Bone Marrow Transplantation, (1997) 19, 1163–1168  1997 Stockton Press All rights reserved 0268–3369/97 $12.00

Review Transplant of bone marrow and cord blood hematopoietic stem cells in pediatric practice, revisited according to the fundamental principles of bioethics

GR Burgio and F Locatelli

Department of Pediatrics, University of Pavia, IRCCS Policlinico San Matteo, Pavia, Italy

Summary: cells. This comes as no surprise, since the ethical problems related to bone marrow transplantation (BMT) in pediatrics, The two most widely used sources of hematopoietic stem first applied successfully almost 30 years ago,1,2 have not cells for allogeneic transplants in pediatric practice are been entirely settled. It must also be emphasized that, in bone marrow (BM) and cord blood (CB). While bone children, the use of peripheral blood stem cells mobilized marrow transplantation (BMT) is reaching its 30th year through hematopoietic growth factors is not accepted rou- of application, human umbilical cord blood transplan- tinely, as the possibility of long-term adverse effects from tation (HUCBT) is approaching its 10th. Although these this practice has not yet been ruled out and it is approved procedures have basically the same purpose, a number occasionally for specific indications, such as second trans- of biological differences distinguish them. In particular, plant after a first rejection of donor marrow. the intrinsically limited quantity of CB stem cells and Although well-grounded consensus on application3–7 pre- their immunological naivete´ confer peculiar character- vails for marrow transplantation over what are now merely istics to these hematopoietic progenitors. From a bio- occasional reservations,8 it seems relevant to compare the ethical point of view, the problems which have repeat- prerogatives of the two practices (BMT and HUCBT) and edly been raised when the BM donor is a child are well- their bioethical profile in pediatrics, revisiting them as known. Different but no less important ethical problems plainly as possible in the light of the four now traditional are raised when one considers HUCBT; in this regard and basic guiding principles of bioethics, namely autonomy, the most important issues are the easier propensity of nonmaleficence, beneficence, and justice. programming a CB donor in comparison with a BM A concise review, dedicated separately to each donor (clearly due to the shorter time interval needed procedure, is basically inspired by a comparison of the two, to collect the hematopoietic progenitors); the in utero ultimately allowing an approach to their respective HLA-typing; the implication of employing ‘blood prerogatives. belonging to a neonate’ for a third party; the need to perform a number of investigations both on the CB of the donor and on the mother and the implications that Bone marrow transplantation as a traditional the discovery of disease may have for them, but also the approach for transplanting hematopoietic stem cells need to establish banks for storing CB, with the accompanying administration and management prob- As in all choices and decisions that concern the child, with lems. All these different aspects of UCBT will be dis- its intrinsic lack of autonomy or with its limitations (also cussed in the light of the four fundamental and tra- applicable to the adolescent), in BMT too any decision can ditional principles of bioethics, namely autonomy, only be validated by the informed consent of the parents nonmaleficence, beneficence and justice. (or guardians). The information made available to them Keywords: bioethics; bone marrow transplantation; cord must be as accurate and objective as possible and must blood transplantation; informed consent; cost/benefit ratio always be the groundwork for any autonomy in decision; otherwise this autonomy is not valid. Actually, there are far more serious problems for organ donations from children,9 while the usually harmless nature Since 1988, the year of its first successful application, of the harvesting of bone marrow (a tissue which regener- excellent articles have been published concerning the ates in approximately 3 weeks) still causes some reser- bioethical problems of human umbilical cord blood trans- vations,8 although not on a dramatic level. plantation (HUCBT) as a source of hematopoietic stem This finding and the potentially life-saving value of BMT are the grounds for considerations about nonmaleficence. Correspondence: Prof G Burgio, Clinica Pediatrica, Universita` di Pavia, Fundamentally, for BMT and for any medical practice bur- IRCCS Policlinico San Matteo, P le Golgi 2, I-27100 Pavia, Italy dened by bioethical doubt, it is important to revisit the Received 30 December 1996; accepted 5 March 1997 ancient concept of primum non nocere (‘do not harm’), now Bioethics of BMT and CBT in childhood GR Burgio and F Locatelli 1164 23 centuries old, as well as the need to rephrase it10 as ‘do Transplant of cord blood progenitor cells as little harm as possible’ or ‘do no harm unless that harm is necessarily associated with a compensating benefit’. This transplant, used clinically only in recent times (the If, in the risk/benefit (or cost/benefit or cost-detriment/ first use was