- Email: [email protected]
Toward the ethical evaluation and use of maternal-fetal surgery
CURRENT COMMENTARY
Toward the Ethical Evaluation and Use of Maternal-Fetal Surgery Anne Drapkin Lyerly, MD, Elena A. Gates, MD, Robert C. Cefalo, MD, PhD, and Jeremy Sugarman, MD, MPH Bioethics Institute, Johns Hopkins University, Baltimore, Maryland; Kennedy Institute of Ethics, Georgetown University, Washington, DC; Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, California; Department of Obstetrics and Gynecology, University of North Carolina, Durham, North Carolina; and Center for the Study of Medical Ethics and Humanities, Duke University Medical Center, Durham, North Carolina.
BACKGROUND: Important clinical, social, and ethical questions are associated with the evaluation and use of surgical approaches aimed at correcting fetal anatomic abnormalities. In particular, the expansion of maternal-fetal surgery to ameliorate nonlethal fetal conditions has intensified the need to address issues about the adequacy of technology assessment and the safety of those who undergo these novel procedures. APPROACH: After discussions at a multidisciplinary conference, we reviewed the development and current practices of maternal-fetal surgery and analyzed the relevant ethical issues concerning the use of maternal-fetal surgery for nonlethal conditions, focusing on the correction of myelomeningocele. FINDINGS: Characterizing nonvalidated maternal-fetal surgery procedures as “innovative therapy” blurs the boundaries between research and therapy and creates uncertainty about the obligations of clinicians and researchers. Further, maternal-fetal surgery raises ethical issues related to maternal risks and benefits, informed consent, distinguishing lethal from nonlethal conditions, withholding unproven treatments, entrepreneurship, and prioritization. RECOMMENDATIONS: To help ensure that maternal-fetal surgery will be studied and eventually applied in a scienThe opinions and recommendations in this article are those of the authors and do not necessarily represent the views of the speakers at, or participants in, the NIH Workshop on Current Scientific, Ethical and Clinical Considerations of MaternalFetal Surgery. Address reprint requests to: Jeremy Sugarman, MD, MPH, Center for the Study of Medical Ethics and Humanities, Box 3040, Duke University Medical Center, 108 Seeley G. Mudd Building, Durham, NC 27710-3040; E-mail: [email protected].
tifically and ethically sound manner, we offer several recommendations. First, innovation in maternal-fetal surgery should be conducted and evaluated as research. Second, women must be considered research subjects in these trials. Third, the informed consent process must ensure adequate comprehension and genuine voluntariness in those considering participation. Fourth, discriminatory and fearful attitudes toward individuals with disabilities should be addressed explicitly prior to making a decision to proceed with maternal-fetal surgery in an attempt to correct such disabilities. Fifth, maternal-fetal surgery should not be performed for cosmetic indications unless and until there is reliable evidence that maternal-fetal surgery can be performed safely and that long-term side effects on women and their offspring are minimal. Sixth, centers of excellence should be established for conducting research and providing maternal-fetal surgery. Seventh, funding for research on maternal-fetal surgery should be considered in the context of societal needs. (Obstet Gynecol 2001;98:689 –97. © 2001 by the American College of Obstetricians and Gynecologists.)
Improved techniques in prenatal diagnosis have ushered in dramatic changes in reproductive medicine. Maternal serum screening, prenatal imaging, and diagnostic procedures such as amniocentesis have provided expectant parents and clinicians with increasingly accurate information about the health of the fetus. The primary application of this information has been in reproductive counseling, but a growing amount of scientific and clinical activity has been directed at therapies for prenatally diagnosed conditions. Surgical approaches to correct fetal anatomic abnormalities (maternal-fetal surgery) raise important clinical, social, and ethical questions about their appropriate applications. Exposing healthy women and premature fetuses to novel procedures raises difficult clinical and ethical questions. Are there good clinical reasons for intervening before birth? If so, what standards should guide the evaluation and the translation of maternal-fetal surgery into clinical practice? Should these considerations differ in maternal-fetal surgery directed at correcting nonlethal versus lethal fetal anomalies, and if so, how? How are professional obligations to ensure the safety of both pregnant women and their fetuses satisfied in the unique setting of maternal-fetal surgery? Are the requirements for valid informed consent being satisfied in ongoing activities? Should training programs in these techniques, designed to enable surgeons to perform these procedures on their own, be offered before the safety or efficacy of these procedures has been established? The
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rapid integration of some techniques into practice in the absence of proven efficacy, along with the expansion of efforts to ameliorate nonlethal fetal conditions,1,2 has intensified the need to answer such questions. To examine relevant issues concerning maternal-fetal surgery, a multidisciplinary group of experts convened at the National Institutes of Health (NIH) on July 16 –18, 2000 (Current Scientific, Ethical and Clinical Considerations of Maternal-Fetal Surgery; the names of members of this group are listed at the end of this article). In this article, we offer an analysis of the major issues that emerged from the exchange of ideas, perspectives, and expertise at the conference. Nevertheless, the conclusions and recommendations represent the views of the authors and do not constitute a consensus statement of the workshop participants or of the NIH. Although surgical interventions directed at correction of fetal disease traditionally have been called “fetal surgery,” the term “maternal-fetal surgery” was used at the NIH conference and we use the term here, because novel surgical interventions directed at fetal disease necessarily constitute interventions in both women and fetuses. DEVELOPING MATERNAL-FETAL SURGERY A. William Liley often is credited with the initiation of modern maternal-fetal surgery. In 1963, he successfully performed a blood transfusion into the peritoneal cavity of a fetus with severe anemia due to Rh incompatibility,3 saving a fetus from what had been considered a lethal disease. After Liley’s initial success, consensus regarding the appropriate use of new maternal-fetal surgery procedures has been elusive; however, important lessons about the requirements for, and likelihood of success of, maternal-fetal surgery have been learned. The prenatal treatment of Rh incompatibility inspired efforts to obtain direct access to the fetus. Freda and Adamsons,4 using an open surgical procedure, gained direct access to fetal vessels for complete exchange transfusion. Although the hysterotomy and transfusion were accomplished, preterm labor and delivery at 27 weeks’ gestation resulted, and the infant died. Because of persistently discouraging results and the evolution of medical treatments to prevent Rh disease, the open surgical approach to treat the disease was abandoned. In the 1970s, the advent of real-time sonographic imaging and high-frequency transducers allowed for accurate visualization of the fetus. Serial sonographic observation and postnatal follow-up led to improvements in the understanding of the natural history, pathophysiology, and prognosis associated with anatomic malformations. Of particular interest was the possibility of
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correcting anatomic malformations that led to life-threatening conditions that rarely, if ever, could be treated successfully in the newborn.5 A group led by Michael Harrison pioneered prenatal interventions for such conditions. The team initially studied the natural history of more than 1000 human fetuses with anomalies potentially amenable to treatment, performed animal studies on fetal lambs and nonhuman primates, and developed techniques for anesthesia, monitoring, and tocolysis.6 In 1981, Harrison performed a hysterotomy on an 18-year-old primigravida for the treatment of severe hydronephrosis in a fetus at 21 weeks’ gestation.7,8 Despite successful tocolysis and delivery at 35 weeks, the neonate died; autopsy revealed dysplastic kidneys and lung hypoplasia. Three years intervened before the procedure was attempted again, and with a better understanding of criteria for patient selection, the second neonate survived, and was alive at the time of writing (Jonsen A. Social issues related to advanced technology: Specifically to fetal surgery. Current Scientific, Ethical and Clinical Considerations of Maternal-Fetal Surgery. National Institutes of Health, Bethesda, MD, July 16 –18, 2000.).9 This experience with maternal-fetal surgery served to underscore that an understanding of natural history, pathophysiology, and appropriate patient selection criteria were critical in defining indications for maternal-fetal surgery. Maternal-fetal surgery techniques have been tried for other conditions at several centers worldwide. However, the list of conditions considered amenable to open maternal-fetal surgery has contracted rather than expanded. The treatment of fetal hydrocephalus with maternal-fetal surgery, for example, held early promise. In the early 1980s, investigators placed intracranial shunts to drain fetal cerebrospinal fluid (CSF) in an effort to prevent damage to the fetal brain.10 Specific criteria for intrauterine therapy were established by the Fetal Medicine and Surgery Society, and outcomes were collected in a registry. However, results were “less than salutary,”11 for a number of reasons. It was later discovered that other anomalies frequently coexist with ventriculomegaly. Furthermore, interventions were associated with a high rate of procedure-related fetal death, and of those infants who survived, more than half were extremely disabled. As a result, in utero treatment of hydrocephalus was abandoned. This experience further emphasized the critical need for understanding the natural history and pathophysiology of a congenital disease before intervening. Other unsuccessful investigative efforts have inspired innovation, as the continuing evolution of potential treatments, still under investigation, for congenital diaphragmatic hernia suggests.12 To prevent the severe lung
