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An Overview of Surgical Techniques, Research Trials, and Future Directions of Fetal Therapy
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An Overview of Surgical Techniques, Research Trials, and Future Directions of Fetal Therapy Jody Farrell and Lori J. Howell
Correspondence Jody Farrell, MSN, PNP, UCSF Fetal Treatment Center, 400 Parnassus Ave, Room A-123, San Francisco, CA 94143-0570. [email protected]
ABSTRACT During the latter part of the 20th century, the fetus became recognized as a patient separate from the mother. Powerful imaging and sampling techniques provided insight into normal fetal development and the opportunity to detect anomalies. In this overview of the rapidly evolving fetal surgery field, we describe the evolution of surgical techniques, clinical trials, and emerging research. We hope to ignite interest among professionals in this growing area of patient care.
JOGNN, 00, 1-7; 2012. DOI: 10.1111/j.1552-6909.2012.01356.x Accepted October 2011
Keywords fetal diagnosis fetal treatment fetal surgery congenital anomaly
Jody Farrell, MSN, PNP, is the director of the UCSF Fetal Treatment Center, San Francisco, CA. Lori J. Howell, RN, MS, is executive director of the Center for Fetal Diagnosis and Treatment, The Children’s Hospital of Philadelphia, Philadelphia, PA.
pproximately three decades ago, the fetus began to be recognized as a patient separate from the mother, which led to advances in fetal in-utero treatments (Deprest, Devlieger, et al., 2010; Deprest, Flake, et al., 2010; Watanabe & Flake, 2010). As providers gained experience in fetal therapy, what has become unequivocally clear is the fact that the mother and fetus are a complicated and interdependent dyad. Thus, a multidisciplinary approach to diagnosis and treatment of fetal diseases has advanced this highly specialized field of medicine. This article provides a brief overview of advances in fetal therapy, including the evolution of surgical techniques, experience with fetal intervention for congenital diaphragmatic hernia, the development of the ex utero intrapartum (EXIT) procedure, the first fetal surgery clinical trials, and an overview of the future direction of fetal treatment.
A
Advances in Fetal Therapy
The authors report no conflict of interest or relevant financial relationships.
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Advances in technology were largely responsible for identifying fetuses as a new patient population (Deprest, Devlieger, et al., 2010; Deprest, Flake, et al., 2010; Watanabe & Flake, 2010). Initially, the advent of ultrasound and laboratory techniques enabled sonologists, maternal/fetal medicine spe-
cialists, and geneticists to follow the natural history of birth defects by examining the untreated conditions through gestation and developing the ability to accurately diagnosis fetal problems before birth. However, despite this newfound ability to diagnose fetal abnormalities in utero, the standard of care for affected fetuses was medical and/or surgical treatment after birth. Neonatologists and surgeons were particularly frustrated with the inability to change the course of certain problems in the newborn and improve neonatal outcomes, as many of these infants had already suffered irreversible damage by the time of delivery. The presentation of the fetus with a diagnosed defect and the newborn with an uncorrectable disorder led to the realization that some fetal diseases might be best managed before birth (Harrison, 1982). From a strategic standpoint, fetal therapy and more specifically fetal surgery promised to be a reasonable solution. As a pioneer in 1963, Sir William Liley was the first doctor to administer a blood transfusion to a fetus prior to birth (Liley, 1963). While working as a senior research fellow at an Army hospital, he developed and successfully performed fetal intraabdominal blood transfusion to temporarily mitigate the effects of severe hemolytic disease (hydrops fetalis caused by Rh sensitization-induced
C 2012 AWHONN, the Association of Women’s Health, Obstetric and Neonatal Nurses
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An Overview of Surgical Techniques, Research Trials, and Future Directions of Fetal Therapy
Early achievements in fetal therapy were not related to disease management but demonstrated that the fetus is accessible and regarded as a patient.
to retrospective analysis to randomized clinical trials (Jancelewicz & Harrison, 2009).
