Development and in-vitro characterization of a novel fetal vesicoamniotic shunt - The Vortex shunt.

OBJECTIVES: To develop and test a novel vesicoamniotic shunt (VAS) to treat fetal lower urinary tract obstruction (LUTO), decrease dislodgement and optimize shunt deployment in-vitro. METHODS: Vesicoamniotic shunt design objectives included: (1) robust and atraumatic fixation elements, (2) kink resistant conduit to adjust to fetal movement and growth, (3) one-way pressure valve to facilitate bladder cycling, and (4) echogenic deployment visualization aids. The force to dislodge the novel Vortex shunt was compared with existing commercially available shunts in a bench-top porcine bladder model. Sonographic echogenicity was evaluated with ultrasound-guided deployment, and the shunt valve pressure measured. RESULTS: A prototype novel Vortex shunt was developed using braided nitinol "umbrella-type" ends with a kink-resistant stem incorporating an internal one-way valve. The peak force required to dislodge the Vortex shunt was significantly higher than commercially available shunts (p < 0.01). Shunt deployment in the bench-top model was easily confirmed with ultrasound guidance and the brisk decompression of the inflated porcine bladder thereafter. In-vitro valve gauge pressure testing mirrored bladder pressures in human LUTO cases. CONCLUSION: In-vitro testing shows that the Vortex shunt may improve deployment, sonographic visualization, kink resistance, and dynamic size adjustment. Validation in preclinical animal models are warranted and currently underway.

Strategies for intra-amniotic administration of fetal therapy in a rabbit model of intrauterine growth restriction.

Intrauterine growth restriction affects up to 10% of all pregnancies, leading to fetal programming with detrimental consequences for lifelong health. However, no therapeutic strategies have so far been effective to ameliorate these consequences. Our previous study has demonstrated that a single dose of nutrients administered into the amniotic cavity, bypassing the often dysfunctional placenta via intra-amniotic administration, improved survival at birth but not birthweight in an intrauterine growth restriction rabbit model. The aim of this study was to further develop an effective strategy for intra-amniotic fetal therapy in an animal model. Intrauterine growth restriction was induced by selective ligation of uteroplacental vessels on one uterine horn of pregnant rabbits at gestational day 25, and fetuses were delivered by cesarean section on GD30. During the five days of intrauterine growth restriction development, three different methods of intra-amniotic administration were used: continuous intra-amniotic infusion by osmotic pump, multiple intra-amniotic injections, and single fetal intraperitoneal injection. Technical feasibility, capability to systematically reach the fetus, and survival and birthweight of the derived offspring were evaluated for each technique. Continuous intra-amniotic infusion by osmotic pump was not feasible owing to the high occurrence of catheter displacement and amnion rupture, while methods using two intra-amniotic injections and one fetal intraperitoneal injection were technically feasible but compromised fetal survival. Taking into account all the numerous factors affecting intra-amniotic fetal therapy in the intrauterine growth restriction rabbit model, we conclude that an optimal therapeutic strategy with low technical failure and positive fetal impact on both survival and birthweight still needs to be found.

Suture techniques and patch materials using an in-vitro model for watertight closure of in-utero spina bifida repair.

PURPOSE: Despite proven benefits of in-utero spina bifida (SB) repair, ≥30% of children at birth have Chiari II malformation or cerebrospinal fluid (CSF) leakage from the repair site. Our study's purpose was to determine CSF pressures in the myelomeningocele sac during mid-gestation in order to design an in-vitro model for evaluating different surgical methods used for watertight closure during in-utero SB repair. METHODS: CSF pressures were measured during in-utero SB repair at mid-gestation. An in-vitro chicken thigh model, simulating fetal tissue, tested watertight closure when attached to the base of a water column. Primary closure methods were evaluated using defect sizes of 20 × 3 mm for minimal traction or 20 × 8 mm for moderate traction. Additionally, 3 common in-utero repair patches were compared using 15 × 15 mm defects. RESULTS: Using 6-12.5 cm pre-determined CSF pressures, 165 in-vitro experiments were performed. Regardless of methodology we found that in 66 primary-based closures that minimal versus moderate wound edge traction provided better seals. The locking method was superior to the non-locking technique for watertight closure in 99 patch-based closures. CONCLUSIONS: Minimal wound edge traction was best for primary closures, and locking sutures ideal for patch-based closures, however surgical techniques should be individualized to improve upon clinical outcomes.

