The introduction of routine fetal ultrasound and the technical improvements in ultrasound equipment have greatly increased our ability to diagnose fetal anomalies. As a consequence, congenital anomalies are diagnosed today earlier and in a greater number of patients than ever before. The development of fetal intervention and fetal surgery techniques, improved anesthesia methodology, and sophisticated perinatal care at the limits of viability, have now made prenatal management of some birth defects or fetal malformations a reality. The increasing number of indications for fetal therapy and the apparent desire of parents to seek out these procedures have raised concern regarding the ethical issues related to the therapy. While fetal therapy may have a huge impact on the prenatal management of some congenital birth defects and/or fetal malformations, because of the invasive nature of these procedures, the lack of sufficient data regarding long-term outcomes, and the medical/ethical uncertainties associated with some of these interventions there is cause for concern. This chapter aims to highlight some of the most important ethical considerations pertaining to fetal therapy, and to provide a conceptual ethical framework for a decision-making process to help in the choice of management options.
Highlights
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Fetal therapy has graduated from experimental observation into clinical reality.
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Any transition from to standard of care should be carried out in an ethically responsible fashion.
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Adherence to ethical principles determines the feasibility, safety and efficacy of fetal therapy.
Introduction
Congenital birth defects or fetal malformations affect 3% of babies born in the United States and account for 20% of all infant deaths . The evolution of high-resolution imaging studies and perinatal testing techniques has revolutionized the prenatal diagnosis of structural abnormalities and innovations in surgical equipment and minimally invasive techniques, combined with improved anesthesia and perinatal care, have allowed the prenatal management of some fetal malformations. Over the last four decades, fetal therapy for a select group of conditions has graduated from experimental observation into standard of care and clinical reality . Careful introduction and oversight of these innovative therapies has enabled the medical community to, for the most part, endorse their safety and benefit for a number of conditions including medical therapy (e.g. maternal transplacental administration of digoxin in supraventricular tachycardia), fetal surgery (e.g. fetoscopic endotracheal occlusion for isolated left sided congenital diaphragmatic hernia), and interventions focused on the placenta (e.g. laser ablation of placental anastomoses for twin to twin transfusion syndrome). Published literature has shown that the risk of procedure-related risk of maternal-fetal complications is acceptable in terms of the risk-benefit proposition. Developmental malformations and fetal conditions amenable to fetal intervention can be usefully categorized into five evidence-based groups :
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Conditions that benefit from fetal therapy based on Level I (a, b and c) evidence (including systematic reviews of randomized controlled trials – RCT, individual RCTS’s, or “all or none” case series). This is small group and includes only 4 conditions:
- a.
Twin to twin transfusion syndrome (TTTS)
- b.
Myelomeningocele (MMC) ,
- c.
Lower urinary tract obstruction (LUTO) ,
- d.
Congenital diaphragmatic hernia (CDH) .
- a.
These conditions are associated with significant mortality or very severe morbidity if left untreated.
- 2.
Conditions that benefit from fetal therapy based on Level 2 (a and b) evidence obtained from systematic reviews of cohort studies, or cohort studies. This includes such therapies as intrauterine transfusion (IUT) for the treatment of fetal alloimmune anaemia and parvovirus B19 infection and medical therapy for fetal tachycardia .
- 3.
Conditions that may benefit from fetal therapy based on Level 3 (a and b) evidence derived from systematic reviews of case-control studies (a) or individual case-control studies (b) which have shown probable benefits such as lower urinary tract obstruction .
- 4.
Conditions that may benefit from fetal therapy based on Level 4 evidence derived from small case series/reports including amniotic-band syndrome , congenital cystic adenomatoid malformations (CCAM) , sacrococcygeal teratoma , aortic stenosis , hydrothorax , placenta chorioangioma and vasa previa .
- 5.
Conditions in which the use of fetal therapy is still considered controversial such as osteogenesis imperfecta , aqueductal stenosis , fetal heart block , renal vein thrombosis , and twin anemia polycythemia sequence (TAPS) .
