Antenatal embolization of a large chorioangioma by percutaneous Glubran 2 injection.

We describe a case of a large chorioangioma diagnosed at 18 weeks' gestation. Because of advanced fetal heart failure at 23 weeks' gestation, embolization of the chorioangioma's vessels was performed by percutaneous injection of Glubran 2 surgical glue. There was no immediate secondary effect of treatment. Devascularization was complete and durable. Signs of fetal cardiac failure normalized after 1 month and a healthy infant was delivered at 38 weeks. To our knowledge this is the first reported case of perinatal survival after successful embolization of a chorioangioma using tissue glue.

The 'PLUG' odyssey: adventures in experimental fetal tracheal occlusion.

In animal experiments, it has been shown that tracheal occlusion counteracts the pulmonary hypoplasia associated with congenital diaphragmatic hernia (CDH). Successful clinical implementation requires a reliable, reversible, and atraumatic technique of occluding the fetal trachea. With this clinical goal in mind, the authors evaluated the following three methods of tracheal occlusion in a fetal lamb CDH model: (1) an occluded foam-cuffed endotracheal tube, (2) a foam-cuffed endotracheal tube with a magnetically controlled flow valve, and (3) a tracheal insert constructed of a water-impermeable, expandable, polymeric foam, which is placed by a translaryngeal approach. The foam-cuffed endotracheal tube did not provide consistently reliable fetal tracheal occlusion. Although the magnetically triggered flow valve functioned well, it was not necessary to open the valve in utero (to prevent overdistension of the lungs), and the presence of the valve contributed to several occlusive failures. In contrast, the foam insert was easy to position and to remove from the trachea, while providing reliable tracheal occlusion for several weeks with consequent enlarged fetal lungs, increased lung fluid volumes, complete reduction of abdominal viscera, and improved pulmonary gas exchange after birth. Bronchoscopic evaluation of the foam-occluded neonatal tracheas showed little or no tracheal damage, which was confirmed during necropsy by gross and histological examination. Translaryngeal placement of a compressible, water-impermeable polymeric foam appears to be a simple and safe technique to achieve fetal tracheal occlusion.

Nasopharyngeal teratoma. Report of a case with prenatal diagnosis and postnatal management.

BACKGROUND: Oral teratomas are rare entities. CASE: A patient was referred for elevations in the maternal serum alpha-fetoprotein. On ultrasound examination, a cyst was seen protruding from the fetal mouth. Postnatally, a teratoma was found to be filling the neonate's oral cavity. CONCLUSION: This case illustrates problems in determining the etiology of head and neck masses antenatally. It also shows that teratomas can appear to regress and yield positive amniotic fluid alpha-fetoprotein and acetyl-cholinesterase. The appropriate perinatal management of this potentially devastating disorder includes preparation for establishing an airway following delivery.

An ovine preimmune foetal model to study the effect of cellular therapies for myocardic diseases.

The ovine foetus is an ideal model for preclinical medical studies of cell therapies. It allows us to follow the behaviour of repairing cells inserted into a favourable physiological microenvironment in an animal species more closely related to humans than the rat or rabbit. In addition, the preimmune foetus is able to support cell engraftment by eliminating the problems of tissue rejection. Labelled fibroblasts were transplanted into the myocardium of preimmune foetuses, injecting through a disposable bowed mouth pipette into the left ventricular apex. Two weeks later, foetuses were isolated by laparotomy and each heart was collected and morphologically analyzed. No cases of abortion or postoperative complications in mothers or foetuses occurred. Macroscopically, the isolated hearts did not display any abnormality apart from a small petechia at the injection site. Tissue sections did not show any sign of acute tissue inflammation and viable labelled cells were easily identified among myocardiocytes. This model system guarantees a reduced damage in the engrafted tissue, a high survival and easy retrieval of the injected cells. The direct injection of cells into the preimmune ovine foetus myocardium can be satisfactorily performed to control tissue delivery and to reduce the risk of cell loss and dispersion.

Gene therapy for genetic diseases.

