Fetal Treatment 2017: The Evolution of Fetal Therapy Centers - A Joint Opinion from the International Fetal Medicine and Surgical Society (IFMSS) and the North American Fetal Therapy Network (NAFTNet)

In 1982, practitioners from a dozen institutions in 5 countries gathered to discuss the emerging field of “fetal therapy” - a new approach to prenatally diagnosed congenital anomalies potentially amenable to intervention before birth - with the goal of changing the natural history of diseases including hydrocephalus, obstructive uropathy, and pulmonary hypoplasia secondary to a congenital diaphragmatic hernia (CDH). Their consensus regarding the state of the art and basic tenets and challenges regarding the science and ethics of interventions which involved 2 patients in order to benefit the unborn child were published as a short letter in the New England Journal of Medicine later that year [1]. Over the last 3 decades, the field has progressed rapidly [2,3,4]. Fetal therapy centers (FTCs) have developed worldwide as a consequence of advances in prenatal diagnosis, fetal imaging, instrumentation, interventional techniques, and expertise. Our understanding of maternal-fetal pathophysiology in a broad range of conditions has also expanded greatly. Examples include ultrasound-guided procedures, such as fetal blood sampling or intrauterine transfusion, vesico- or thoraco-amniotic shunt placement [5], cardiac balloon valvuloplasty and stent placement [6], vascular occlusion procedures (bipolar electrocautery, radiofrequency ablation, interstitial laser ablation, or thrombogenic coil injection) for complex monochorionic twin pregnancies, hydropic lung lesions or sacrococcygeal teratomas, and prenatal stem cell transplantation [7]. Fetoscopic techniques have been developed for laser treatment of twin-twin transfusion syndrome (TTTS) [8], tracheal balloon occlusion for CDH [9], and ultrasound-guided fetal delivery of mesenchymal stem cells [7]. Open fetal surgical techniques predominantly for myelomeningocele [10] and also for some congenital pulmonary airway malformations or sacrococcygeal teratomas have been refined. Finally, ex utero intrapartum treatment has been developed for the delivery of neonates with major obstructive airway anomalies [11,12,13].

Despite these advances, the basic tenets (Table 1) applied to fetal treatment have not been reevaluated in a scientific forum, although some, e.g., placental laser ablation for monochorionic twin pregnancies with TTTS, have departed from the original dictum that “only singletons should be considered as candidates for fetal therapy.” As both diagnostic and surgical techniques have evolved, we have begun to reconsider the role of fetal therapy in conditions that were hitherto under a moratorium, e.g., fetal aqueductal stenosis. As the focus of fetal therapy has shifted from not just enabling the survival of a neonate with an otherwise lethal condition to improving its quality of life (e.g., fetal myelomeningocele repair), concerns have arisen regarding the practice of fetal medicine in the context of a maternal intervention. In 2011, a joint statement of the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics [14,15] discussed many issues in this emerging field, emphasizing the principles of maternal autonomy, careful assessment of the risk-benefit relationship, advocacy for both mother and fetus in the context of research and innovation, avoidance of unintentional coercion [16], and the need for collaborative models and centers of excellence. In essence, fetal therapy presents challenges to observing the ethical principles of justice, nonmaleficence, and beneficence. As the inherent duality of the maternal-fetal dyad potentially puts optimizing fetal outcome in conflict with what is best for maternal health, FTCs have an ethical obligation to carefully consider both maternal and fetal wellbeing when any form of in utero intervention is being contemplated. Thus, 34 years after the basic tenets of fetal treatment were first published, it is evident that a new approach should be defined that takes into account the numerous advances in the field, the shift in the ethical paradigm of fetal intervention to include the reduction not only of mortality but also of significant morbidity, and the clear obligations that all health-care providers have in caring for both the mother and her fetus [1]. In response, members of both the North American Fetal Therapy Network (NAFTNet) and the International Fetal Medicine and Surgical Society (IFMSS) have convened to produce the present statement.

With all technologies, there are 2 distinct evolutionary phases. First, a “development” phase in which a small number of investigators - usually, but not necessarily, at academic medical centers - pioneers a new approach, evaluates complications, refines techniques, tests, and possibly patents, and publishes their findings. Over time, the technology is recognized, and clinical demand increases beyond the capability of the originators to reasonably perform all cases or tests. At that point, there is a “diffusion” phase as the technology expands to multiple locations to give increasing numbers of patients the benefits of the new approach. During this phase, utilization rapidly expands but is often paralleled by a corresponding increase in procedure-related complications. Eventually, experience expands and performance improves across the board. There is a complicated balance between the pioneers' interests in ensuring the success of new approaches and the potential benefits to patients, while at the same time not being overly protective or exclusionary in controlling “trade” in an open market.