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hypoplasia usually associated with congenital diaphragmatic hernia, a technique was developed to repair the diaphragmatic defect in utero. Initial efforts at open intrauterine congenital diaphragmatic hernia repair in fetuses with liver herniation resulted in unacceptable rates of fetal loss because placement of the liver back below the diaphragm compromised umbilical venous flow and led to fetal bradycardia and cardiac arrest. However, because open repair met with technical success in fetuses without liver herniation, this procedure was studied further. In a prospective trial comparing maternal-fetal surgery and postdelivery repair of congenital diaphragmatic hernia without liver herniation, there was no difference in neonatal survival.13 These data prompted a moratorium on this approach to the correction of congenital diaphragmatic hernia in fetuses without liver herniation. Nonetheless, infants with congenital diaphragmatic hernia with liver herniation continued to have very poor outcomes. Having previously acknowledged the difficulty with open repair in fetuses with liver herniation, investigators developed a new approach involving fetal tracheal occlusion. On the basis of findings of animal studies suggesting that occlusion of the fetal trachea would prevent lung hypoplasia by decreasing the egress of fluid from the lung, techniques to occlude the fetal trachea by open and endoscopic procedures now are being studied in a randomized clinical trial. CURRENT APPROACHES The benefits of maternal-fetal surgery always must be considered in the context of potential risks of surgery to both the mother and the fetus. Preterm labor, often called the Achilles’ heel of fetal intervention,14 correlates strongly with maternal and fetal morbidity and occurs in the majority of patients who undergo maternal-fetal surgery. For the fetus, the risks of maternal-fetal surgery primarily include premature delivery, which occurs in almost all cases, and its associated morbidity and mortality, as well as death due to surgical complications. The evidence delineating the degree of risks, however, is limited. In 1998, Gibbs et al15 reported a case series of 11 children who had undergone open maternal-fetal surgery for congenital cystic adenomatoid malformation or congenital diaphragmatic hernia. Two of the 11 children were reported to have “abnormal neurologic outcomes,” and another two had mild cognitive delays. The authors concluded that maternal-fetal surgery “does not appear to put these survivors at greater risk of poor neurologic and developmental outcome beyond already identified medical risk factors related to prematurity and lung disease that contribute to poor neurodevelopmental out-
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come.”15 However, the morbidities associated with prematurity, particularly chronic lung disease and neurodevelopmental disabilities including cerebral palsy, mental retardation, sensory impairment, and school and behavioral problems, are independent factors that may attenuate the observed initial benefits of antepartum interventions. Systematic outcomes data would permit a more comprehensive assessment of the pediatric implications of maternal-fetal surgery. Maternal-fetal surgery carries substantial maternal risks, including those associated with preterm labor (especially complications resulting from tocolytic management, such as postoperative pulmonary edema), preterm premature rupture of membranes (including chorioamnionitis and sepsis), uterine rupture, placental abruption, and the need for blood transfusion, as well as other risks of major abdominal surgery.1,6 Nevertheless, evidence delineating the character and degree of risk is limited, in part because of the paucity of systematic studies of maternal outcome. An important source of risk stems from the fact that all women who undergo open maternal-fetal surgery are committed to delivering by cesarean in the current and subsequent pregnancies, because of the risk of uterine rupture associated with the size and placement of the uterine incision for maternal-fetal surgery. A few women who underwent maternal-fetal surgery and labored during a subsequent pregnancy had scar dehiscence along the prior uterine incision16; uterine rupture has been reported elsewhere.1 Moreover, the impact of maternal-fetal surgery on many other aspects of maternal health is unknown. No studies have been reported regarding the psychosocial impact on women and their families of decisions to undergo or forgo maternal-fetal surgery. Finally, the impact on future fertility is unknown. In a single retrospective survey of women who had undergone maternal-fetal surgery, 45 of the 70 patients recruited responded; 10% of those who attempted pregnancy were unable to conceive.16 Although these results might be reassuring, they seem insufficient to declare maternal-fetal surgery safe in terms of a woman’s future fertility. Evidence of benefit obviously is required to justify maternal-fetal surgery, particularly given the associated risks. Although the status of many maternal-fetal surgery procedures remains controversial because of the lack of randomized studies demonstrating safety and efficacy, procedures currently being used in some settings include open surgical management of congenital cystic adenomatoid malformation and sacrococcygeal teratoma when complicated by hydrops. In addition, less invasive maternal-fetal surgery techniques are being used in attempts to avert the morbidity associated with hysterotomy. These include endoscopic placement of shunts for mac-
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rocystic congenital cystic adenomatoid malformation and idiopathic pleural effusion and urinary obstruction.17 Randomized data regarding two other less invasive techniques— endoscopic tracheal occlusion for congenital diaphragmatic hernia and laser ablation of placental vascular shunts in twin-twin transfusion syndrome— are forthcoming. Such data are not available to inform decision making about any currently used maternal-fetal surgery procedures. Until recently, it was believed that maternal-fetal surgery was indicated only for conditions that otherwise would be lethal to the fetus despite optimal postnatal treatment.18 However, in the last few years, maternalfetal surgery has been used to correct fetal anomalies that are not lethal but might result in disability in the affected child after birth. Myelomeningocele, or spina bifida, is a congenital anomaly that results when the primitive neural tube fails to close at about the 4th week of pregnancy. Those born with spina bifida often have impaired functioning or paralysis of the lower extremities and difficulties with bladder and sometimes bowel continence. Many infants develop hindbrain herniation and hydrocephalus requiring CSF shunting; a significant minority also might have developmental delay and impaired cognitive functioning. On the basis of the theory and limited animal evidence that some of the damage resulting from spina bifida is caused not only by the initial error in development but also by exposure of the neural tissue to the amniotic fluid during gestation,19 maternal-fetal surgeons at two institutions recently pioneered closure of myelomeningocele in utero.1,2 The reported data suggest a decrease in the incidence of hindbrain herniation and the need for CSF shunting. Unfortunately, the expected benefit of improvement in neurologic function has not been apparent in the results reported to date. In fact, no difference in functional outcomes such as ambulation or bowel and bladder continence has been demonstrated. Further, obstetric complications including preterm labor and delivery, oligohydramnios, and maternal pulmonary edema were common. These reports have been followed by debate in scholarly publications,11 the media,20 and academia (Fetal Surgery: The Moral Presence of the Fetus; Vanderbilt University Medical Center, Nashville, TN; March 11–12, 2000). The blurring of boundaries between research and practice associated with this rapidly developing technology raises concerns about the adequacy of clinical trial design and the protection of patients from the risks of unproved therapies. EVIDENCE AND INNOVATION As demonstrated by past experience with maternal-fetal surgery for hydrocephalus and congenital diaphrag-
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matic hernia, evidence is critical to ensuring that ostensibly promising therapies are in fact safe and efficacious. Ideally, clinical trials and a systematic analysis of outcomes should precede integration of new therapies into clinical practice. However, validation of new procedures might be hindered if new procedures continue to be considered “innovative therapy” rather than research. Although the first few uses of a new intervention might be motivated primarily by a desire to benefit particular patients, once it is clear that the intervention is feasible and potentially beneficial, the “innovative therapy” paradigm should be replaced with a “research” paradigm to determine whether the innovation is safe and effective. The integration of novel therapies without the oversight generally afforded in the context of research is due in part to the difficulty in defining what constitutes research.21 Dame Mary Warnock noted, “There is no way of distinguishing new and untried treatment from research. All treatment is, in some sense, a contribution to research, or may be such.”22 The National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research, in its landmark Belmont Report, also recognized the problems associated with the blurring of boundaries of research and practice.23 The Commission defined research as “an activity designed to test an hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge (expressed, for example, in theories, principles, or statements of relationships).” Practice, on the other hand, was defined as “interventions that are designed solely to enhance the well-being of an individual patient or client and that have a reasonable expectation of success.”23 Novel interventions in maternal-fetal surgery such as repair of myelomeningocele, which might be designed solely to enhance the well-being of a fetus, but which has unpredictable benefit, might not fit neatly into a classification of research or practice. However, The Belmont Report addresses new and untested procedures that depart in a significant way from standard practice: Radically new procedures . . . should, however, be made the object of formal research at an early stage in order to determine whether they are safe and effective. Thus, it is the responsibility of medical practice committees, for example, to insist that a major innovation be incorporated into a formal research project.23
The decision to operate on a congenital malformation in utero is clearly a radical departure from the standard practice of neonatal surgical repair. Accordingly, even if certain unproved maternal-fetal surgery procedures are undertaken in attempts to enhance the well-being of a
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fetus, they ought to be conducted according to the rigorous standards of research with human subjects. Harm can result when innovative therapy is conducted under a “treatment” rather than a “research” protocol.24,25 When clinicians report outcomes in a case series, such as outcomes reported regarding maternalfetal surgery for myelomeningocele,1,2 they generally are reporting outcomes achieved in “treating” patients, rather than outcomes of participants in a systematic research protocol. One problem with this approach is that there is no assurance that the information reported is scientifically valid. A related problem is that long-term outcomes might not be assessed carefully and data on side effects and harmful complications might not be accumulated in a timely and comprehensive way. An important hazard of such reporting is that the procedure will enter into practice before necessary data are collected regarding whether it is effective. Consistent with arguments for evidence-based medical practice, a controlled clinical trial is required to reduce confounding factors and produce data to help women make informed decisions about their health and the health of their fetuses.26 At the very least, the lack of systematic knowledge about the benefit of maternal-fetal surgery for myelomeningocele creates a moral obligation to perform a welldesigned prospective trial to evaluate these novel and risky interventions. Finally, approaching maternal-fetal surgery as “treatment” does not afford the protections inherent to research that is conducted with oversight. For instance, prospective review by an institutional review board of the procedures to be used involves explicit consideration of maximizing benefits and minimizing harms, the informed consent process, and the manner in which subjects are selected.27 The American College of Obstetricians and Gynecologists28 recently issued a statement addressing these issues, stating that as an investigational procedure, maternal-fetal surgery for myelomeningocele should be evaluated in a multicenter randomized controlled trial. Further, after the NIH conference, three major centers— the University of California at San Francisco, the Children’s Hospital of Pennsylvania, and Vanderbilt University— held a series of meetings and agreed to collaborate in a randomized controlled trial sponsored by NIH. The study investigators plan to compare maternal-fetal surgery for myelomeningocele at 22–25 weeks with standard postnatal repair. ETHICAL CONSIDERATIONS As efforts to evaluate maternal-fetal surgery continue, the unique ethical issues associated with it need to be