Evolution of Surgical Techniques
anemia) in an affected fetus. The significance of his achievement was not so much a major advance in the management of hydrops fetalis but rather a demonstration that antenatal fetal diagnosis and treatment were plausible (Hawgood, 2005). From a medical point of view, he opened the door for future fetal therapies; from a medical ethics point of view, his work suggested the fetus could be regarded as a patient. Over the past three decades, fetal surgery for congenital disease has evolved from a mere concept to a medical subspecialty field. Techniques for open hysterotomy, minimal-access hysteroscopy, and image-guided percutaneous fetal access have become well established, first in animal models and subsequently in humans. At the same time, major advances in fetal imaging, diagnoses, and anesthesia have allowed fetal intervention to become a vital tool for subsets of patients who would otherwise face significant morbidity and mortality (Luks, 2011). However, all fetal intervention is a combined maternal/fetal intervention. A continual balance exists between weighing the benefits of a fetal intervention against the potential risks to the mother’s health and her ability to have other children (Jelin & Lee, 2009). For instance, follow-up studies regarding maternal outcomes have found that short-term morbidities include increased rates of cesarean birth, treatment in intensive care, prolonged hospitalization, and blood transfusion, all of which were more common with hysterotomy when compared with other techniques. However, maternal/fetal surgery has been performed without maternal death and without affecting the woman’s future reproductive potential. These findings are useful in counseling prospective patients (Farrell et al., 1999; Golombeck et al., 2006; Longaker et al., 1991). Several significant milestones in fetal therapy include the evolution of surgical techniques from open surgery by hysterotomy to less invasive fetoscopic techniques, the transition from anatomic repair to physiologic manipulation for severe congenital diaphragmatic hernia (CDH), and the progression from clinical description or case studies
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Three general fetal intervention approaches have been developed in the last few decades. Whether to perform a minimally or more extensive invasive fetal surgery is dependent on the fetal condition. Open fetal surgery is the most invasive intervention. Guided by ultrasound, the surgery requires general anesthesia for maternal pain control, uterine relaxation, and fetal anesthesia. During the procedure, a low transverse incision is performed on the maternal abdomen and the uterus is exposed. Guided by intraoperative ultrasound, the fetus is administered a narcotic and paralytic agent such as pancuronium bromide and fentanyl intramuscularly. During the repair, only the fetal body part needing the repair is exposed rather than the entire fetus. After the defect is repaired, the fetal body part is returned to the uterus, amniotic fluid is replaced with warmed Ringer’s lactate, and the uterus is closed. An epidural provides postoperative pain control, and hospitalization is generally less than one week. During the immediate postoperative period, pain is managed with epidural anesthesia. Subsequently, due to the risk of preterm labor, tocolytic administration is required throughout the gestation along with close surveillance for signs and symptoms of preterm labor. Because of the hysterotomy, the mother must deliver by cesarean for the current and future pregnancies. Minimally invasive fetal surgery is another technique that has been adapted from laparoscopic surgery and early fetoscopy. Laser surgery for the treatment of twin–twin transfusion syndrome is an example of fetoscopy. “Fetendo” is the name applied to intervention involving surgical manipulation of the fetus with very small instruments guided by direct fetoscopic viewed on a television monitor (Sydorak, Nijagal, & Albanese, 1991). As these techniques evolved and were refined, simultaneous use of dual-visualization techniques was determined to be best for imaging. Dual-visualization techniques images the fetus in real time using endoscopic (through the telescope) and sonographic (cross-sectional imaging of the fetus) pictures that are displayed on two separate screens. The combination of two visual images to guide manipulation proved to be successful in treating a number of fetal problems such as twin–twin transfusion syndrome, congenital diaphragmatic hernia, and fetal bladder obstruction.
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Fetendo intervention is performed either percutaneously or in some circumstances may require a maternal minilaparotomy. The fetendo surgery requires spinal anesthesia. During the procedure, the surgeon inserts 1mm to 5 mm trocars and scopes through the uterine wall, performs the procedure, removes the trocars, and closes the port sites. The patient may require an overnight hospital stay. This less invasive approach avoids maternal morbidities such as bleeding and preterm labor that are associated with a large abdominal incision and hysterotomy. Fetendo surgery allows vaginal delivery for current and subsequent pregnancies. The least invasive technique is fetal image-guided surgery for intervention or therapy (FIGS-IT), a method of fetal intervention without an incision in the uterus or an endoscopic view inside the uterus. The method uses ultrasonic guidance in adjunct to procedures such as amniocentesis and radiofrequency ablation for the treatment of twinreversed arterial perfusion (TRAP). Being the least invasive technique, FIGS-IT has the least risk of preterm labor, maternal discomfort, and hospitalization postprocedure. Unfortunately, neither fetendo nor FIGS-IT has eliminated the problem of preterm labor, necessitating the need for preterm labor surveillance and possible tocolytic therapy. Finally, the EXIT procedure is a type of intervention that occurs at the time of birth (Hirose, Farmer, Lee, Nobuhara, & Harrison, 2004; Howell, Burns, Lengetti, & Kerr, 2002). It is performed in instances of suspected neonatal airway compromise that may require surgical intervention as in congenital high airway obstruction syndrome (CHAOS) or with tracheal occlusion for congenital diaphragmatic hernia (CDH). The EXIT procedure provides the infant with a functioning airway, so oxygen can be delivered to the lungs after the infant is separated from the placenta. The EXIT procedure is a planned, specialized delivery involving the mother and the infant that should be performed by a medical team consisting of a pediatric surgeon, obstetrician, anesthesiologist, and neonatologist only. The procedure is similar to a cesarean birth under general anesthesia to ensure complete uterine relaxation. After delivery of the head, the pediatric surgeon assesses the infant’s airway with a laryngoscope or bronchoscope. Depending on the type of blockage, the surgeon may insert an endotracheal tube for ventilation. Conversely, if a tube cannot be inserted orally through the obstruction, the surgeon performs a neck incision and inserts a tracheostomy tube below the level of the
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airway blockage. Once oxygen is delivered via a patent airway, the infant is delivered and the umbilical cord cut. Further surgical interventions are elective, for example, resection of the neck mass or airway reconstruction. Careful planning and an experienced multidisciplinary team are crucial to the success of the EXIT procedure.
