Special Article
Bone Marrow Transplantation for Sickle Cell Disease — A Study of Parents' Decisions
N Engl J Med 1991; 325:1349-1353November 7, 1991
- Abstract
- Abstract
Background.
Bone marrow transplantation has been shown to cure sickle cell disease, but it carries a 15 percent mortality risk. To determine whether parents would accept this risk to cure their children of sickle cell disease, we interviewed parents of children with sickle cell disease who were being followed in a university hospital clinic.
Methods.
We assessed parents' attitudes by using questions based on the standard reference-gamble paradigm. After we gave them descriptions of bone marrow transplantation and graft-versus-host disease (GVHD), the parents were presented with a series of hypothetical situations. In the first situation, bone marrow transplantation was described as offering certain (100 percent) survival with cure of sickle cell disease. In subsequent descriptions, the mortality rate associated with bone marrow transplantation was increased by 5 percent increments. The parents indicated the highest mortality risk at which they would consent to the procedure in order to cure their children.
Results.
In order to obtain a cure for their children, 36 of 67 parents (54 percent) were willing to accept some risk of short-term mortality, 25 of 67 (37 percent) were willing to accept at least the 15 percent short-term mortality risk we estimate to be the current figure for bone marrow transplantation, and 8 of 67 (12 percent) were willing to accept a short-term mortality risk of 50 percent or more. Nine parents (13 percent) said they would accept both a mortality risk of 15 percent or more and an additional 15 percent risk of GVHD. The parents' decisions were not related to the clinical severity of their children's illness.
Conclusions.
At current rates of mortality and morbidity with bone marrow transplantation, a substantial minority of the parents of children with sickle cell disease may consent to bone marrow transplantation for their children. Parental attitudes should be factored into decisions about whether to offer bone marrow transplantation to children with sickle cell disease. (N Engl J Med 1991;325: 1349–53.)
Media in This Article
Figure 1
Number of Parents of Children with Sickle Cell Disease Who Said They Would Choose Bone Marrow Transplantation at Different Estimates of the Mortality Rate Associated with the Procedure.Article Activity
- Article
BONE marrow transplantation is the only therapy that has been reported to cure patients with sickle cell disease.1 2 3 However, when performed for currently accepted indications, this procedure is associated with a 10 to 50 percent risk of mortality and substantial additional risk of morbidity due to graft-versus-host disease (GVHD).4 5 6 7 8 The mortality and morbidity have been readily accepted when bone marrow transplantation is used for life-threatening diseases, such as leukemia, for which no better treatment is available. But is this treatment appropriate for diseases that are not immediately life-threatening, such as sickle cell disease?
Sickle cell disease has an extremely variable natural history. Although some children with the disease die in infancy9 or have devastating complications such as strokes,10 acute chest syndrome,11 and recurrent vasoocclusive pain crises, others have few medical complications or none. Recent data show that older patients with more frequent painful episodes have higher mortality rates.12 Although actuarial data on the life expectancy of patients with sickle cell disease are lacking, hematology textbooks suggest that patients with this disease rarely survive beyond middle age.13 , 14 Because of the unpredictable course of the disease and its tendency to cause chronic debilitation rather than death, the use of bone marrow transplantation for children with sickle cell disease raises difficult clinical and ethical dilemmas.
In July 1988, clinicians at the University of Chicago submitted a proposal to the institutional review board to offer bone marrow transplantation to carefully selected patients with sickle cell disease. The proposal generated a great deal of controversy over whether this treatment should be offered to any patients with sickle cell disease and, if so, what criteria should be used to select appropriate candidates.15 The institutional review board decided to allow investigators to offer bone marrow transplantation to two groups of children: those who had already had a stroke and were therefore given monthly blood transfusions to lessen the risk of another stroke, and those with recurrent pain crises so severe that they had been hospitalized for narcotic analgesia during more than 60 percent of the past year. In approving this protocol, the institutional review board decided that, for these selected high-risk patients, the risk—benefit ratio for bone marrow transplantation matched that for conventional treatment; thus, the parents of these children might reasonably choose either course of treatment.