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considered. These relate to maternal risks and benefits, informed consent, distinguishing lethal from nonlethal conditions, withholding unproved treatments, entrepreneurship, and prioritization. Maternal Risks and Benefits The paucity of data regarding the impact of maternalfetal surgery on women’s health raises serious concerns. George Annas warned of the tendency to treat the pregnant woman as “a fetal container, a nonperson without rights to bodily integrity.”29 Pregnant women who undergo maternal-fetal surgery must have at least the same protections afforded to other research subjects, and studies should be designed to assess the full impact of risks and benefits of maternal-fetal surgery. This includes the prospective evaluation of the impact of maternal-fetal surgery on women’s health, including future reproduction, and the psychosocial impact of decisions regarding maternal-fetal surgery. Although concerns about maternal safety traditionally have been recognized by investigators as “paramount,”14 maternal outcomes have not been measured sufficiently to guide an analysis of efficacy and safety of maternalfetal surgery for women who undergo such surgery. Accordingly, research on maternal-fetal surgery must be conducted in a way that recognizes that both the woman and the fetus are research subjects. Future studies of maternal-fetal surgery must measure both maternal and fetal well-being. Informed Consent Obtaining informed consent for all research on therapies can be challenging because of problems such as “therapeutic misconception”—the presumption that an experimental intervention is designed to be therapeutic, even when the likelihood of benefit is unproved.30 In the case of maternal-fetal surgery, with the language and imagery of wonder-working present in the media and on the Internet, patients are likely to enter the informed consent process with the expectations of benefit. Despite the fact that improvement in neurologic function has not been demonstrated in infants who have undergone maternalfetal surgery for myelomeningocele, and the fact that only limited evidence exists regarding improvement in hindbrain herniation or the need for shunting, patients still might decide to undergo maternal-fetal surgery perhaps falsely expecting benefit. For instance, patients’ testimonies regarding maternal-fetal surgery for myelomeningocele suggest that despite the extensive counseling that patients reportedly undergo before surgery, prospective parents seem to presume a therapeutic benefit for their fetuses:
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XXXX and I were on the phone the next week finding out information on this Fetal Surgery that the doctors there said could prevent further damage to my daughter’s spinal cord. Because of the fetal surgery, XXXX went from being someone who would have to be in a wheelchair her whole life with very little bowel and bladder control to someone who will be able to walk with a leg brace and be able to control her bowel and bladder.31
Such optimism ostensibly was endorsed by some of those performing maternal-fetal surgery: Performing neurosurgery on fetuses months before birth can dramatically reverse a potentially devastating nervous system condition that occurs in severe forms of the birth defect spina bifida.32
Such powerful messages likely serve to promote a therapeutic misconception and pose an obstacle to a clear understanding of the risks and benefits of experimental procedures. When informed consent is being obtained, it is critical to ensure that the decision to proceed with maternal-fetal surgery is autonomous and voluntary. It is often assumed that women, particularly those who actively seek out maternal-fetal surgery, are autonomous and that their consent to surgery is voluntary. However, women’s decisions may be influenced, and at times, their autonomy may be compromised by societal expectations about the responsibilities of pregnant women and the insistence of others in their families and communities. Maternal feelings of guilt regarding a fetal anomaly also can have an important effect on decisions regarding pregnancy management. Additionally, when patients receive donations from community or religious organizations with which they are affiliated, to cover expenses associated with maternal-fetal surgery, they also might feel guilty about not proceeding with surgery once they have gone through the counseling process. This is not to say that voluntary decision-making in the setting of maternal-fetal surgery is not possible; however, obtaining informed consent must be done with an appreciation of the social context in which these decisions are being made. Lethal Versus Nonlethal Conditions As discussed earlier, the use of maternal-fetal surgery for myelomeningocele challenged the prior practice of using maternal-fetal surgery for lethal conditions. Yet it is difficult to justify risking maternal or fetal morbidity or fetal demise in attempts to reduce the chances of a woman having a child with a disability. Advocates for those with disabilities have argued that some presumed neutral medical practices, such as prenatal diagnosis and selective abortion, are problematic in that
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they send a derogatory message to people with disabilities and create negative attitudes that are dangerous toward children.33 A similar argument could be made against risking fetal well-being to decrease the chances that the child will be born with a disability. After all, myelomeningocele is a serious birth defect compatible with normal life. Parents might not have a fully balanced perception of what having a child with myelomeningocele would mean and might not understand that carrying a child with spina bifida to term is a possible and acceptable option. Another problem heralded by the provision of maternal-fetal surgery for nonlethal conditions is that maternal-fetal surgery has been proposed for other nonlethal and “cosmetic” indications such as cleft lip and palate.34 Although functional and cosmetic improvements in neonatal outcomes are desirable, the full effects of maternalfetal surgery, regardless of the indication, remain unknown. Therefore, before interventions for cosmetic indications such as repair of cleft lip or palate are explored, it is necessary to be more certain that maternalfetal surgery can be performed safely, that there are minimal long-term side effects on women, and that children are not harmed overall by in utero intervention. Withholding Improved Interventions An important concern relates to the ethics of withholding unproved maternal-fetal surgery from patients who request it. For instance, if maternal-fetal surgery for myelomeningocele repair became available only in the context of a randomized controlled trial, would it be ethical to withhold elective and off-protocol use of the intervention even though it had previously been available and used in the absence of data? The question raises important issues related to access to experimental treatments. On the one hand, surgeons do not have an obligation to perform unproved procedures. Rather, they have an obligation to promote the responsible use of these procedures, including the formal investigation of those that appear to be promising. Once the professional community has agreed that a procedure requires formal investigation, off-protocol use of an intervention in an effort to benefit a particular patient risks undermining the discipline’s obligation both to develop treatments that are safe and effective and to not cause unintended harm. On the other hand, some may claim that patients should have access to new interventions if alternative treatments are not available;35 however, most conditions for which randomized trials of maternal-fetal surgery are planned or under way are conditions for which care after birth is standard treatment. Furthermore, offering maternal-fetal surgery off protocol might reinforce a therapeutic misconception, in that patients might presume benefit if clinicians are willing to offer the innovative treatment outside an ongoing
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randomized trial. Such a practice therefore could undermine the ability to obtain valid informed consent not only from the individual requesting off-protocol maternal-fetal surgery but also from persons contemplating entry into the trial. An additional issue related to making participation in clinical trials a requirement of access to novel interventions is that strong desires for maternal-fetal surgery might create a situation in which patients feel pressured to participate in research. In the case at hand, the two unwelcome options would be participating in research or forgoing any chance of maternal-fetal surgery. The ethical conduct of research requires that participation in research be voluntary, and so the possibility of impinging on a voluntary informed consent process is ethically problematic. Thus, it is incumbent on those conducting research in such settings to use a rigorous informed consent process that emphasizes the uncertain risks and benefits of maternal-fetal surgery. Entrepreneurship Issues about the ethics of withholding unproved interventions become more challenging with the growth of maternal-fetal surgery outside established centers. Fascination with the “new and neat,” along with the belief that new and innovative techniques are always better, likely has contributed to the increase in the number of centers performing maternal-fetal surgery. Further, maternalfetal surgery has substantial financial implications for individuals and institutions that perform and promote it. Some insurance payers cover maternal-fetal surgery; further, having an active maternal-fetal surgery program may attract patients—not only those with the particular conditions being studied but also those seeking hope for an innovative approach. Such factors may serve as incentives to start a maternal-fetal surgery program. However, given the experimental nature of maternal-fetal surgery, the proliferation of centers performing maternal-fetal surgery is difficult to justify. There are other problems with the further growth of the enterprise of maternal-fetal surgery. First, growth could undermine the feasibility of research that is crucial to the proper introduction of maternal-fetal surgery into practice. Even if major centers agree to cooperate and conduct randomized trials, the existence of new centers offering maternal-fetal surgery off protocol could undermine the research endeavor by affecting accrual of patients, who might opt for treatment off protocol at another center if randomized to the standard-treatment arm of a randomized trial. Of note, after the NIH conference, it was agreed that once the multicenter randomized controlled trial of myelomeningocele started, there would be no off-protocol use at participating centers.