Anatomic Repair to Physiologic Manipulation for Severe Congenital Diaphragmatic Hernia (CDH) The history and evolution of fetal diagnosis and therapy for a CDH is perhaps the best illustration of the the success and failure of innovations that are developed and refined in the rapidly changing field of fetal surgery. Occurring in about 1 in 3,000 live births, a CDH is characterized by an incomplete formation of the diaphragm that allows abdominal viscera to herniate into the thorax. The herniated abdominal contents impair lung development resulting in pulmonary hypoplasia. The prognosis and outcome for fetuses with congenital diaphragmatic hernia vary in each pregnancy. The position of the liver (the so-called liver up or liver down) and the lung-to-head ratio (LHR) confirmed by ultrasound determine the severity of the defect and whether the fetus may benefit from prenatal intervention (Metkus, Filly, Stringer, Harrison, & Adzick, 1996). Although recent advances in neonatal care (particularly neonatal ventilatory management) have substantially reduced mortality, fetuses with severe lung hypoplasia continue to have a poor prognosis (Gucciardo et al., 2008). The first definitive attempt to repair a CDH with open fetal surgery (maternal abdominal incision and hysterotomy) was in 1984 (Harrison et al., 1990). Via a fetal abdominal incision the viscera was removed from the chest, a patch placed on the diaphragm, and an abdominal silo constructed (to reduce the intra-abdominal pressure). Overall, this surgical approach had a dismal outcome, particularly if a portion of the liver had herniated into the chest. After many failures, the procedure was abandoned for fetuses presenting with the most severe of CDH cases. However, the strategy of in-utero repair for a CDH was not abandoned completely. Instead, selection criteria were better defined to identify fetuses that would most benefit from intervention. This refinement in selection criteria led to the very first randomized controlled trial comparing fetal surgery to standard postnatal care for fetuses with a less severe form of CDH, that is, those with no liver herniated into
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the thorax, or “liver down.” At the conclusion of the study, survival rates of the two groups were comparable, and as a result this approach for liver down CDH was abandoned (Harrison et al., 1993). Continued research to develop a prenatal treatment for CDH led to a serendipitous approach. Fetuses diagnosed with CHAOS present with either trachea or laryngeal stenosis or atresia. Physiologically, the fetal lungs constantly produce fluid under the positive pressure environment while in utero. Because of the airway blockage from CHAOS, the lung fluid cannot escape out of the fetal mouth, and the fetal lungs become distended with fluid. Observation of the physiologic effects of CHAOS led investigators to apply these same principles of fluid dynamics toward a new approach to fetal intervention for CDH (Hedrick et al., ??). The strategy of in-utero temporary tracheal occlusion (TO) is based on the premise that creating a temporary obstruction in the fetal trachea will interfere with the normal egress of lung fluid, expand and promote growth of the lungs, and therefore improve lung function. A significant learning curve was associated with the TO technique leading to the evolution of the procedure during a decade of research. Tracheal occlusion was first accomplished with open fetal surgery for trachea plug placement (Hedrick et al.) and later accomplished with the use of external tracheal clips (VanderWall et al., 1996). Both procedures were major operations for the mother who required a hysterotomy that often resulted in preterm labor and birth. In an attempt to decrease maternal morbidity, researchers developed an endoscopic approach to TO (Kohl, 2010). In selected fetuses between 24 and 28 weeks’ gestation, the surgeon performed fetal bronchoscopic surgery through the uterine wall and inflated a balloon in the trachea to obstruct the flow of fetal lung fluid. Once the procedure was perfected, a National Institutes of Health (NIH) sponsored a prospective randomized clinical trial to compare two groups of patients: fetuses with the TO intervention and neonates with optimal standard postnatal care. The trial results did not demonstrate improved survival in the TO group (both groups had a 90-day survival of 75%). Researchers hypothesized that a flaw in the study design confounded these results. These researchers believed that the inclusion criteria for the study sample were too broad and did not target the fetuses with the most severe form of CDH (LHR < 1.0) (Harrison et al., 2003). An upcoming clinical
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trial will target pregnant women with fetuses diagnosed with CDH, liver up, and a LHR < 1.0, as neonatal survival based on these prognostic factors is less than 60%. In this next trial, participants will undergo reversal of the TO (removal of the balloon) between 32 and 34 weeks’ gestation by minimally invasive techniques. The advantage of balloon removal prior to birth is twofold: the mother can deliver vaginally, and removing the tracheal obstruction allows normal development of surfactant-producing type II pneumocytes (Flageole et al., 1998).
Progression from Case Studies to Retrospective Analysis to Randomized Clinical Trials Open neural tube defects are a group of congenital abnormalities that arise by day 28 postconception when some portion of the neural tube fails to close. In the United States annually approximately 2,500 to 3,000 fetuses are affected with some sort of open neural tube defect, one half of which are open spina bifida. The Centers for Disease Control and Prevention estimated the annual medical care and surgical costs for persons with spina bifida exceeds $200 million per year (Centers for Disease Control [CDC], 1989). Open spina bifida can occur either as a flat defect without a fluid filled sac covering (myeloschisis), with a membranous covering (meningocele), or membranous covering with extrusion of the spinal cord into the fluid-filled sac (myelomeningocele [MMC]). Myelomeningocele is the most severe form of spina bifida with approximately 600 to 1,100 newborns affected annually in the United States (Boulet et al., 2008). The sequelae of this condition affect the central and peripheral nervous systems. In most cases, the altered cerebral spinal fluid dynamics result in the Chiari II malformation (hindbrain herniation) and hydrocephalus. The damage to the exposed spinal cord results in lifelong lower extremity neurological dysfunction, bowel and bladder incontinence, and skeletal deformities. This defect carries enormous personal, familial, and societal costs. Until the 1990s, the only prenatal options available to expectant couples after a fetus was diagnosed with a MMC were expectant management with cesarean birth and postnatal therapy for the child, or pregnancy termination. Neonatal management consisted of prompt closure of the defect in an attempt to prevent infection or further injury to the exposed neural elements.