It was not known how many parents would accept the risk of early death from bone marrow transplantation in exchange for the prospect of a cure for their children and what factors might predict parents' willingness to consent to transplantation on behalf of their children. We therefore decided to study parents' attitudes about acceptable risks entailed by treatment to cure their children of sickle cell disease. If parents disagreed with the institutional review board about the appropriate use of bone marrow transplantation for sickle cell disease, it would raise a fundamental question about the ethics of innovative therapy in pediatrics: Who should decide whether children should undergo innovative medical treatment with the potential for both great risk and great benefit?
Methods
After obtaining informed consent for their participation in a study regarding a new treatment for sickle cell disease, we interviewed parents of children with sickle cell disease at the time of their visits to the pediatric hematology clinic at the University of Chicago. The subjects were selected at random from among the parents attending the clinic on each study day, regardless of the severity of the children's disease. No parent was allowed to participate more than once. Parents were told explicitly that their responses would remain confidential and that the interview would have no effect on their children's medical care.
We conducted a structured interview with each parent. After obtaining relevant information about the demographic characteristics of the family and the patient's medical history, we described the process of bone marrow transplantation. The information we gave parents about bone marrow transplantation was based on the informed-consent form approved by the institutional review board. The portions of the description that we read to the parents included the following:
One potential treatment for sickle cell disease is called bone marrow transplantation. This treatment has been used in the past for other diseases, but is not yet used for sickle cell disease. In the procedure strong medications are given to the patient to destroy his or her bone marrow.... If no problems occur, the entire procedure requires hospitalization for about one month. Although this treatment has very serious risks, if successful it would probably cure sickle cell disease.... The next set of questions involves trying to find out how much risk you would be willing for your child to accept for a bone marrow transplant to cure [him or her].
A board-certified pediatrician specializing in hematology and oncology, who is knowledgeable about both bone marrow transplantation and sickle cell disease, conducted the majority of the interviews and supervised the others. The parents were given several opportunities to ask questions. The interview did not proceed until the interviewer was certain that parents understood the information they had been given.
We assessed parents' decisions about acceptable risks of mortality and morbidity by using questions based on the standard reference-gamble paradigm.16 The standard reference gamble and its variants are decision-analysis techniques that have been used in the past to elicit adults' preferences among treatments for lung cancer,17 laryngeal cancer,18 and prostate cancer.19 The technique has not to our knowledge been used previously with parents' being asked to make decisions for their children.
The parents were asked whether they would consent to bone marrow transplantation for their children in various hypothetical situations. In the first situation, bone marrow transplantation was described as offering 100 percent survival (no risk of mortality from the transplantation) and certain cure of sickle cell disease. In subsequent descriptions, the mortality rate associated with bone marrow transplantation was gradually increased by 5 percent increments. Graphic representations of survival and mortality rates accompanied each question in order to facilitate clear understanding of the risks. In this way, each parent indicated the highest risk of mortality that he or she would accept in exchange for the prospect of cure for his or her child. The first situation in which the parent answered "no" was registered as the point of too much risk, and this section of the interview was concluded. For example, the fourth question was accompanied by a pie chart showing 15 percent mortality and 85 percent survival; the text read as follows:
Suppose that for the transplant 85 percent lived and 15 percent died from the treatment. That is: 85 out of every 100 children lived and were cured of sickle cell disease, but 15 out of 100 died in the first 30 days after the treatment. If these were the risks, would you want [your child] to have this treatment?
We posed an additional question only to those parents who were willing to accept a risk of mortality of 15 percent or more. This question asked the parents to consider the additional risk of chronic morbidity due to GVHD. Our description of GVHD was based on the informed-consent form approved by the institutional review board for the protocol to offer transplantation to patients with sickle cell disease and read, in part:
After having a bone marrow transplantation, some patients develop a new problem called graft-versus-host disease.... Of those who survive [transplantation], most will be cured, but some will have graft-versus-host disease. Graft-versus-host disease is a chronic illness that some people who have had a bone marrow transplant develop. It can affect the lungs, liver, gastrointestinal tract, and skin. People with graft-versus-host disease can be very sick and die from it.... Less is known about graft-versus-host disease than sickle cell disease because it is a newer problem than sickle cell disease.