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Ideally, a similar agreement will be reached before randomized trials of other maternal-fetal surgery procedures are begun. Further, the learning curve that exists when new procedures are used creates risks for patients that would likely exceed those that they would be subjected to in the hands of an experienced team. To expose a woman and fetus to risks beyond those inherent to the experimental procedure is not justified until benefits are supported by findings of randomized controlled trials. Prioritization Issues of justice are central to the ethical analysis of new interventions such as maternal-fetal surgery. These issues should be explored at the point that decisions about funding of research are made.35 Should research on surgery for rare conditions be a funding priority? Or should more resources be committed to research on prevention or to the treatment of conditions affecting a larger number of children? Discussions regarding maternal-fetal surgery for myelomeningocele should address strategies to facilitate prevention, such as education regarding prenatal folic acid supplementation, and explicitly account for the trade-offs that funding of research on maternal-fetal surgery necessarily creates. POLICY CONSIDERATIONS How should novel surgical interventions aimed at alleviating prenatally diagnosed disease, particularly nonlethal disease, be evaluated and, if found to be safe and effective, integrated into clinical practice? Given the issues addressed earlier, we offer several suggestions for the evaluation and use of maternal-fetal surgery procedures. 1. Innovation in maternal-fetal surgery should be conducted and evaluated as research. Randomized controlled trials should be conducted and comprehensive data should be systematically collected and monitored before procedures become available outside the research setting or are integrated into clinical practice. Immediate and long-term outcomes of maternal-fetal surgery should be studied. 2. Women must be considered research subjects in trials evaluating maternal-fetal surgery. Clinical trials should be designed that measure outcomes specific to women, in addition to fetuses. Such an approach involves performance of prospective studies measuring the impact of maternalfetal surgery on future pregnancies, fertility, nonreproductive health, and the psychosocial impact of decisions regarding maternal-fetal surgery. The latter would include but not be limited to evaluating how burdens such as long-term caregiving and financial costs compare among patients who undergo mater-
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3.
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nal-fetal surgery, those who elect standard therapy, and those who choose to terminate their pregnancies. The informed consent process must ensure adequate comprehension and genuine voluntariness among those considering participation. The informed consent process should compensate for potential bias among patients toward presuming benefit from maternal-fetal surgery and should recognize how the media and information obtained on the Internet may affect understanding of the risks and benefits of the intervention. Individuals obtaining informed consent for randomized controlled trials must be capable of communicating the uncertainty in the scientific community about whether maternal-fetal surgery is an appropriate course of action. In the counseling process, the woman should be given time alone with the individual obtaining consent, to ensure that her stated convictions are truly her own and in an attempt to minimize the impact of potentially unwanted family and societal pressures. Discriminatory and fearful attitudes toward individuals with disabilities should be addressed explicitly. Before patients are offered surgery for nonlethal conditions with associated disabilities, such as myelomeningocele, they should understand the experiences and perspectives of those with that particular disability or of individuals who have had a child with the disability. Ideally this would involve direct communication with such persons, but at least they should be provided with educational materials that promote a balanced view of life with the disability in question, and be given the opportunity to ask questions and gain a more balanced understanding of the practical implications of living with a disability. Counseling regarding these issues should not only precede decisions about maternal-fetal surgery but also be provided whenever a birth defect is diagnosed prenatally. Maternal-fetal surgery should not be performed for cosmetic indications unless and until there is reliable evidence that maternal-fetal surgery can be performed safely and that longterm side effects on women and their offspring are minimal. Given the amount of uncertainty regarding risk and the possibility of correction postpartum, there seems no reasonable justification to proceed with such interventions at this time. Centers of excellence should be established for conducting research and providing maternal-fetal surgery. Training programs designed to enable surgeons to set up new centers should not be offered when the safety and effectiveness of procedures has not been established. Should these procedures prove safe and effective and demand exceed the capabilities of existing centers, consideration could be given to creating additional centers after extensive training of those who would staff these centers.
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7. Funding for research on maternal-fetal surgery should be considered in the context of societal needs. Resources should be directed not only toward maternal-fetal surgery but also, where relevant, toward strategies for preventing congenital anomalies, such as education regarding prenatal folic acid supplementation for prevention of myelomeningocele. We believe that these recommendations will improve the likelihood that new applications of maternal-fetal surgery will be evaluated and applied in a scientifically valid as well as an ethically sound manner. SPEAKERS AT AND ORGANIZERS OF THE NIH WORKSHOP ON CURRENT SCIENTIFIC, ETHICAL AND CLINICAL CONSIDERATIONS OF MATERNAL-FETAL SURGERY Scott Adzick, MD, Children’s Hospital of Pennsylvania; Craig Albanese, MD, University of California, San Francisco; Duane Alexander, MD, National Institutes of Health; Marilee Allen, MD, Johns Hopkins Hospital; Beryl Benacerraf, MD, Diagnostic Ultrasound Associates; Lillian Blackmon, MD, University of Maryland; Todd Blumenkopf, PhD, Pfizer Global Research and Development; Joseph Bruner, MD, Vanderbilt University; Charlotte Catz, MD, National Institutes of Health; Robert Cefalo, MD, PhD, University of North Carolina; Alan Flake, MD, Children’s Hospital of Pennsylvania; John Fletcher, PhD, University of Virginia School of Medicine; Joel Frader, MD, Children’s Memorial Hospital, Chicago; Elena Gates, MD, University of California, San Francisco; James Goldberg, MD, California Pacific Medical Center; Zola Golub, MEd, RN, Northern Westchester Hospital Center; Michael Harrison, MD, University of California, San Francisco; Kurt Hecher, MD, AK Barmbeck, Germany; Michael Heyman, MD, University of California, San Francisco; Julien Hoffman, MD, University of California, San Francisco; Lori Howell, RN, MS, Children’s Hospital of Pennsylvania; Mark Johnson, MD, Children’s Hospital of Pennsylvania; Albert Jonsen, PhD, University of Washington; Patricia King, JD, Georgetown University Law Center; Mary B. Mahowald, PhD, University of Chicago; Susan Meikle, MD, National Institutes of Health; John Robertson, JD, University of Texas Law School; Albert Rosenfeld, MD, March of Dimes Birth Defects Foundation; Jonelle Rowe, MD, National Institutes of Health; Michael Socol, MD, Northwestern University Medical School; Jeremy Sugarman, MD, MPH, MA, Duke University Medical Center; Joan Weiss, MSW, LCSW, Genetic Alliance; Susan Wolf, JD, University of Minnesota Law School.
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REFERENCES 1. Bruner JP, Tulipan N, Paschall RL, Boehm FH, Walsh WF, Silva SR, et al. Fetal surgery for myelomeningocele and the incidence of shunt-dependent hydrocephalus. JAMA 1999;282:1819 –25. 2. Sutton LN, Adzick NS, Bilaniuck LT, Johnson MP, Crombleholme TM, Flake AW. Improvement in hindbrain herniation demonstrated by serial fetal magnetic resonance imaging following fetal surgery for myelomeningocele. JAMA 1999;282:1826 –31. 3. Liley AW. Intrauterine transfusion of foetus in haemolytic disease. BMJ 1963;2:1107–9. 4. Freda VJ, Adamsons K. Exchange transfusion in utero: Report of a case. Am J Obstet Gynecol 1964;89:817–21. 5. Zona JZ. Advances in fetal surgery. Pediatr Clin North Am 1998;45:599 – 604. 6. Longaker MT, Golbus MS, Filly RA, Rosen MA, Chang SW, Harrison MR. Maternal outcome after open fetal surgery: A review of the first 17 cases. JAMA 1991;265:737– 41. 7. Harrison MR, Golbus MS, Filly RA. Management of the fetus with a correctable congenital defect. JAMA 1981;246: 774 –7. 8. Harrison MR, Filly RA, Parer JT, Faer MJ, Jacobson JB, de Lorimier AA. Management of the fetus with a urinary tract malformation. JAMA 1981;246:635–9. 9. Harrison MR, Golbus MS, Filly RA, Anderson RL, Flake AW, Rosen M, et al. Fetal hydronephrosis: Selection and surgical repair. J Pediatr Surg 1987;22:556 – 8. 10. Clewell WH, Johnson ML, Meier PR, Newkirk JB, Zide SL, Hendee RW, et al. A surgical approach to the treatment of fetal hydrocephalus. N Engl J Med 1982;306:1320 –5. 11. Simpson JL. Fetal surgery for myelomeningocele: Promise, progress, problems. JAMA 1999;282:1873– 4. 12. Kitano Y, Flake AW, Crombleholme TM, Johnson MP, Adzick NS. Open fetal surgery for life-threatening fetal malformations. Semin Perinatol 1999;23:448 – 61. 13. Harrison MR, Adzick NS, Bullard KM, Farrell JA, Howell LJ, Rosen MA, et al. Correction of congenital diaphragmatic hernia in utero, VII: A prospective trial. J Pediatr Surg 1997;32:1637– 42. 14. Harrison MR. Fetal surgery. Am J Obstet Gynecol 1996; 174:1255– 64. 15. Gibbs DL, Piecuch RE, Graf JL, Leonard CH, Farrell JA, Harrison MR. Neurodevelopmental outcome after fetal surgery. J Pediatr Surg 1998;33:1254 – 6. 16. Farrell JA, Albanese CT, Jennings RW, Kilpatrick SJ, Bratton BJ, Harrison MR. Maternal fertility is not affected by fetal surgery. Fetal Diagn Ther 1999;14:190 –2. 17. Freedman AL, Johnson MP, Gonzalez R. Fetal therapy for obstructive uropathy: Past, present . . . future? Pediatr Nephrol 2000;14:167–76. 18. Jennings RW, Adzick NS, Harrison MR. Fetal surgery. In:
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19.