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In cases of MMC, the primary defect is in the bony aspect of the spinal column, which then exposes the normal spinal cord to trauma from amniotic fluid exposure and uterine wall friction. This revelation led to experimental work in the fetal sheep model, which attempted to patch over and protect the spinal cord in-utero to minimize the sequelae (Meuli et al., 1995). By 1997, the first human fetal surgery cases of MMC repair were being performed at Children’s Hospital of Philadelphia, Vanderbilt University Medical Center, and the University of California San Francisco (Adzick, Sutton, Crombleholme, & Flake, 1998). Fetal repair in this initial clinical experience decreased hindbrain herniation and the development of hydrocephalus and therefore the need for ventricular shunting. Children also had better-than-predicted lower extremity function (Bruner et al., 1999; Sutton et al., 1999). These promising results led to a cooperative agreement to conduct a NIH-sponsored, randomized controlled clinical trial titled the Management of Myelomeningocele Study or MOMS study. The purpose of this trial was to compare the safety and efficacy of in-utero repair of MMC with that of the standard postnatal repair. The two primary end points were improvement of outcome, as measured by death or the need for ventricular decompressing shunting by one year of age and improvement in neurologic function at 30 months corrected age as measured by a combined rank score of the Bayley Scales of Infant Development mental development index and the difference between the functional motor level versus anatomic lesion level. Enrollment at the three MOMS study sites began in 2003, and by December 2010, the MOMS’s Data and Safety Monitoring Board (DSMB) recommended ending study recruitment for reasons of efficacy of prenatal surgery, not for safety concerns. Study end points were found to be statistically significantly different between the surgery groups. In short, the prenatal surgery group was found to have a decreased need for a ventriculoperitoneal shunt and were also more likely to walk unassisted (Adzick et al., 2011). The DSMB recommended further follow-up of the children until school age to observe whether the results were sustained. That separate long-term follow-up study will be completed in 2016.
The Future of Fetal Therapy With the fetus established as a patient, improvements in prenatal diagnosis may add significantly to the treatable population. For example,
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Fetal therapy expands the options available to families after a fetus is diagnosed with an anomaly.
fetuses with inherited diseases such as severe combined immunodeficiency disease syndrome, hemophilia, enzyme deficiencies, and sickle-cell anemia may be diagnosed in utero and benefit from gene therapy or stem cell transplantation (Wagner, Schoeberlein, & Surbek, 2009). Most promising is transplantation of allogeneic stem cells into the early gestational fetus, a treatment termed in utero hematopoietic cell transplantation (IUHCTx). Prenatal transplant could overcome the limitations of bone marrow transplants and avoid graft rejection and the use of immunosuppression (Peranteau et al., 2009). At present, clinical use of IUHCTx has been hampered by poor engraftment, possibly due to a host immune response against the graft. Nijagal et al. (2011) hypothesized that maternal cells crossing into the fetus may pose the true barrier to effective IUHCTx, because the fetal immune system itself is relatively immature. The investigators demonstrated that the mother had increased T cell production after in utero transplantation of the fetus and further determined that there was a marked improvement in fetal engraftment if the mother lacked T cells but not B cells, indicating that maternal T cells are the main barrier to total engraftment. This study suggests that the clinical success of IUHCTx may be improved by transplanting the fetus with cells matched to the mother. In addition, key to the future of potential therapies is the discovery that the immune system of fetuses and, to some degree newborns, is designed specifically to tolerate foreign bodies to prevent it from attacking its own developing cells or its host mother’s cells (Ichinohe, 2010). Essentially this response is the opposite response of the adult immune system, which aggressively attacks threats such as tumors and viruses, bacteria, and fungi that cause infection. This discovery not only challenges the long-held assumption that fetuses and newborn babies have weak, immature immune systems that need time to build up to full strength after birth, but also could have profound effects on how to study and treat a wide variety of human ailments, from HIV and sickle-cell disease, to childhood allergies. Prior to this work, the general belief was that fetal immune cells were immature and nonfunctional. Instead, researchers have found that the cells in the fetus are functional
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Advances in fetal therapy should be developed and implemented in the best interest of the mother/fetus patient dyad.
and in fact have a robust, albeit nonaggressive, immune response against cells that are foreign. Researchers hope to use fetal immune tolerance to prenatally treat and maybe even cure diseases before birth (Roifman, Fischer, Notarangelo, de la Morena, & Seger, 2010). One example is sicklecell disease, which can be cured with stem cell transplants that encourage the body to produce new, healthy blood cells. Transplant rejection has been a major obstacle. Stem cells transplanted into fetuses to cure conditions before birth have almost always been rejected, most likely because the mother’s immune system is fighting them off. If the stem cells that are a match to the mother, or better yet, if the mother’s own cells could be transplanted, the infant could be born almost cured of the disease.
standard of care. This specialized field of high-risk obstetrics provides us with hope to help fetuses with a correctable problem but humbles us to know there is potential for doing harm (Dickens & Cook, 2011). Fetal therapy does offer hope to expectant couples with a fetus with a correctable defect but with the potential of also doing harm. The advances in the field have been made possible with laboratory testing, advancements in technology, and mastery of surgical techniques but are implemented only after the thorough and honest multidisciplinary counseling of families. Fetal survival, regardless of the treatment sequelae, may not be the right reason to offer an intervention. Just because a procedure can be done does not always mean it should be done. It is the responsibility of the health care teams involved to further the field of fetal therapy, keeping in mind the best interests of both patients: mother and fetus.
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N. S., & Harrison, M. R. (1996). Fetal endoscopici (‘Fetendo’)
plantation. Chimerism, 1, 39–43. Jancelewicz, T., & Harrison, M. R. (2009). A history of fetal surgery. Clinics in Perinatology, 36, 227–236. Jelin, E., & Lee, H. (2009). Tracheal occlusion for fetal congenital diaphragmatic hernia: The US experience. Clinics in Perinatology, 36, 349–361.
