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First fruits: genetic screening.

And when the woman saw that the tree was good for food, and that it was pleasant to the eyes, and a tree to be desired to make one wise, she took of the fruit thereof, and did eat, and gave also unto her husband with her; and he did eat.

One of the first fruits of the Human Genome Project will be many new markers for traits and diseases believed to have a genetic base but so far lacking an identified gene (or genes). Most of these markers can be developed into diagnostic tests quite easily, greatly expanding the range of genetic diagnostic options potentially available to individuals for themselves, or as parents and prospective parents.

However, the sheer mass of genetic information that may become available, along with the complex patterns of information offered by many of the new markers, has generated concern about the extent and rapidity with which these new markers should move from the laboratory bench into various clinical uses. In particular, critics of modern obstetric practices have taken note of the ways in which increased diagnostic surveillance can change the character and mood of pregnancy, and they have urged special caution about increased prenatal genetic testing. This paper explores these issues and suggests the need for national standards articulating criteria for introducing and funding new genetic tests as a part of normal prenatal care.

Genetic Testing in Prenatal Care

Having a baby is an exciting and emotionally demanding process for parents. Here is a new life, forged from complex physical and emotional bonds between its parents, and manifesting the powerful and mysterious intertwining of their previously distinct genetic heritages. Whether planned or unanticipated, pregnancy emerges replete with potential: a potential child with an almost infinite range of needs, desires, and attributes.

From a parent's perspective, pregnancy is thus filled with both curiosity and concern. What kind of baby will this be? Who will it look like? Will it be a girl or a boy? Will it be healthy?

This last question - "Will my baby be healthy?" - helps propel parents into the obstetrician's or midwife's office, as they seek to fulfill their responsibility to protect and promote the well-being of their developing offspring. Joining with the health professional, they construct a history of the developing fetus via a series of physical examinations and selected diagnostic tests.

Although few parents realize it, none of these tests, singly or in combination, can prove that the pregnancy is proceeding normally. In fact, even directly examining the baby after birth is not fool-proof against unsuspected conditions. Nonetheless, prenatal and even pre-conceptual screening of various sorts can identify many problems, sometimes at very early stages. Parents and health care professionals have therefore increasingly turned to amniocentesis, ultrasound, alpha-feto-protein assays, and other tests in an attempt to gain information and to detect and treat conditions for which prenatal interventions are available.

Genetic screening has until recently played a relatively minor role in this process. Because genetic testing was expensive and time-consuming, and because most detectable conditions were quite rare, specialized testing for inherited disorders (other than chromosomal analysis and the diagnosis of disorders of hemoglobin formation, such as sickle cell disease) has not generally been recommended as a part of normal prenatal care, except in those situations where a family history or a previously affected child indicates an increased risk.

However, this aspect of prenatal care may undergo enormous change over the next two decades. The prospect of dozens or even hundreds of relatively inexpensive new genetic diagnostic tests emerging rapidly from the genome project has been held out as likely by both the project's advocates and its opponents. Many of these markers will identify genes related to common illnesses and other traits and conditions that were previously well outside prenatal health professionals' routine range of concern.

Various professional, political, and policy stances can influence the degree to which the introduction of more genetic markers into normal prenatal care is accepted, or indeed, encouraged. The question is, then, Will such markers actually improve the quality of prenatal care, and at what cost? The need for an answer to this question will only become more pressing if, as some hope, it soon becomes possible to screen maternal blood for fetal lymphocytes, which can be safely and easily subjected to testing with genetic markers.

Diagnostic Options

What prenatal diagnostic tests to pursue has always been something of a judgment question. Risks for Down syndrome and other chromosomal abnormalities increase precipitously at a maternal age of approximately thirty-five years, leading health care professionals to recommend amniocentesis at that point; nonetheless, the majority of infants with Down syndrome in the United States actually born to younger mothers, where the frequency of chromosomal abnormalities is lower but the number of births is much higher. Alpha-feto-protein screening is also becoming more common despite concerns about its low predictive value (requiring expensive follow-up testing for many women whose pregnancies will ultimately prove uneventful) and despite the absence of treatment (other than abortion) for many of the problems the screening identifies.

In addition, serious debate has attended consideration of both routine prenatal screening for HIV infection, which some health professionals advocate, and elective screening for identification of fetal sex, which some parents request for personal reasons (including the desire to abort a fetus of an unacceptable sex).