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21. 22. 23.
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26. 27. 28.
29. 30.
31. 32.
33.
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35.
Evans MI, ed. Reproductive risks and prenatal diagnosis. Norwalk, Connecticut: Appleton & Lange, 1992:311–20. Heffez DS, Aryanpur J, Hutchins GM, Freeman JM. The paralysis associated with myelomeningocele: Clinical and experimental data implicating a preventable spinal cord injury. Neurosurgery 1990;26:987–92. Okie S. Over the tiniest patients, big ethical questions: Fetal surgery’s growing reach raises issues of needs and risks. Washington Post, April 12, 2000. Levine RJ. Ethics and regulation of clinical research, 2nd ed. New Haven: Yale University Press, 1988. Warnock M. The regulation of technology. Camb Q Healthc Ethics 1998;7:173–5. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report. Washington, DC: US Government Printing Office, 1979. Gates E. Two challenges for research ethics: Innovative treatment and fetal therapy. Womens Health Issues 1999; 9:208 –10. Gates E. Ethical considerations in the incorporation of new technologies into gynecologic practice. Clin Obstet Gynecol 2000;43:540 –50. Pocock SJ, Elbourne DR. Randomized trials or observational tribulations? N Engl J Med 2000;342:1907–9. Office for Protection From Research Risks. The common rule. 56 Federal Register 28012, 18 June 1991. American College of Obstetricians and Gynecologists. Fetal surgery for open neural tube defects. ACOG committee opinion no. 252. Washington, DC: American College of Obstetricians and Gynecologists, 2001. Annas GJ. Protecting the liberty of pregnant patients. N Engl J Med 1987;316:1213– 4. Appelbaum PS, Roth LH, Lidz CW, Benson P, Winslade W. False hopes and best data: Consent to research and the therapeutic misconception. Hastings Cent Rep 1987;17:20–4. Fetal diagnosis and therapy at Vanderbilt University Medical Center. http://fetalsurgeons.com. Accessed 2000 Oct. The Center for Fetal Diagnosis and Treatment, Children’s Hospital of Pennsylvania. http://fetalsurgery.chop.edu. Accessed 2000 Oct. Parens E, Asch A. The disability rights critique of prenatal genetic testing: Reflections and recommendations. Hastings Cent Rep 1999;29:S1–22. Hedrick MH, Longaker MT, Harrison MR. A fetal surgery primer for plastic surgeons. Plast Reconstr Surg 1998; 101:1709 –29. Kahn JP, Mastroianni AC, Sugarman J. Beyond consent: Seeking justice in research. New York: Oxford University Press, 1998.
Received January 2, 2001. Received in revised form April 30, 2001. Accepted June 17, 2001.
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Toward the Ethical Evaluation and Use of Maternal-Fetal Surgery Anne Drapkin Lyerly, MD, Elena A. Gates, MD, Robert C. Cefalo, MD, PhD, and Jeremy Sugarman, MD, MPH Bioethics Institute, Johns Hopkins University, Baltimore, Maryland; Kennedy Institute of Ethics, Georgetown University, Washington, DC; Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, California; Department of Obstetrics and Gynecology, University of North Carolina, Durham, North Carolina; and Center for the Study of Medical Ethics and Humanities, Duke University Medical Center, Durham, North Carolina.
BACKGROUND: Important clinical, social, and ethical questions are associated with the evaluation and use of surgical approaches aimed at correcting fetal anatomic abnormalities. In particular, the expansion of maternal-fetal surgery to ameliorate nonlethal fetal conditions has intensified the need to address issues about the adequacy of technology assessment and the safety of those who undergo these novel procedures. APPROACH: After discussions at a multidisciplinary conference, we reviewed the development and current practices of maternal-fetal surgery and analyzed the relevant ethical issues concerning the use of maternal-fetal surgery for nonlethal conditions, focusing on the correction of myelomeningocele. FINDINGS: Characterizing nonvalidated maternal-fetal surgery procedures as “innovative therapy” blurs the boundaries between research and therapy and creates uncertainty about the obligations of clinicians and researchers. Further, maternal-fetal surgery raises ethical issues related to maternal risks and benefits, informed consent, distinguishing lethal from nonlethal conditions, withholding unproven treatments, entrepreneurship, and prioritization. RECOMMENDATIONS: To help ensure that maternal-fetal surgery will be studied and eventually applied in a scienThe opinions and recommendations in this article are those of the authors and do not necessarily represent the views of the speakers at, or participants in, the NIH Workshop on Current Scientific, Ethical and Clinical Considerations of MaternalFetal Surgery. Address reprint requests to: Jeremy Sugarman, MD, MPH, Center for the Study of Medical Ethics and Humanities, Box 3040, Duke University Medical Center, 108 Seeley G. Mudd Building, Durham, NC 27710-3040; E-mail: [email protected].
tifically and ethically sound manner, we offer several recommendations. First, innovation in maternal-fetal surgery should be conducted and evaluated as research. Second, women must be considered research subjects in these trials. Third, the informed consent process must ensure adequate comprehension and genuine voluntariness in those considering participation. Fourth, discriminatory and fearful attitudes toward individuals with disabilities should be addressed explicitly prior to making a decision to proceed with maternal-fetal surgery in an attempt to correct such disabilities. Fifth, maternal-fetal surgery should not be performed for cosmetic indications unless and until there is reliable evidence that maternal-fetal surgery can be performed safely and that long-term side effects on women and their offspring are minimal. Sixth, centers of excellence should be established for conducting research and providing maternal-fetal surgery. Seventh, funding for research on maternal-fetal surgery should be considered in the context of societal needs. (Obstet Gynecol 2001;98:689 –97. © 2001 by the American College of Obstetricians and Gynecologists.)
Improved techniques in prenatal diagnosis have ushered in dramatic changes in reproductive medicine. Maternal serum screening, prenatal imaging, and diagnostic procedures such as amniocentesis have provided expectant parents and clinicians with increasingly accurate information about the health of the fetus. The primary application of this information has been in reproductive counseling, but a growing amount of scientific and clinical activity has been directed at therapies for prenatally diagnosed conditions. Surgical approaches to correct fetal anatomic abnormalities (maternal-fetal surgery) raise important clinical, social, and ethical questions about their appropriate applications. Exposing healthy women and premature fetuses to novel procedures raises difficult clinical and ethical questions. Are there good clinical reasons for intervening before birth? If so, what standards should guide the evaluation and the translation of maternal-fetal surgery into clinical practice? Should these considerations differ in maternal-fetal surgery directed at correcting nonlethal versus lethal fetal anomalies, and if so, how? How are professional obligations to ensure the safety of both pregnant women and their fetuses satisfied in the unique setting of maternal-fetal surgery? Are the requirements for valid informed consent being satisfied in ongoing activities? Should training programs in these techniques, designed to enable surgeons to perform these procedures on their own, be offered before the safety or efficacy of these procedures has been established? The
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rapid integration of some techniques into practice in the absence of proven efficacy, along with the expansion of efforts to ameliorate nonlethal fetal conditions,1,2 has intensified the need to answer such questions. To examine relevant issues concerning maternal-fetal surgery, a multidisciplinary group of experts convened at the National Institutes of Health (NIH) on July 16 –18, 2000 (Current Scientific, Ethical and Clinical Considerations of Maternal-Fetal Surgery; the names of members of this group are listed at the end of this article). In this article, we offer an analysis of the major issues that emerged from the exchange of ideas, perspectives, and expertise at the conference. Nevertheless, the conclusions and recommendations represent the views of the authors and do not constitute a consensus statement of the workshop participants or of the NIH. Although surgical interventions directed at correction of fetal disease traditionally have been called “fetal surgery,” the term “maternal-fetal surgery” was used at the NIH conference and we use the term here, because novel surgical interventions directed at fetal disease necessarily constitute interventions in both women and fetuses. DEVELOPING MATERNAL-FETAL SURGERY A. William Liley often is credited with the initiation of modern maternal-fetal surgery. In 1963, he successfully performed a blood transfusion into the peritoneal cavity of a fetus with severe anemia due to Rh incompatibility,3 saving a fetus from what had been considered a lethal disease. After Liley’s initial success, consensus regarding the appropriate use of new maternal-fetal surgery procedures has been elusive; however, important lessons about the requirements for, and likelihood of success of, maternal-fetal surgery have been learned. The prenatal treatment of Rh incompatibility inspired efforts to obtain direct access to the fetus. Freda and Adamsons,4 using an open surgical procedure, gained direct access to fetal vessels for complete exchange transfusion. Although the hysterotomy and transfusion were accomplished, preterm labor and delivery at 27 weeks’ gestation resulted, and the infant died. Because of persistently discouraging results and the evolution of medical treatments to prevent Rh disease, the open surgical approach to treat the disease was abandoned. In the 1970s, the advent of real-time sonographic imaging and high-frequency transducers allowed for accurate visualization of the fetus. Serial sonographic observation and postnatal follow-up led to improvements in the understanding of the natural history, pathophysiology, and prognosis associated with anatomic malformations. Of particular interest was the possibility of
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correcting anatomic malformations that led to life-threatening conditions that rarely, if ever, could be treated successfully in the newborn.5 A group led by Michael Harrison pioneered prenatal interventions for such conditions. The team initially studied the natural history of more than 1000 human fetuses with anomalies potentially amenable to treatment, performed animal studies on fetal lambs and nonhuman primates, and developed techniques for anesthesia, monitoring, and tocolysis.6 In 1981, Harrison performed a hysterotomy on an 18-year-old primigravida for the treatment of severe hydronephrosis in a fetus at 21 weeks’ gestation.7,8 Despite successful tocolysis and delivery at 35 weeks, the neonate died; autopsy revealed dysplastic kidneys and lung hypoplasia. Three years intervened before the procedure was attempted again, and with a better understanding of criteria for patient selection, the second neonate survived, and was alive at the time of writing (Jonsen A. Social issues related to advanced technology: Specifically to fetal surgery. Current Scientific, Ethical and Clinical Considerations of Maternal-Fetal Surgery. National Institutes of Health, Bethesda, MD, July 16 –18, 2000.).9 This experience with maternal-fetal surgery served to underscore that an understanding of natural history, pathophysiology, and appropriate patient selection criteria were critical in defining indications for maternal-fetal surgery. Maternal-fetal surgery techniques have been tried for other conditions at several centers worldwide. However, the list of conditions considered amenable to open maternal-fetal surgery has contracted rather than expanded. The treatment of fetal hydrocephalus with maternal-fetal surgery, for example, held early promise. In the early 1980s, investigators placed intracranial shunts to drain fetal cerebrospinal fluid (CSF) in an effort to prevent damage to the fetal brain.10 Specific criteria for intrauterine therapy were established by the Fetal Medicine and Surgery Society, and outcomes were collected in a registry. However, results were “less than salutary,”11 for a number of reasons. It was later discovered that other anomalies frequently coexist with ventriculomegaly. Furthermore, interventions were associated with a high rate of procedure-related fetal death, and of those infants who survived, more than half were extremely disabled. As a result, in utero treatment of hydrocephalus was abandoned. This experience further emphasized the critical need for understanding the natural history and pathophysiology of a congenital disease before intervening. Other unsuccessful investigative efforts have inspired innovation, as the continuing evolution of potential treatments, still under investigation, for congenital diaphragmatic hernia suggests.12 To prevent the severe lung