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tracheal clip. Journal of Pediatric Surgery, 31, 1101–1103. Wagner, A. M., Schoeberlein, A., & Surbek, D. (2009). Fetal gene therapy: Opportunities and risks. Advanced Drug Delivery Reviews, 10, 813–821. Watanabe, M., & Flake, A. W. (2010). Fetal surgery: Progress and perspectives. Advances in Pediatrics, 57, 353–372.
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An Overview of Surgical Techniques, Research Trials, and Future Directions of Fetal Therapy Jody Farrell and Lori J. Howell
Correspondence Jody Farrell, MSN, PNP, UCSF Fetal Treatment Center, 400 Parnassus Ave, Room A-123, San Francisco, CA 94143-0570. [email protected]
ABSTRACT During the latter part of the 20th century, the fetus became recognized as a patient separate from the mother. Powerful imaging and sampling techniques provided insight into normal fetal development and the opportunity to detect anomalies. In this overview of the rapidly evolving fetal surgery field, we describe the evolution of surgical techniques, clinical trials, and emerging research. We hope to ignite interest among professionals in this growing area of patient care.
JOGNN, 00, 1-7; 2012. DOI: 10.1111/j.1552-6909.2012.01356.x Accepted October 2011
Keywords fetal diagnosis fetal treatment fetal surgery congenital anomaly
Jody Farrell, MSN, PNP, is the director of the UCSF Fetal Treatment Center, San Francisco, CA. Lori J. Howell, RN, MS, is executive director of the Center for Fetal Diagnosis and Treatment, The Children’s Hospital of Philadelphia, Philadelphia, PA.
pproximately three decades ago, the fetus began to be recognized as a patient separate from the mother, which led to advances in fetal in-utero treatments (Deprest, Devlieger, et al., 2010; Deprest, Flake, et al., 2010; Watanabe & Flake, 2010). As providers gained experience in fetal therapy, what has become unequivocally clear is the fact that the mother and fetus are a complicated and interdependent dyad. Thus, a multidisciplinary approach to diagnosis and treatment of fetal diseases has advanced this highly specialized field of medicine. This article provides a brief overview of advances in fetal therapy, including the evolution of surgical techniques, experience with fetal intervention for congenital diaphragmatic hernia, the development of the ex utero intrapartum (EXIT) procedure, the first fetal surgery clinical trials, and an overview of the future direction of fetal treatment.
A
Advances in Fetal Therapy
The authors report no conflict of interest or relevant financial relationships.
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Advances in technology were largely responsible for identifying fetuses as a new patient population (Deprest, Devlieger, et al., 2010; Deprest, Flake, et al., 2010; Watanabe & Flake, 2010). Initially, the advent of ultrasound and laboratory techniques enabled sonologists, maternal/fetal medicine spe-
cialists, and geneticists to follow the natural history of birth defects by examining the untreated conditions through gestation and developing the ability to accurately diagnosis fetal problems before birth. However, despite this newfound ability to diagnose fetal abnormalities in utero, the standard of care for affected fetuses was medical and/or surgical treatment after birth. Neonatologists and surgeons were particularly frustrated with the inability to change the course of certain problems in the newborn and improve neonatal outcomes, as many of these infants had already suffered irreversible damage by the time of delivery. The presentation of the fetus with a diagnosed defect and the newborn with an uncorrectable disorder led to the realization that some fetal diseases might be best managed before birth (Harrison, 1982). From a strategic standpoint, fetal therapy and more specifically fetal surgery promised to be a reasonable solution. As a pioneer in 1963, Sir William Liley was the first doctor to administer a blood transfusion to a fetus prior to birth (Liley, 1963). While working as a senior research fellow at an Army hospital, he developed and successfully performed fetal intraabdominal blood transfusion to temporarily mitigate the effects of severe hemolytic disease (hydrops fetalis caused by Rh sensitization-induced
C 2012 AWHONN, the Association of Women’s Health, Obstetric and Neonatal Nurses
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An Overview of Surgical Techniques, Research Trials, and Future Directions of Fetal Therapy
Early achievements in fetal therapy were not related to disease management but demonstrated that the fetus is accessible and regarded as a patient.
to retrospective analysis to randomized clinical trials (Jancelewicz & Harrison, 2009).