Treatment of twin-reversed arterial perfusion sequence using high-intensity focused ultrasound.

We describe our experience of high-intensity focused ultrasound (HIFU) for fetal therapy in twin-reversed arterial perfusion (TRAP) sequence. Six pregnant women underwent HIFU therapy, five before 16 weeks and one at 26 weeks. Two types of HIFU system were used: the first-generation system, which comprised a biaxial transducer and continuous exposure pattern, and the second-generation system, which comprised a coaxial transducer and sequential exposure pattern. The first-generation apparatus was used in four cases and the second-generation apparatus was used in two. In three cases, occlusion of the blood vessels mediating flow to the acardiac twin was achieved by HIFU. Two cases experienced intrauterine fetal death despite vessel occlusion. The total survival rate of pump fetuses 2 years after HIFU was 67% and the efficiency rate (the proportion of cases with occlusion or reduced blood flow on ultrasound after HIFU) was 83%. After more than 2 years of follow-up, the surviving infants had no severe clinical complications and no postnatal developmental problems. There was no significant difference in survival rate compared with TRAP cases managed expectantly. Given that complete occlusion of the blood vessels was not achieved in half of the cases, we could not show that HIFU therapy is superior to other treatments. However, HIFU can reduce the cardiac load of the pump fetus and, as it does not require uterine puncture for fetal therapy, there were no fatal complications, such as bleeding, rupture of membranes or infection. Thus, HIFU therapy may represent a less-invasive treatment for TRAP sequence in early pregnancy. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Design and Testing of a Transcutaneous RF Recharging System for a Fetal Micropacemaker.

We have developed a rechargeable fetal micropacemaker in order to treat severe fetal bradycardia with comorbid hydrops fetalis. The necessarily small form factor of the device, small patient population, and fetal anatomy put unique constraints on the design of the recharging system. To overcome these constraints, a custom high power field generator was built and the recharging process was controlled by utilizing pacing rate as a measure of battery state, a feature of the relaxation oscillator used to generate stimuli. The design and in vitro and in vivo verification of the recharging system is presented here, showing successful generation of recharging current in a fetal lamb model.

Basic study of less invasive high-intensity focused ultrasound (HIFU) in fetal therapy for twin reversed arterial perfusion (TRAP) sequence.

PURPOSE: The objective of the present study was to develop a high-intensity focused ultrasound (HIFU) transducer more suitable for clinical use in fetal therapy for twin reversed arterial perfusion (TRAP) sequence. MATERIALS AND METHODS: We created a cooling and degassed water-circulating-type HIFU treatment device. HIFU was applied to renal branch vessels in three rabbits. Sequential HIFU irradiation contains a trigger wave, heating wave, and rest time. The duration of HIFU application was 10 s/course. Targeting could be achieved by setting the imaging probe in the center and placing the HIFU beam and imaging ultrasonic wave on the same axis. RESULT: We confirmed under sequential HIFU irradiation with a total intensity of 1.94 kW/cm(2) (spatial average temporal average intensity) that the vein and artery were occluded in all three rabbits. CONCLUSION: Simultaneous occluding of the veins and arteries was confirmed with trigger waves and a resting phase using the HIFU transducer treatment device created for this study. Clinical application appears possible and may represent a promising option for fetal therapy involving TRAP sequence.

Ultrasound-Guided Retrieval and Position Replacement of a Dislodged Fetal Pleuro-Amniotic Shunt: A Novel Approach for a Known Complication of Feto-Amniotic Shunting.

