- Email: [email protected]
Ethics of maternal–fetal surgery
Seminars in Fetal & Neonatal Medicine (2007) 12, 426e431
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/siny
Ethics of maternalefetal surgery Frank A. Chervenak a,*, Laurence B. McCullough b a
New York Presbyterian Hospital, 525 East 68th Street-J130, New York, NY 10021, USA Center for Medical Ethics and Health Policy, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
b
KEYWORDS Ethics; Human subjects research; Fetal patient; Fetal research; Maternalefetal surgery; Spina bifida
Summary The transition from innovation to standard of care for maternalefetal surgery should be guided by ethical as well as scientific considerations. This chapter provides an ethical framework that identifies criteria for the investigation of maternalefetal surgery. Using this framework, physicians should address the initiation and assessment of clinical trials to determine whether they establish a standard of care, use an appropriately informed consent process to recruit and enroll subjects, consider whether selection criteria should include the abortion preferences of the pregnant woman, and consider whether physicians have an obligation to offer referral to such investigation. This ethical framework, in a clinically comprehensive fashion, takes account of the physician’s obligations to the fetal patient, the pregnant woman, and future fetal and pregnant patients. The ethical framework is illustrated by the example of fetal surgery for spina bifida. ª 2007 Elsevier Ltd. All rights reserved.
Introduction Medical innovation has often been unmanaged in that interventions have gone from innovation to standard of care without adequate scientific and ethical evaluation.1 This is especially the case for surgery and surgically related specialties, including obstetrics. Mammary artery ligation for the management of angina is a classical example of unmanaged innovation which can impair scientific progress and put the health and even lives of patients at unnecessary risk. Until recently, maternalefetal surgery shared this history of unmanaged innovation, although with impact on far fewer patients. Recent innovations in maternale fetal surgery for spina bifida, a relatively common fetal anomaly that is usually diagnosed in the second trimester,
* Corresponding author. Tel.: þ1 212 746 3184; fax: þ1 212 746 8727. E-mail address: [email protected] (F.A. Chervenak).
raise the possibility of maternalefetal surgery for a much greater number of patients.2e4 These developments challenge the medical community to guide ongoing innovations in maternalefetal surgery in an ethically responsible fashion,5 for which there is widespread support in the professional community.6 The purpose of this chapter is to provide a comprehensive ethical framework for the responsible management of fetal research from innovation to standard of care, and to illustrate the clinical application of this framework in an analysis of research on maternale fetal surgery for spina bifida. This chapter is based on our previous work on this topic.7e9 The ethical framework is based on a central concept of obstetric ethics, the concept of the fetus as a patient,10 and is articulated in five parts. We (1) identify ethical criteria for preliminary investigation of maternalefetal surgery; (2) identify ethical criteria for the initiation of clinical trials and for the assessment of the results of such trials (i.e. whether they establish a standard of care); (3) describe the informed consent process that should be followed for
1744-165X/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2007.06.001
Ethics of maternalefetal surgery research in recruiting and enrolling subjects; (4) consider whether selection criteria should include the abortion preferences of the woman; and (5) consider whether practicing physicians have an obligation to offer referral to clinical trials investigating maternalefetal surgery. We then illustrate this five-part ethical framework with investigational maternalefetal surgery for spina bifida.
Ethical framework for fetal research The concept of the fetus as a patient We have argued elsewhere that the concept of the fetus as a patient should not be understood in terms of the independent moral status of the fetus, i.e., some feature(s) of the fetus that, independently of other entities e including the pregnant woman, the physician, and the state e generates obligations of others to it. This is because all attempts to establish such independent moral status have ended in failure and continued to do so; there are irreconcilable differences among the philosophical and theological methods deployed over the centuries of debate about the independent moral status of the fetus.10 A philosophically more sound and clinically more useful line of argument is that the moral status of the fetus depends on whether it can be reliably expected later to achieve the relatively unambiguous moral status of a child and, still later, the even more unambiguous moral status of a person. The fetus is a patient when reliable links exist between it and its later achieving the moral status of a child and then a person. There are two such links pertaining, respectively, to the viable and to the pre-viable fetus. The first link between a fetus and its later achieving moral status as a child, and then as a person, is viability, the ability of the fetus to exist ex utero with technological support as necessary. Viability thus requires levels of technological intervention necessary to support immature or impaired anatomy and physiology through delivery when childhood exists, and into the second year of life, the latest a time at which, it has been argued, personhood exists.10 Viability is therefore not an intrinsic characteristic of the fetus, but a function of both biology and technology. In developed countries, fetal viability occurs approximately at the 24th week of gestational age, as determined by competent and reliable ultrasound dating.11,12 When the viable fetus and the pregnant woman are presented to the physician, the viable fetus is a patient. The second link between a fetus and its later achieving moral status as a child and then as a person is the decision of the pregnant woman to continue a pre-viable pregnancy to viability and thus to term. This is because the only link between a pre-viable fetus and its later achieving moral status as a child and then as a person is the pregnant woman’s autonomy, exercised in the decision not to terminate her pregnancy, because technological factors do not exist that can sustain the pre-viable fetus ex utero. When the pregnant woman decides not to terminate her pregnancy, and when the pre-viable fetus and pregnant woman are presented to the physician, the pre-viable fetus is a patient.10 In summary, when the pregnant woman presents for medical care, the viable fetus is a patient. The pre-viable
427 fetus is a patient as a function of the pregnant woman’s decision to confer this status on the fetus and present herself for care. It cannot be emphasized too much that the existence of a fetal research project does not establish that the fetus is a patient, because, by definition, research interventions have not been established as clinically beneficial to the fetus. A pregnant woman’s decision to enroll in a clinical study of maternalefetal surgery therefore does not mean that the pre-viable fetus irrevocably has the status of being a patient, because before viability the pregnant woman can withdraw the status of being a patient from her fetus even after having earlier conferred that status on it. When the fetus is a patient, the physician has beneficence-based obligations to protect its life and health. These obligations must in all cases be considered along with beneficence-based and autonomy-based obligations to the pregnant woman.10 In other words, the fetus should not be considered as a separate patient. Ethical criteria to guide innovation in maternalefetal surgery must therefore take account of beneficence-based obligations to the fetal patient and beneficence-based and autonomy-based obligations to the pregnant woman. Failure to consider all of these obligations results in an inadequate ethical framework to guide innovations in maternalefetal surgery.