We then asked this group of parents if they would want bone marrow transplantation for their child if the risk of mortality were 15 percent, the risk of GVHD were 15 percent, and the chance for cure without GVHD were 70 percent. These percentages reflect the likely outcome of transplantation among such patients today and are based on data obtained from the experience with bone marrow transplantation in patients with thalassemia8 and aplastic anemia.20
To analyze our data, we compared parents who accepted some risk associated with transplantation with those who did not by using the continuity-adjusted chi-square test for dichotomous variables and the Wilcoxon rank-sum test for ordinal variables. We then used a Wilcoxon analysis of the variable we called "too much risk" to look at factors that related to the degree of risk parents were willing to accept with transplantation. Finally, we performed a multivariate analysis with a linear regression model to examine the intercorrelation of associated variables. The study was approved by the institutional review board of the University of Chicago.
Results
We interviewed 67 parents or guardians (we shall refer to both parents and guardians as "parents") of 67 children (35 girls and 32 boys) with sickle cell disease between October 1989 and April 1990. No parent whom we approached declined to participate. The children ranged from infancy to 20 years of age, with a mean age of 10 years. Seven (10 percent) of the children were 18 years old or older. Because our study was designed to assess parents' views, these young adults were not interviewed. All the children had homozygous disease. The parents ranged in age from 18 to 64 years, with a mean age of 34. They included 53 mothers, 3 fathers, 3 aunts, 4 grandmothers, 2 adult siblings, and 2 other guardians. Fifty-five of the 67 parents (82 percent) were currently unmarried.
Sixteen of 67 parents (24 percent) were unwilling to accept any risk of short-term mortality (death within 30 days) in order for their children to be cured of sickle cell disease. These parents said no to transplantation at the 100 percent survival-cure level (100 percent probability of cure and 0 percent short-term mortality). Another 15 parents (22 percent) were probably not willing to accept any risk. These 15 said yes to transplantation at the 100 percent survival-cure level but said no at the 95 percent level (95 percent probability of cure and 5 percent risk of short-term mortality). Thirty-six of the 67 parents (54 percent) were willing to accept some risk of short-term mortality for their children in exchange for a cure (Fig. 1Figure 1
Number of Parents of Children with Sickle Cell Disease Who Said They Would Choose Bone Marrow Transplantation at Different Estimates of the Mortality Rate Associated with the Procedure.). Twenty-five of the 67 parents (37 percent) were willing to accept a 15 percent or greater risk of short-term mortality, which we estimate to be the current risk for such a procedure. Eight parents (12 percent of our sample) were willing to accept a 50 percent or greater risk of short-term mortality due to transplantation in exchange for a cure for sickle cell disease.We asked only the 25 parents who accepted a 15 percent or greater mortality risk about the additional risk of GVHD, to determine how a 15 percent risk of GVHD would modify their decision. Nine of the 25 (36 percent) were willing to accept both a short-term mortality risk of 15 percent and an additional 15 percent risk of GVHD. Thus, 9 of 67 parents (13 percent) said they would consent to bone marrow transplantation for their children given current estimates of the risk of morbidity and mortality, or worse conditions.
Parents who accepted some risk in exchange for a cure for their children were different in several ways from those who did not accept risk. Parents who had graduated from high school were significantly more likely to accept some risk in exchange for cure than those who were not high-school graduates (28 of 43 vs. 8 of 24, P = 0.012). Parents who were employed or in school were more likely to accept some risk than those who were not occupied outside the home (19 of 28 vs. 17 of 39, P = 0.05). Parents who had more than one child with sickle cell disease were more willing to risk mortality to obtain a cure (8 of 10 vs. 23 of 47, P = 0.07). Finally, parents were more willing to consent to bone marrow transplantation for girls than for boys (23 of 35 vs. 13 of 32, P = 0.04). Clinical factors such as the number of hospital admissions in the past year, history of stroke, admission to the intensive care unit, the frequency of pain medication, and the frequency of absence from school because of sickle cell disease were not significantly associated with parents' acceptance of risk.