Several fetal interventions that were once innovative (including those for TTTS, myelomeningocele, and CDH) have been evaluated in randomized clinical trials [8,9,10,17], whereas others (balloon valvuloplasty for fetal critical aortic stenosis and intrauterine stem cell therapy for osteogenesis imperfecta) are currently either undergoing trials or are being included in registries. These successes make it probable that as technology advances, the field of fetal therapy may evolve at a pace that outstrips our ability to anticipate or initiate regulation in the field. As practitioners, we must take the initiative to set standards of care for the performance of all fetal procedures in order to achieve the most favorable outcomes, ensure maternal and fetal safety, minimize complications, and provide appropriate resources for their management if complications occur. In addition to proposing a modification to the original philosophical and systems principles (Table 1), we maintain that there should be expectations for the resources, expertise, credentialing, and infrastructure for an organization, medical staff, and personnel who work in a FTC (Table 2). Additionally, since many fetal diseases represent medically and ethically complex situations, we strongly advocate the development of multidisciplinary therapy teams as appropriate.

Our proposed modification assumes that all prenatal interventions should be in compliance with the basic principles of fetal therapy (Table 1). Within this scope, fetal therapy can be divided into medical or surgical approaches that aim to achieve a complete prenatal cure, alleviate severe pediatric developmental or functional deficiencies, or optimize the fetal transition to extrauterine life. Fetal interventions are classified broadly to include the following: (1) ultrasound-guided needle procedures (e.g., fetal blood sampling, intrauterine transfusion, shunts, balloon valvuloplasty, and radiofrequency ablation or interstitial laser coagulation); (2) fetoscopic procedures (placental laser ablation for TTTS, umbilical cord occlusion, tracheal balloon occlusion, amniotic band release, laser ablation for lower urinary tract obstruction, and myelomeningocele repair); (3) open fetal surgery (myelomeningocele repair or resection of some lung masses or teratomas), and (4) ex utero intrapartum treatment procedures for the management of anomalies compromising the newborn's airway. Though some overlap may exist in the procedures that are offered for a given condition, in our proposed modification, “open” fetal surgery refers to any procedure requiring a hysterotomy in contrast to those involving only the insertion of a fetoscope.

A FTC is more difficult to define, but it should at a minimum be able to provide advanced imaging services, a variety of established fetal therapies and innovative approaches to fetal disease, and possibly conduct, facilitate, or participate in research if appropriate to the setting within its particular health-care delivery system. A FTC may be either a freestanding self-contained center or may draw on expertise and resources from physically separate facilities to provide consultation or therapy and to manage any fetal or maternal complications (including pregnancy termination if this is an option) that may result from the fetal condition or the therapy. It may be more logical to consider the necessary components in the context of diseases that are treated and services that are provided (Table 2), with a pragmatic approach to inclusion of components suggested in the context of services provided at any given center.

Fetal interventions should be subjected to scientific scrutiny by inclusion in institutional, national, regional, or international trials and registries. Initially, the pioneers in this area recognized the need for transparency in reporting outcomes (Table 1). To some extent, this has been realized, albeit sporadically, though efforts have largely focused on disease-specific clinical trials or registries. To date, randomized controlled trials for laser therapy for TTTS, open repair of fetal myelomeningocele, early treatment for acardiac twins, and tracheal occlusion for fetal CDH have been completed or are underway, and registries exist for fetal cardiac interventions [6], post-trial myelomeningocele repair [18], and fetal monochorionic twin complications and interventions. However, many fetal procedures are not being evaluated rigorously, and none of the registries are public or funded beyond their initial startup costs. One attempt to address this need is being made within the NAFTNet, a consortium of over 30 medical centers in the United States and Canada, which collaborate on research in fetal diseases. Reporting a center's clinical experience is a prerequisite for membership, and funding is through institutional membership dues.

