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In the developed world, extreme prematurity is the leading cause of neonatal mortality and morbidity due to a combination of organ immaturity and iatrogenic injury. Until now, efforts to extend gestation using extracorporeal systems have achieved limited success. Here we report the development of a system that incorporates a pumpless oxygenator circuit connected to the fetus of a lamb via an umbilical cord interface that is maintained within a closed ‘amniotic fluid’ circuit that closely reproduces the environment of the womb. We show that fetal lambs that are developmentally equivalent to the extreme premature human infant can be physiologically supported in this extra-uterine device for up to 4 weeks. Lambs on support maintain stable haemodynamics, have normal blood gas and oxygenation parameters and maintain patency of the fetal circulation. With appropriate nutritional support, lambs on the system demonstrate normal somatic growth, lung maturation and brain growth and myelination. The ability to support the development of a premature fetus in the form of an extracorporeal system has had limited success. Here, the authors show that an extra-uterine device that mimics the intra-uterine environment can provide physiologic support for the extreme premature lamb fetus for four weeks.

The so called “Artificial Placenta” and “Artificial Womb” (EXTEND) technologies share a common goal of improving outcomes for extreme premature infants. Beyond that goal, they are very dissimilar and, in our view, differ sufficiently in their technology, intervention strategy, demonstrated physiology, and risk profiles that bundling them together for consideration of the ethical challenges in designing first in human trials is misguided. In this response to the commentary by Kukora and colleagues, we will provide our perspective on these differences, and how they impact ethical clinical study design for first-in-human trials of safety/feasibility, and subsequently efficacy of the two technologies.

Abstract BACKGROUND The Management of Myelomeningocele Study (MOMS) demonstrated that fetal myelomeningocele (fMMC) closure results in improved hydrocephalus and hindbrain herniation when compared to postnatal closure. OBJECTIVE To report on the outcomes of a single institution's experience in the post-MOMS era, with regard to hydrocephalus absence and hindbrain herniation resolution. METHODS A single-center retrospective study of a subset of post-MOMS patients who underwent fetal/postnatal myelomeningocele closure was performed. Primary outcomes included cerebrospinal fluid (CSF) diversion status and hindbrain herniation resolution. Families were contacted via telephone for outcome information if care was transitioned to outside institutions. Univariate/multivariable analyses were performed using several prenatal and postnatal variables. RESULTS From January 2011 to May 2016, data were reviewed from families of 62 postnatal and 119 fMMC closure patients. In the postnatal group, 80.6% required CSF diversion compared to 38.7% fetal cases (P < .01). Hindbrain herniation resolution occurred in 81.5% fetal repairs compared to 32.6% postnatal (P < .01). In the fetal group, fetal/premature neonatal demise occurred in 6/119 (5.0%) patients. There was a 42.0% decrease (95% CI –55.2 to –28.8) and 48.9% increase (95% CI 33.7 to 64.1) in risk difference for CSF diversion and hindbrain herniation resolution, respectively, in the fetal group. On univariate analysis for both groups, prenatal atrial diameter, frontal–occipital horn ratio, and hindbrain herniation resolution were significantly associated with the absence of clinical hydrocephalus. The treatment of hydrocephalus was significantly delayed in the fetal group compared to the postnatal group (10 mo vs 13.8 d). CONCLUSION This study demonstrates the benefits of fMMC closure with regard to CSF dynamics. Graphical Abstract Graphical Abstract

Our group has developed an extra-uterine environment for newborn development (EXTEND) using an ovine model, that aims to mimic the womb to improve short and long-term health outcomes associated with prematurity. This study’s objective was to determine the histologic and transcriptomic consequences of EXTEND on the brain. Histology and RNA-sequencing was conducted on brain tissue from three cohorts of lambs: control pre-term (106–107 days), control late pre-term (127 days), and EXTEND lambs who were born pre-term and supported on EXTEND until late pre-term age (125–128 days). Bioinformatic analysis determined differential gene expression among the three cohorts and across four different brain tissue sections: basal ganglia, cerebellum, hippocampus, and motor cortex. There were no clinically relevant histological differences between the control late pre-term and EXTEND ovine brain tissues. RNA-sequencing demonstrated that there was greater differential gene expression between the control pre-term lambs and EXTEND lambs than between the control late pre-term lambs and EXTEND lambs (Supplemental Figs. 1 and 2 ). Our study demonstrates that the use of EXTEND to support pre-term lambs until they reach late pre-term gestational age results in brain tissue gene expression that more closely resembles that of the lambs who reached late pre-term gestation within their maternal sheep’s womb than that of the lambs who were born prematurely.

