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Abstract

Fetal surgery has developed from concept to investigation using animal models in the laboratory, to innovation and research with pregnant and fetal patients, and to introduction into clinical practice during the past several decades. This technological and clinical transformation has been propelled forward by such factors as the introduction of advanced perinatal technology and the increasing integration of obstetrics and pediatrics in perinatal medicine. Once available only in a few centers in developed countries, fetal surgery has become available in additional specialized perinatal centers. This entry explains why fetal surgery should be understood as maternal fetal surgery. The concepts of innovation and research are explained. Relevant ethical concepts are then introduced: the ethical principles of beneﬁcence and respect for autonomy, the ethical concept of being a patient, and the ethical concepts of the pregnant woman as a patient and of the fetus as a patient. Two approaches to the ethics of maternal-fetal surgery are described. The ﬁrst focuses on the ethics of research on maternal-fetal surgery, appealing to US research regulations. The second provides a clinically comprehensive focus on clinical innovation, clinical research, and the professionally responsible transition to clinical practice, appealing to the ethical concepts of the pregnant woman and fetus as patients.

Introduction

This entry characterizes fetal surgery, a technological and clinical development of recent decades, as maternal-fetal surgery. This is because any attempt to manage the fetus’ condition medically or surgically must by its very nature be done through the pregnant woman’s body. Innovation, research, and clinical practice of maternal-fetal surgery are deﬁned. The ethical principles of beneﬁcence and respect for autonomy, the ethical concept of being a patient, and the ethical concepts of the pregnant woman as a patient and of the fetus as a patient are explained. Two approaches to the ethics of maternal-fetal surgery are then examined. The ﬁrst focuses on the ethics of research, taking the US research regulations as a point of departure. The second is comprehensive and focuses on innovation, research, and the professionally responsible transition from research to clinical practice.

History And Development

Fetal surgery has developed from concept to investigation using animal models in the laboratory, to innovation with pregnant and fetal patients and research with pregnant and fetal subjects, and to the transition into clinical practice, all during the past several decades (Harrison et al. 2001). This remarkable technological and clinical transformation has been propelled forward by such factors as the introduction of advanced obstetric ultrasound and fetal echocardiography, the development of coordinated maternal and fetal anesthesia, the creation of new instrumentation, and the increasing integration of obstetrics and pediatrics in perinatal medicine. Fetal surgery has become available in highly specialized perinatal centers in developed countries, known as “fetal centers” and by other names (Sala et al. 2014; Moise 2014). Responding to this important trend, the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics have published joint recommendations about such matters as informed consent, the oversight of fetal centers, and the need to gather data on outcomes (American College of Obstetricians and Gynecologists and American Academy of Pediatrics 2011).

Fetal Surgery As Maternal-Fetal Surgery

Medical and surgical intervention for fetal beneﬁt should in all cases be understood to be maternal fetal intervention. This is because medications or surgical techniques for fetal beneﬁt must be administered via the pregnant woman’s body. Medical maternal-fetal intervention occurs when the pregnant woman is given medication that can cross the placenta and thus affect fetal physiology. For example, medications can be given to the pregnant woman to manage fetal arrhythmias. Surgical maternal-fetal intervention occurs when the pregnant woman undergoes a surgical procedure to correct abnormal fetal anatomy with the goal of eliminating or mitigating pathological anatomy and thereby improving fetal physiology. Both medical and surgical maternal-fetal interventions are undertaken to manage life-threatening pathophysiology with the goal of preventing in utero fetal demise and increasing the probability of live birth. Medical and surgical maternal-fetal interventions are also undertaken to manage diseases and disabling conditions with the goal of mitigating their effects during gestation and therefore their effects on the future child.