Although fetal diagnosis and therapy create opportunities for the treatment of fetuses with congenital birth defects, there are a number of mitigating factors that need to be considered before recommendations can be made. These include (but are not limited to) the heterogeneous nature of these conditions, the invasiveness of the proposed surgical intervention(s) , the potential complications associated with the fetal therapy , and the paucity of data on long-term outcomes . These factors may significantly restrict the offering of therapeutic options, and complicate the mother’s (parents’) decision making.
Any transition from innovation to standard of care in the arena of fetal therapy should be carried out in an ethically responsible fashion and should be based on adequate scientific evidence . Adherence to these principles will determine the feasibility, safety, and efficacy of fetal therapy, as well as help the medical and lay communities understand the balance between innovation and harm and pure experimentation from improved quality of care . This chapter aims to highlight important ethical considerations in fetal therapy and to provide a conceptual ethical framework for the decision-making process in determining appropriate management options.
Ethically justified decision making
Fetal therapy must meet the following three criteria to be ethically permissible:
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It should be a life-saving or should prevent or substantially mitigate serious or irreversible disease, injury, or handicap to the fetus or the child to be.
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The proposed therapy should have a low mortality risk for the fetus and low or manageable risk of serious disease, injury, or handicap to the fetus or born child.
- 3)
The maternal mortality and morbidity (disease or injury, or handicap) risk to the mother should be very low or manageable .
In any kind of fetal therapy, three core ethical concepts should be considered: (i) respect for the autonomy of the pregnant woman, (ii) respect for the fetus as a patient, and respect for the individual conscience of the physician .
Autonomy of the pregnant woman
Gaining access to the fetus or placenta occurs solely through the pregnant woman’s body and for this reason her wishes and decisions are the major drivers of any kind of fetal therapy. The counseling of and informed consent process with a pregnant woman with regard to fetal therapy as either a standard of care or with regard to a clinical trial, is of fundamental importance. Even though fetal therapy is generally considered an alternative to postnatal care, in some cases physicians who fail to inform pregnant women about the potential benefits of fetal therapy as a treatment option may face legal liability for negligence .
The antenatal diagnosis of a previously unknown congenital birth defect or fetal malformation is usually associated with shock and grief, and leads to an immediate change in the perception of the pregnancy . The pregnant woman’s subsequent decision making is frequently shaped by hope for a better outcome. This hope is often created by a number of factors including the advice and counseling of her provider(s) regarding innovative treatments, the wishes of her family, her socioeconomic circumstances, and in some cases specific legal considerations . These conditions can jeopardize the patient’s autonomy and may even result in subtle or hidden coercion. Pregnant women have no legally enforceable duties regarding the choosing of any specific type of fetal therapy and they are allowed to decline intervention However, some experts who believe in recognizing fetal personhood at viability, or even at conception, believe that pregnant women can be subjected to judicially ordered interventions for fetal protection .
Despite our best efforts, it has to be recognized that even under the most optimal of circumstances fetal therapy is invasive in nature and may negatively impact both the pregnant woman and her fetus. Any counseling session must include a balanced discussion of the uncertainties, complications, and failures of the therapy, and that such information is as important as any discussion regarding the potential favorable outcome(s). In many cases the absolute diagnosis, mechanisms, and natural history of the malformation may still be unclear, and an acknowledgment of the unknown magnitude of any possible risk-benefit ratio of an innovative proposed treatment has to be clearly disclosed. A provider’s failure to fully disclose uncertainties, complications, and alternatives of fetal therapy might result in subsequent disappointment and resulting litigation and claims. The reasonable-patient standard for informed consent and patient-centered communication supports a collaborative physician-patient relationship, and promotes detailed counseling and consenting, which improves shared decision making . Via this approach, physicians are obligated to inform patients about all available evidence rather than simply what they themselves, or the majority of experts, have recognized.
In most cases fetal therapy has no direct clinical benefit to the pregnant woman. Despite the best that contemporary fetal therapy can offer, under most circumstances it is still considered a high risk proposition for the woman and her fetus. As such there are significant potential complications that may occur acutely, postoperatively, and during the remainder of the pregnancy, and pregnancy risks that go beyond the index pregnancy into subsequent pregnancies .
