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Current Research |
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Children's Advanced Fetal Care Center is studying the disease processes of various fetal anomalies in utero and developing intervention strategies with cellular, biological, and/or genetic solutions. The following are some of our current research projects:
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Experimental Model of Hemangioma
Principal Investigator: Steven Fishman, MD
Hemangiomas are the most common tumors of childhood. Despite their benign nature, however, they can be associated with several serious complications, including death. To date, their cause remains unclear and there is no experimental model of this disease. This project is an effort to shed light on the pathophysiology of hemangiomas and, hopefully, describe the first experimental model of this type of tumor.
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Fetal Physiology During Videofetoscopy
Principal Investigators: Dario Fauza, MD, Steven Fishman, MD
Since its introduction early in the last decade, minimally invasive fetal surgery has been shown to be a viable alternative as a therapeutic intervention for specific conditions in the human fetus. A warmed, isosmotic and acid-base neutral liquid, such as saline, is a natural choice for videofetoscopic surgery medium. Not only is it comparable with normal physiologic conditions, it also minimizes the risk of sudden temperature changes, known to provoke spasm of umbilical vessels. Moreover, it helps provide a large working space, due to the non-compressible nature of liquids. However, there are relative optic and operational limitations related to the use of saline, namely lower depth of field and the need for continuous infusion for clearance of the amniotic liquid, usually by a perfusionist. Although a gaseous medium may pose the risk of embolism in the fetoplacental circulation, it is easier to use and has better optical characteristics. This project is aimed at studying the effects of different electrically and acid-base neutral fluid media, both liquid and gaseous, upon umbilical blood flow, carotid blood flow, oxygen delivery, blood pressure, acid-base status, blood electrolytes, and other physiologic variables in the fetus, at various intra-amniotic pressures, as used during videofetoscopic intervention, in order to maximize the safety of this procedure.
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Fetal Tissue Engineering
Principal Investigator: Dario Fauza, MD
Birth defects entail loss and/or malformation of tissues or organs. The definitive treatment of many congenital anomalies at birth is often impeded by the scarce availability of normal tissues or organs available for reconstruction. The well-known severe donor shortage observed in practically all areas of transplantation is even more critical during the neonatal period. Likewise, autologous (one's own tissue) grafting is frequently not an option in newborns, due to donor site size limitations. The purposes of this project is to develop a novel concept in perinatal surgery, involving minimally invasive harvest of fetal tissue, which is then engineered in vitro while pregnancy is allowed to continue, so that a newborn with a prenatally diagnosed birth defect can benefit from having autologous, expanded tissue promptly available for definitive surgical treatment in the neonatal period. This concept has already been applied successfully, in the laboratory, to the following anomalies:
Congenital diaphragmatic hernia
Tracheal defects
Bladder exstrophy
Heart defects
Chest wall defects
Esophageal atresia
Cleft lip/palate
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Fetal Tissue Engineering: Immunology of Fetal Cells
Principal Investigator: Dario Fauza, MD
This project is aimed at studying the immunological characteristics of fetal cells. Our first results point to the fact that some of those cells are immunologically privileged, thus bettering their chances of engraftment after transplantation among different individuals. This may have many implications in fetal tissue engineering and fetal cell therapy applications.
Fetal Tissue Engineering: The Amniotic Fluid as a Source of Cells
Principal Investigator: Dario Fauza, MD
Harvesting fetal tissue as a cell source for tissue engineering is not without complications. Potential morbidities include maternal complications, direct fetal injury and induction of premature labor, which are seen in both open and minimally invasive tissue harvest techniques. This project has shown that fetal cells normally found in the amniotic fluid can be consistently isolated and expanded in sufficient numbers in vitro to be useful in fetal tissue engineering applications. Ongoing studies involve further analyzes of this concept in fetal cell therapy and fetal tissue engineering.
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Osmotic Control of Fetal Lung Liquid Volume
Principal Investigators: Dario Fauza, MD, Russell Jennings, MD
Almost 10 years ago, we first showed that by simply occluding the fetal trachea, lung growth could be dramatically accelerated, with obvious implications for the treatment of fetal pulmonary hypoplasia, for instance that associated with diaphragmatic hernia. However, clinical application of this concept in the mid- to late-nineties has led to limited success. In addition to premature labor, erratic post-operative lung liquid production has been one of the reasons for that. In this project, we have demonstrated that positive intra-pulmonary oncotic pressure by an isosmotic agent can maximize the short-term effects of fetal tracheal occlusion late in gestation, by expanding lung liquid volume, without any evidence of cell damage. Given the facts that clinical fetal tracheal occlusion is usually performed in the third trimester of gestation (because of fetal viability) and post-operative preterm labor frequently results in a short window between surgery and delivery, it is reasonable to speculate that delivery of an oncotic agent into the fetal lung at the time of tracheal occlusion could improve the currently disappointing results. Further refinement of this concept is currently ongoing, before clinical application.
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Prevention of Premature Labor After Fetal Surgery
Principal Investigator: Dario Fauza, MD
Preterm labor remains as the foremost complication of fetal surgery, as well as the overall leading cause of fetal and neonatal mortality. Current tocolysis regimens include assorted drugs delivered systemically, but have met with limited success, particularly after surgical fetal intervention. In this project, we have shown that a local strategy, namely a prolonged excitatory blockade of the myometrium by direct local drug delivery, prevented premature delivery in experimental models of fetal surgery. This excitatory blockade can be obtained with a suspension of biodegradable microspheres loaded with a local anesthetic, and/or with botulinus toxin (Botox®). Further development and refinement of this concept, including the use of other drugs, is currently ongoing.