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hypoplasia usually associated with congenital diaphragmatic hernia, a technique was developed to repair the diaphragmatic defect in utero. Initial efforts at open intrauterine congenital diaphragmatic hernia repair in fetuses with liver herniation resulted in unacceptable rates of fetal loss because placement of the liver back below the diaphragm compromised umbilical venous flow and led to fetal bradycardia and cardiac arrest. However, because open repair met with technical success in fetuses without liver herniation, this procedure was studied further. In a prospective trial comparing maternal-fetal surgery and postdelivery repair of congenital diaphragmatic hernia without liver herniation, there was no difference in neonatal survival.13 These data prompted a moratorium on this approach to the correction of congenital diaphragmatic hernia in fetuses without liver herniation. Nonetheless, infants with congenital diaphragmatic hernia with liver herniation continued to have very poor outcomes. Having previously acknowledged the difficulty with open repair in fetuses with liver herniation, investigators developed a new approach involving fetal tracheal occlusion. On the basis of findings of animal studies suggesting that occlusion of the fetal trachea would prevent lung hypoplasia by decreasing the egress of fluid from the lung, techniques to occlude the fetal trachea by open and endoscopic procedures now are being studied in a randomized clinical trial. CURRENT APPROACHES The benefits of maternal-fetal surgery always must be considered in the context of potential risks of surgery to both the mother and the fetus. Preterm labor, often called the Achilles’ heel of fetal intervention,14 correlates strongly with maternal and fetal morbidity and occurs in the majority of patients who undergo maternal-fetal surgery. For the fetus, the risks of maternal-fetal surgery primarily include premature delivery, which occurs in almost all cases, and its associated morbidity and mortality, as well as death due to surgical complications. The evidence delineating the degree of risks, however, is limited. In 1998, Gibbs et al15 reported a case series of 11 children who had undergone open maternal-fetal surgery for congenital cystic adenomatoid malformation or congenital diaphragmatic hernia. Two of the 11 children were reported to have “abnormal neurologic outcomes,” and another two had mild cognitive delays. The authors concluded that maternal-fetal surgery “does not appear to put these survivors at greater risk of poor neurologic and developmental outcome beyond already identified medical risk factors related to prematurity and lung disease that contribute to poor neurodevelopmental out-
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come.”15 However, the morbidities associated with prematurity, particularly chronic lung disease and neurodevelopmental disabilities including cerebral palsy, mental retardation, sensory impairment, and school and behavioral problems, are independent factors that may attenuate the observed initial benefits of antepartum interventions. Systematic outcomes data would permit a more comprehensive assessment of the pediatric implications of maternal-fetal surgery. Maternal-fetal surgery carries substantial maternal risks, including those associated with preterm labor (especially complications resulting from tocolytic management, such as postoperative pulmonary edema), preterm premature rupture of membranes (including chorioamnionitis and sepsis), uterine rupture, placental abruption, and the need for blood transfusion, as well as other risks of major abdominal surgery.1,6 Nevertheless, evidence delineating the character and degree of risk is limited, in part because of the paucity of systematic studies of maternal outcome. An important source of risk stems from the fact that all women who undergo open maternal-fetal surgery are committed to delivering by cesarean in the current and subsequent pregnancies, because of the risk of uterine rupture associated with the size and placement of the uterine incision for maternal-fetal surgery. A few women who underwent maternal-fetal surgery and labored during a subsequent pregnancy had scar dehiscence along the prior uterine incision16; uterine rupture has been reported elsewhere.1 Moreover, the impact of maternal-fetal surgery on many other aspects of maternal health is unknown. No studies have been reported regarding the psychosocial impact on women and their families of decisions to undergo or forgo maternal-fetal surgery. Finally, the impact on future fertility is unknown. In a single retrospective survey of women who had undergone maternal-fetal surgery, 45 of the 70 patients recruited responded; 10% of those who attempted pregnancy were unable to conceive.16 Although these results might be reassuring, they seem insufficient to declare maternal-fetal surgery safe in terms of a woman’s future fertility. Evidence of benefit obviously is required to justify maternal-fetal surgery, particularly given the associated risks. Although the status of many maternal-fetal surgery procedures remains controversial because of the lack of randomized studies demonstrating safety and efficacy, procedures currently being used in some settings include open surgical management of congenital cystic adenomatoid malformation and sacrococcygeal teratoma when complicated by hydrops. In addition, less invasive maternal-fetal surgery techniques are being used in attempts to avert the morbidity associated with hysterotomy. These include endoscopic placement of shunts for mac-
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rocystic congenital cystic adenomatoid malformation and idiopathic pleural effusion and urinary obstruction.17 Randomized data regarding two other less invasive techniques— endoscopic tracheal occlusion for congenital diaphragmatic hernia and laser ablation of placental vascular shunts in twin-twin transfusion syndrome— are forthcoming. Such data are not available to inform decision making about any currently used maternal-fetal surgery procedures. Until recently, it was believed that maternal-fetal surgery was indicated only for conditions that otherwise would be lethal to the fetus despite optimal postnatal treatment.18 However, in the last few years, maternalfetal surgery has been used to correct fetal anomalies that are not lethal but might result in disability in the affected child after birth. Myelomeningocele, or spina bifida, is a congenital anomaly that results when the primitive neural tube fails to close at about the 4th week of pregnancy. Those born with spina bifida often have impaired functioning or paralysis of the lower extremities and difficulties with bladder and sometimes bowel continence. Many infants develop hindbrain herniation and hydrocephalus requiring CSF shunting; a significant minority also might have developmental delay and impaired cognitive functioning. On the basis of the theory and limited animal evidence that some of the damage resulting from spina bifida is caused not only by the initial error in development but also by exposure of the neural tissue to the amniotic fluid during gestation,19 maternal-fetal surgeons at two institutions recently pioneered closure of myelomeningocele in utero.1,2 The reported data suggest a decrease in the incidence of hindbrain herniation and the need for CSF shunting. Unfortunately, the expected benefit of improvement in neurologic function has not been apparent in the results reported to date. In fact, no difference in functional outcomes such as ambulation or bowel and bladder continence has been demonstrated. Further, obstetric complications including preterm labor and delivery, oligohydramnios, and maternal pulmonary edema were common. These reports have been followed by debate in scholarly publications,11 the media,20 and academia (Fetal Surgery: The Moral Presence of the Fetus; Vanderbilt University Medical Center, Nashville, TN; March 11–12, 2000). The blurring of boundaries between research and practice associated with this rapidly developing technology raises concerns about the adequacy of clinical trial design and the protection of patients from the risks of unproved therapies. EVIDENCE AND INNOVATION As demonstrated by past experience with maternal-fetal surgery for hydrocephalus and congenital diaphrag-
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matic hernia, evidence is critical to ensuring that ostensibly promising therapies are in fact safe and efficacious. Ideally, clinical trials and a systematic analysis of outcomes should precede integration of new therapies into clinical practice. However, validation of new procedures might be hindered if new procedures continue to be considered “innovative therapy” rather than research. Although the first few uses of a new intervention might be motivated primarily by a desire to benefit particular patients, once it is clear that the intervention is feasible and potentially beneficial, the “innovative therapy” paradigm should be replaced with a “research” paradigm to determine whether the innovation is safe and effective. The integration of novel therapies without the oversight generally afforded in the context of research is due in part to the difficulty in defining what constitutes research.21 Dame Mary Warnock noted, “There is no way of distinguishing new and untried treatment from research. All treatment is, in some sense, a contribution to research, or may be such.”22 The National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research, in its landmark Belmont Report, also recognized the problems associated with the blurring of boundaries of research and practice.23 The Commission defined research as “an activity designed to test an hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge (expressed, for example, in theories, principles, or statements of relationships).” Practice, on the other hand, was defined as “interventions that are designed solely to enhance the well-being of an individual patient or client and that have a reasonable expectation of success.”23 Novel interventions in maternal-fetal surgery such as repair of myelomeningocele, which might be designed solely to enhance the well-being of a fetus, but which has unpredictable benefit, might not fit neatly into a classification of research or practice. However, The Belmont Report addresses new and untested procedures that depart in a significant way from standard practice: Radically new procedures . . . should, however, be made the object of formal research at an early stage in order to determine whether they are safe and effective. Thus, it is the responsibility of medical practice committees, for example, to insist that a major innovation be incorporated into a formal research project.23
The decision to operate on a congenital malformation in utero is clearly a radical departure from the standard practice of neonatal surgical repair. Accordingly, even if certain unproved maternal-fetal surgery procedures are undertaken in attempts to enhance the well-being of a