Ethical criteria for an initiation and assessment of clinical trials Innovation in maternalefetal surgery should begin with the design of an intervention and its implementation in the form of a single case and then case series, preceded by work on appropriate animal models when they exist. This approach is necessary to determine the feasibility, safety, and efficacy of innovations, and to protect future research subjects from potentially harmful innovation. We identified three criteria, all of which must be satisfied in order to conduct such preliminary investigations in an ethically responsible fashion, i.e., one that takes into account beneficence-based obligations to both the fetal patient and the pregnant woman. The pre-viable fetus is a patient in these cases because the woman has made a decision to continue her pregnancy in order to have the opportunity of gaining the potential benefits of the innovation. She remains free to withdraw that status before viability. The viable fetus is a patient in these cases by virtue of its viability. The three criteria are as follows. 1. The proposed fetal intervention can be reliably expected, on the basis of previous animal studies, to be either life saving or able to prevent serious and irreversible disease, injury, or disability for the fetus. 2. Among possible alternative designs, the intervention is designed in such a way as to involve the least risk of mortality and morbidity to the fetal patient (which is required by beneficence and will satisfy the US research requirement of minimizing risk to the fetus).13,14 3. On the basis of animal studies and analysis of theoretical risks both for the current and future pregnancies, the mortality risk to the pregnant woman can be reliably expected to be low, and the risk of disease, injury,
428
F.A. Chervenak, L.B. McCullough or disability to the pregnant woman can be reliably expected to be low or manageable.7
The first two criteria implement beneficence-based obligations to the fetal patient. Research on animal models should suggest that there would be therapeutic benefit without disproportionate iatrogenic fetal morbidity or mortality. If animal studies result in high rates of mortality or morbidity for the fetal subject, then innovation should not be introduced to human subjects until these rates improve in subsequent animal studies. The third criterion is important because surgery for potential fetal benefit is also maternal surgery. This criterion reminds investigators that the willingness of a subject, in this case the pregnant woman, to consent to risk does not establish whether the risk/benefit ratio is favorable. Investigators have an independent beneficence-based obligation to protect human subjects from unreasonably risky research and should use beneficence-based riskebenefit analyses. The phrase ‘maternalefetal surgery’ is useful if it reminds investigators of the need for such comprehensive analysis. If it is used to systematically subordinate fetal interest to maternal interest and rights, thus undermining the concept of the fetus as a patient in favor of the concept that the fetus is merely a part of the pregnant woman, we reject this phrase. Preliminary innovation should cease and randomized clinical trials begin when there is clinical equipoise. Clinical equipoise means that there is ‘a remaining disagreement in the expert clinical community, despite the available evidence, about the merits of the intervention to be tested’.14 Brody notes that one challenge here is identifying how much disagreement can remain for they are still to be equipoise.14 Lilford has suggested that when two thirds of the expert community, measured reliably, no longer disagree, equipoise is not satisfied.15 A newly emerging concept of equipoise is known as normative equipoise. This means that equipoise should exist when a rigorous, evidencebased evaluation of outcomes supports the judgment that neither is better than the other.16 When the experimental intervention should be judged to be clinically more harmful than non-intervention, equipoise cannot be achieved. We propose that the satisfaction of the previous three criteria, with slight modifications, should count as normative equipoise in the expert community: 1. the initial case series indicates that the proposed fetal intervention is reliably expected either to be life saving or to prevent serious and irreversible disease, injury, or disability; 2. among possible alternative designs, the intervention continues to involve the least risk of morbidity and mortality to the fetus; and 3. the case series indicates that the mortality risk to the pregnant woman is reliably expected to be low, and the risk of disease, injury, or disability to the pregnant woman e including for future pregnancies e is reliably expected to be low or manageable.7 One good test for the satisfaction of the first and third criteria is significant trends in the data from the case series. When normative equipoise has been achieved on the
basis of these three criteria, randomized clinical trials should commence as the means to responsibly innovate and thus improve patient care. Trials should have relevant and clearly defined primary and secondary endpoints and a design adequate to measure these endpoints. The above three criteria can be used in a straightforward manner to define stopping rules for clinical trials. When the data support a rigorous clinical judgment that either the first or the third criterion is not satisfied, the trial should be stopped because normative equipoise will no longer exist. When the clinical trial is completed, its outcome can be assessed to determine whether the innovative maternale fetal surgery should be regarded as standard of care. The trial results should meet the following three criteria in order to establish the innovation as standard of care: 1. the maternalefetal surgery has a significant probability of being life saving or preventing serious or irreversible disease, injury, or disability for the fetus; 2. the surgery involves low mortality and low or manageable risk of serious and irreversible disease, injury, or disability to the fetus; and 3. the mortality risk to the pregnant woman is low, and the risk of disease, injury or disability is low or manageable, including for future pregnancies.7 Brody has underscored the value of data safety and monitoring boards to prevent investigator bias and to protect subjects.14 Such boards should be used in fetal research on maternalefetal surgical interventions, especially to ensure adherence to the above-mentioned ethical criteria as a basis for monitoring such research.