Evolution of Surgical Techniques
anemia) in an affected fetus. The significance of his achievement was not so much a major advance in the management of hydrops fetalis but rather a demonstration that antenatal fetal diagnosis and treatment were plausible (Hawgood, 2005). From a medical point of view, he opened the door for future fetal therapies; from a medical ethics point of view, his work suggested the fetus could be regarded as a patient. Over the past three decades, fetal surgery for congenital disease has evolved from a mere concept to a medical subspecialty field. Techniques for open hysterotomy, minimal-access hysteroscopy, and image-guided percutaneous fetal access have become well established, first in animal models and subsequently in humans. At the same time, major advances in fetal imaging, diagnoses, and anesthesia have allowed fetal intervention to become a vital tool for subsets of patients who would otherwise face significant morbidity and mortality (Luks, 2011). However, all fetal intervention is a combined maternal/fetal intervention. A continual balance exists between weighing the benefits of a fetal intervention against the potential risks to the mother’s health and her ability to have other children (Jelin & Lee, 2009). For instance, follow-up studies regarding maternal outcomes have found that short-term morbidities include increased rates of cesarean birth, treatment in intensive care, prolonged hospitalization, and blood transfusion, all of which were more common with hysterotomy when compared with other techniques. However, maternal/fetal surgery has been performed without maternal death and without affecting the woman’s future reproductive potential. These findings are useful in counseling prospective patients (Farrell et al., 1999; Golombeck et al., 2006; Longaker et al., 1991). Several significant milestones in fetal therapy include the evolution of surgical techniques from open surgery by hysterotomy to less invasive fetoscopic techniques, the transition from anatomic repair to physiologic manipulation for severe congenital diaphragmatic hernia (CDH), and the progression from clinical description or case studies
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Three general fetal intervention approaches have been developed in the last few decades. Whether to perform a minimally or more extensive invasive fetal surgery is dependent on the fetal condition. Open fetal surgery is the most invasive intervention. Guided by ultrasound, the surgery requires general anesthesia for maternal pain control, uterine relaxation, and fetal anesthesia. During the procedure, a low transverse incision is performed on the maternal abdomen and the uterus is exposed. Guided by intraoperative ultrasound, the fetus is administered a narcotic and paralytic agent such as pancuronium bromide and fentanyl intramuscularly. During the repair, only the fetal body part needing the repair is exposed rather than the entire fetus. After the defect is repaired, the fetal body part is returned to the uterus, amniotic fluid is replaced with warmed Ringer’s lactate, and the uterus is closed. An epidural provides postoperative pain control, and hospitalization is generally less than one week. During the immediate postoperative period, pain is managed with epidural anesthesia. Subsequently, due to the risk of preterm labor, tocolytic administration is required throughout the gestation along with close surveillance for signs and symptoms of preterm labor. Because of the hysterotomy, the mother must deliver by cesarean for the current and future pregnancies. Minimally invasive fetal surgery is another technique that has been adapted from laparoscopic surgery and early fetoscopy. Laser surgery for the treatment of twin–twin transfusion syndrome is an example of fetoscopy. “Fetendo” is the name applied to intervention involving surgical manipulation of the fetus with very small instruments guided by direct fetoscopic viewed on a television monitor (Sydorak, Nijagal, & Albanese, 1991). As these techniques evolved and were refined, simultaneous use of dual-visualization techniques was determined to be best for imaging. Dual-visualization techniques images the fetus in real time using endoscopic (through the telescope) and sonographic (cross-sectional imaging of the fetus) pictures that are displayed on two separate screens. The combination of two visual images to guide manipulation proved to be successful in treating a number of fetal problems such as twin–twin transfusion syndrome, congenital diaphragmatic hernia, and fetal bladder obstruction.
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Fetendo intervention is performed either percutaneously or in some circumstances may require a maternal minilaparotomy. The fetendo surgery requires spinal anesthesia. During the procedure, the surgeon inserts 1mm to 5 mm trocars and scopes through the uterine wall, performs the procedure, removes the trocars, and closes the port sites. The patient may require an overnight hospital stay. This less invasive approach avoids maternal morbidities such as bleeding and preterm labor that are associated with a large abdominal incision and hysterotomy. Fetendo surgery allows vaginal delivery for current and subsequent pregnancies. The least invasive technique is fetal image-guided surgery for intervention or therapy (FIGS-IT), a method of fetal intervention without an incision in the uterus or an endoscopic view inside the uterus. The method uses ultrasonic guidance in adjunct to procedures such as amniocentesis and radiofrequency ablation for the treatment of twinreversed arterial perfusion (TRAP). Being the least invasive technique, FIGS-IT has the least risk of preterm labor, maternal discomfort, and hospitalization postprocedure. Unfortunately, neither fetendo nor FIGS-IT has eliminated the problem of preterm labor, necessitating the need for preterm labor surveillance and possible tocolytic therapy. Finally, the EXIT procedure is a type of intervention that occurs at the time of birth (Hirose, Farmer, Lee, Nobuhara, & Harrison, 2004; Howell, Burns, Lengetti, & Kerr, 2002). It is performed in instances of suspected neonatal airway compromise that may require surgical intervention as in congenital high airway obstruction syndrome (CHAOS) or with tracheal occlusion for congenital diaphragmatic hernia (CDH). The EXIT procedure provides the infant with a functioning airway, so oxygen can be delivered to the lungs after the infant is separated from the placenta. The EXIT procedure is a planned, specialized delivery involving the mother and the infant that should be performed by a medical team consisting of a pediatric surgeon, obstetrician, anesthesiologist, and neonatologist only. The procedure is similar to a cesarean birth under general anesthesia to ensure complete uterine relaxation. After delivery of the head, the pediatric surgeon assesses the infant’s airway with a laryngoscope or bronchoscope. Depending on the type of blockage, the surgeon may insert an endotracheal tube for ventilation. Conversely, if a tube cannot be inserted orally through the obstruction, the surgeon performs a neck incision and inserts a tracheostomy tube below the level of the
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airway blockage. Once oxygen is delivered via a patent airway, the infant is delivered and the umbilical cord cut. Further surgical interventions are elective, for example, resection of the neck mass or airway reconstruction. Careful planning and an experienced multidisciplinary team are crucial to the success of the EXIT procedure.