Maternal-fetal surgery now includes repair of various forms of spina biﬁda (a defect in the closure of the spine that results in both injury to the spinal cord from exposure to neurotoxic amniotic ﬂuid that can result in paralysis and altered brain anatomy that results in hydrocephalus that may require shunting), the use of laser ablation to close off connecting vessels between twin fetuses (a condition known as twin-to-twin transfusion syndrome), placing shunts or opening blocked anatomical passages to treat lower urinary tract obstruction (known as LUTO), and puncturing and opening the interior heart wall to promote blood ﬂow with the goal of preventing the further development of hypoplastic left heart syndrome.

Conceptual Clarification

Innovation, Research, And The Transition To Clinical Practice

Maternal-fetal surgery should be ﬁrst undertaken as clinical innovation and clinical research, to provide the evidence base for the professionally responsible introduction of these surgical techniques into clinical practice. Innovation and research are both forms of experimentation, i.e., forms of clinical management the outcomes of which cannot be reliably predicted. Clinical innovation is an experiment performed on a patient for the clinical beneﬁt of that individual patient. Innovation in maternal-fetal surgery is performed on both the pregnant and fetal patients for the beneﬁt of the fetal patient. Clinical research is an experiment performed on a research subject who is also a patient with the goal of creating generalizable knowledge that is intended to beneﬁt future patients. Clinical innovation cannot produce generalizable knowledge because clinical success from a clinical innovation on a single pregnant patient-fetal patient pair is not sufﬁcient in scientiﬁc methodology to test a hypothesis. Clinical innovation can establish the initial feasibility of a form of maternal-fetal surgery and may warrant the formulation of a hypothesis of fetal beneﬁt and acceptable maternal and fetal risk, which hypothesis should then be tested in early-phase research for efﬁcacy and safety. To maintain clarity about the scientiﬁc and ethical relationship between clinical innovation and clinical research, the former should be undertaken as pre-research for the clinical beneﬁt of an individual fetal patient and to generate hypotheses to be investigated in subsequent clinical research.

In 2008 in the United States, the Society of University Surgeons proposed that clinical innovation in surgery should become accountable for its scientiﬁc, clinical, and ethical integrity. Surgical departments should provide oversight of all clinical innovation through prospective review and approval by a Surgical Innovation Committee (Bifﬂ et al. 2008). In the present context, this committee should be constituted as a Perinatal Innovation Review Committee (Chervenak and McCullough 2014). The perinatal physicians considering a planned clinical innovation for fetal beneﬁt should prepare a proposal that describes the innovation; its prior use in animal models (when feasible) and in cases reported in the peer reviewed literature; the clinical beneﬁt intended for the patient (including the reduction of the risks of mortality, morbidity, and disability); the short-term and long-term risks of mortality, morbidity, and disability for both the pregnant and fetal patient; and the informed consent process. The informed consent process should make clear that the proposed clinical innovation is an experiment: its outcome for both the fetal and pregnant patients cannot be reliably predicted. It should be emphasized that the proposed clinical innovation is not an accepted clinical practice. The pregnant woman should be informed that she therefore has no ethical obligation to her fetus or future child to undergo the proposed innovative maternal-fetal surgery.

When maternal-fetal surgery is proposed as research, it must receive prospective review and approval by an Institutional Review Board (IRB)/ Research Ethics Committee (REC). The protocol must address such matters as the nature of the maternal-fetal surgery, why (on the basis of previous animal models and case reports of clinical innovation) it should be considered to have an acceptable beneﬁt/risk ratio for pregnant patient in this and subsequent pregnancies, as well as for the fetal and neonatal patient, and the informed consent process. The informed consent process should make clear that the proposed clinical research is an experiment: its outcome for both the fetal and pregnant patients cannot be reliably predicted. It should be emphasized that the proposed clinical research is not an accepted clinical practice. The pregnant woman should be informed that she therefore has no ethical obligation to her fetus or future child to undergo the proposed maternal-fetal surgical research.