The informed consent process The informed consent process should always be led by a physician competent to explain the intervention and its alternatives, with their benefits and risks. This requirement means that, as a rule, the physician investigator should lead the consent process or be readily available to answer questions. Having a physician who is not involved in the research project lead the consent process is an acceptable alternative only if that physician possesses the requisite competence and experience with the procedure under investigation. Like all consent processes for human subject research,17 counseling the pregnant woman about initial innovation or clinical trials should be rigorously non-directive. That is, participation should only be offered, not recommended. Investigators should be sure to emphasize the distinction between research and treatment to prevent therapeutic misconception. Technically, ‘therapeutic misconception’ occurs when the potential subject thinks that all aspects of research design are based on judgments of clinical benefit. However, this is not the case for research design components, such as randomization and blinding. More recently, ‘therapeutic misconception’ has come also to mean that belief of potential subjects that research, like treatment, will be beneficial and not involve disadvantages that do not occur in the therapeutic setting, e.g., beliefs that the purpose of a randomized trial is to treat his or
Ethics of maternalefetal surgery her condition or that his or her physician will select the best treatment for his or her condition.18 To prevent therapeutic misconception in both its meanings, the word ‘treatment’ or ‘therapy’, should never be used by investigators to describe the intervention. The investigators should be explicit about the fact that the surgical technique is ‘research’ or ‘experimentation’. Potential subjects in a case series should be told about the results of animal studies and potential subjects in clinical trials should be told about the results of the case series. The nature of the surgical procedure should be described to the pregnant woman in detail, including the risks to future pregnancies. The alternatives of termination of pregnancy and of postpartum management should be presented, along with their benefits and risks. In the consent process, words such as ‘mother’, ‘father’, and ‘baby’ should not be used by investigators, because these suggest moral relationships and moral statuses that do not apply.19 Words such as ‘pregnant woman’, ‘potential father’, ‘fetus’, and ‘fetal patient’ should be used instead. The pregnant woman should be clearly informed that she is under no obligation to the fetal patient to enroll it in a clinical research project. Clinical experience teaches that in fetal research there can be considerable internal and external pressures on women to enroll. The consent process should be altered to mitigate these effects. The woman should have time for reflecting on her decision, asking questions, and having her questions answered to her satisfaction. To protect a woman from being coerced, her husband or partner and other family members should be reminded that while they may have strong views for or against her participation, their role should be to support and respect the woman’s decisionmaking process and its outcome. Their relationship to her is primarily one of obligation to respect and support her decision. Family members do not have the right to make decisions for her. When necessary, this aspect of the informed consent should be made clear to family members. Clinical investigators should ensure that everyone involved in the consent process takes strictly non-directive approach. While not currently required in federal consent regulations, prospective monitoring of the consent process e e.g. in random sampling e could be used to enforce the non-directive approach. Publicity about either a case series investigation or a clinical trial should be non-directive because it is the first step in the informed consent process. Press releases, media interviews, patient education materials, websites, and other forms of publicity should be strictly nondirective, an especially important consideration since websites are now often the first point of contact for potential subjects to learn about clinical trials. The above restrictions on word choice should be followed strictly. ‘Science by press conference’ should be avoided. The data and safety monitoring board should assume oversight responsibilities in these areas. Investigators face an ethical challenge when a pregnant woman refuses to enter a randomized trial and insists on maternalefetal surgery. The investigator should explain that the assumption that surgery would benefit the fetal patient has no scientific basis and that, on balance, maternalefetal surgery could turn out to be harmful, depending on the results of the trial. Acquiescing to such
429 requests only encourages and potentially exploits false hopes. The ethically justified response is to refuse all such requests, no matter how insistent. Institutional review boards should refuse requests for compassionate exceptions unless a compelling case can be made for them, a steep burden of proof. US federal regulations are distinctive in the international context in continuing to require the consent of the father for fetal research, including maternalefetal surgery. It should be clear from the preceding that this requirement lacks ethical foundations. Indeed, it is unethical in that it allows for undue influence or even control over the pregnant woman’s autonomy by someone who, while he surely has an interest in the woman’s decisions, bears none of the medical risks.7e9
Selection criteria based on abortion preference It is an accepted feature of study design in general that clinical trials should be conducted in such a way as to control for the idiosyncratic effects of patients’ preferences on results. This, for example, justifies such strategies as randomization and blinding. For maternalefetal surgery this general rule of study design raises significant ethical issues. From the perspective of investigators, to obtain the cleanest results about outcomes for fetuses and future children one would not want any pregnancies in which maternalefetal surgery occurred to result in elective abortions. From the perspective of pregnant women who would accept elective termination, it might be desirable to prevent e through abortion before viability e adverse outcomes of maternalefetal surgery. To address the first problem, study design could exclude women who indicated any willingness to consider elective abortion. To address the second problem, study design could exclude women who were opposed to abortion. These solutions share a disabling ethical problem: such study designs in effect decide for the pregnant woman whether the pre-viable fetus is or is not a patient, an unjustifiable violation of her autonomy in favor of research considerations. To avoid such unacceptable ethical study designs, there should be no exclusion criteria in research on maternale fetal surgery based on willingness to countenance elective abortion. Study designs should therefore include elective abortion and birth of adversely affected infants as endpoints. In addition, investigators should understand that the decision of a pregnant woman to enroll herself and her pre-viable fetus in research does not mean that she has irrevocably conferred the status of being a patient on the pre-viable fetus subject. The informed consent process should make this clear to all pregnant women recruited to fetal surgery research.
Cooperation of practicing physicians with clinical investigation It is widely accepted that practicing physicians are justified in informing their patients about relevant clinical investigation, and, with the patient’s consent, referring them to the investigators. In our view, there is also an ethical obligation to do so in the case of maternalefetal surgery. The justification for this ethical obligation cannot appeal to
430 benefit the pregnant woman or fetal patient, because by definition the existence of clinical investigation does not establish clinical benefit. However, there is an obligation to future patients, pregnant and fetal alike, to establish whether investigative fetal intervention improves the current standard of care or not. All physicians should take seriously their obligation to both pregnant and fetal patients of the future to assure that innovation has the opportunity to be validated scientifically and ethically, rather than introduced in an unmanaged fashion or simply ignored.
Application of ethical framework to investigational surgery for spina bifida Animal investigation of maternalefetal surgery for spina bifida suggested that there would be therapeutic benefit without disproportionate morbidity or mortality.20 The three criteria for investigation with human subjects of feasibility, safety, and efficacy were therefore satisfied. The results of the case series reported in the literature and clinical experience meet the three criteria for equipoise. There has been a reduction in the ArnoldeChiari malformation and subsequent reduction in the necessity for shunt placement, with the prevention of mortality and morbidity associated with this malformation. Improvement in spinal cord function and overall functional status and quality of life has not been clearly demonstrated. The intervention continues to have very low rates of fetal mortality and maternal morbidity.2,3 Equipoise having been established, it is both ethically justified and warranted to undertake a well-designed, randomized clinical trial in the very few centers qualified to perform the procedure. Such a trial should have welldefined endpoints. There are two main clinical concerns about spina bifida. First, it results in loss of motor and sensory functions of the lower extremities, as well as bowel and bladder impairment. Second, the associated Arnolde Chiari malformation results in hydrocephalus, with its resultant shunt dependency and complications. The primary endpoints of the clinical trial should therefore address both outcomes, as well as rates of fetal and maternal surgical complications, both short-term and (to the extent possible) long-term, and iatrogenic prematurity. Equipoise means that there is no established benefit for the procedure, and that it should be investigated according to scientific standards. This means that the procedure should not be offered outside the context of a clinical trial, even in response to the most urgent requests of pregnant women or referral by colleagues for the procedure. This restriction is a powerful antidote to the problem of the technological imperative. Stopping rules should be established at the beginning of the trial, and their application should be based on statistical evidence of clear net benefit or net harm. The data and safety monitoring board should approve the study design and endpoints, define the stopping rules, and set up a procedure to closely monitor the trial, including recruitment and the informed consent process. The informed consent process should be rigorously nondirective, which will be challenging for physicians who have
F.A. Chervenak, L.B. McCullough participated in the innovation phase and have championed the procedure. Expressions of clinical judgment about the benefits of the procedure or other forms of enthusiasm have no place in the informed consent process for a randomized clinical trial. Consent forms, as well as websites and other marketing materials, should take great care with word choice, as described above. In particular, there should be no use of words such as ‘treatment’ or ‘therapy’. Instead, ‘research’, ‘experimental intervention’, and the like should be used. The use of such language in both oral and written communication is a powerful antidote to the problem of therapeutic misconception.18 It should also be made abundantly clear to the pregnant woman and her partner that she is under no obligation to place herself or her fetus in the clinical trial, because no benefit from the procedure has been established and it might prove, on balance, to be harmful. Selection criteria should make no reference to the woman’s willingness to terminate or continue pregnancy before or during the trial. The consent process should make clear to her that her preferences for the disposition of her pregnancy will be respected, just as they would in the nonexperimental, clinical setting. Participating centers should report the results of the research at professional meetings and in the scientific literature. Only after reports have appeared in the scientific literature should inquiries by the lay press be accommodated and addressed. ‘Science by press conference’ should be assiduously avoided. Referring physicians should be clear that the procedure remains experimental and is available in a clinical trial. They should emphasize that this means that the benefits and risks of the procedure have not been established and that there is therefore no obligation on the part of the pregnant woman to her fetus or future child to enroll in the trial. Her judgment about the importance of her obligation to future pregnant and fetal patients should be explored non-directively.