The fruits of the genome project hold the potential to multiply these options exponentially. We can reasonably expect the development of genetic probes for most major, early onset genetic diseases caused by a single gene, but researchers will also likely discover markers that provide some degree of information about the genetics of a wide range of other conditions, of varying severity and of complex etiology. In fact, genome project and other federally sponsored research has already led to the development of markers for late onset diseases such as Huntington chorea and adult onset polycystic kidney disease, as well as for susceptibility or vulnerabihty to various abnormal blood lipid patterns and certain forms of cancer.

Markers for these "contingent conditions" - conditions that are related to the presence of certain genes but not fully or immediately predicted by them - may turn out to be very plentiful. Moreover, markers will likely be available for behavioral conditions, such as schizophrenia and manic depressive disorder, and conditions of relatively minor severity, such as obesity, freckling, myopia, and some learning disorders. It will also be possible to identify carriers of recessive and sex-linked disorders; they win not themselves manifest the condition, but they will be capable of transmitting its gene(s) to future generations.

Which of these markers to develop into diagnostic tests for widespread use has already proved to be a difficult question for postnatal populations. For example, widespread screening for adult carriers of cystic fibrosis was recently discouraged by two national scientific organizations after substantial study, despite great media excitement about the new developments and the readiness of several biotechnology firms to begin marketing their new diagnostic probes.

Moving the question to prenatal populations introduces several additional layers of complication. First, it is much less clear who is being served by diagnostic testing: is it the parents, who acquire information about their pregnancy and subsequent offspring, or is it the offspring, considered as a second (fetal, embryonic, or pre-embryonic) patient?

Similarly, how are the benefits and burdens of testing to be estimated? Can we say anything intelligent about the importance of diagnosing late onset and other contingent conditions, or conditions of limited severity? What about conditions for which successful postnatal treatment is available? And, again, whose perspective on benefits and burdens should we consider: the parents'? the offspring's? geneticists'? other health professionals'? society's?

We can also responsibly ask, Should any limits be placed on the availability of such probes or the use of such information? Will parents understand what the markers do and do not offer in terms of diagnosis and prognosis? Do we want to have large panels of markers available for prenatal use? Are we willing to have pregnancy decisions, including abortion, turn on the presence or absence of genes for late onset conditions, contingent conditions, or conditions of limited or questionable severity? And, finally, who will pay for whatever testing is available?

Planning for the Introduction of

New Markers

One of the main grounds offered in support of efforts to obtain funding for the genome project has been the potential for genetic information to improve medical care. Thus, the very existence of the project serves as an impetus to move newly discovered markers rapidly into the clinical arena. In the absence of prospective planning, new diagnostic tests will likely be introduced rapidly, in response to both market and professional forces.

The market forces are obvious: if biotechnology firms own patents on either the new markers or on techniques for bringing them into the clinical arena, there are clear financial incentives to make testing a more routine part of prenatal care.

The professional forces are also straightforward. First, there is a general tendency in medicine to view new developments, especially those perceived to be of low risk, as beneficial. Despite theoretical support for pilot studies and even randomized clinical trials of new diagnostic or therapeutic interventions, many clinicians assume that care will be improved by offering the new "services," and they are frequently reluctant to wait for formal evaluations of them. Of course, the Food and Drug Administration includes formal testing in the process for licensing new drugs, but its jurisdiction over and willingness to review diagnostic tests arising from the genome project are uncertain.

Perhaps more importantly, health care professionals providing prenatal care may feel compelled to use new tests as soon as they become available so they can obtain increased security against possible malpractice suits for failure to diagnose a given condition. The fear of possible wrongful birth suits (and "wrongful life" suits in the few states that allow children as well as parents a cause of action) has been cited as a major factor in the dissemination of alpha-fetoprotein screening, and harried clinicians may attempt to reduce their perceived threat of liability by offering the broadest possible panel of diagnostic tests. This problem is exacerbated by the current absence of any professional or societal guidance about which tests should be considered essential, and which optional, unnecessary, or relatively contraindicated. Even if patients are offered the option of refusing testing, in the absence of mechanisms to provide education about the value of obtaining various types of genetic information, the tendency will likely be for patients to accept everything available, since that is what appears to be "recommended." Moreover, when ignorance is the only alternative, patients may actually prefer a full range of "information," no matter what its relevance and quality.