Untreated fetal pleural effusion can cause significant perinatal morbidity and mortality. Treatment of pleural effusions with pleuro-amniotic shunting has been shown to improve outcomes. Pleuro-amniotic shunting is associated with complications including ruptured membranes, preterm labor and shunt dislodgement into either the amniotic cavity or the fetal thorax. Shunt dislodgement into the thoracic cavity can cause prenatal complications from the shunt itself or may necessitate neonatal surgery for removal. We present a case where a novel ultrasound-guided technique was used to replace the dislodged pleural shunt in utero, thereby effectively draining the effusion while simultaneously obviating the need for neonatal surgery and decreasing possible perinatal complications.

Successful treatment of fetal bilateral primary chylothorax--report of the two cases.

Primary fetal chylothorax is an uncommon complication, associated with high perinatal morbidity and mortality. In our report, we describe two cases of fetal bilateral primary chylothorax successfully treated with pleuro-amniotic shunting. In both cases, ultrasound scans showed bilateral, hypoechoic fluid in the pleural space without any associated structural malformations and features of infection and aneuploidy Laboratory analysis of pleural fluids revealed 79% and 92% of lymphocytes, respectively confirming chylothorax in both fetuses. In the first case, pleuro-amniotic shunts were successfully inserted at 31 weeks and 6 days of gestation. Ultrasound scan after two weeks showed expansion of the left lung and lack of fluid in both pleural cavities. At 39 weeks of gestation, a 2660 g baby boy was delivered by cesarean section (Apgar score: 9). The child did not require surgical intervention and was discharged home on day 16 of life. In the second case, the insertion of shunts (at 24 weeks and 6 days of gestation) also significantly reduced the amount of the fluid in the pleural cavities, but one shunt had to be surgically removed after birth. At 30 weeks and 2 days of gestation, a cesarean section was performed due to maternal cholestasis. A female weighing 1400 g was delivered (Apgar score: 7). The chest X-ray revealed only a small amount of fluid in the left pleural cavity The infant was discharged on postnatal day 26, in good condition and with body weight of 2150 g. Pleuro-amniotic shunt insertion is a method of choice in the treatment of confirmed primary fetal chylothorax.

Thoracoscopy-assisted removal of a thoracoamniotic shunt double-basket catheter dislodged into the fetal thoracic cavity: report of three cases.

The indications for and timing of surgical removal of a dislodged thoracoamniotic shunt double-basket catheter are not established, and the side effects of the dislodged into the thoracic cavity remain controversial. The double-basket catheter was designed to reduce the incidence of catheter dislodgement; however, we have encountered four cases of thoracoamniotic shunt double-basket catheter dislodgement into the fetal thorax. The dislodged shunt catheters were removed safely with thoracoscopic assistance within several days of birth, when additional treatments for pleural effusion were needed, such as thoracic drainage tube insertion and adhesion treatment of the thorax. We report the clinical courses of three of these cases of thoracoamniotic shunt tube dislocation. By waiting several days postnatally for stabilization of respiratory and circulatory status and the effective use of thoracoscopic assistance, the dislodged catheter was safely removed from the neonatal thorax. The accumulation of case reports will help establish suitable treatments, and their indication, for a dislodged thoracoamniotic shunt catheter within the fetal thoracic cavity.

Retrospective review of thoracoamniotic shunting using a double-basket catheter for fetal chylothorax.