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Repopulation of the Spinal Cord with Neural Stem Cells in Fetal Myelomeningocele
Principal Investigators: Dario Fauza, MD, Russell Jennings, MD, Evan Snider, MD
Myelomeningocele, a form of spina bifida, is one of the most common major birth defects. It is a devastating anomaly, not only to the patient, but also the family, and society. Current fetal treatment has involved simply closure of the defect in utero. This has minimized the severity of hydrocephalus, often associated with this disease, but has had limited impact on spinal cord function, probably because the defect occurs very early in gestation. This project is aimed at looking at whether neural stem cells delivered to spinal cord in utero can reverse at least some of the neural damage. The first results have been very encouraging, showing selective re-population of the spinal cord by the neural stem cells. Further studies are ongoing.
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Ultrasound-Guided Fetal Tracheal Occlusion
Principal Investigator: Rusell Jennings, MD
One of the reasons clinical application of fetal tracheal occlusion has met with limited success is the ever present premature labor triggered by fetal surgery. Although the less invasive videofetoscopic approach leads to better outcomes than those reported after open procedures, the overall results have been disappointing for both techniques. This project is aimed at examining the feasibility of fetal tracheal occlusion by an even less invasive approach, guided exclusively by ultra-sound. Ultrasound-guided fetal intervention has been, by far, the most frequent method of direct fetal manipulation for decades. It is less invasive than videofetoscopy, can be performed under local anesthesia, is more amenable to transplacental approach, and has had much lower complication rates when compared with "conventional" surgical intervention, be it open or endoscopic. Our first results have demonstrated that accurate access to the fetal trachea and local delivery of an occlusive, detachable silicone balloon are consistently feasible exclusively under real time ultrasound guidance, with current instrumentation and imaging technology, in an animal model. Further refinements of the technical principles of this procedure are currently ongoing, before clinical application.
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Genotype-phenotype correlations and prenatal diagnosis of abnormalities of the corpus callosum
Principal Investigator: Omar Khwaja
Fetal stroke and intracranial hemorrhage: prenatal diagnosis and outcomes
Principal Investigator: Omar Khwaja
Pre-natal Ultrasound and MRI for Fetal Chest Masses
Principal Investigator: Valerie Ward, MD
This study is helping to determine what information MRI can provide for fetal chest masses compared to ultrasound.
Feasibility of the Sheep Animal Model in the Study of Human Fetal Development
Principal Investigator: Valerie Ward, MD, John Kirkpatrick, MD, Carol Barnewolt, MD, Judy Estroff, MD
This MRI study will help further examine the gestation of sheep and its feasibility as a model for human gestation. Investigators are comparing ultrasound and MRI images to correlate imaging characteristics and fetal organ measurements.
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Prenatal Diagnosis of Vascular Anomalies
Principal Investigators: Jennifer J. Marler, MD Steven J. Fishman, MD, Joseph Upton, MD, Patricia E. Burrows, MD, Harriet J. Paltiel, MD, Russell W. Jennings, MD, and John B. Mulliken, MD
Abstract Purpose: Vascular anomalies are diagnosed prenatally with increasing frequency. We reviewed a group of children treated at our center who had an abnormal prenatal diagnosis to determine: (1) fetal age at which the vascular anomaly was detected, (2) general diagnostic accuracy and (3) impact on ante- and postnatal care. Our findings are compared with reported cases and case series. We clarify appropriate terminology and underscore the need for interdisciplinary participation of specialists in the field of vascular anomalies.
Methods: Patients referred during prenatal life and children with a history of abnormal antenatal findings seen at our vascular anomalies center during a one-year period (September 1999 through August 2000) were included in this study. The fetal age at diagnosis, pre- and postnatal diagnoses, antenatal course, and neonatal outcome were obtained from the parents, through chart reviews, and through telephone interviews with the treating obstetricians.
Results: Twenty-nine patients with vascular anomalies were identified: seventeen had a correct prenatal diagnosis and twelve had an incorrect diagnosis, an overall diagnostic sensitivity of 59%. Capillary-lymphatic-venous malformations (CLVM) was most often correctly diagnosed (67%), followed by lymphatic malformation (LM) (62%) and hemangioma (59%). In the infants who received correct diagnoses in utero, there were no fetal deaths and no identified neonatal morbidity. Maternal steroids were administered for a fetus with an intrahepatic hemangioma and deteriorating cardiac function, with subsequent stabilization and successful delivery of a healthy neonate. Among infants with incorrect diagnoses, there was one postnatal death, one case of erroneous gender assignment secondary, one case of unnecessary fetal surgery, one unnecessary neonatal laparotomy, and one delay in diagnosis of a malignancy. Cesareans were done for 65% of correctly-diagnosed cases, [including 2 EXIT (ex-utero intrapartum) procedures] and for 33% of incorrectly-diagnosed cases. Most diagnoses were made during the mid- to late second trimester and third trimester; only 4 cases (14%) were detected before 20 weeks.
Conclusions: In our series, accurate diagnosis optimized antenatal care by providing an opportunity for planning deliveries, for pharmacologic fetal intervention in one case, and for appropriate parental counseling. Inaccurate diagnosis was associated with significantly increased morbidity and mortality. Finally, the intrauterine diagnosis of LM should be distinguished from posterior nuchal translucency, an obstetric term applied to fetal lymphatic abnormalities detected in the first and second trimesters which do not manifest as postnatal LM.
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