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fetus, they ought to be conducted according to the rigorous standards of research with human subjects. Harm can result when innovative therapy is conducted under a “treatment” rather than a “research” protocol.24,25 When clinicians report outcomes in a case series, such as outcomes reported regarding maternalfetal surgery for myelomeningocele,1,2 they generally are reporting outcomes achieved in “treating” patients, rather than outcomes of participants in a systematic research protocol. One problem with this approach is that there is no assurance that the information reported is scientifically valid. A related problem is that long-term outcomes might not be assessed carefully and data on side effects and harmful complications might not be accumulated in a timely and comprehensive way. An important hazard of such reporting is that the procedure will enter into practice before necessary data are collected regarding whether it is effective. Consistent with arguments for evidence-based medical practice, a controlled clinical trial is required to reduce confounding factors and produce data to help women make informed decisions about their health and the health of their fetuses.26 At the very least, the lack of systematic knowledge about the benefit of maternal-fetal surgery for myelomeningocele creates a moral obligation to perform a welldesigned prospective trial to evaluate these novel and risky interventions. Finally, approaching maternal-fetal surgery as “treatment” does not afford the protections inherent to research that is conducted with oversight. For instance, prospective review by an institutional review board of the procedures to be used involves explicit consideration of maximizing benefits and minimizing harms, the informed consent process, and the manner in which subjects are selected.27 The American College of Obstetricians and Gynecologists28 recently issued a statement addressing these issues, stating that as an investigational procedure, maternal-fetal surgery for myelomeningocele should be evaluated in a multicenter randomized controlled trial. Further, after the NIH conference, three major centers— the University of California at San Francisco, the Children’s Hospital of Pennsylvania, and Vanderbilt University— held a series of meetings and agreed to collaborate in a randomized controlled trial sponsored by NIH. The study investigators plan to compare maternal-fetal surgery for myelomeningocele at 22–25 weeks with standard postnatal repair. ETHICAL CONSIDERATIONS As efforts to evaluate maternal-fetal surgery continue, the unique ethical issues associated with it need to be
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considered. These relate to maternal risks and benefits, informed consent, distinguishing lethal from nonlethal conditions, withholding unproved treatments, entrepreneurship, and prioritization. Maternal Risks and Benefits The paucity of data regarding the impact of maternalfetal surgery on women’s health raises serious concerns. George Annas warned of the tendency to treat the pregnant woman as “a fetal container, a nonperson without rights to bodily integrity.”29 Pregnant women who undergo maternal-fetal surgery must have at least the same protections afforded to other research subjects, and studies should be designed to assess the full impact of risks and benefits of maternal-fetal surgery. This includes the prospective evaluation of the impact of maternal-fetal surgery on women’s health, including future reproduction, and the psychosocial impact of decisions regarding maternal-fetal surgery. Although concerns about maternal safety traditionally have been recognized by investigators as “paramount,”14 maternal outcomes have not been measured sufficiently to guide an analysis of efficacy and safety of maternalfetal surgery for women who undergo such surgery. Accordingly, research on maternal-fetal surgery must be conducted in a way that recognizes that both the woman and the fetus are research subjects. Future studies of maternal-fetal surgery must measure both maternal and fetal well-being. Informed Consent Obtaining informed consent for all research on therapies can be challenging because of problems such as “therapeutic misconception”—the presumption that an experimental intervention is designed to be therapeutic, even when the likelihood of benefit is unproved.30 In the case of maternal-fetal surgery, with the language and imagery of wonder-working present in the media and on the Internet, patients are likely to enter the informed consent process with the expectations of benefit. Despite the fact that improvement in neurologic function has not been demonstrated in infants who have undergone maternalfetal surgery for myelomeningocele, and the fact that only limited evidence exists regarding improvement in hindbrain herniation or the need for shunting, patients still might decide to undergo maternal-fetal surgery perhaps falsely expecting benefit. For instance, patients’ testimonies regarding maternal-fetal surgery for myelomeningocele suggest that despite the extensive counseling that patients reportedly undergo before surgery, prospective parents seem to presume a therapeutic benefit for their fetuses:
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XXXX and I were on the phone the next week finding out information on this Fetal Surgery that the doctors there said could prevent further damage to my daughter’s spinal cord. Because of the fetal surgery, XXXX went from being someone who would have to be in a wheelchair her whole life with very little bowel and bladder control to someone who will be able to walk with a leg brace and be able to control her bowel and bladder.31
Such optimism ostensibly was endorsed by some of those performing maternal-fetal surgery: Performing neurosurgery on fetuses months before birth can dramatically reverse a potentially devastating nervous system condition that occurs in severe forms of the birth defect spina bifida.32
Such powerful messages likely serve to promote a therapeutic misconception and pose an obstacle to a clear understanding of the risks and benefits of experimental procedures. When informed consent is being obtained, it is critical to ensure that the decision to proceed with maternal-fetal surgery is autonomous and voluntary. It is often assumed that women, particularly those who actively seek out maternal-fetal surgery, are autonomous and that their consent to surgery is voluntary. However, women’s decisions may be influenced, and at times, their autonomy may be compromised by societal expectations about the responsibilities of pregnant women and the insistence of others in their families and communities. Maternal feelings of guilt regarding a fetal anomaly also can have an important effect on decisions regarding pregnancy management. Additionally, when patients receive donations from community or religious organizations with which they are affiliated, to cover expenses associated with maternal-fetal surgery, they also might feel guilty about not proceeding with surgery once they have gone through the counseling process. This is not to say that voluntary decision-making in the setting of maternal-fetal surgery is not possible; however, obtaining informed consent must be done with an appreciation of the social context in which these decisions are being made. Lethal Versus Nonlethal Conditions As discussed earlier, the use of maternal-fetal surgery for myelomeningocele challenged the prior practice of using maternal-fetal surgery for lethal conditions. Yet it is difficult to justify risking maternal or fetal morbidity or fetal demise in attempts to reduce the chances of a woman having a child with a disability. Advocates for those with disabilities have argued that some presumed neutral medical practices, such as prenatal diagnosis and selective abortion, are problematic in that
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they send a derogatory message to people with disabilities and create negative attitudes that are dangerous toward children.33 A similar argument could be made against risking fetal well-being to decrease the chances that the child will be born with a disability. After all, myelomeningocele is a serious birth defect compatible with normal life. Parents might not have a fully balanced perception of what having a child with myelomeningocele would mean and might not understand that carrying a child with spina bifida to term is a possible and acceptable option. Another problem heralded by the provision of maternal-fetal surgery for nonlethal conditions is that maternal-fetal surgery has been proposed for other nonlethal and “cosmetic” indications such as cleft lip and palate.34 Although functional and cosmetic improvements in neonatal outcomes are desirable, the full effects of maternalfetal surgery, regardless of the indication, remain unknown. Therefore, before interventions for cosmetic indications such as repair of cleft lip or palate are explored, it is necessary to be more certain that maternalfetal surgery can be performed safely, that there are minimal long-term side effects on women, and that children are not harmed overall by in utero intervention. Withholding Improved Interventions An important concern relates to the ethics of withholding unproved maternal-fetal surgery from patients who request it. For instance, if maternal-fetal surgery for myelomeningocele repair became available only in the context of a randomized controlled trial, would it be ethical to withhold elective and off-protocol use of the intervention even though it had previously been available and used in the absence of data? The question raises important issues related to access to experimental treatments. On the one hand, surgeons do not have an obligation to perform unproved procedures. Rather, they have an obligation to promote the responsible use of these procedures, including the formal investigation of those that appear to be promising. Once the professional community has agreed that a procedure requires formal investigation, off-protocol use of an intervention in an effort to benefit a particular patient risks undermining the discipline’s obligation both to develop treatments that are safe and effective and to not cause unintended harm. On the other hand, some may claim that patients should have access to new interventions if alternative treatments are not available;35 however, most conditions for which randomized trials of maternal-fetal surgery are planned or under way are conditions for which care after birth is standard treatment. Furthermore, offering maternal-fetal surgery off protocol might reinforce a therapeutic misconception, in that patients might presume benefit if clinicians are willing to offer the innovative treatment outside an ongoing
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randomized trial. Such a practice therefore could undermine the ability to obtain valid informed consent not only from the individual requesting off-protocol maternal-fetal surgery but also from persons contemplating entry into the trial. An additional issue related to making participation in clinical trials a requirement of access to novel interventions is that strong desires for maternal-fetal surgery might create a situation in which patients feel pressured to participate in research. In the case at hand, the two unwelcome options would be participating in research or forgoing any chance of maternal-fetal surgery. The ethical conduct of research requires that participation in research be voluntary, and so the possibility of impinging on a voluntary informed consent process is ethically problematic. Thus, it is incumbent on those conducting research in such settings to use a rigorous informed consent process that emphasizes the uncertain risks and benefits of maternal-fetal surgery. Entrepreneurship Issues about the ethics of withholding unproved interventions become more challenging with the growth of maternal-fetal surgery outside established centers. Fascination with the “new and neat,” along with the belief that new and innovative techniques are always better, likely has contributed to the increase in the number of centers performing maternal-fetal surgery. Further, maternalfetal surgery has substantial financial implications for individuals and institutions that perform and promote it. Some insurance payers cover maternal-fetal surgery; further, having an active maternal-fetal surgery program may attract patients—not only those with the particular conditions being studied but also those seeking hope for an innovative approach. Such factors may serve as incentives to start a maternal-fetal surgery program. However, given the experimental nature of maternal-fetal surgery, the proliferation of centers performing maternal-fetal surgery is difficult to justify. There are other problems with the further growth of the enterprise of maternal-fetal surgery. First, growth could undermine the feasibility of research that is crucial to the proper introduction of maternal-fetal surgery into practice. Even if major centers agree to cooperate and conduct randomized trials, the existence of new centers offering maternal-fetal surgery off protocol could undermine the research endeavor by affecting accrual of patients, who might opt for treatment off protocol at another center if randomized to the standard-treatment arm of a randomized trial. Of note, after the NIH conference, it was agreed that once the multicenter randomized controlled trial of myelomeningocele started, there would be no off-protocol use at participating centers.