Gene therapy provides the potential to permanently cure selected genetic diseases. However, a major obstacle is the effective delivery of the normal gene to specific target sites of pathology and continuous expression at therapeutic levels. A variety of viral and non-viral vectors have been developed to deliver genes to various cells, tissues and organs by ex vivo and in vivo strategies. Among the viral-based vectors, retroviruses, adenovirus, adeno-associated virus and herpes virus have been the most extensively studied. Among non-viral-based vectors, liposomes have been used to introduce plasmid DNA directly into animals, and DNA protein conjugates are being developed to exploit receptor-mediated uptake pathways. Each of these gene delivery systems is reviewed here and their advantages and disadvantages compared. In addition, the current status and future prospects for human gene therapy trials for genetic diseases are discussed.

Possible mechanism of gene transfer into early to mid-gestational mouse fetuses by tail vein injection.

Our aim is to develop a simple gene transfer method into egg cylinder and mid-gestational murine embryos. We examined whether plasmid/lipid complexes injected into the tail veins of pregnant transgenic mice can be transferred to fetuses at E 4.5-13.5. When pregnant CETZ-17 mice carrying a transgene consisting of a ubiquitous promoter, floxed EGFP/CAT and the LacZ gene, were injected with a Cre expression vector DNA/lipid complex, Cre-mediated excision of the transgenes, as evaluated by X-gal staining, occurred in 10-50% of fetuses treated at E 11.5-13.5. Although younger embryos remained unstained, PCR analysis revealed low levels of the Cre vector DNA and recombined transgene. To examine the fate of a solution given intravenously, we injected trypan blue or fluorescence-labeled plasmid DNA/lipid complexes into females at E 5.5-11.5 and E 6.5, respectively. Both collected in the visceral endoderm (VE) lineage, but were undetectable in the embryo proper. These findings suggest that substances in maternal blood are delivered to post-implantation embryos via cells of the VE lineage and placenta, but that most are trapped in the VE. If significantly improved, gene transfer to fetuses by injection into the maternal circulation may become a promising tool in fetal gene therapy and embryological studies.

Nonviral gene transfer into fetal mouse livers (a comparison between the cationic polymer PEI and naked DNA).

We investigated the efficacy and safety of the cationic polymer polyethylenimine (PEI) as a potential tool for intrauterine gene delivery into livers of fetal mice in the last trimester of pregnancy (E17.5). Using luciferase as a reporter gene, transferrin-conjugated and ligand-free PEI/DNA complexes (containing 3 microg DNA) with varying PEI-nitrogen/DNA-phosphate (N/P) ratios and different PEI forms, branched (800, 25 kDa) and linear (22 kDa), were compared with naked DNA. Transgene expression was measured 48 h after administration of PEI/DNA complexes or naked DNA. Highest luciferase activity (9.8 x 10(3) relative light units (RLU)/mg of tissue protein) was observed with ligand-free PEI22/DNA mixtures at N/P 6.0. In addition, this formulation was associated with very low toxicity as compared to the other PEI/DNA-injected groups. Using beta-galactosidase as a reporter gene, transfection of single, but also small, clusters of cells was demonstrated throughout the liver. Injection of 3 microg naked DNA resulted in an 11-fold lower transgene expression value (0.9 x 10(3) RLU/mg of tissue protein) as compared to PEI22/DNA complexes. However, the administration of higher concentrated naked DNA (9 microg) into fetal livers yielded expression levels of 3.2 x 10(4) RLU/mg of tissue protein, a more than three-fold increase compared to PEI22/DNA complexes. Furthermore, the gene transfer efficacy of concentrated naked DNA was approximately 40 times higher in fetuses than in adults (0.8 x 10(3) RLU/mg of tissue protein), indicating that fetal tissue is especially amenable to the uptake and expression of naked DNA.

Rapidly polymerizing hydrogel prevents balloon dislodgement in a model of fetal tracheal occlusion.