Anatomic Repair to Physiologic Manipulation for Severe Congenital Diaphragmatic Hernia (CDH) The history and evolution of fetal diagnosis and therapy for a CDH is perhaps the best illustration of the the success and failure of innovations that are developed and refined in the rapidly changing field of fetal surgery. Occurring in about 1 in 3,000 live births, a CDH is characterized by an incomplete formation of the diaphragm that allows abdominal viscera to herniate into the thorax. The herniated abdominal contents impair lung development resulting in pulmonary hypoplasia. The prognosis and outcome for fetuses with congenital diaphragmatic hernia vary in each pregnancy. The position of the liver (the so-called liver up or liver down) and the lung-to-head ratio (LHR) confirmed by ultrasound determine the severity of the defect and whether the fetus may benefit from prenatal intervention (Metkus, Filly, Stringer, Harrison, & Adzick, 1996). Although recent advances in neonatal care (particularly neonatal ventilatory management) have substantially reduced mortality, fetuses with severe lung hypoplasia continue to have a poor prognosis (Gucciardo et al., 2008). The first definitive attempt to repair a CDH with open fetal surgery (maternal abdominal incision and hysterotomy) was in 1984 (Harrison et al., 1990). Via a fetal abdominal incision the viscera was removed from the chest, a patch placed on the diaphragm, and an abdominal silo constructed (to reduce the intra-abdominal pressure). Overall, this surgical approach had a dismal outcome, particularly if a portion of the liver had herniated into the chest. After many failures, the procedure was abandoned for fetuses presenting with the most severe of CDH cases. However, the strategy of in-utero repair for a CDH was not abandoned completely. Instead, selection criteria were better defined to identify fetuses that would most benefit from intervention. This refinement in selection criteria led to the very first randomized controlled trial comparing fetal surgery to standard postnatal care for fetuses with a less severe form of CDH, that is, those with no liver herniated into
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the thorax, or “liver down.” At the conclusion of the study, survival rates of the two groups were comparable, and as a result this approach for liver down CDH was abandoned (Harrison et al., 1993). Continued research to develop a prenatal treatment for CDH led to a serendipitous approach. Fetuses diagnosed with CHAOS present with either trachea or laryngeal stenosis or atresia. Physiologically, the fetal lungs constantly produce fluid under the positive pressure environment while in utero. Because of the airway blockage from CHAOS, the lung fluid cannot escape out of the fetal mouth, and the fetal lungs become distended with fluid. Observation of the physiologic effects of CHAOS led investigators to apply these same principles of fluid dynamics toward a new approach to fetal intervention for CDH (Hedrick et al., ??). The strategy of in-utero temporary tracheal occlusion (TO) is based on the premise that creating a temporary obstruction in the fetal trachea will interfere with the normal egress of lung fluid, expand and promote growth of the lungs, and therefore improve lung function. A significant learning curve was associated with the TO technique leading to the evolution of the procedure during a decade of research. Tracheal occlusion was first accomplished with open fetal surgery for trachea plug placement (Hedrick et al.) and later accomplished with the use of external tracheal clips (VanderWall et al., 1996). Both procedures were major operations for the mother who required a hysterotomy that often resulted in preterm labor and birth. In an attempt to decrease maternal morbidity, researchers developed an endoscopic approach to TO (Kohl, 2010). In selected fetuses between 24 and 28 weeks’ gestation, the surgeon performed fetal bronchoscopic surgery through the uterine wall and inflated a balloon in the trachea to obstruct the flow of fetal lung fluid. Once the procedure was perfected, a National Institutes of Health (NIH) sponsored a prospective randomized clinical trial to compare two groups of patients: fetuses with the TO intervention and neonates with optimal standard postnatal care. The trial results did not demonstrate improved survival in the TO group (both groups had a 90-day survival of 75%). Researchers hypothesized that a flaw in the study design confounded these results. These researchers believed that the inclusion criteria for the study sample were too broad and did not target the fetuses with the most severe form of CDH (LHR < 1.0) (Harrison et al., 2003). An upcoming clinical
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trial will target pregnant women with fetuses diagnosed with CDH, liver up, and a LHR < 1.0, as neonatal survival based on these prognostic factors is less than 60%. In this next trial, participants will undergo reversal of the TO (removal of the balloon) between 32 and 34 weeks’ gestation by minimally invasive techniques. The advantage of balloon removal prior to birth is twofold: the mother can deliver vaginally, and removing the tracheal obstruction allows normal development of surfactant-producing type II pneumocytes (Flageole et al., 1998).
Progression from Case Studies to Retrospective Analysis to Randomized Clinical Trials Open neural tube defects are a group of congenital abnormalities that arise by day 28 postconception when some portion of the neural tube fails to close. In the United States annually approximately 2,500 to 3,000 fetuses are affected with some sort of open neural tube defect, one half of which are open spina bifida. The Centers for Disease Control and Prevention estimated the annual medical care and surgical costs for persons with spina bifida exceeds $200 million per year (Centers for Disease Control [CDC], 1989). Open spina bifida can occur either as a flat defect without a fluid filled sac covering (myeloschisis), with a membranous covering (meningocele), or membranous covering with extrusion of the spinal cord into the fluid-filled sac (myelomeningocele [MMC]). Myelomeningocele is the most severe form of spina bifida with approximately 600 to 1,100 newborns affected annually in the United States (Boulet et al., 2008). The sequelae of this condition affect the central and peripheral nervous systems. In most cases, the altered cerebral spinal fluid dynamics result in the Chiari II malformation (hindbrain herniation) and hydrocephalus. The damage to the exposed spinal cord results in lifelong lower extremity neurological dysfunction, bowel and bladder incontinence, and skeletal deformities. This defect carries enormous personal, familial, and societal costs. Until the 1990s, the only prenatal options available to expectant couples after a fetus was diagnosed with a MMC were expectant management with cesarean birth and postnatal therapy for the child, or pregnancy termination. Neonatal management consisted of prompt closure of the defect in an attempt to prevent infection or further injury to the exposed neural elements.