Conclusion It has long been recognized that maternalefetal surgery is fraught with ethical issues.21,22 This chapter has provided an ethical framework for responsibly managing the transition from innovation in maternalefetal surgery, to clinical trials, to offering it to pregnant women as a standard of care for the management of fetal anomalies. This chapter has argued that the informed consent process for innovation and research should be strictly non-directive, and has emphasized that the pregnant woman has no ethical obligation to the fetal patient to enroll it and herself in such an investigation. Selection criteria based on abortion preference, pro or con, have been shown to have no place in the ethical design of research on maternalefetal surgery. This chapter has also argued that the practice community has an obligation to offer referral to clinical investigation of maternalefetal surgery. The ethical integrity of all forms of fetal research is just as important as their scientific integrity. The current controversy concerning clinical investigation of maternalefetal surgery for spina bifida can be reliably addressed using this ethical framework.
Ethics of maternalefetal surgery
Practice points Surgery on the fetus is always surgery also on the pregnant woman, and so ethical obligations to both must be taken into account in the design and conduct of research on maternalefetal surgery. Adequate study design should justify the initiation of randomized clinical trials to determine whether they meet the condition of normative equipoise, assessed to determined whether their results establish a new standard of care, use an appropriately informed consent process to recruit and enroll subjects, and not include selection criteria based on the abortion preferences of the pregnant woman. The informed consent process for maternalefetal surgery should be non-directive and should seek to avoid therapeutic misconception, especially in language use. Physicians should inform eligible pregnant women about relevant clinical trials of maternalefetal surgery that meet conditions for both scientific and ethical integrity.
Research directions Research should be conducted in ways to improve the informed consent process for trials of maternalefetal surgery to ensure that this process is non-directive, provides women with information that they need to make decisions, and protects potential subjects from undue influence or coercion in their decision-making.
References 1. Frader JE, Caniano DA. Research and innovation in surgery. In: McCullough LB, Jones JW, Brody BA, editors. Surgical ethics. New York: Oxford University Press; 1998. p. 216e41. 2. Bruner JP, Tulipan N, Paschall RL, Boehm FH, Walsh WF, Silva SR, et al. Maternalefetal surgery for myelomeningocele and the incidence of shunt-dependent hydrocephalus. JAMA 1999;282:1819e25.
431 3. Sutton LN, Adzick NS, Bilanivic LT, Bilaniuk LT, Johnson MP, Crombelhome TM, et al. Improvement in hindbrain herniation demonstrated by serial fetal magnetic resonance imaging following maternalefetal surgery for myelomeningocele. JAMA 1999;282:1826e31. 4. Simpson JL. Maternalefetal surgery for myelomeningocele. promise, progress and problems. JAMA 1999;282:1873e4. 5. Lyerly AD, Gates EA, Cefalo RC, Sugarman JS. Toward the ethical evaluation and use of maternalematernalefetal surgery. Obstet Gynecol 2001;98:689e97. 6. Lyerly AD, Cefalo RC, Socol M, Fogarty L, Sugarman J. Attitudes of maternalefetal specialists concerning maternalematernale fetal surgery. Am J Obstet Gynecol 2001;185:1052e8. 7. Chervenak FA, McCullough LB. A comprehensive ethical framework for fetal research and its application to fetal surgery for spina bifida. Am J Obstet Gynecol 2002;187:10e4. 8. McCullough LB, Coverdale JH, Chervenak FA. A comprehensive ethical framework for responsibly designing and conducting pharmacologic research that involves pregnant women. Am J Obstet Gynecol 2005;193:901e7. 9. McCullough LB, Coverdale JH, Chervenak FA. Preventive ethics for including women of childbearing potential in clinical trials. Am J Obstet Gynecol 2006;194:1221e7. 10. McCullough LB, Chervenak FA. Ethics in obstetrics and gynecology. New York: Oxford University Press; 1994. 11. Chervenak FA, McCullough LB. The limits of viability. J Perinat Med 1997;25:418e20. 12. Chervenak FA, McCullough LB, Levene MI. An ethically justified, clinically comprehensive approach to peri-viability: gynaecological, obstetric, perinatal, and neonatal dimensions. J Obstet Gynaecol 2007;27:3e7. 13. Department of Health and Human Services. Regulations for the Protection of Human Subjects. 45 CFR 46. 14. Brody BA. The ethics of biomedical research: an international perspective. New York: Oxford University Press; 1998. 15. Lilford RJ. The substantive ethics of clinical trials. Clin Obstet Gynecol 1992;35:837e45. 16. Brody BA, McCullough LB, Sharp RR. Consensus and controversy in research ethics. JAMA 2005;294:1411e4. 17. Faden RR, Beauchamp TL. A history of theory of informed consent. New York: Oxford University Press; 1986. 18. Appelbaum PS, Roth LH, Lidz CW, Benson P, Winslade W. False hopes and best data: consent to research and the therapeutic misconception. Hastings Cont Rep 1987;17:20e4. 19. DeCrespigny L, Chervenak F, McCullough L. Mothers and babies, pregnant women and fetuses. Br J Obstet Gynaecol 1999;106:1235e7. 20. Meuli M, Meuli-Simmen C, Hutchins GM, Yingling CD, Hoffman KM, Harrison MR, et al. In utero surgery rescues neurological function at birth in sheep with spina bifida. Nat Med 1995;1:342e7. 21. Barclay WR, McCormick RA, Sidbury JB, Michejda M, Hodgen GD. The ethics of in utero surgery. JAMA 1981;246: 1551e2, 1554e1555. 22. Fletcher JC, Jonsen AR. Ethical considerations of fetal therapy. In: Harrison MR, Golbus MS, Filly RA, editors. Unborn patient. 2nd ed. Orlando: Grune & Stratton; 1990. p. 159e70.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/siny
Ethics of maternalefetal surgery Frank A. Chervenak a,*, Laurence B. McCullough b a
New York Presbyterian Hospital, 525 East 68th Street-J130, New York, NY 10021, USA Center for Medical Ethics and Health Policy, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
b
KEYWORDS Ethics; Human subjects research; Fetal patient; Fetal research; Maternalefetal surgery; Spina bifida
Summary The transition from innovation to standard of care for maternalefetal surgery should be guided by ethical as well as scientific considerations. This chapter provides an ethical framework that identifies criteria for the investigation of maternalefetal surgery. Using this framework, physicians should address the initiation and assessment of clinical trials to determine whether they establish a standard of care, use an appropriately informed consent process to recruit and enroll subjects, consider whether selection criteria should include the abortion preferences of the pregnant woman, and consider whether physicians have an obligation to offer referral to such investigation. This ethical framework, in a clinically comprehensive fashion, takes account of the physician’s obligations to the fetal patient, the pregnant woman, and future fetal and pregnant patients. The ethical framework is illustrated by the example of fetal surgery for spina bifida. ª 2007 Elsevier Ltd. All rights reserved.