Clinical intervention that has been developed through the process of pre-research or innovation followed by research may be introduced into clinical practice when the outcomes of research support the clinical ethical judgment that the intervention is reliably expected to result in net clinical beneﬁt for the fetal patient and acceptable risk to the pregnant patient. Such clinical intervention should be considered medically reasonable. In the informed consent process, the physician has the professional responsibility to present all medically reasonable alternatives to the patient or the surrogate decision maker for a patient not able to participate in the informed consent process or not permitted by law to provide consent. The physician should attempt to ascertain that the patient understands this information and that the patient’s decision-making process is voluntary, i.e., free of controlling internal or external inﬂuences.

Maternal-fetal surgery for spina biﬁda was shown in a randomized controlled clinical trial (Adzick et al. 2011), known as the MOMS Trial, to be clinically beneﬁcial for children and acceptably risky for the fetal and pregnant patients in a population deﬁned by inclusion and exclusion criteria. This form of in utero surgery decreased rates of disability and the need for shunting for hydrocephalus in children when compared to expectant obstetric management followed by neonatal surgical repair, with acceptable rates of maternal morbidity and fetal mortality and morbidity. It follows that in utero repair for spina biﬁda for pregnant patients who meet the MOMS Trial criteria is medically reasonable. All pregnant women whose fetus has been diagnosed to have spina biﬁda and who meet the MOMS Trial criteria should therefore be offered both in utero repair and expectant obstetric management followed by neonatal repair. The physician should attempt to ascertain that the pregnant woman understands that in utero repair is maternal-fetal surgery, the nature of the procedure, its morbidity risks for the pregnant woman in her current and future pregnancies, and the mortality and morbidity risks for the fetal patient and future child. The physician should also make a reasonable effort to ensure that the pregnant woman’s decision-making process is free of internal or external controlling inﬂuences.

Ethical Dimension

Relevant Ethical Concepts

The Ethical Principle of Beneﬁcence. The ethical principle of beneﬁcence obligates the physician and other healthcare professionals to provide clinical management that is reliably expected to result in net clinical beneﬁt for the patient, i.e., a greater balance of clinical goods over clinical harms. Such judgments should be based on the best available evidence.

The Ethical Principle of Respect for Autonomy. The ethical principle of respect for autonomy obligates the physician to empower the pregnant woman to make decisions by providing her with information that she needs to exercise her autonomy meaningfully in decision making about the clinical management of her pregnancy, the nature of the proposed clinical management and why it is medically reasonable, the medically reasonable alternatives, and the clinical beneﬁts and risks of each medically reasonable alternative. The physician should attempt to ascertain that the pregnant woman understands this information and that her decision-making process is voluntary.

Ethical Concept of Being a Patient. The ethical concept of being a patient was introduced into the history of medical ethics in the eighteenth century by the Scottish physician-ethicist, John Gregory (1724–1773). The concept is beneﬁcence based: an individual human being is presented to a physician or other healthcare professionals, and there exist forms of clinical management that are reliably expected to result in net clinical beneﬁt for that individual (McCullough 1998). This concept is not autonomy-based: an individual human being can become a patient without his or her consent. Thus, infants and minor children can become patients, as can adult patients in clinical emergencies (life-threatening conditions for which there is safe and effective treatment that must be provided immediately, making it impossible to engage the patient in the informed consent process) or adult patients who have lost the capacity to make decisions, either from diseases such as severe dementia or iatrogenic ally from sedation or anesthesia. This is also a concept free of metaphysical requirements, especially the requirement that the individual human being also be a person. The ethical concept of being a patient is both clinical and practical, with comprehensive application in clinical practice, innovation, and research, unlike the metaphysical concept of being a person.

The Ethical Concept of the Pregnant Woman as a Patient. The pregnant woman becomes a patient when she is presented to a physician or other healthcare professionals, because there exist forms of obstetric management that are reliably expected to clinically beneﬁt her, her fetus(es), or future child(ren). The physician and other healthcare professionals involved in the pregnant woman’s clinical care have both beneﬁcence based and autonomy-based obligations to her (McCullough and Chervenak 1994).