in 1988),19,20 has now been put to the test by benefit) balance, the minimal risks affecting the donor are approximately 300 procedures. It covers areas which used compensated, according to a reasonable prediction, by sig- to be within the scope of BMT, but its bioethical profile is nificant potential benefits for the recipient-patient, as occurs significantly different. for allogeneic BMT from an HLA-compatible sibling or The placenta and the umbilical cord are temporary, short- unrelated volunteer, compliance with nonmaleficence lived structures whose physiological function is important becomes immediately evident. though limited in time. Apart from use for research (which The cost/benefit evaluation is also based on this issue. also entails careful ethical thought),21 the placenta has not The fact that compliance with beneficence is achieved been used in practice except in the last 8 years; indeed, it almost as a consequence seems indeed a corollary, at least used to be routinely disposed of at the end of the delivery. as regards the recipient-patient; but some thought has been Their temporary and disposable nature have placed the rightfully given to the role of the donor, since the existential placenta and the cord among ‘discarded tissues’: a classi- reward related to ‘having donated one’s own in order to fication which is certainly significant also from an ethical save someone’11–13 abundantly repays the donor of any viewpoint concerning the value of using these tissues,22,23 risks and costs caused by possible suffering. including the possibility of not having to obtain the ‘con- On the other hand, one cannot rule out a possible sense sent’ of the donor (of the pregnant woman and possibly of 22 of guilt as a consequence of a refusal to donate.14,15 A very her partner). young child donor may experience gratification or, vice However, this simplification has been promptly neg- 24 versa, a sense of guilt later on and include them in his or lected. Parents may make decisions as guardians for their her life experience. child and their actions should be measured in terms of the 25 Obviously, even such a globally favorable assessment of benefit of their decision to the child. Indeed, the consent BMT does not implicitly comply with the principle of jus- of the parents (especially of the mother) to use cord blood tice, since this principle involves at least evaluations con- (CB) is considered standard practice. In particular, infor- cerning the context; for example, the financial resources med consent to donate should appropriately be obtained available, which must be taken into account, especially for from the woman before she is emotionally involved in populations having a modest per capita income level. Other delivery (ie during the last 3 months of pregnancy). However, one must still ask oneself, with regard to these context-related evaluations, which might induce problems considerations, who would ever have claimed ‘ownership’ regarding justice, could also arise within the family or from of the placenta and the cord before today? Yet today the considerations related to particular circumstances. Hence, placenta has acquired immense dignity, since the hemato- for example, the intense debate in Europe and in the United poietic stem cells that its blood contains have been recog- States on the problem of transplants from a sibling con- nized as a precious ‘life-saving’ capital. Therefore, the pre- ceived with the hope of producing a compatible donor for viously mentioned question, which was irrelevant a previous child requiring BMT: ‘programming a bone mar- historically, now takes on an increasingly important sig- row donor’;16 ‘conceiving a child to save a child’;17 ‘the 18 nificance. child conceived to give life’. ‘Ownership’ of the placenta, which is well-known to Our experience with a child with chronic myelogenous 4,16 ‘belong’ to the neonate, becomes important because of the leukemia is now over 10 years old and has been extra- destination of its blood, which might be needed by another ordinarily rewarding for the family who experienced it. Of ‘recipient’ (for an allotransplant) within the family or out- course, any decision to conceive a child for the sole purpose side it, or in theory by the very child who had been nour- of making it become a bone marrow donor (or a cord blood ished by it during prenatal life, in other words by the donor) entails belittling the value of the individual to be ‘donor’, with the prospect of an autotransplant. Manage- born, viewed as a human being having a dignity of its own. ment of cord blood therefore assumes a very specific mean- However, it cannot be ignored that it is extremely difficult ing: avoiding the elimination of a ‘life-saving’ capital can to separate the reasons that lead to the conception of a child be important, to the point of raising commercial interests, solely for the joy of procreating from those linked to the with the risk of severe ethical failures. possibility of saving a living, sick child. Whoever has the right to decide over the placenta (it In summary, regarding BMT in pediatrics, one can con- seems obvious to consider the parents, also because they clude that it has been confirmed as an ethical