Wilcoxon analysis to examine the degree of risk parents were willing to accept also demonstrated that having at least a high-school education was most strongly associated (P = 0.004) with the degree of risk accepted. Parents who had more than one child with sickle cell disease (P = 0.03), whose children were girls (P = 0.05), and who were employed or in school (P = 0.1) also accepted more risk to obtain a cure than did other parents. As before, the clinical severity of sickle cell disease did not correlate with the degree of risk parents were willing to accept in exchange for the cure of their children.
Finally, we used a linear regression model in which the degree of risk was the dependent variable and the parent's education level, the sex of the child, the presence of other children with sickle cell disease in the family, the number of hospital admissions in the past year, the number of days of school missed, and previous admissions to the intensive care unit were the independent variables. When we used this model, the variable for female sex lost its statistical significance. Parental education and the presence of another child with sickle cell disease in the family remained significantly associated with a willingness to accept greater risk.
Discussion
Thirty-seven percent of the parents we interviewed were apparently willing to consent to bone marrow transplantation with a 15 percent or greater risk of short-term mortality for their children. Thirty-six percent of this group (13 percent of the entire cohort) said they would consent to transplantation if it entailed a 15 percent risk of chronic morbidity due to GVHD in addition to a 15 percent or greater risk of short-term mortality. Thus, at least 13 percent of parents might be expected to consent to bone marrow transplantation for sickle cell disease given current rates of morbidity and mortality. These data suggest that parents would weigh the risks and benefits of bone marrow transplantation for sickle cell disease in a different way from the members of our institutional review board. The results raise the question of whose judgment should prevail.
Before addressing this question, we should note four limitations of this study. First, the decisions made by the parents we interviewed were explicitly hypothetical, and therefore they may not accurately reflect the decisions that parents would make if their children were actually offered bone marrow transplantation. Second, our cohort may be skewed toward parents of children with more severe disease because these are presumably the parents who bring their children to the hematology clinic more frequently. If more severe illness would predispose parents to consent to transplantation, this selection bias might lead us to overestimate the number of parents who would consent to the procedure.
Third, it is possible that some parents did not understand the standard-gamble questions, despite the pie charts and the simple question format used in the interview. Nevertheless, our presentation of the quantitative risks and benefits was probably as clear and understandable as that which parents would receive if they were actually offered the option of transplantation.
Finally, we may not have conveyed qualitative information about morbidity due to bone marrow transplantation graphically enough for parents to understand it fully. Previous studies have demonstrated that the language used to describe a procedure can dramatically affect the rate of consent.21 We modeled our description of bone marrow transplantation and GVHD on the descriptions in the informed-consent form approved by the institutional review board, which parents would be given if their children were actually offered the option of transplantation. Specific details of the medications used and their potential complications were omitted, but the major organ-system complications were discussed, and the possibility that GVHD might be worse than sickle cell disease was stated. As with the quantitative information, our descriptions were comparable to what parents are told in real informed-consent situations. In all cases, the interviewer answered all questions from each parent.
Our data raise questions about decision making for children with sickle cell disease. At the outset of this study, we hypothesized that parents, like members of the institutional review board, would consider the severity of illness to be the most relevant factor in deciding whether to consent to bone marrow transplantation for their children, and we wondered what degree of severity parents would consider sufficient to justify the risks associated with transplantation. Unlike doctors, however, parents did not base their decisions on clinical factors indicating the severity of illness. Thus, parents may not think about risks and benefits the way doctors do.
Parents' decisions were related to certain social and demographic factors. Parents with more than one child with sickle cell disease tended to choose transplantation more often, and at higher risk levels, than those with only one affected child. This difference may reflect more intimate knowledge of the disease, or it may be an indication of the burdens of caring for children with sickle cell disease. The parents' education level was also strongly correlated with an acceptance of transplantation — a finding that is in sharp contrast to the results of a study that showed that parental education was inversely associated with willingness to allow children to participate in research.22
The differences between the parents' decisions and the criteria of the institutional review board raise a difficult question. Which set of factors is most appropriate in determining whether a child should be offered or allowed to undergo bone marrow transplantation to treat sickle cell disease? Do the medical indications used by the institutional review board protect children from well-intentioned, well-informed, but perhaps overzealous or desperate parents? Or do institutional review boards represent a paternalistic infringement on parents' right to make medical decisions for their children?