OBJECTIVE: From a single-center retrospective cohort with fetal chylothorax, we evaluated the factors related to the decision to use shunting, poor prognostic factors, and reported shunting outcomes with a new double basket-catheter device. METHODS: A retrospective single-center study was performed in 35 cases of fetal chylothorax. RESULTS: There were 35 cases of chylothorax: 23 with hydrops and 12 without hydrops. Twenty-one procedures were performed on 15 fetuses (11 with hydrops) with a single shunt in 11, two shunts in 3 and four shunts in 1. All 12 nonhydropic cases survived. In 23 hydropic cases, overall survival rates with and without thoracoamniotic shunting were 46 and 33%, respectively. The mortality rates of fetal hydropic cases with and without ascites were 93 and 11%, respectively. Fetal ascites, progression of fetal hydrops, and premature delivery at <33 weeks were significant risk factors for a poor prognosis. Progression of polyhydramnios after shunting was also associated with a poor prognosis. Obstruction of the catheter was observed in 38%. There were no direct fetal deaths associated with shunting. CONCLUSION: Thoracoamniotic shunting should be considered for pleural effusion before development of fetal hydrops, or at least before the appearance of fetal ascites. A double-basket catheter tends to be obstructive, but may be less invasive for fetuses.

Human induced pluripotent stem cell-derived neural crest stem cells integrate into the injured spinal cord in the fetal lamb model of myelomeningocele.

BACKGROUND/PURPOSE: Neurological function in patients with myelomeningocele (MMC) is limited even after prenatal repair. Neural crest stem cells (NCSCs) can improve neurological function in models of spinal cord injury. We aimed to evaluate the survival, integration, and differentiation of human NCSCs derived from induced pluripotent stem cells (iPSC-NCSCs) in the fetal lamb model of MMC. METHODS: Human iPSCs derived from skin fibroblasts were differentiated into NCSCs in vitro, mixed with hydrogel, and seeded on nanofibrous scaffolds for surgical transplantation. Fetal lambs (n=2) underwent surgical MMC creation and repair with iPSC-NCSC seeded scaffolds. Gross necropsy and immunohistochemistry were performed at term. RESULTS: IPSC-NCSCs expressed NCSC markers, maintained > 95% viability, and demonstrated neuronal differentiation in vitro. Immunohistochemical analysis of repaired spinal cords thirty days after transplantation demonstrated the co-localization of human nuclear mitotic apparatus protein (NuMA) and Neurofilament M subunit (NFM) in the area of spinal cord injury. No gross tumors were identified. CONCLUSIONS: Human iPSC-NCSCs survived, integrated, and differentiated into neuronal lineage in the fetal lamb model of MMC. This is the first description of human stem cell engraftment in a model of fetal MMC and supports the concept of using NCSCs to address spinal cord damage in MMC.

[Prenatal management of a fetal pericardial teratoma with pericardio-amniotic shunting: a case report]. / Prise en charge prénatale d'un tératome péricardique par drainage péricardio-amniotique : présentation d'un cas.

Fetal intrapericardial teratomas are uncommon and usually benign. Their histology is the same as that of teratomas located elsewhere. They may cause death from non-immune hydrops fetalis and cardiac tamponade. We report a case that was successfully managed prenatally by placement of a pericardial amniotic shunt.

Monochorionic twin pregnancy: screening, pathogenesis of complications and management in the era of microinvasive fetal surgery.

OBJECTIVE: The management of monochorionic (MC) twin pregnancies varies in different medical centers. This paper compares screening methods to predict the complications of the MC twin pregnancy and different treatment methods. METHODS: We performed a literature search without language restriction in Cochrane library and PubMed (1970-2009). Case series and cohort screening studies, pathogenesis and management of complications of MC pregnancy were included. RESULTS: Elevated risk for intrauterine fetal death (IUFD) and twin-to-twin transfusion syndrome (TTTS) can be detected sonographically. Monitoring of MC pregnancies at increased risk and regular training sessions for the operating team combined with reduced fetoscopic amniotic membrane damage increase fetal survival rate from laser coagulation to nearly 100% for at least one fetus and to 90% for both. CONCLUSION: Monitoring of MC pregnancies at increased risk and laser treatment of TTTS in medical centers with sufficient experience might improve neonatal outcome.

[Recent developments in fetal surgery. Technical, organizational and ethical considerations]. / Développements récents de la chirurgie foetale. Aspects techniques, organisationnels et éthiques.