practice, are ‘naturally’ responsible for the neonate and for the because its benefits abundantly prevail over its costs and decisions to be made in his best interests)21 must be able risks, because it fully complies with primum non nocere to do so in autonomy and therefore must be informed not as rephrased,10 because it is an act of rewarding altruism only of the intrinsic and natural transience of the func- (sometimes perhaps an involuntary one), and because it is tionality of the placenta, but also of any expectation and in any case a practice of solidarity. Ultimately, it is an intention to use it (or its blood) and of any implication, example of one of the advanced biotechnologies which including the need for numerous diagnostic tests on the have progressively been proposed with the very purpose of blood of the mother and on the cord blood before using it increasing the possibilities of life or of improving the (a complex issue requiring consideration, also according to quality of life. the principle of justice, to which we will return). Bioethics of BMT and CBT in childhood GR Burgio and F Locatelli 1165 Table 1 Advantages associated with transplant of umbilical cord cells. On the contrary, in the same perspective, it must be blood cells in comparison with bone marrow transplantation remembered that minors cannot donate bone marrow for unrelated recipients. For the recipient As regards HUCBT practice, justice is, however, affected Prompt availability (reduced waste of time between donor identification and stem cell transplantation) by various problems, only some of which are the same as No risk of donor refusal those whose knowledge is indispensable for decision auto- Reduction of time required to identify an unrelated HLA-compatible nomy. All these problems must be analyzed and com- donor mented on in detail. However, in addition to involving who- Reduced risk of both acute and chronic GVHD Possibility of performing transplant using 1 or 2 antigen ever is responsible for deciding the use of the CB HLA-disparate donor (substantially, the parents of the neonate), it is indispens- Low risk of viral contamination (ie HCMV, EBV), with able to involve structures which have social-sanitary and consequently low risk of transmission of infectious disease social-organizational roles, whose function, too, entails problems in terms of justice. One might consider the hospi- For the donor Ease and safety of collection, without the risks associated with tal where the birth occurred, this was the structure which general anesthesia (requested for marrow harvesting) used to eliminate the placenta; now it might be interested Lower incidence of psychological problems related to the figure of in managing or helping with its management,29 especially the child-donor and to possible transplant failure since the placenta, far from continuing to be classified among discarded tissues, can be considered a ‘bank’ organ (or tissue), with all the implications entailed by this pro- gram, which unfortunately also includes the interest of This peculiar transplant, as in any case all others, must commercial companies, with the prospect of profit and produce beneficence; that is to say, it must provide advan- therefore with a risk for ethics and for the pedagogical tages (possibly better ones than those offered by any alter- image.22 native method). The fact that broadly speaking this pro- cedure complies with nonmaleficence is already obvious, Consider also the preservation of the blood itself, on the since at the time of collection no tissue truly useful to the one hand (with its associated costs) and the different and donor is removed and no pain at all is caused. possibly contrasting purpose for which it is stored Whether a somewhat early clamping of the umbilical (allotransplant or hypothetically, autotransplant), on the cord (5–10 s26 or 34–45 s27 ‘after birth’), while being other hand. Obviously, since the CB cells to be transplanted responsible for a mild anemia,21 can negatively affect the are intrinsically available in limited quantity, the possibility neonate in any way has been the subject of discussion,28 but of an allotransplant would in fact irreparably damage the has also been conclusively disproved.29 Besides, unwanted donor, preventing autotransplantation. Indeed, Gluckman et 30 effects in the recipient, for example, graft-versus-host dis- al quite correctly considered, among the clauses which ease, are if anything, significantly less worrisome than should be accepted for consent, mutual anonymity of donor those which can occur after BMT (see also Tables 1 and 2 and recipient and non-commitment to autotransplantation. for advantages and disadvantages associated with cord Moreover, to allow the decision to mature and become blood transplantation). Accordingly, the ethical assessment well-thought consent, the woman and the father of her child of this dyad (nonmaleficence–beneficence) is particularly must immediately be made aware that it is necessary to favorable, besides being easy, for the use of CB progenitor perform all the tests required to recognize suitable and usable cord blood, with no risk of transmitting to the recipient any disease carried by the cells which