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Ideally, a similar agreement will be reached before randomized trials of other maternal-fetal surgery procedures are begun. Further, the learning curve that exists when new procedures are used creates risks for patients that would likely exceed those that they would be subjected to in the hands of an experienced team. To expose a woman and fetus to risks beyond those inherent to the experimental procedure is not justified until benefits are supported by findings of randomized controlled trials. Prioritization Issues of justice are central to the ethical analysis of new interventions such as maternal-fetal surgery. These issues should be explored at the point that decisions about funding of research are made.35 Should research on surgery for rare conditions be a funding priority? Or should more resources be committed to research on prevention or to the treatment of conditions affecting a larger number of children? Discussions regarding maternal-fetal surgery for myelomeningocele should address strategies to facilitate prevention, such as education regarding prenatal folic acid supplementation, and explicitly account for the trade-offs that funding of research on maternal-fetal surgery necessarily creates. POLICY CONSIDERATIONS How should novel surgical interventions aimed at alleviating prenatally diagnosed disease, particularly nonlethal disease, be evaluated and, if found to be safe and effective, integrated into clinical practice? Given the issues addressed earlier, we offer several suggestions for the evaluation and use of maternal-fetal surgery procedures. 1. Innovation in maternal-fetal surgery should be conducted and evaluated as research. Randomized controlled trials should be conducted and comprehensive data should be systematically collected and monitored before procedures become available outside the research setting or are integrated into clinical practice. Immediate and long-term outcomes of maternal-fetal surgery should be studied. 2. Women must be considered research subjects in trials evaluating maternal-fetal surgery. Clinical trials should be designed that measure outcomes specific to women, in addition to fetuses. Such an approach involves performance of prospective studies measuring the impact of maternalfetal surgery on future pregnancies, fertility, nonreproductive health, and the psychosocial impact of decisions regarding maternal-fetal surgery. The latter would include but not be limited to evaluating how burdens such as long-term caregiving and financial costs compare among patients who undergo mater-
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nal-fetal surgery, those who elect standard therapy, and those who choose to terminate their pregnancies. The informed consent process must ensure adequate comprehension and genuine voluntariness among those considering participation. The informed consent process should compensate for potential bias among patients toward presuming benefit from maternal-fetal surgery and should recognize how the media and information obtained on the Internet may affect understanding of the risks and benefits of the intervention. Individuals obtaining informed consent for randomized controlled trials must be capable of communicating the uncertainty in the scientific community about whether maternal-fetal surgery is an appropriate course of action. In the counseling process, the woman should be given time alone with the individual obtaining consent, to ensure that her stated convictions are truly her own and in an attempt to minimize the impact of potentially unwanted family and societal pressures. Discriminatory and fearful attitudes toward individuals with disabilities should be addressed explicitly. Before patients are offered surgery for nonlethal conditions with associated disabilities, such as myelomeningocele, they should understand the experiences and perspectives of those with that particular disability or of individuals who have had a child with the disability. Ideally this would involve direct communication with such persons, but at least they should be provided with educational materials that promote a balanced view of life with the disability in question, and be given the opportunity to ask questions and gain a more balanced understanding of the practical implications of living with a disability. Counseling regarding these issues should not only precede decisions about maternal-fetal surgery but also be provided whenever a birth defect is diagnosed prenatally. Maternal-fetal surgery should not be performed for cosmetic indications unless and until there is reliable evidence that maternal-fetal surgery can be performed safely and that longterm side effects on women and their offspring are minimal. Given the amount of uncertainty regarding risk and the possibility of correction postpartum, there seems no reasonable justification to proceed with such interventions at this time. Centers of excellence should be established for conducting research and providing maternal-fetal surgery. Training programs designed to enable surgeons to set up new centers should not be offered when the safety and effectiveness of procedures has not been established. Should these procedures prove safe and effective and demand exceed the capabilities of existing centers, consideration could be given to creating additional centers after extensive training of those who would staff these centers.
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7. Funding for research on maternal-fetal surgery should be considered in the context of societal needs. Resources should be directed not only toward maternal-fetal surgery but also, where relevant, toward strategies for preventing congenital anomalies, such as education regarding prenatal folic acid supplementation for prevention of myelomeningocele. We believe that these recommendations will improve the likelihood that new applications of maternal-fetal surgery will be evaluated and applied in a scientifically valid as well as an ethically sound manner. SPEAKERS AT AND ORGANIZERS OF THE NIH WORKSHOP ON CURRENT SCIENTIFIC, ETHICAL AND CLINICAL CONSIDERATIONS OF MATERNAL-FETAL SURGERY Scott Adzick, MD, Children’s Hospital of Pennsylvania; Craig Albanese, MD, University of California, San Francisco; Duane Alexander, MD, National Institutes of Health; Marilee Allen, MD, Johns Hopkins Hospital; Beryl Benacerraf, MD, Diagnostic Ultrasound Associates; Lillian Blackmon, MD, University of Maryland; Todd Blumenkopf, PhD, Pfizer Global Research and Development; Joseph Bruner, MD, Vanderbilt University; Charlotte Catz, MD, National Institutes of Health; Robert Cefalo, MD, PhD, University of North Carolina; Alan Flake, MD, Children’s Hospital of Pennsylvania; John Fletcher, PhD, University of Virginia School of Medicine; Joel Frader, MD, Children’s Memorial Hospital, Chicago; Elena Gates, MD, University of California, San Francisco; James Goldberg, MD, California Pacific Medical Center; Zola Golub, MEd, RN, Northern Westchester Hospital Center; Michael Harrison, MD, University of California, San Francisco; Kurt Hecher, MD, AK Barmbeck, Germany; Michael Heyman, MD, University of California, San Francisco; Julien Hoffman, MD, University of California, San Francisco; Lori Howell, RN, MS, Children’s Hospital of Pennsylvania; Mark Johnson, MD, Children’s Hospital of Pennsylvania; Albert Jonsen, PhD, University of Washington; Patricia King, JD, Georgetown University Law Center; Mary B. Mahowald, PhD, University of Chicago; Susan Meikle, MD, National Institutes of Health; John Robertson, JD, University of Texas Law School; Albert Rosenfeld, MD, March of Dimes Birth Defects Foundation; Jonelle Rowe, MD, National Institutes of Health; Michael Socol, MD, Northwestern University Medical School; Jeremy Sugarman, MD, MPH, MA, Duke University Medical Center; Joan Weiss, MSW, LCSW, Genetic Alliance; Susan Wolf, JD, University of Minnesota Law School.
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Received January 2, 2001. Received in revised form April 30, 2001. Accepted June 17, 2001.
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