Complications secondary to fetal therapy may affect the pregnant woman, her fetus, or both. Pregnancy complications may include hemorrhage, infection, oligohydramnios, chorion-amniotic membrane separation, need for fetal resuscitation, increased risk of preterm labor (PTL), fetal bradycardia, placental abruption, maternal transfusion at delivery, and preterm premature rupture of membranes. Maternal complications specific to fetal therapy include pulmonary edema, coagulopathy, need for hysterectomy, anesthetic accidents, and even potential maternal death . Fetal therapy, especially open fetal surgery, might result in changes in fetal to maternal cellular trafficking and there is the theoretical risk of increased trafficking of maternal cells in fetal blood, and/or proliferation of fetal cells in maternal blood. The risks of such trafficking are unknown . The upper segment hysterotomy incision most frequently associated with open fetal surgery may put women at higher risk of uterine thinning or dehiscence of the uterine scar . Women who are planning to have open fetal surgery should understand that they will deliver the index, as well as all future pregnancies, via a cesarean section, and that this will increase their risk for a morbidly adherent placenta in subsequent pregnancies.
Less invasive methods such as those using a fetoscopic approach or a mini-hysterotomy may be associated with a lower rate of complete dehiscence, focal dehiscence, and/or markedly thin hysterotomy scar, and may allow vaginal delivery as opposed to mandatory index and repeat cesarean sections. It should be stated that fetoscopic approaches are still regarded as experimental and require appropriate consent procedures, data safety monitoring oversight and Institutional Review Board (or Research Ethics Committee) approval .
The changing level of sophistication in technique and technology has mandated a dynamic approach to the medical and ethical approach to fetal surgery. Morbidity and complications (such as excessive blood loss, abruption placentae, uterine rupture and uterine dehiscence) seen in early studies have not been seen to the same extent in later studies, and the reproductive potential and the complication rates in subsequent pregnancies in women with the history of fetal surgery are generally comparable to the general population . Despite the reduction in complication rate, the risks must still be considered and dealt with when counseling pregnant women who are candidates for fetal surgery. The issue of what constitutes standard of care is a thorny one and, in our opinion, must be made by unbiased experts using high-quality evidence from the most recent peer-reviewed literature . Obviously regional and inter-institutional variation has to be considered, as do the means of the patient and family, the social circumstances, and the availability of the required services.
Based on the underlying cause of the fetal condition and the gestational age at the time of diagnosis, a wide spectrum of options may be available, ranging from expectant management, to fetal intervention, or to termination of the pregnancy. Care providers have an ethical obligation to make sure all available options are discussed with the patient and her family during counseling sessions in order to truly obtain an informed consent. Because of the complexity, uncertainty, and/or controversy related to prenatal diagnosis and fetal therapy, physicians should pay careful attention that the patient’s decision making is not influenced by inappropriate or unrealistic optimism or pessimism . Providers doing the counseling should determine the patient’s expectations of the particular fetal therapy under discussion and ensure that such expectations are realistic.
It is important that physicians allow the patient and her family sufficient time to make critical decisions, and that the words and phrases used in the counseling are carefully chosen . In the case of research within the setting of a randomized controlled trial, words such as treatment or therapy should be replaced with phrases that clearly distinguish the research or experimental interventions from those that might be standard of care. In addition, clinical research initiatives should be clearly discussed with the pregnant woman and the alternatives to the experimental therapy should be detailed. Words that contain non-existent moral relationships (e.g. father, mother, and baby) must be avoided .
Fetus as a patient
The concept of the fetus as a patient, developed and promulgated with great eloquence by McCullough and Chervenak is governed by (1) the viability of the fetus, and (2) the decision of a pregnant woman to continue, or to terminate, her pre-viable pregnancy. A fetus should be regarded as a patient when a pregnant woman seeking healthcare has a viable fetus (usually regarded in most states as one with a gestational age at or beyond 24 weeks by reliable ultrasound documentation) or when she has made the decision to continue her pregnancy with a pre-viable fetus . A pregnant woman with a pre-viable fetus can withdraw the moral status of being a patient before viability. Once a fetus is considered a patient (viable or pre-viable), physicians are obligated to care for that fetus based on the ethical principle of beneficence. The significance of this ethical obligation becomes more evident when an intervention may result in significant harm, or there is adequate scientific evidence to prevent the establishment of clinical equipoise. The beneficence-based obligations of a physician to a fetal patient are balanced by their professional obligations to the pregnant woman’s autonomy and by beneficence-based obligations to her .