Introduction Medical innovation has often been unmanaged in that interventions have gone from innovation to standard of care without adequate scientific and ethical evaluation.1 This is especially the case for surgery and surgically related specialties, including obstetrics. Mammary artery ligation for the management of angina is a classical example of unmanaged innovation which can impair scientific progress and put the health and even lives of patients at unnecessary risk. Until recently, maternalefetal surgery shared this history of unmanaged innovation, although with impact on far fewer patients. Recent innovations in maternale fetal surgery for spina bifida, a relatively common fetal anomaly that is usually diagnosed in the second trimester,
* Corresponding author. Tel.: þ1 212 746 3184; fax: þ1 212 746 8727. E-mail address: [email protected] (F.A. Chervenak).
raise the possibility of maternalefetal surgery for a much greater number of patients.2e4 These developments challenge the medical community to guide ongoing innovations in maternalefetal surgery in an ethically responsible fashion,5 for which there is widespread support in the professional community.6 The purpose of this chapter is to provide a comprehensive ethical framework for the responsible management of fetal research from innovation to standard of care, and to illustrate the clinical application of this framework in an analysis of research on maternale fetal surgery for spina bifida. This chapter is based on our previous work on this topic.7e9 The ethical framework is based on a central concept of obstetric ethics, the concept of the fetus as a patient,10 and is articulated in five parts. We (1) identify ethical criteria for preliminary investigation of maternalefetal surgery; (2) identify ethical criteria for the initiation of clinical trials and for the assessment of the results of such trials (i.e. whether they establish a standard of care); (3) describe the informed consent process that should be followed for
1744-165X/$ - see front matter ª 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2007.06.001
Ethics of maternalefetal surgery research in recruiting and enrolling subjects; (4) consider whether selection criteria should include the abortion preferences of the woman; and (5) consider whether practicing physicians have an obligation to offer referral to clinical trials investigating maternalefetal surgery. We then illustrate this five-part ethical framework with investigational maternalefetal surgery for spina bifida.
Ethical framework for fetal research The concept of the fetus as a patient We have argued elsewhere that the concept of the fetus as a patient should not be understood in terms of the independent moral status of the fetus, i.e., some feature(s) of the fetus that, independently of other entities e including the pregnant woman, the physician, and the state e generates obligations of others to it. This is because all attempts to establish such independent moral status have ended in failure and continued to do so; there are irreconcilable differences among the philosophical and theological methods deployed over the centuries of debate about the independent moral status of the fetus.10 A philosophically more sound and clinically more useful line of argument is that the moral status of the fetus depends on whether it can be reliably expected later to achieve the relatively unambiguous moral status of a child and, still later, the even more unambiguous moral status of a person. The fetus is a patient when reliable links exist between it and its later achieving the moral status of a child and then a person. There are two such links pertaining, respectively, to the viable and to the pre-viable fetus. The first link between a fetus and its later achieving moral status as a child, and then as a person, is viability, the ability of the fetus to exist ex utero with technological support as necessary. Viability thus requires levels of technological intervention necessary to support immature or impaired anatomy and physiology through delivery when childhood exists, and into the second year of life, the latest a time at which, it has been argued, personhood exists.10 Viability is therefore not an intrinsic characteristic of the fetus, but a function of both biology and technology. In developed countries, fetal viability occurs approximately at the 24th week of gestational age, as determined by competent and reliable ultrasound dating.11,12 When the viable fetus and the pregnant woman are presented to the physician, the viable fetus is a patient. The second link between a fetus and its later achieving moral status as a child and then as a person is the decision of the pregnant woman to continue a pre-viable pregnancy to viability and thus to term. This is because the only link between a pre-viable fetus and its later achieving moral status as a child and then as a person is the pregnant woman’s autonomy, exercised in the decision not to terminate her pregnancy, because technological factors do not exist that can sustain the pre-viable fetus ex utero. When the pregnant woman decides not to terminate her pregnancy, and when the pre-viable fetus and pregnant woman are presented to the physician, the pre-viable fetus is a patient.10 In summary, when the pregnant woman presents for medical care, the viable fetus is a patient. The pre-viable
427 fetus is a patient as a function of the pregnant woman’s decision to confer this status on the fetus and present herself for care. It cannot be emphasized too much that the existence of a fetal research project does not establish that the fetus is a patient, because, by definition, research interventions have not been established as clinically beneficial to the fetus. A pregnant woman’s decision to enroll in a clinical study of maternalefetal surgery therefore does not mean that the pre-viable fetus irrevocably has the status of being a patient, because before viability the pregnant woman can withdraw the status of being a patient from her fetus even after having earlier conferred that status on it. When the fetus is a patient, the physician has beneficence-based obligations to protect its life and health. These obligations must in all cases be considered along with beneficence-based and autonomy-based obligations to the pregnant woman.10 In other words, the fetus should not be considered as a separate patient. Ethical criteria to guide innovation in maternalefetal surgery must therefore take account of beneficence-based obligations to the fetal patient and beneficence-based and autonomy-based obligations to the pregnant woman. Failure to consider all of these obligations results in an inadequate ethical framework to guide innovations in maternalefetal surgery.