Providing Guidance

Traditionally, the ethics of prenatal genetic counseling has required that prospective parents be given full information and then be allowed to choose which, if any, genetic diagnostic tests to pursue. Out of respect for reproductive decisionmaking and genetic privacy, and to prevent abuses such as attempts at eugenic control, virtually all genetic counselors espouse the ideals of value-neutral counseling and autonomous decisionmaking. This model is theoretically extremely appealing, and it works well in settings where well-trained counselors are available and affordable, and where counselors and clients share a common cultural background.

Yet the demands of routine prenatal care make it difficult simply to transpose this ethical framework into the obstetric or primary care clinic. The volume of patients is large, there is little enough time as it is to attend to patients' physical and psychological needs, and there are frequently quite prominent gaps between the social and cultural backgrounds of prenatal health care professionals and their patients. Moreover, genetic counselors have in the past generally been able, based on specific clinical indications, to focus their attention on one disease or syndrome at a time, while in the future, decisionmaking will likely encompass a broad spectrum of conditions for which prospective parents may be at no particularly increased risk. In the language of public health specialists, the issue will thus be one of screening rather than testing.

There are also matters of substance that argue in favor of a new model for providing guidance to prospective parents. Most importantly, the benefits of widespread screening have yet to be documented, and there are potential burdens that also need investigation, including increased anxiety about the pregnancy or about the parent's own health, risks associated with follow-up testing, possible changes in insurance coverage, overall increased costs, and the general effect on families and society of having parents prospectively evaluate their offspring in this fashion. Thus, while access to a broad range of genetic screening should remain available to those who specifically request it, new markers should not be offered as part of normal prenatal care.

Who, then, should decide which markers to incorporate into routine practice? Individual health professionals are poorly suited, both because of financial and liability pressures and because most lack sufficient information to guide such decisionmaking. Geneticists have a useful role to play, but are likely to be reluctant to issue sweeping recommendations without public input lest they rekindle fears of eugenics. Regulatory agencies are too insulated and also too bureaucratic, lacking the flexibility that will be necessary if recommendations are to be based on information somewhat less rigorous than formal pilot studies and controlled trials.

The default solution would be to let financial matters take precedence, considering as routine only those markers that are covered through state or federal funding or through private insurance. Yet this alternative too is unresponsive to the desire to have public input into decisionmaking, and it is unclear that it would totally alleviate clinicians' concerns about liability.

No doubt a perfect solution is unattainable. A reasonable pragmatic approach, however, might be to seek out the guidance of professional genetics and genetic counseling organizations, asking them to help develop procedures for gathering information, generating interdisciplinary and public comment, and making nonbinding recommendations about which tests need to be offered routinely in order to meet standards of normal prenatal care. Examples of such a process can be seen in the American Academy of Pediatrics' "Red Book Committee," which publishes recommendations for routine pediatric immunization practices, and the American Fertility Society's Committee on Ethics, which has formulated voluntary but highly influential guidelines for those involved in infertility services and research. For genetic screening issues, substantial collaboration with consumer groups, such as the Alliance of Genetic Support Groups, would be essential to insure a balanced representation of values. Such efforts could proceed at both the state and federal level, perhaps with funding from the genome project itself.

Leaving the Garden

When Adam and Eve ate of the fruit of the tree of knowledge of good and evil, they were expelled from the Garden of Paradise and entered a world of suffering and toil. So too may we be leaving behind what some would consider blissful days of ignorance about our future genetic legacies. We will soon have the power to evaluate ourselves and our prospective offspring, to peer into previously opaque genetic mysteries, to gain an understanding that seems clear. Whether we will reap benefits from seeking this knowledge, collectively and as individuals, is still quite uncertain. Thus, if we truly seek wisdom, we must consider most carefully in what manner and how deeply we will taste the genome project's tempting fruits.
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Title Annotation:Genetic Grammar: 'Health,' 'Illness,' and the Human Genome Project
Author:Nolan, Kathleen
Publication:The Hastings Center Report
Date:Jul 1, 1992
Previous Article:But is he genetically diseased?
Next Article:Genetic diagnosis of human embryos.

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