To assure both access to care for patients and an adequate patient volume to maintain expertise for practitioners and teams, more attention needs to be focused on resource planning, publication, dissemination and quality benchmarking of outcomes and complications, public reporting, and the larger context of facilitating patient access to appropriate care. There is evidence to support the regionalization of subspecialty care in other areas of medicine [19,20,21,22]. In certain types of fetal therapy (e.g., laser for TTTS and intrauterine transfusion for red blood cell alloimmunization), the benefits of regionalization of care and concentration of volume have been clearly demonstrated [13,23,24,25], but in others, support comes from expert opinion only [26]. In fact, it is equally clear that mere volume and/or individual experience do not guarantee excellence in clinical outcomes when center-based medicine is examined (e.g., the “Bristol experience” in which imposed regionalization of congenital cardiac care actually led to worse outcomes for children in the UK) [27]. Nevertheless, it seems reasonable to assume that regionalization of care for rare conditions and procedures would allow centers not only to maintain adequate volume and expertise for the fetal interventions per se, but also to develop crucial supportive components of care, such as evaluation, counseling, and education. Eventually, formalized training and credentialing programs - similar to those regarding nuchal translucency screening or cervical length screening, for instance - might be a reasonable goal. Although often politically daunting, task forces to develop formal recommendations regarding the number and geographic distribution of FTCs should be formed to address these issues as well as the overarching issue of patient access to care.

We must also plan to train the next generation of fetal therapists. There is currently no formal international program for training in fetal therapy. Several centers in the United States, Canada, UK, and Europe offer nonaccredited fetal intervention “fellowships” that can be entered after completion of formal training in either pediatric surgery or maternal fetal medicine. Many physicians then enter into an even less well-defined “apprenticeship” model in which junior faculty are gradually allowed to develop the requisite skill set to operate independently. Systems should be developed that allow for more formalized training in fetal intervention, and minimum standards for proficiency - which will vary with provider role and type of procedure - should be discussed in an open forum with practitioners, training program administrators, and graduate medical education or the equivalent officials. These efforts should begin formally as soon as reasonably feasible. The best framework for this effort and the appropriate participants have not been determined, but a formal dialog among major centers in the Americas, Europe, and Asia has already begun.

Centers that perform invasive fetal procedures should report their maternal, fetal, and newborn outcomes as transparently as possible, for example under the auspices of clinical trials or in registries. For certain procedures (particularly those still considered as innovative or under research), a nonpartisan, objective, multidisciplinary institutional oversight committee is important. Such committees should include individuals not directly involved in clinical care of the patients and could consist of maternal-fetal medicine specialist(s), hospital ethicist(s), pediatric surgeon(s), neonatologist(s), medical staff office chief of staff, and other members as necessary, including patients themselves. These committees may sometimes also serve as reviewing bodies for the purposes of institutional or ethical review board presubmission review for research proposals or clinical trials.

Rapid evolution in the field of fetal therapy has led to the need to revise the initial guiding principles set forth by Harrison et al. [1] more than 3 decades ago. FTCs are ethically obliged to consider both maternal and fetal wellbeing and complications when any fetal intervention is being considered. Centers are also obliged to ensure that appropriate training, credentialing, infrastructure, and institutional support and oversight are in place. A core organizational structure and expertise level will be essential for all fetal therapeutic procedures and for maternal care. Additional infrastructure and subspecialty availability will be necessary for others. Rather than hindering innovation, appropriate and thoughtful preparation and requirements for infrastructural support and commitment should encourage advancement of the field in the decades to come. In all settings, mechanisms for the provision of training, regulation, and oversight should be developed. Multidisciplinary, collaborative, and multi-institutional experience sharing in the form of registries and collaborative multicenter prospective research are essential to continue moving this field forward. As the field matures, the development of robust and sustainable training programs will be essential for continual development of fetal therapy. The most appropriate and reasonable balance between safe innovation, development of new high-quality centers, acquisition and maintenance of skills, and realistic patient access to care within or even outside of highly specialized centers must be carefully considered.

A conceptual framework is presented for redefining the field of fetal treatment, including necessary expertise and systems base for provision of interventions involving mother and fetus.

We would like to acknowledge Pamela Derish in the UCSF Department of Surgery for her assistance in preparing this manuscript.

NAFTNet is supported by grant #5R13HD059293-05 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

M.E.N. was a co-principal investigator for clinical trial NCT0145167 sponsored by Ariosa Diagnostics. Her institution received unrestricted research funding for her research program from Natera. The other authors report no conflicts of interest.

Presented at the 35th Annual Meeting of the International Fetal Medicine and Surgical Society, August 2-7, 2016, Kasane, Botswana.