would be Table 2 Theoretical disadvantages associated with transplant of transfused to the recipient: disorders which are genetically umbilical cord blood cells in comparison with bone marrow transplan- transmissible along the various hematopoietic and immuno- tation poietic cell series or, vice versa, viral infections, both of which perhaps had never been suspected by the parents. For the recipient Increased risk of graft failure A test not requested by the parents and not included in Routine applicability only in patients with a body weight of less any screening prescribed by routine neonatal care would be than 40 kg (?) an arbitrary act. In asking for ‘consent’ to proceed, and Delayed platelet and neutrophil recovery after obtaining it, one must ensure maximum respect for Absence of adoptive transfer of specific immunity towards infections agents due to fetal immune immaturity and lack of privacy and professional confidentiality regarding the previous antigenic exposure results. The parents should also be clearly informed as to Increased risk of transmission of inherited disorders the time required for the tests to be carried out on the preg- Possible risk of transmitting viral diseases (in particular AIDS), not nant mother: some, which relate to infectious diseases, must identifiable if cord blood collection has occurred during the period of serological conversion be performed in particular on another blood sample ‘after quarantine’, that is to say, when the placental blood has For the donor already been stored in the bank,30 to avoid the risk of a Ethical problems associated with donation (ie increased propensity first negative response caused by a ‘window period’ to conceive a child to save a child) Possible unavailability of donor’s own cord blood stem cells if (consider AIDS in particular). he/she subsequently should develop a disorder requiring The following questions have also been posed: Should transplantation of hematopoietic progenitor cells the donor’s name be kept on file for follow-up? Should a sample of the infant’s blood be stored for future laboratory Bioethics of BMT and CBT in childhood GR Burgio and F Locatelli 1166 testing as additional assays for stem cells and genetic dis- cells per kg of the recipient or at least 4 × 106 of CD34+ eases become available?24 cells per kg of recipient body weight,41 whereas the mini- Information and clinical checks as to the health of the mum number of cells to be infused for a successful CB infant and the mother must in any case be gathered accord- transplantation has been claimed to be 1 × 107 nucleated ing to a ‘look-forward’ program.31 Moreover, it will be cells per kg of recipient body weight.20 However, recent necessary to consider the possibility of performing future data suggest that the higher the infused cellular load, the tests on the placental blood, if new tests are proposed in higher the likelihood of success of the transplant. Specifi- the future to check for diseases which cannot be detected cally, the dose of 3.7 × 107 nucleated cells per kg of recipi- at present: we face the possibility of ‘informed consent for ent body weight seems to be the critical minimum allow- look-back testing’. Should this policy fail to be able value.42 These considerations explain why processes implemented, or should the possibility of donor control be for the in vitro expansion of cord blood progenitor cells lost, any recipient ought to be warned of this fact.31 by using cytokines continue to be extremely interesting for However, when one considers the practical application routine application of HUCBT in adults.21,22 of these problems, questions arise immediately. In parti- In any case, there is a great ‘quantitative’ difference in cular, what kind of behavior should be adopted by the the cell availability provided by the two different tissues: medical operator who works with a woman (or with the bone marrow is the only one of the two which regenerates parents of a child) if a hereditary disease for which there continuously, and should an allotransplant donor require is no therapy is detected in the infant?24 One might recall, some for an autotransplant, he would have it available, in this regard, that it has been stated that ‘The purpose of whereas of course placental blood is only available in the ethics in medicine is to reduce the likelihood of moral tra- amount collected and stored (only once). In other words, gedy by subjecting moral dilemmas to systematic, rational if the cell repertory of a cord blood were assigned to an analysis’.32 Moreover, it must be noted that a 1994 Institute allotransplant, the donor would not have it available if he of Medicine review recommends that minors not be tested needed it for an autologous transplant. An important prob- for abnormal genes unless there is an effective curative or lem of justice, indeed a fundamental one, has developed preventive treatment that must be instituted early in life.33 out of this lack of availability: if the parents decide ‘in In presenting the above considerations, we have mainly the best interests’ of their newborn child, the only goal of taken into account the model of use of the CB cells of the preservation (banking) of placental blood