Institutional review boards were created to protect the rights and welfare of human subjects of research. Children are considered an especially vulnerable population, and research involving children is generally permissible only if it involves minimal risk (or none) to the child. Any research proposal that involved a 15 percent risk of death and a 15 percent risk of serious illness would almost surely be prohibited. If a treatment protocol is not research, however, then patients are not research subjects, and institutional review boards should not control the selection of patients. Instead, clinicians and parents must decide together whether the risks and burdens of treatment outweigh the benefits. Thus, a key question in deciding whether parents or an institutional review board should decide which children with sickle cell disease should be offered bone marrow transplantation is whether the procedure is considered clinical research or innovative therapy.
Research and the practice of medicine often overlap. Although it acknowledges that there will always be some ambiguity, the Declaration of Helsinki distinguishes between "medical research in which the aim is essentially diagnostic or therapeutic for a patient, and medical research, the essential object of which is purely scientific."23 The declaration then states that "the doctor must be free to use a new diagnostic and therapeutic measure, if in his or her judgment it offers hope of saving life, reestablishing health, or alleviating suffering." Research, according to Levine, is an activity "designed to develop or contribute to generalizable knowledge."24 The practice of medicine, by contrast, is an activity "designed solely to enhance the wellbeing of an individual patient or client."24 According to these definitions, we suggest, bone marrow transplantation for sickle cell disease need not be considered research, and thus may not require approval from an institutional review board.
The regulations of the Department of Health and Human Services, which permit risky research involving children only if it "holds out the prospect of direct benefit for the individual subject,"25 apply only to projects that have already been deemed to be research. The regulations do not address the issue of how to weigh the prospect of benefit to the patient against the goal of collecting generalizable knowledge in order to determine which innovations require approval from an institutional review board.
The primary motivation of the clinicians who wanted to offer bone marrow transplantation to children with sickle cell disease was to benefit the patient. Much is known about the use of bone marrow transplantation for other hemoglobinopathies.8 , 26 , 27 Although some knowledge may be gained from offering transplantation to patients with sickle cell disease, we suggest that the use of transplantation for patients with sickle cell disease is not primarily a matter of research.
This is not to say that bone marrow transplantation should be offered to all patients with sickle cell disease. Clinicians who specialize in the procedure and in the care of patients with this disease must first decide whether they feel the procedure is medically indicated. The distinction between research and therapy has few implications for the doctor–patient relationship. Physicians must still judge the risks and benefits of various treatments and discuss the options realistically with patients and their parents.
Parents' views of the risks and benefits of bone marrow transplantation, and the factors they consider relevant in deciding whether to consent to the procedure for their children with sickle cell disease, challenge us to examine the reasons why such therapy should or should not be offered. In making clinical decisions, rigorous analysis of the risks and benefits of therapy should be combined with careful consideration of the values that underlie treatment decisions. Studies of the values that underlie parental choices might help clinicians to understand better the relation between clinical and moral factors in deciding how best to use innovative therapies.
The Center for Clinical Medical Ethics is supported by grants from the Henry J. Kaiser Family Foundation, the Andrew W. Mellon Foundation, and the Pew Charitable Trusts.
We are indebted to Linda Drawhorn, R.N., Uma Subramanian, M.D., and Ruth Rudinsky, M.D., for their help with the enrollment of subjects, and to Aine Kresheck for assistance with the data collection.
Source Information
From the Department of Pediatrics and the Center for Clinical Medical Ethics, University of Chicago Pritzker School of Medicine, Chicago, and the Department of Medicine and Centre for Bioethics, University of Toronto, Toronto, Ont. Address reprint requests to Dr. Kodish at the Department of Pediatrics, University of Chicago, Box 97, 5841 S. Maryland Ave., Chicago, IL 60637.
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