Chapple J Dalziel M Harrington K Williams C et al.Screening for carriers of cystic fibrosis through primary health care services.BMJ. 1991; 303: 504-507Crossref PubMed Scopus (102) Google Scholar, 39Raeburn S Screening for carriers of cystic fibrosis.BMJ. 1994; 308: 1451-1452Crossref PubMed Scopus (7) Google Scholar Even among nonpregnant patients in a primary care setting, the uptake was 70% when patients were approached directly and invited to undergo testing at that time. This dropped to 25% when the patients were approached directly but given an opportunity to make an appointment to be tested. The authors concluded that “it remains to be resolved whether the high uptake rates achieved by active recruitment indicate a supply push for this new test rather than a demand from the population.” 27Bekker H Modell M Denniss G Silver A Mathew C Bobrow M et al.Uptake of cystic fibrosis testing in primary care: supply push or demand pull?.BMJ. 1993; 306: 1584-1586Crossref PubMed Scopus (159) Google ScholarHow many accept the test will depend heavily on how it is presented. The ACOG guidelines stress the optional nature of testing and the importance of reinforcing that “carrier screening for CF is a personal decision and not a clinical decision or a routine medical test,” yet the guidelines advise practitioners to obtain written informed consent to request or decline screening among all pregnant couples. This is contrasted with the recommendations for couples in ethnic groups at lower risk, where the intention is “to make screening available…on request,” so “the use of the consent process to decline testing is not necessary.” If it is not a routine test, and if it is only being offered—not recommended or pushed—it is unclear why a couple must provide written confirmation that they are not interested.This requirement that patients must provide written evidence that they want to “opt out” would be unusual even for a routine test, so its purpose in this setting is unclear at best and problematic at worst. It implies that the provider considers this to be an unusually important test. If the purpose of requiring this signature is to protect physicians from liability for a wrongful birth suit, they could achieve that goal in the usual ways, ie, by recording in the medical record that the patient had been informed of the availability of the test, had been given informational materials, and by having written office operating procedures that document this routine practice.There is one other asymmetry in the ACOG guidelines regarding populations assumed to be at “high” or “low” risk. Providers are advised to distribute written material to low-risk patients, provide additional information or counseling when requested, and provide screening only “if they understand the information.” The requirement for a demonstration that consent is truly informed is laudable but problematic in 2 regards. It suggests that persons who cannot demonstrate appropriate understanding will be denied access to testing. This is a very high standard and unusual in traditional clinical practice. It also leaves unclear why testing in couples at “high” risk is not being held to the same standard.Finally, the advent of widespread population screening for CF carrier testing will raise questions about eugenic goals. Several authors have projected that the costs of CF carrier screening could be offset by the savings from averting births of affected persons and lifetime costs of medical care for these patients. 24Cuckle HS Richardson GA Sheldon TA Quirke TA Cost effectiveness of antenatal screening for cystic fibrosis.BMJ. 1995; 311: 1460-1464Crossref PubMed Scopus (48) Google Scholar, 40Burn J Screening for cystic fibrosis in primary care.BMJ. 1993; 306: 1558-1559Crossref PubMed Scopus (8) Google Scholar, 41Asch DA Hershey JC Pauly MV Patton JP Jedrziewski KM Mennuti MT Genetic screening for reproductive planning: methodological and conceptual issues in policy analysis.Am J Public Health. 1996; 86: 684-690Crossref PubMed Scopus (24) Google Scholar If all pregnant couples were to be tested, the costs could be $500 million per year. Cost/benefit projections about such a program depend on the validity of projections about the level of interest in testing, ie, the “uptake rate,” and the proportion of couples at risk who would take actions to avert the birth of an affected child, generally through prenatal diagnosis and selective abortion.Implicit in these analyses is the expectation that widespread carrier screening will or should lead to a reduction in live births of persons with CF. Such a goal is contrary to the commonly stated view that genetic screening programs should not have eugenic goals, and that genetic counseling should be nondirective and value-neutral as much as possible. 38Watson EK Mayall E Chapple J Dalziel M Harrington K Williams C et al.Screening for carriers of cystic fibrosis through primary health care services.BMJ. 1991; 303: 504-507Crossref PubMed Scopus (102) Google Scholar Whether genetic counseling can or should be nondirective has been questioned. 23Andrews LB Fullarton JE Holtzman NA Motulsky AG Assessing genetic risks: implications for health and social policy. : National Academy Press, Washington (DC)1994Google Scholar In addition, the history of eugenics suggests that some clinicians are likely to convey a bias toward eugenic goals in their communications with families. 42Kevles DJ In the name of eugenics: genetics and the uses of human heredity. : Harvard University Press, Cambridge (MA)1995Google Scholar Although the goal of “more informed reproducers” 38Watson EK Mayall E Chapple J Dalziel M Harrington K Williams C et al.Screening for carriers of cystic fibrosis through primary health care services.BMJ. 1991; 303: 504-507Crossref PubMed Scopus (102) Google Scholar is laudable, it might be difficult to justify the expenditure of such large amounts of money if there were not some public health benefit, namely, a reduction in CF incidence. If an expensive national screening program resulted only in an increase in “more informed reproducers,” those responsible for the prudent allocation of limited health care funds would have difficulty justifying such a program.These cost/benefit calculations are more problematic when CF screening is extended to racial groups that unquestionably have a lower incidence of CF, such as Asian Americans. Costs are harder to justify when the incidence is low. 43Haddow JE Palomaki GE Glenn E Bradley LA Doherty RA Screening for cystic fibrosis.JAMA. 1998; 279: 1068-1069Crossref PubMed Scopus (12) Google Scholar In addition, the 2-tiered policy recommended by ACOG will undoubtedly stir up claims about unfair discrimination. Because CF carrier frequency is more common than anticipated in African Americans and Hispanics, 9Bobadilla JL Macek Jr, M Fine JP Farrell PM Cystic fibrosis: a worldwide analysis for CFTR mutations—correlation with incidence data and application to screening.Human Mutat. 2002; 19: 575-606Crossref PubMed Scopus (783) Google Scholar an assumption of “low risk” could lead to inappropriate exclusion of minorities. Indeed, it will be difficult to argue that a 1 in 30 probability is substantially higher than 1 in 50, even with lower CFTR testing sensitivity. Also, the sensitivity can be increased by including more than the 25 recommended 3Grody WW Cutting GR Klinger KW Richards CS Watson MS Desnick RJ Laboratory standards and guidelines for population-based cystic fibrosis carrier screening.Genet Med. 2001; 3: 149-153Abstract Full Text Full Text PDF PubMed Scopus (389) Google Scholar mutations in the panel. 44Bobadilla JL
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