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In cases of MMC, the primary defect is in the bony aspect of the spinal column, which then exposes the normal spinal cord to trauma from amniotic fluid exposure and uterine wall friction. This revelation led to experimental work in the fetal sheep model, which attempted to patch over and protect the spinal cord in-utero to minimize the sequelae (Meuli et al., 1995). By 1997, the first human fetal surgery cases of MMC repair were being performed at Children’s Hospital of Philadelphia, Vanderbilt University Medical Center, and the University of California San Francisco (Adzick, Sutton, Crombleholme, & Flake, 1998). Fetal repair in this initial clinical experience decreased hindbrain herniation and the development of hydrocephalus and therefore the need for ventricular shunting. Children also had better-than-predicted lower extremity function (Bruner et al., 1999; Sutton et al., 1999). These promising results led to a cooperative agreement to conduct a NIH-sponsored, randomized controlled clinical trial titled the Management of Myelomeningocele Study or MOMS study. The purpose of this trial was to compare the safety and efficacy of in-utero repair of MMC with that of the standard postnatal repair. The two primary end points were improvement of outcome, as measured by death or the need for ventricular decompressing shunting by one year of age and improvement in neurologic function at 30 months corrected age as measured by a combined rank score of the Bayley Scales of Infant Development mental development index and the difference between the functional motor level versus anatomic lesion level. Enrollment at the three MOMS study sites began in 2003, and by December 2010, the MOMS’s Data and Safety Monitoring Board (DSMB) recommended ending study recruitment for reasons of efficacy of prenatal surgery, not for safety concerns. Study end points were found to be statistically significantly different between the surgery groups. In short, the prenatal surgery group was found to have a decreased need for a ventriculoperitoneal shunt and were also more likely to walk unassisted (Adzick et al., 2011). The DSMB recommended further follow-up of the children until school age to observe whether the results were sustained. That separate long-term follow-up study will be completed in 2016.
The Future of Fetal Therapy With the fetus established as a patient, improvements in prenatal diagnosis may add significantly to the treatable population. For example,
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Fetal therapy expands the options available to families after a fetus is diagnosed with an anomaly.
fetuses with inherited diseases such as severe combined immunodeficiency disease syndrome, hemophilia, enzyme deficiencies, and sickle-cell anemia may be diagnosed in utero and benefit from gene therapy or stem cell transplantation (Wagner, Schoeberlein, & Surbek, 2009). Most promising is transplantation of allogeneic stem cells into the early gestational fetus, a treatment termed in utero hematopoietic cell transplantation (IUHCTx). Prenatal transplant could overcome the limitations of bone marrow transplants and avoid graft rejection and the use of immunosuppression (Peranteau et al., 2009). At present, clinical use of IUHCTx has been hampered by poor engraftment, possibly due to a host immune response against the graft. Nijagal et al. (2011) hypothesized that maternal cells crossing into the fetus may pose the true barrier to effective IUHCTx, because the fetal immune system itself is relatively immature. The investigators demonstrated that the mother had increased T cell production after in utero transplantation of the fetus and further determined that there was a marked improvement in fetal engraftment if the mother lacked T cells but not B cells, indicating that maternal T cells are the main barrier to total engraftment. This study suggests that the clinical success of IUHCTx may be improved by transplanting the fetus with cells matched to the mother. In addition, key to the future of potential therapies is the discovery that the immune system of fetuses and, to some degree newborns, is designed specifically to tolerate foreign bodies to prevent it from attacking its own developing cells or its host mother’s cells (Ichinohe, 2010). Essentially this response is the opposite response of the adult immune system, which aggressively attacks threats such as tumors and viruses, bacteria, and fungi that cause infection. This discovery not only challenges the long-held assumption that fetuses and newborn babies have weak, immature immune systems that need time to build up to full strength after birth, but also could have profound effects on how to study and treat a wide variety of human ailments, from HIV and sickle-cell disease, to childhood allergies. Prior to this work, the general belief was that fetal immune cells were immature and nonfunctional. Instead, researchers have found that the cells in the fetus are functional
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Advances in fetal therapy should be developed and implemented in the best interest of the mother/fetus patient dyad.
and in fact have a robust, albeit nonaggressive, immune response against cells that are foreign. Researchers hope to use fetal immune tolerance to prenatally treat and maybe even cure diseases before birth (Roifman, Fischer, Notarangelo, de la Morena, & Seger, 2010). One example is sicklecell disease, which can be cured with stem cell transplants that encourage the body to produce new, healthy blood cells. Transplant rejection has been a major obstacle. Stem cells transplanted into fetuses to cure conditions before birth have almost always been rejected, most likely because the mother’s immune system is fighting them off. If the stem cells that are a match to the mother, or better yet, if the mother’s own cells could be transplanted, the infant could be born almost cured of the disease.
standard of care. This specialized field of high-risk obstetrics provides us with hope to help fetuses with a correctable problem but humbles us to know there is potential for doing harm (Dickens & Cook, 2011). Fetal therapy does offer hope to expectant couples with a fetus with a correctable defect but with the potential of also doing harm. The advances in the field have been made possible with laboratory testing, advancements in technology, and mastery of surgical techniques but are implemented only after the thorough and honest multidisciplinary counseling of families. Fetal survival, regardless of the treatment sequelae, may not be the right reason to offer an intervention. Just because a procedure can be done does not always mean it should be done. It is the responsibility of the health care teams involved to further the field of fetal therapy, keeping in mind the best interests of both patients: mother and fetus.
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