Ethical criteria for an initiation and assessment of clinical trials Innovation in maternalefetal surgery should begin with the design of an intervention and its implementation in the form of a single case and then case series, preceded by work on appropriate animal models when they exist. This approach is necessary to determine the feasibility, safety, and efficacy of innovations, and to protect future research subjects from potentially harmful innovation. We identified three criteria, all of which must be satisfied in order to conduct such preliminary investigations in an ethically responsible fashion, i.e., one that takes into account beneficence-based obligations to both the fetal patient and the pregnant woman. The pre-viable fetus is a patient in these cases because the woman has made a decision to continue her pregnancy in order to have the opportunity of gaining the potential benefits of the innovation. She remains free to withdraw that status before viability. The viable fetus is a patient in these cases by virtue of its viability. The three criteria are as follows. 1. The proposed fetal intervention can be reliably expected, on the basis of previous animal studies, to be either life saving or able to prevent serious and irreversible disease, injury, or disability for the fetus. 2. Among possible alternative designs, the intervention is designed in such a way as to involve the least risk of mortality and morbidity to the fetal patient (which is required by beneficence and will satisfy the US research requirement of minimizing risk to the fetus).13,14 3. On the basis of animal studies and analysis of theoretical risks both for the current and future pregnancies, the mortality risk to the pregnant woman can be reliably expected to be low, and the risk of disease, injury,
428
F.A. Chervenak, L.B. McCullough or disability to the pregnant woman can be reliably expected to be low or manageable.7
The first two criteria implement beneficence-based obligations to the fetal patient. Research on animal models should suggest that there would be therapeutic benefit without disproportionate iatrogenic fetal morbidity or mortality. If animal studies result in high rates of mortality or morbidity for the fetal subject, then innovation should not be introduced to human subjects until these rates improve in subsequent animal studies. The third criterion is important because surgery for potential fetal benefit is also maternal surgery. This criterion reminds investigators that the willingness of a subject, in this case the pregnant woman, to consent to risk does not establish whether the risk/benefit ratio is favorable. Investigators have an independent beneficence-based obligation to protect human subjects from unreasonably risky research and should use beneficence-based riskebenefit analyses. The phrase ‘maternalefetal surgery’ is useful if it reminds investigators of the need for such comprehensive analysis. If it is used to systematically subordinate fetal interest to maternal interest and rights, thus undermining the concept of the fetus as a patient in favor of the concept that the fetus is merely a part of the pregnant woman, we reject this phrase. Preliminary innovation should cease and randomized clinical trials begin when there is clinical equipoise. Clinical equipoise means that there is ‘a remaining disagreement in the expert clinical community, despite the available evidence, about the merits of the intervention to be tested’.14 Brody notes that one challenge here is identifying how much disagreement can remain for they are still to be equipoise.14 Lilford has suggested that when two thirds of the expert community, measured reliably, no longer disagree, equipoise is not satisfied.15 A newly emerging concept of equipoise is known as normative equipoise. This means that equipoise should exist when a rigorous, evidencebased evaluation of outcomes supports the judgment that neither is better than the other.16 When the experimental intervention should be judged to be clinically more harmful than non-intervention, equipoise cannot be achieved. We propose that the satisfaction of the previous three criteria, with slight modifications, should count as normative equipoise in the expert community: 1. the initial case series indicates that the proposed fetal intervention is reliably expected either to be life saving or to prevent serious and irreversible disease, injury, or disability; 2. among possible alternative designs, the intervention continues to involve the least risk of morbidity and mortality to the fetus; and 3. the case series indicates that the mortality risk to the pregnant woman is reliably expected to be low, and the risk of disease, injury, or disability to the pregnant woman e including for future pregnancies e is reliably expected to be low or manageable.7 One good test for the satisfaction of the first and third criteria is significant trends in the data from the case series. When normative equipoise has been achieved on the
basis of these three criteria, randomized clinical trials should commence as the means to responsibly innovate and thus improve patient care. Trials should have relevant and clearly defined primary and secondary endpoints and a design adequate to measure these endpoints. The above three criteria can be used in a straightforward manner to define stopping rules for clinical trials. When the data support a rigorous clinical judgment that either the first or the third criterion is not satisfied, the trial should be stopped because normative equipoise will no longer exist. When the clinical trial is completed, its outcome can be assessed to determine whether the innovative maternale fetal surgery should be regarded as standard of care. The trial results should meet the following three criteria in order to establish the innovation as standard of care: 1. the maternalefetal surgery has a significant probability of being life saving or preventing serious or irreversible disease, injury, or disability for the fetus; 2. the surgery involves low mortality and low or manageable risk of serious and irreversible disease, injury, or disability to the fetus; and 3. the mortality risk to the pregnant woman is low, and the risk of disease, injury or disability is low or manageable, including for future pregnancies.7 Brody has underscored the value of data safety and monitoring boards to prevent investigator bias and to protect subjects.14 Such boards should be used in fetal research on maternalefetal surgical interventions, especially to ensure adherence to the above-mentioned ethical criteria as a basis for monitoring such research.
The informed consent process The informed consent process should always be led by a physician competent to explain the intervention and its alternatives, with their benefits and risks. This requirement means that, as a rule, the physician investigator should lead the consent process or be readily available to answer questions. Having a physician who is not involved in the research project lead the consent process is an acceptable alternative only if that physician possesses the requisite competence and experience with the procedure under investigation. Like all consent processes for human subject research,17 counseling the pregnant woman about initial innovation or clinical trials should be rigorously non-directive. That is, participation should only be offered, not recommended. Investigators should be sure to emphasize the distinction between research and treatment to prevent therapeutic misconception. Technically, ‘therapeutic misconception’ occurs when the potential subject thinks that all aspects of research design are based on judgments of clinical benefit. However, this is not the case for research design components, such as randomization and blinding. More recently, ‘therapeutic misconception’ has come also to mean that belief of potential subjects that research, like treatment, will be beneficial and not involve disadvantages that do not occur in the therapeutic setting, e.g., beliefs that the purpose of a randomized trial is to treat his or
Ethics of maternalefetal surgery her condition or that his or her physician will select the best treatment for his or her condition.18 To prevent therapeutic misconception in both its meanings, the word ‘treatment’ or ‘therapy’, should never be used by investigators to describe the intervention. The investigators should be explicit about the fact that the surgical technique is ‘research’ or ‘experimentation’. Potential subjects in a case series should be told about the results of animal studies and potential subjects in clinical trials should be told about the results of the case series. The nature of the surgical procedure should be described to the pregnant woman in detail, including the risks to future pregnancies. The alternatives of termination of pregnancy and of postpartum management should be presented, along with their benefits and risks. In the consent process, words such as ‘mother’, ‘father’, and ‘baby’ should not be used by investigators, because these suggest moral relationships and moral statuses that do not apply.19 Words such as ‘pregnant woman’, ‘potential father’, ‘fetus’, and ‘fetal patient’ should be used instead. The pregnant woman should be clearly informed that she is under no obligation to the fetal patient to enroll it in a clinical research project. Clinical experience teaches that in fetal research there can be considerable internal and external pressures on women to enroll. The consent process should be altered to mitigate these effects. The woman should have time for reflecting on her decision, asking questions, and having her questions answered to her satisfaction. To protect a woman from being coerced, her husband or partner and other family members should be reminded that while they may have strong views for or against her participation, their role should be to support and respect the woman’s decisionmaking process and its outcome. Their