Based on these ethical obligations, fetal therapy should be limited to the treatment of only those malformations that are severe, and to potentially lethal conditions in which such therapy has been proven to improve the survival and/or preserve normal or near normal function . In order to maximize benefit to the patient, to prevent non-beneficial interventions, to prevent inappropriate application of emerging technologies, and to ensure data quality and cooperation between research groups, the International Fetal Medicine and Surgery Society (IFMSS) created and published, in the early 1980’s, a suggested framework for those groups undertaking fetal interventions . However, 35 years after designing and publishing this framework, there is still a paucity of data, partly due to the rarity of some conditions and partly due to the lack of international and institutional collaboration on large multi-center studies. These obstacles remain an important limitation in the better understanding of the natural history, outcomes, and postnatal management of fetal malformations.
In any kind of fetal therapy, health care professionals should be mindful of the preoperative, intraoperative, and postoperative fetal physiologic changes. A deterioration in physiologic or pathologic status may rapidly result in fetal demise.
Although data regarding the conscious perception of pain in a fetus are still minimal or lacking, fetal analgesia and anesthesia should be provided if possible via placental transfer, or via direct intravenous, or intramuscular, administration to the fetus prior to and during fetal therapy where pain could be a consideration. It is important to note that data on the long term positive and negative effects of such analgesia/anesthesia on fetal neurodevelopment are still unclear .
Conscience of the physician
In 1974 Charles Fried introduced the concept for equipoise in his book Medical Experimentation: Personal Integrity and Social Policy . Clinical equipoise is a state in which the available evidence does not satisfy all experts and there is remaining disagreement regarding pros and cons of a suggested (fetal) therapy . Chervenak and McCullough proposed 3 criteria to define evidence-based equipoise in the expert community. These criteria may be used to adjudicate in those situations where healthcare professionals disagree regarding the merits of fetal therapy: There is equipoise when:
- 1)
An initial case series indicates that the proposed fetal intervention is reliably expected either to be life-saving or to prevent serious and irreversible disease, injury, or handicap.
- 2)
Among possible alternative designs, the intervention continues to involve the least risk of morbidity and death to the fetus.
- 3)
The case series indicates that the mortality risk to the pregnant woman is expected reliably to be low and that the risk of disease, injury, or handicap to the pregnant woman, including for future pregnancies, is expected reliably to be low or manageable.
In case of clinical equipoise, experimental fetal therapy must be offered only in the context of a RCT . It is worthwhile mentioning that when clinical equipoise exists, the efficacy and safety of the therapy in question have not been proven in an evidence-based way and cannot be categorized as the standard of care. When this is the case, the parent should be clearly and unequivocally informed of the experimental nature of the intervention.
Assessing the pregnant woman’s understanding of the fetus’ condition is important in providing targeted education and counseling. However, such counseling should avoid directing the patient’s choices. Non-directive counseling is an appropriate approach for physicians to maintain when there is equipoise as regards the choice of termination (death) versus continued pregnancy (life) .
Standardization and the reduction of variation in patient counseling regarding fetal therapy may improve the quality of care . However, physicians’ views about many aspects of fetal intervention, particularly as regards termination of pregnancy and the role of fetal therapy in dealing with fetuses with severe malformations or illness, may be widely divergent. In fetuses with a confirmed lethal condition, i.e., a life-taking condition for which there is no fetal intervention, most would agree that counseling should be focused on palliative care. However, in some cases, religious or other beliefs may complicate issues and make intervention reasonable. An example would be the delivery by cesarean section of a fetus with anencephaly in order to ensure a live birth because of the religious importance of this to the parents. It is important to remember that simply being able to perform a treatment or apply a fetal therapy does justify acquiescing to the parents’ request for such therapy. The performance of fetal intervention should follow beneficence-based obligations, and clearly non-beneficial and/or futile interventions should neither be offered nor performed.