BACKGROUND/PURPOSE: This study examined whether an injectable hydrogel could buttress the balloon used in fetal tracheal occlusion, thus preventing its displacement. METHODS: Fetal lambs (n = 11) underwent tracheal occlusion through local delivery of a detachable silicone balloon and were divided in 2 groups: group I had no further manipulations, and group II received an intratracheal injection of a rapidly polymerizing hydrogel, cranially to the balloon. Near term, balloon placement was examined, the lung volume-to-body weight ratio (LV:BW) was determined, and tracheal histology was performed. Statistical analysis was by the Fisher's Exact test, with significance set at P <.05. RESULTS: Complete tracheal occlusion was achieved in all fetuses intraoperatively. The rate of balloon dislodgement was significantly higher in group I (4 of 7, or 57.1%) than in group II (0 of 4). In group II, balloons were recovered in situ with a column of residual hydrogel reinforcing their cephalad position. Animals in which balloon occlusion was maintained had significantly higher LV:BW, with no evidence of tracheal damage. CONCLUSIONS: Intratracheal delivery of a rapidly polymerizing hydrogel cephalad to detachable silicone balloons results in improved fetal tracheal occlusion, with no harmful effects to the trachea. This adjuvant principle may enhance minimally invasive balloon tracheal occlusion for treatment of severe fetal pulmonary hypoplasia.

Airway management during an EXIT procedure for a fetus with dysgnathia complex.

Nonsyndromal dysgnathia is a rare disorder with a probable genetic basis characterized by a hypoplastic or absent mandible (agnathia), microstomia, microglossia, and ear anomalies secondary to a defect in the ventral portion of the first branchial arch caused by defective neural crest migration or proliferation. Dysgnathic newborn infants often suffer fatal respiratory failure from airway obstruction. Nineteen children with isolated dysgnathia complex are described in the literature--six were stillborn, eight died shortly after birth, and only five survived infancy. All survivors required tracheostomy to maintain an airway. It is difficult to intubate the trachea of these children and early airway management planning is important. We report a neonate who presented with a prenatal ultrasound diagnosis of severe micrognathia, polyhydramnios and a family history of severe micrognathia. Airway management was achieved with fiberoptic intubation through a laryngeal mask airway (LMA) during an ex utero intrapartum treatment procedure. Fiberoptic intubation was hampered by copious amounts of amniotic fluid. This child and her sibling are the first two siblings with isolated dysgnathia complex to have survived infancy and provide further support for a genetic basis to this condition.

Antenatal and postnatal treatment of pleural effusion and extra-lobar pulmonary sequestration.

An infant is reported who was identified antenatally to have an extralobar sequestration and a pleural effusion. Chronic drainage of the effusion was achieved by placement of a pleuroamniotic shunt. After delivery the infant underwent several thoracocenteses and then definitive surgery to remove an extralobar sequestration. The postnatal course was documented by lung function measurements.

Lung growth and maturation after tracheal occlusion in diaphragmatic hernia.

Tracheal occlusion (TO) was performed at 120 d of gestation by noninvasive endoscopic technique using a releasable latex balloon, in fetal lambs with diaphragmatic hernia (DH) established at 85 d. The lungs were studied at 139 d in five fetuses with DH + TO, five fetuses with DH only, and six control fetuses. Fluid retention consecutive to TO allowed fetal lungs to grow. Histological pulmonary structure was more mature in DH + TO than in DH alone. The growth-inducing effect of TO was however incomplete, with an increased protein/DNA ratio. Tissue phospholipids were increased, but this was not reflected in the surfactant compartment. The major surfactant component, disaturated phosphatidylcholine, was reduced to 58% of its control value in DH, and further reduced to 17.5% of its control value in DH + TO. The proportion of surfactant protein B immunoreactive cells, assumed to represent the proportion of type II cells, was increased in DH (27% of all parenchymal cells), and reduced in DH + TO (7.8%) as compared with control fetuses (15%). In conclusion, although noninvasive tracheal occlusion in utero is feasible and may partly compensate the adverse effects of DH on lung organogenesis, it reduces the number of type II cells and induces a dramatic surfactant deficit. Using this technique in human fetuses requires careful consideration until further evaluation of lung functional characteristics has been achieved in this experimental model.