Progress in prenatal diagnosis has led to more frequent detection of fetal abnormalities which, if left untreated, would be fatal or cause severe disabilities despite optimal postnatal care. Intrauterine surgery is possible in selected cases. Most procedures involve microendoscopy with local or regional analgesia. Fetal analgesia is indicated for procedures that are directly invasive for the fetus. Surgical treatment of twin-to-twin transfusion is so far the only example of successful fetal therapy, as demonstrated in a randomized controlled trial. The most severe forms of congenital diaphragmatic hernia may also benefit from temporary occlusion of the fetal trachea in order to allow lung growth and prevent pulmonary hypoplasia. The future of open fetal surgery will depend partly on the results of the ongoing MOM study of intrauterine coverage of myelomeningocele. These developments also raise ethical questions, including the competence of the surgical team, and the borderline between therapeutic innovation, experimental surgery, and standard of care. The possibility of therapeutic termination should not be overlooked.

Thoracoamniotic shunting with double-basket catheters for fetal chylothorax in the second trimester.

The progress of a fetal severe pleural effusion at mid-trimester is extremely poor. We encountered a fetus that developed a severe left pleural effusion at 21 weeks of gestation. The pleural effusion was removed by thoracocentesis at 22 weeks. Cytology revealed abundant lymphocytes, suggesting chylothorax. However, a reaccumulation of pleural effusion with hydrops was subsequently noted, and a thoracoamniotic shunt with double-basket catheters was installed at 23 weeks. The pleural effusion decreased after 24 weeks and completely disappeared at 26 weeks. At 40 weeks of gestation, a female infant was born by vaginal delivery, with no evidence of pleural effusion. We would like to stress that thoracoamniotic shunt with double-basket catheters in the second trimester is effective for pleural effusion with hydrops.

Successful intrauterine therapy for congenital cystic adenomatoid malformation of the lung. A case report.

Congenital cystic adenomatoid malformation (CCAM) of the lung is a rare abnormality which is amenable to be diagnosed by prenatal ultrasonography. In general, CCAM associated with non-immune hydrops has a poor prognosis unless a fetal intervention is performed. In some series almost 100% of either prenatal or early neonatal deaths are observed without intervention. Recently the cystic adenomatoid malformation volume ratio (CVR) has been proposed as an index to predict the development of hydrops in this condition. If the CVR is >1.6, the risk of hydrops is approximately 75%. We report a case of CCAM (macrocystic type) of the left lung referred to our center at 21 weeks of gestation. Fetal therapy was considered owing to enlargement of the CCAM volume, severe mediastinal shift, right lung compression, polyhydramnios and ascites from 21 to 26 weeks. Thoracoamniotic shunting was performed successfully at 26 weeks with resolution of the cystic mass. At 37 weeks a male infant was born vaginally weighing 3,210 g with Apgar scores of 5 and 10. Resection of the mass was performed uneventfully on day 3. The infant is currently 22 months of age, asymptomatic and in good condition.

Aortic valvuloplasty in the fetus: technical characteristics of successful balloon dilation.

OBJECTIVES: To describe technical aspects of successful fetal aortic valvuloplasty, with particular attention to balloon size. STUDY DESIGN: We retrospectively reviewed all procedural records and echocardiograms pertaining to 26 attempts at fetal aortic valve dilation performed at a single center over a period of 4 years. We assessed the effect of valvuloplasty as determined by echocardiographic appearance at the time of intervention and in follow-up. RESULTS: In 20 of 26 fetuses who had technically successful aortic valve dilation (median balloon:annulus ratio=1.1), all had improved antegrade flow and 12 had at least mild regurgitation after dilation. Use of an oversized balloon was associated with the onset of moderate or severe aortic regurgitation, seen in 5 fetuses. This aortic regurgitation was well tolerated and improved through the remainder of gestation. CONCLUSIONS: These data imply that fetal aortic valves can be dilated safely with larger balloons than are commonly used for postnatal dilation. The observation of spontaneous improvement in postdilation aortic regurgitation further suggests that fetal valve tissue behaves uniquely.