relationship to her is primarily one of obligation to respect and support her decision. Family members do not have the right to make decisions for her. When necessary, this aspect of the informed consent should be made clear to family members. Clinical investigators should ensure that everyone involved in the consent process takes strictly non-directive approach. While not currently required in federal consent regulations, prospective monitoring of the consent process e e.g. in random sampling e could be used to enforce the non-directive approach. Publicity about either a case series investigation or a clinical trial should be non-directive because it is the first step in the informed consent process. Press releases, media interviews, patient education materials, websites, and other forms of publicity should be strictly nondirective, an especially important consideration since websites are now often the first point of contact for potential subjects to learn about clinical trials. The above restrictions on word choice should be followed strictly. ‘Science by press conference’ should be avoided. The data and safety monitoring board should assume oversight responsibilities in these areas. Investigators face an ethical challenge when a pregnant woman refuses to enter a randomized trial and insists on maternalefetal surgery. The investigator should explain that the assumption that surgery would benefit the fetal patient has no scientific basis and that, on balance, maternalefetal surgery could turn out to be harmful, depending on the results of the trial. Acquiescing to such
429 requests only encourages and potentially exploits false hopes. The ethically justified response is to refuse all such requests, no matter how insistent. Institutional review boards should refuse requests for compassionate exceptions unless a compelling case can be made for them, a steep burden of proof. US federal regulations are distinctive in the international context in continuing to require the consent of the father for fetal research, including maternalefetal surgery. It should be clear from the preceding that this requirement lacks ethical foundations. Indeed, it is unethical in that it allows for undue influence or even control over the pregnant woman’s autonomy by someone who, while he surely has an interest in the woman’s decisions, bears none of the medical risks.7e9
Selection criteria based on abortion preference It is an accepted feature of study design in general that clinical trials should be conducted in such a way as to control for the idiosyncratic effects of patients’ preferences on results. This, for example, justifies such strategies as randomization and blinding. For maternalefetal surgery this general rule of study design raises significant ethical issues. From the perspective of investigators, to obtain the cleanest results about outcomes for fetuses and future children one would not want any pregnancies in which maternalefetal surgery occurred to result in elective abortions. From the perspective of pregnant women who would accept elective termination, it might be desirable to prevent e through abortion before viability e adverse outcomes of maternalefetal surgery. To address the first problem, study design could exclude women who indicated any willingness to consider elective abortion. To address the second problem, study design could exclude women who were opposed to abortion. These solutions share a disabling ethical problem: such study designs in effect decide for the pregnant woman whether the pre-viable fetus is or is not a patient, an unjustifiable violation of her autonomy in favor of research considerations. To avoid such unacceptable ethical study designs, there should be no exclusion criteria in research on maternale fetal surgery based on willingness to countenance elective abortion. Study designs should therefore include elective abortion and birth of adversely affected infants as endpoints. In addition, investigators should understand that the decision of a pregnant woman to enroll herself and her pre-viable fetus in research does not mean that she has irrevocably conferred the status of being a patient on the pre-viable fetus subject. The informed consent process should make this clear to all pregnant women recruited to fetal surgery research.
Cooperation of practicing physicians with clinical investigation It is widely accepted that practicing physicians are justified in informing their patients about relevant clinical investigation, and, with the patient’s consent, referring them to the investigators. In our view, there is also an ethical obligation to do so in the case of maternalefetal surgery. The justification for this ethical obligation cannot appeal to
430 benefit the pregnant woman or fetal patient, because by definition the existence of clinical investigation does not establish clinical benefit. However, there is an obligation to future patients, pregnant and fetal alike, to establish whether investigative fetal intervention improves the current standard of care or not. All physicians should take seriously their obligation to both pregnant and fetal patients of the future to assure that innovation has the opportunity to be validated scientifically and ethically, rather than introduced in an unmanaged fashion or simply ignored.
Application of ethical framework to investigational surgery for spina bifida Animal investigation of maternalefetal surgery for spina bifida suggested that there would be therapeutic benefit without disproportionate morbidity or mortality.20 The three criteria for investigation with human subjects of feasibility, safety, and efficacy were therefore satisfied. The results of the case series reported in the literature and clinical experience meet the three criteria for equipoise. There has been a reduction in the ArnoldeChiari malformation and subsequent reduction in the necessity for shunt placement, with the prevention of mortality and morbidity associated with this malformation. Improvement in spinal cord function and overall functional status and quality of life has not been clearly demonstrated. The intervention continues to have very low rates of fetal mortality and maternal morbidity.2,3 Equipoise having been established, it is both ethically justified and warranted to undertake a well-designed, randomized clinical trial in the very few centers qualified to perform the procedure. Such a trial should have welldefined endpoints. There are two main clinical concerns about spina bifida. First, it results in loss of motor and sensory functions of the lower extremities, as well as bowel and bladder impairment. Second, the associated Arnolde Chiari malformation results in hydrocephalus, with its resultant shunt dependency and complications. The primary endpoints of the clinical trial should therefore address both outcomes, as well as rates of fetal and maternal surgical complications, both short-term and (to the extent possible) long-term, and iatrogenic prematurity. Equipoise means that there is no established benefit for the procedure, and that it should be investigated according to scientific standards. This means that the procedure should not be offered outside the context of a clinical trial, even in response to the most urgent requests of pregnant women or referral by colleagues for the procedure. This restriction is a powerful antidote to the problem of the technological imperative. Stopping rules should be established at the beginning of the trial, and their application should be based on statistical evidence of clear net benefit or net harm. The data and safety monitoring board should approve the study design and endpoints, define the stopping rules, and set up a procedure to closely monitor the trial, including recruitment and the informed consent process. The informed consent process should be rigorously nondirective, which will be challenging for physicians who have
F.A. Chervenak, L.B. McCullough participated in the innovation phase and have championed the procedure. Expressions of clinical judgment about the benefits of the procedure or other forms of enthusiasm have no place in the informed consent process for a randomized clinical trial. Consent forms, as well as websites and other marketing materials, should take great care with word choice, as described above. In particular, there should be no use of words such as ‘treatment’ or ‘therapy’. Instead, ‘research’, ‘experimental intervention’, and the like should be used. The use of such language in both oral and written communication is a powerful antidote to the problem of therapeutic misconception.18 It should also be made abundantly clear to the pregnant woman and her partner that she is under no obligation to place herself or her fetus in the clinical trial, because no benefit from the procedure has been established and it might prove, on balance, to be harmful. Selection criteria should make no reference to the woman’s willingness to terminate or continue pregnancy before or during the trial. The consent process should make clear to her that her preferences for the disposition of her pregnancy will be respected, just as they would in the nonexperimental, clinical setting. Participating centers should report the results of the research at professional meetings and in the scientific literature. Only after reports have appeared in the scientific literature should inquiries by the lay press be accommodated and addressed. ‘Science by press conference’ should be assiduously avoided. Referring physicians should be clear that the procedure remains experimental and is available in a clinical trial. They should emphasize that this means that the benefits and risks of the procedure have not been established and that there is therefore no obligation on the part of the pregnant woman to her fetus or future child to enroll in the trial. Her judgment about the importance of her obligation to future pregnant and fetal patients should be explored non-directively.