The Ethical Concept of the Fetus as a Patient. Chervenak and McCullough (1994) have argued that the previable fetus becomes a patient when the pregnant woman is presented to a healthcare professional and she confers the moral status of being a patient of her fetus, according to her own values and beliefs. They have also argued that the viable fetus (24 weeks gestational age in developed countries) becomes a patient when the pregnant woman is presented to a healthcare professional. When the fetus is a patient, the physician and other healthcare professionals involved in the pregnant woman’s clinical care have beneﬁcence-based obligations to the fetal patient. Healthcare professionals also have beneﬁcence-based and autonomy-based obligations to the pregnant woman. Clinical ethical evaluation of any form of maternal-fetal surgery requires all three obligations to be identiﬁed and balanced against each other. Clinical ethical judgments about maternal fetal surgery based solely on beneﬁcence-based obligations to the fetus as a patient are ethically inadequate because they wrongly assume that ethically the fetus is a separate patient.

Two Approaches To Clinical Ethical Judgment About Maternal-Fetal Surgery

Clinical Ethical Judgment Based on US Research Regulations. Strong (2011) has proposed an approach to the ethical evaluation of maternal fetal surgical research that calls for clinical ethical judgment warranted by research regulations in the United States. Such clinical ethical judgment should evaluate fetal and maternal risk “in relation to the degree of anticipated beneﬁt and the importance of the knowledge to be gained” (Strong 2011, p. 3). Strong does not address the moral status of the fetus but focuses instead on the prevention of injury to the future child, a pediatric beneﬁcence-based consideration, and the prevention of unacceptable risk to the pregnant woman, an obstetric beneﬁcence-based consideration.

Strong elaborates on this clinical ethical judgment by identifying its ﬁve components:

Risks to the fetus are justiﬁed by the anticipated beneﬁts to the fetus.
The relation of the anticipated beneﬁt to the risk is at least as favorable to the fetus as that presented by available alternative approaches.
Risks to the fetus are minimized.
Risks to the pregnant woman are reasonable in relation to any anticipated beneﬁts to the fetus and pregnant woman and the importance of the knowledge that may reasonably be expected to result.
Risks to the pregnant woman are minimized, to the extent that doing so is consistent with minimizing risks to the fetus (Strong 2011, p. 5).

Strong focuses on research generally and therefore does not address the distinct ethical dimensions of innovation, the different phases of research and their ethically distinct differences, or the responsible transition from research to clinical practice. Because his focus is on the prevention of unacceptable risk to the future child, Strong also does not address maternal-fetal surgery that is intended to prevent imminent fetal mortality, such as in utero removal of sacrococcygeal teratoma that has become so large that the fetus is in end-stage, life-taking heart failure. The resulting approach is therefore not clinically comprehensive. Strong’s ethical considerations, while they address risks to the pregnant woman, are not explicit about the need to identify and evaluate risks to the pregnant woman in her current pregnancy as well as in future pregnancies. Finally, Strong does not explicate the clinical scope of risk to the fetus or the pregnant woman or provide guidance on how these risks should be balanced against the hypothesized beneﬁt and the hypothesized value of knowledge that might be gained.

Chervenak and McCullough (2011) have offered a comprehensive ethical framework that addresses clinical ethical judgment about the initiation of innovation, early-phase research, randomized controlled clinical trials, and the responsible transition to clinical practice. Their approach is based explicitly on the ethical concept of the fetus as a patient, beneﬁcence-based obligations of the pregnant woman to the fetal patient, and the pregnant woman’s beneﬁcence-based ethical obligation to take only reasonable risks to herself for fetal beneﬁt. Beneﬁcence-based obligations support criteria to address potential beneﬁt and risk to the fetal patient, as well as potential beneﬁt and risk to the pregnant woman in the current and future pregnancies. Their approach identiﬁes risks of mortality, morbidity, and disability. Because their approach includes an account of the moral status of the fetus as a patient, their approach is clinically applicable to maternal-fetal surgery to prevent imminent fetal and neonatal mortality and disability.