Background: Fetal myelomeningocele (fMMC) repair has become accepted as a standard of care option in selected circumstances. We reviewed our outcomes for fMMC repair from referral and evaluation through surgery, delivery and neonatal discharge. Material and Methods: All patients referred for potential fMMC repair were reviewed from January 1, 2011 through March 7, 2014. Maternal and neonatal data were collected on the 100 patients who underwent surgery. Results: 29% of those evaluated met the criteria and underwent fMMC repair (100 cases). The average gestational age was 21.9 weeks at evaluation and 23.4 weeks at fMMC repair. Complications included membrane separation (22.9%), preterm premature rupture of membranes (32.3%) and preterm labor (37.5%). Average gestational age at delivery was 34.3 weeks and 54.2% delivered at ≥35 weeks. The perinatal loss rate was 6.1% (2 intrauterine fetal demises and 4 neonatal demises); 90.8% of women delivered at the Children's Hospital of Philadelphia and 3.4% received transfusions. With regard to the neonates, 2 received ventriculoperitoneal shunts prior to discharge; 71.1% of neonates had no evidence of hindbrain herniation on MRI. Of the 80 neonates evaluated, 55% were assigned a functional level of one or more better than the prenatal anatomic level. Conclusion: In an experienced program, maternal and neonatal outcomes for patients undergoing fMMC repair are comparable to results of the MOMS trial.

Myelomeningocele (MMC), the most severe form of spina bifida, is a common and devastating malformation. Over two decades of experimental work in animal models have led to the development and clinical application of open fetal surgery for the repair of the MMC defect. This approach offers improved neurofunctional outcomes and is now a clinical option for the management of prenatally diagnosed MMC in selected patients. However, there are still opportunities for further improvement in the prenatal treatment of MMC. A less invasive approach would allow for an application earlier in gestation, with a reduction in maternal and fetal risks and the potential for reduced neurological injury. Tissue engineering offers a realistic and appealing alternative approach for the prenatal treatment of MMC. This review discusses the rationale for tissue engineering in MMC, addresses recent experimental progress and describes potential future directions.

A major limitation to adeno-associated virus (AAV) gene therapy is the generation of host immune responses to viral vector antigens and the transgene product. The ability to induce immune tolerance to foreign protein has the potential to overcome this host immunity. Acquisition and maintenance of tolerance to viral vector antigens and transgene products may also permit repeat administration thereby enhancing therapeutic efficacy. In utero gene transfer (IUGT) takes advantage of the immunologic immaturity of the fetus to induce immune tolerance to foreign antigens. In this large animal study, in utero administration of AAV6.2, AAV8 and AAV9 expressing green fluorescent protein (GFP) to ~60 day fetal sheep (term: ~150 days) was performed. Transgene expression and postnatal immune tolerance to GFP and viral antigens were assessed. We demonstrate 1) hepatic expression of GFP 1 month following in utero administration of AAV6.2.GFP and AAV8.GFP, 2) in utero recipients of either AAV6.2.GFP or AAV8.GFP fail to mount an anti-GFP antibody response following postnatal GFP challenge and lack inflammatory cellular infiltrates at the intramuscular site of immunization, 3) a serotype specific anti-AAV neutralizing antibody response is elicited following postnatal challenge of in utero recipients of AAV6.2 or AAV8 with the corresponding AAV serotype, and 4) durable hepatic GFP expression was observed up to 6 months after birth in recipients of AAV8.GFP but expression was lost between 1 and 6 months of age in recipients of AAV6.2.GFP. The current study demonstrates, in a preclinical large animal model, the potential of IUGT to achieve host immune tolerance to the viral vector transgene product but also suggests that a single exposure to the vector capsid proteins at the time of IUGT is inadequate to induce tolerance to viral vector antigens.