Conclusion It has long been recognized that maternalefetal surgery is fraught with ethical issues.21,22 This chapter has provided an ethical framework for responsibly managing the transition from innovation in maternalefetal surgery, to clinical trials, to offering it to pregnant women as a standard of care for the management of fetal anomalies. This chapter has argued that the informed consent process for innovation and research should be strictly non-directive, and has emphasized that the pregnant woman has no ethical obligation to the fetal patient to enroll it and herself in such an investigation. Selection criteria based on abortion preference, pro or con, have been shown to have no place in the ethical design of research on maternalefetal surgery. This chapter has also argued that the practice community has an obligation to offer referral to clinical investigation of maternalefetal surgery. The ethical integrity of all forms of fetal research is just as important as their scientific integrity. The current controversy concerning clinical investigation of maternalefetal surgery for spina bifida can be reliably addressed using this ethical framework.
Ethics of maternalefetal surgery
Practice points Surgery on the fetus is always surgery also on the pregnant woman, and so ethical obligations to both must be taken into account in the design and conduct of research on maternalefetal surgery. Adequate study design should justify the initiation of randomized clinical trials to determine whether they meet the condition of normative equipoise, assessed to determined whether their results establish a new standard of care, use an appropriately informed consent process to recruit and enroll subjects, and not include selection criteria based on the abortion preferences of the pregnant woman. The informed consent process for maternalefetal surgery should be non-directive and should seek to avoid therapeutic misconception, especially in language use. Physicians should inform eligible pregnant women about relevant clinical trials of maternalefetal surgery that meet conditions for both scientific and ethical integrity.
Research directions Research should be conducted in ways to improve the informed consent process for trials of maternalefetal surgery to ensure that this process is non-directive, provides women with information that they need to make decisions, and protects potential subjects from undue influence or coercion in their decision-making.
References 1. Frader JE, Caniano DA. Research and innovation in surgery. In: McCullough LB, Jones JW, Brody BA, editors. Surgical ethics. New York: Oxford University Press; 1998. p. 216e41. 2. Bruner JP, Tulipan N, Paschall RL, Boehm FH, Walsh WF, Silva SR, et al. Maternalefetal surgery for myelomeningocele and the incidence of shunt-dependent hydrocephalus. JAMA 1999;282:1819e25.
431 3. Sutton LN, Adzick NS, Bilanivic LT, Bilaniuk LT, Johnson MP, Crombelhome TM, et al. Improvement in hindbrain herniation demonstrated by serial fetal magnetic resonance imaging following maternalefetal surgery for myelomeningocele. JAMA 1999;282:1826e31. 4. Simpson JL. Maternalefetal surgery for myelomeningocele. promise, progress and problems. JAMA 1999;282:1873e4. 5. Lyerly AD, Gates EA, Cefalo RC, Sugarman JS. Toward the ethical evaluation and use of maternalematernalefetal surgery. Obstet Gynecol 2001;98:689e97. 6. Lyerly AD, Cefalo RC, Socol M, Fogarty L, Sugarman J. Attitudes of maternalefetal specialists concerning maternalematernale fetal surgery. Am J Obstet Gynecol 2001;185:1052e8. 7. Chervenak FA, McCullough LB. A comprehensive ethical framework for fetal research and its application to fetal surgery for spina bifida. Am J Obstet Gynecol 2002;187:10e4. 8. McCullough LB, Coverdale JH, Chervenak FA. A comprehensive ethical framework for responsibly designing and conducting pharmacologic research that involves pregnant women. Am J Obstet Gynecol 2005;193:901e7. 9. McCullough LB, Coverdale JH, Chervenak FA. Preventive ethics for including women of childbearing potential in clinical trials. Am J Obstet Gynecol 2006;194:1221e7. 10. McCullough LB, Chervenak FA. Ethics in obstetrics and gynecology. New York: Oxford University Press; 1994. 11. Chervenak FA, McCullough LB. The limits of viability. J Perinat Med 1997;25:418e20. 12. Chervenak FA, McCullough LB, Levene MI. An ethically justified, clinically comprehensive approach to peri-viability: gynaecological, obstetric, perinatal, and neonatal dimensions. J Obstet Gynaecol 2007;27:3e7. 13. Department of Health and Human Services. Regulations for the Protection of Human Subjects. 45 CFR 46. 14. Brody BA. The ethics of biomedical research: an international perspective. New York: Oxford University Press; 1998. 15. Lilford RJ. The substantive ethics of clinical trials. Clin Obstet Gynecol 1992;35:837e45. 16. Brody BA, McCullough LB, Sharp RR. Consensus and controversy in research ethics. JAMA 2005;294:1411e4. 17. Faden RR, Beauchamp TL. A history of theory of informed consent. New York: Oxford University Press; 1986. 18. Appelbaum PS, Roth LH, Lidz CW, Benson P, Winslade W. False hopes and best data: consent to research and the therapeutic misconception. Hastings Cont Rep 1987;17:20e4. 19. DeCrespigny L, Chervenak F, McCullough L. Mothers and babies, pregnant women and fetuses. Br J Obstet Gynaecol 1999;106:1235e7. 20. Meuli M, Meuli-Simmen C, Hutchins GM, Yingling CD, Hoffman KM, Harrison MR, et al. In utero surgery rescues neurological function at birth in sheep with spina bifida. Nat Med 1995;1:342e7. 21. Barclay WR, McCormick RA, Sidbury JB, Michejda M, Hodgen GD. The ethics of in utero surgery. JAMA 1981;246: 1551e2, 1554e1555. 22. Fletcher JC, Jonsen AR. Ethical considerations of fetal therapy. In: Harrison MR, Golbus MS, Filly RA, editors. Unborn patient. 2nd ed. Orlando: Grune & Stratton; 1990. p. 159e70.