is to cater for the neonate with regard to allotransplant. However, in the same possible need for an autotransplant.21 way in which BMT can be performed extemporaneously However, it is evident that from this viewpoint, that is between HLA-compatible related individuals, or can be to say, if one intended to ensure that every possible blood programmed depending on the finding of an unrelated donor had the right possibly to use the donated blood for donor in a registry, so can multiple possibilities be provided himself, there would be no way to provide cord blood units for HUCBT.34 Indeed, there may be an extemporaneous for allotransplants. This is an attitude which obviously will use, that is to say, for a patient for whom a compatible not prevail. While it is true that it would be an authentic sibling is born with good timing; or, vice versa, there may ‘insurance policy’, an enormous amount of material, with be an application from an unrelated donor after finding an equally enormous expense, would remain unused, with compatible CB, stored in a bank perhaps for a long time. a clearly unacceptable cost/benefit balance. Only approxi- In the first case, it is important to stress the inappropri- mately one child in 50 000 in fact requires, every year, cyto- ateness of performing HLA typing in utero. Because of the static therapy in high doses with subsequent support by abortion risks linked to the procedure, it entails the risk of means of hematopoietic progenitor cells. Besides, the very causing the death of a healthy human being and would in nature of the technique, conceived originally for allotrans- any case be deeply despicable if it were used to dispose of plants, would be transformed profoundly and it would pun- a conceived child found to be HLA-incompatible with the ish all of ‘donation ethics’ at its very core. sick patient. HLA typing in utero should be performed, in Those outlined above are certainly not the only problems our opinion, only when other, far more important reasons that form the bioethical burden of justice for CB. The dif- (for example, advanced age of the mother, with consequent ferent political and economic programs for using the finan- higher risk of chromosome 21 trisomy for the fetus) suggest cial resources of individual nations and societies, which the execution of prenatal diagnosis procedures. allow or prevent the establishment of cord banks, with all The second possibility, that is to say, the possibility of the corollary requirements and tasks, obviously come using the placental blood for transplants between unrelated before any personal prospects with regard to the basic individuals, is furthermore the commonest and is necessar- choices (whether to allow or not allow collection and ily associated with efficient bank organizations, which are banking) and are still a highly problematic aspect of the now being fully planned and created in the USA, Europe, project. and Australia.26,30,35–37 The question of private (for-profit vs non-profit) banking It is true that it has been recently demonstrated that even of CB cells has been thoroughly analyzed.22 In any case, adults can be cured by HUCBT despite the infusion of a the involvement of lucrative aspects in the technology of relatively small dose of nucleated cells. This has been cord cell transplantation is not acceptable. The need to cre- ascribed to the particular hematopoietic reconstitution capa- ate banks for collection must not allow for-profit projects; bilities of CB hematopoietic stem cells with respect to bone in particular, CB cells like any part of the human body marrow cells.38–40 Previous estimates indicated that usual should not be commercialized.33,43 To be very cautious in practice in allogeneic BMT is to infuse 1–3 × 108 nucleated an approach that is particularly sensitive to these economic Bioethics of BMT and CBT in childhood GR Burgio and F Locatelli 1167 and organizational problems is a serious commitment to 9 Lantos JD. Children as organ donors: an argument for involun- work according to justice, so that the nonetheless significant tary altruism. In: Burgio GR, Lantos JD (eds). Primum Non advantages possibly entailed by this new technique are not Nocere Today. A Symposium on Pediatric Bioethics. Elsevier: impaired by methods not grounded in the fundamental prin- Amsterdam, 1994, pp 67–75. ciples of bioethics. Apart from simple cost assessments (it 10 Jonsen AR. Do not harm: axiom of medical ethics. In: Speaker SF, Engelhard HT Jr (eds). Philosophical Medical Ethics: Its has been estimated that the cost to obtain, pre-test, and Nature and Significance. D Reidel: Dordrecht, 1977, pp 27– freeze a unit of cord blood is about $1000) and from the 41. organizational problems, many biological and ethical 11 Ethics of Organ Transplant from Living Donors. Transplant comparisons between BMT and HUCBT have been pro- Proc 1992; 24: 2236–2237. posed44 (Tables 1 and 2), and the data currently available 12 Durbin M. Bone marrow transplantation: economic, ethical, certainly encourage the continued application of this and social issues. Pediatrics 1988; 82: 774–783. procedure.37,45,46 13 Alby N. Le cancer, sens et non sens. 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