To investigate whether umbilical cord traction triggers a unique umbilico-neuro-cardio reflex via sympathetic autonomic nervous system (ANS) activation, potentially explaining fetal heart rate (FHR) increases such as the double mountain peak sign and unexplained tachycardia outside labor. Experimental physiological study using the EXTrauterine Environment for Neonatal Development (EXTEND) system. Controlled laboratory environment at The Children's Hospital of Philadelphia with fetal lambs supported by the EXTEND system. Twenty-nine experiments were performed on three fetal lambs: 5 ANS-immature (<110 days gestational age) and 24 ANS-mature (>110 days GA), including subgroups for pharmacological intervention. Umbilical cord traction was performed in 20 experiments (5 ANS-immature, 15 ANS-mature). To investigate autonomic modulation, nine ANS-mature experiments included administration of either periumbilical capsaicin or intravenous propranolol. FHR changes were measured, and norepinephrine levels were sampled before and after interventions. Change in FHR (bpm) and circulating norepinephrine concentrations in response to umbilical cord traction and pharmacologic modulation. Cord traction significantly increased FHR in ANS-mature lambs (mean +42 bpm,  < 0.001), but not in ANS-immature lambs (mean +1 bpm,  = 0.770). Capsaicin also elevated FHR and norepinephrine, while propranolol inhibited both responses. Umbilical cord traction appears to activate an umbilico-neuro-cardiac reflex through sympathetic ANS pathways in ANS-mature fetuses. This mechanism may underlie clinical CTG features such as the double mountain peak sign and fetal tachycardia outside of labor.

Induction of the immune response is a major problem in replacement therapies for inherited protein deficiencies. Tolerance created in utero can facilitate postnatal treatment. In this study, we aimed to induce immune tolerance towards a foreign protein with early gestational cell transplantation into the chorionic villi under ultrasound guidance in the murine model. Pregnant C57BL/6 (B6) mice on day 10 of gestation were anesthetized and imaged by high resolution ultrasound. Murine embryos and their placenta were positioned to get a clear view in B-mode with power mode of the labyrinth, which is the equivalent of chorionic villi in the human. Bone marrow cells (BMCs) from B6-Green Fluorescence Protein (B6GFP) transgenic mice were injected into the fetal side of the placenta which includes the labyrinth with glass microcapillary pipettes. Each fetal mouse received 2 x 105 viable GFP-BMCs. After birth, we evaluated the humoral and cell-mediated immune response against GFP. Bone marrow transfer into fetal side of placenta efficiently distributed donor cells to the fetal mice. The survival rate of this procedure was 13.5%(5 out of 37). Successful engraftment of the B6-GFP donor skin grafts was observed in all recipient (5 out of 5) mice 6 weeks after birth. Induction of anti-GFP antibodies was completely inhibited. Cytotoxic immune reactivity of thymic cells against cells harboring GFP was suppressed by ELISPOT assay. In this study, we utilized early gestational placental injection targeting the murine fetus, to transfer donor cells carrying a foreign protein into the fetal circulation. This approach is sufficient to induce both humoral and cell-mediated immune tolerance against the foreign protein.

Abstract Fibroblast growth factor-10 (FGF10) is a mesenchymal growth factor, involved in epithelial and mesenchymal interactions during lung branching morphogenesis. In the present work, FGF10 overexpression was transiently induced in a temporally and spatially restricted manner, during the pseudoglandular or canalicular stages of rat lung development, by trans-uterine ultrasound-guided intraparenchymal microinjections of adenoviral vector encoding the rfgf10 transgene. The morphologic and histologic classification of the resulting malformations were dependent upon developmental stage and location. Overexpression of FGF10 restricted to the proximal tracheobronchial tree during the pseudoglandular phase resulted in large cysts lined by tall columnar epithelium composed primarily of Clara cells with a paucity of Type II pneumocytes, resembling bronchiolar type epithelium. In contrast, FGF10 overexpression in the distal lung parenchyma during the canalicular phase resulted in small cysts lined by cuboidal epithelial cells composed of primarily Type II pneumocytes resembling acinar epithelial differentiation. The cystic malformations induced by FGF10 overexpression appear to closely recapitulate the morphology and histology of the spectrum of human congenital cystic adenomatoid malformation (CCAM). These findings support a role for FGF10 in the induction of human CCAM and provide further mechanistic insight into the role of FGF10 in normal and abnormal lung development.