Chervenak and McCullough have suggested that in order to satisfy an ethical justification for non-aggressive fetal management two criteria must be fulfilled. First, there must be a very high probability – but sometimes less than complete certainty – that the diagnosis is correct, and secondly, that either (a) there is a very high probability of death as an outcome of the diagnosed anomaly, or (b) that there may be survival but with a very high probability of severe and irreversible cognitive deficiency and minimal or no capacity for cognitive development as a result of the diagnosed anomaly. Health care providers should provide the pregnant woman with adequate information regarding the nature of the fetal condition, a realistic prognosis, potential complications associated with the main anomalies/illness, the required or preferred mode of delivery, the recommended place of delivery, and appropriate level of care following delivery (hospital, home, or perinatal hospice). In cases where there is a lethal anomaly for which palliative care only is recommended, the focus of the care plan should be the pregnant woman and decisions should be made in her best interest. Under this circumstance any unnecessary interventions such as a cesarean delivery for fetal decompensation should be avoided, because they confer risk on the pregnant woman with no fetal benefit. It is important that when such decision are made, adequate grief counseling and support services should be made available to help the patient and her family deal with a stillbirth or neonatal death .
Despite our advancing sophistication in the types of technology and care we offer, it behooves centers that offer fetal therapy to put more emphasis on a more holistic approach, in order to improve not only the level of care, but also the social and community aspects of fetal intervention which include cost-effectiveness, access to care and transparency about outcomes.
Ethical issues regarding Fetal Centers
There are some important principles and requirements that must be satisfied before attempting to establish a multidisciplinary fetal care center. Not only should such centers be capable of providing safe and high quality diagnostic, counselling, and patient education services, but they should be fully capable of providing not only the necessary surgical interventions but they should also be proficient in taking care of any and all complications that may result from such therapies (maternal and/or neonatal). Two further important criteria would be the ability to provide high level multidisciplinary long term care for the treated conditions and to collect and transparently disseminate comprehensive data on short, medium and long term outcomes. Any fetal center providing fetal intervention or fetal surgery must have the ability to provide comprehensive emergency obstetric and neonatal care.
Fetuses should not be regarded as small neonates or as miniature adults. There are important physiological and anatomical differences that make fetal surgery a highly technical undertaking . Clinicians performing these procedures require extensive additional experience and training in the field, and it is important that such specialists be included in the team. Based on the American Congress of Obstetricians and Gynecologists (ACOG) recommendations, centers providing fetal therapy should involve a diverse group of professionals including maternal–fetal medicine specialists, neonatologists, nurses, pediatricians, surgical subspecialists, genetic counsellors, chaplains, ethicists, and other members of institutional ethics committees .
The number of fetal care centers is rapidly growing and advances in this field raise ethical issues regarding costs and reasonable resource allocation . While fetal therapy is based on beneficence-based motivations to improve fetal and neonatal outcomes, special attention should be paid to the fair allocation of resources. It cannot be denied that fetal care centers benefit only a limited number of pregnant women and their fetuses. ACOG and the American Academy of Pediatrics (AAP) have expressed their concerns regarding the potential for the unfair allocation of resources based on possible conflicts of interest that may include financial considerations for the hospital and/or career advancement for the clinicians . It has been suggested that marketing activities should be overseen by independent advisory groups that do not have direct ties to the center involved. Brown et al have demonstrated substantial differences of opinion regarding clinical, legal, and ethical aspects of fetal intervention between maternal-fetal medicine specialists and pediatrics specialists. This highlights the importance of adopting an interdisciplinary approach in counseling and in providing care for pregnant women who are candidates for fetal therapy.
Fetal therapy is a rapidly developing field which has now emerged from the realm of medical curiosity into an exciting, multidisciplinary specialty capable of improving patient outcomes for a wide variety of diseases and conditions. This underscores the importance of training the new generation of fetal surgeons and physicians to further evolve the specialty with a heightened awareness of the medical ethics that play such an important role in the subspecialty.
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