Chervenak and McCullough set forth ethical criteria for clinical innovation, clinical research, and the professionally responsible transition from research to clinical practice.

Clinical Ethical Criteria for Clinical Innovation and Early-Phase Clinical Research for

Efﬁcacy and Safety. The clinical ethical justiﬁcation for clinical innovation and early-phase clinical research should be based on beneﬁcence-based criteria that focus on minimizing the risks of mortality and the risks of morbidity, injury, and disability to both the pregnant and fetal patient:

The proposed fetal intervention is reliably expected on the basis of previous animal studies either to be lifesaving or to prevent serious and irreversible disease, injury, or disability for the fetal patient.
Among the possible alternative designs, the intervention is designed in such a way as to involve the least risk of mortality and morbidity to the fetal patient.
On the basis of animal studies and analysis of theoretical risks for both the current and future pregnancies, the mortality risk to the pregnant woman is reliably expected to be low, and the risk of disease, injury, or disability to the pregnant woman is reliably expected to be low or manageable for current and future pregnancies (Chervenak and McCullough 2011, p. 46).

Clinical Ethical Criteria for Randomized Controlled Clinical Trials (RCTs). When feasible, the initiation of a randomized controlled clinical trial requires equipoise: an evidence-based evaluation of the outcomes of early-phase research requires the scientiﬁcally rigorous clinician to become uncertain about the relative clinical beneﬁt of the maternal-fetal surgery versus expectant obstetric management and neonatal intervention. The beneﬁcence-based criteria focus on continued minimization of the risks of mortality and the risks of morbidity, injury, and disability to both the pregnant and fetal patient:

The initial case series indicates that the proposed fetal intervention is reliably expected either to be lifesaving or to prevent serious and irreversible disease, injury, or disability for the fetal patient.
Among the possible alternative designs, the intervention continues to involve the least risk of morbidity and mortality to the fetal patient.
The case series indicates that the mortality risk to the pregnant woman is reliably expected to be low and the risk of disease, injury, or disability to the pregnant woman, including for future pregnancies, is reliably expected to be low or manageable (Chervenak and McCullough 2011, p. 46).

Clinical Ethical Criteria for the Professionally Responsible Transition to Clinical Practice. The beneﬁcence-based criteria focus on the clinical ethical judgment that the outcomes of either early-phase research (when an RCT is infeasible) or of an RCT support an expectation of signiﬁcant fetal beneﬁt and acceptable risks of mortality, morbidity, injury, and disability for both the pregnant and fetal patient:

The maternal or fetal intervention has positive results, i.e., it has a signiﬁcant probability of being lifesaving or preventing serious or irreversible disease, injury, or disability for the pregnant woman or fetal patient.
The maternal or fetal intervention involves low mortality and low or manageable risk of serious and irreversible disease, injury, or disability to the fetal patient.
The mortality risk to the pregnant woman is low, and the risk of disease, injury, or disability is low or manageable, including for future pregnancies (Chervenak and McCullough 2011, p. 47).

Conclusion

Maternal-fetal surgery has now reached a high degree of scientiﬁc, clinical, and ethical sophistication in highly specialized centers in developed countries. Innovation and research will continue and most likely accelerate. Such clinical innovation and research should be undertaken in a professionally responsible manner. Clinically comprehensive ethical criteria, justiﬁed by appeal to the ethical principle of beneﬁcence, have been proposed to guide professionally responsible maternal-fetal surgery. Professional associations of physicians have also provided ethical guidance.

The resulting use of ethics as a tool of professionally responsible self-regulation by perinatologists serves as a model that can be adapted to other clinical areas.

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