Faculty Bibliography

Congenital aqueduct stenosis AS is a significant cause of fetal obstructive hydrocephalus, characterized by the obliteration of the cerebral aqueduct, leading to cerebrospinal fluid (CSF) accumulation in the ventricular system and secondary brain damage and cerebral maldevelopment. This review explores the progression from basic science to clinical applications of antenatal surgical interventions for AS, emphasizing historical efforts, current research, and translational studies. Despite advances in prenatal imaging and genetic screening, challenges remain in achieving appropriate fetal candidates, consistent ventricular decompression, and standardized surgical protocols. This review highlights the need for further research and innovation to improve prenatal treatment and outcomes for AS-affected fetuses.

The purpose of this review is to provide an overview of the perinatal outcomes of fetuses who underwent fetal surgery for the management of Amniotic Band Syndrome (ABS). A systematic review of studies reporting on the perinatal outcome of fetuses undergoing fetoscopic release of amniotic bands according to the (PRISMA) guidelines was performed. The MEDLINE, Embase, Scopus, and Cochrane Library databases were systematically searched. In total, 17 studies reporting 37 cases of ABS that underwent amniotic band release by fetoscopy were included. The median gestational age at which fetal surgery was performed was 22 weeks (range 18-29 weeks). PPROM occurred in 51.3%, while fetal survival reached 89.2%. The success of fetal surgery was 75.7% in preserving and maintaining the functionality of the affected limb. Fetoscopic release of amniotic bands can preserve the affected limb and its function in cases of ABS and prevent fetal death in cases of ABS involving the umbilical cord. Further studies are needed to determine the optimal criteria for selecting patients who can benefit from fetal surgery, considering that it is an intervention that is not free of perinatal complications.

A biodegradable hybrid polymer patch was invented at the University of Cincinnati to cover gaps on the skin over the spinal column of a growing fetus, characterized by the medical condition spina bifida. The inserted patch faces amniotic fluid (AF) on one side and cerebrospinal fluid on the other side. The goal is to provide a profile of the roughness of a patch over time at 0, 4, 8, 12, and 16 weeks with a 95% confidence band. The patch is soaked in a test tube filled with either amniotic fluid (AF) or phosphate-buffered saline (PBS) in the lab. If roughness is measured at any time point for a patch, the patch is destroyed. Thus, it is impossible to measure roughness at all weeks of interest for any patch. It is important to assess the roughness of a patch because the rougher the patch is, the faster the skin grows under the patch. We use a model-based approach with Monte Carlo simulations to estimate the profile over time with a 95% confidence band. The roughness profiles are similar with both liquids. The profile can be used as a template for future experiments on the composition of patches.

BACKGROUND:External ventricular drain (EVD) insertion is one of the most commonly performed neurosurgical procedures. Herein, we introduce a new concept of a cranial fixation device for insertion of EVDs, that reduces reliance on freehand placement and drilling techniques and provides a simple, minimally invasive approach that provides strong fixation to minimal thickness skulls. METHODS:An experimental device for catheter insertion and fixation was designed and tested in both ex-vivo and in-vivo conditions to assess accurate cannulation of the ventricle and to test the strength of fixation to the skull. The ex-vivo experiments were conducted at Ben-Gurion University of the Negev (BGU) in Be'er Sheva, Israel. These experiments included functionality bench testing and pullout force measurements for the ball mechanism and catheter fixation. For the in-vivo experiments the fixation device was initially tested at the Cincinnati Children's Hospital Medical Center (CCHMC) in Cincinnati, Ohio on one day of life 1 (DOL 1) male control lamb. Additional experiments were conducted on 3 hydrocephalic DOL 0 lambs (1 male 2 female) at the Jesús Usón Minimally Invasive Surgery Centre (JUMISC) in Caceres, Spain. The hydrocephalic animal model used for this study was created with in utero intracisternal injection of BioGlue in fetal lambs. The catheter insertion trajectory was determined using MR imaging to assess the device's impact on the placement accuracy. The fixation device was evaluated on reaching the ventricle and enabling extraction of CSF for all 7 fixations placed. For 5 of the fixation devices, post-mortem pullout force was measured. The general functionality of the device was also evaluated. RESULTS:In the experiments, 7/7 (100%) catheter trajectories successfully reached the ventricle without any apparent complications related to the device or the procedure. The cranial fixation device base demonstrated significant strength in withstanding an average pull-out force of 4.18kgf (STD[Formula: see text]0.72, N = 5) without detachment from the subject's skull for all 5 devices included in this test. Additionally, the EVD catheter pull test was conducted with the addition of a safety loop which did not allow movement of the EVD to a force of 3.6kgf. At this force the catheter tore but did not release from its fixation point. CONCLUSION/CONCLUSIONS:The newly designed experimental device demonstrates initial proof of concept from ex vivo and in vivo testing. It appears suitable for accurate ventricular catheter placement and cranial fixation.

OBJECTIVES/OBJECTIVE:The failure of a fetus to develop to its full potential due to maternal or placental factors is known as intrauterine growth restriction (IUGR). Fetal head growth is usually preserved in that situation producing a potential discordance between head and body size. Our goal is to discover if IUGR has an impact on the prenatal ultrasound measurements taken to assess pulmonary development in congenital diaphragmatic hernia (CDH). METHODS:A retrospective chart review (IRB#2017-6361) was performed on all prenatally diagnosed CDH patients from 2007 to 2016. Patient demographics, fetal and neonatal anthropometric measurements, and fetal lung parameters were the main subjects of the data that were gathered. Fetal growth was assessed by the curves based on US data by Olsen et al. and by Peleg et al. Of 147 CDH patients, 19 (12.9 %) patients were diagnosed with IUGR before the 30th gestational week while there were 20 (13.6 %) patients after the 30th gestational week. RESULTS:Patients with IUGR and the observed-to-expected lung-to-head ratio (O/E LHR) less than 25 % had better survival rates both to discharge and date compared to non IUGR group (p=0.226, OR 2.25 95 % CI 0.60-1.08 and p=0.175, OR 2.40 95 % CI 0.66-1.17, respectively). Moreover, the ECMO need of the patients who had IUGR and O/E LHR less than 25 % was significantly less than the patients without IUGR (38.5 vs. 80.0 %, p=0.005). CONCLUSIONS:This study confirms that the intrauterine measurements to predict pulmonary hypoplasia in CDH patients are misleading in the presence of IUGR and cause an overestimation.

INTRODUCTION/BACKGROUND:Maternal laparotomy-assisted fetoscopic surgery for in-utero myelomeningocele repair has shown that a trans-amniotic membrane suture during fetoscopic port placement can reduce postsurgical complications. Fetoscopic laser photocoagulation (FLP) for complex twins is typically performed percutaneously without a transmembrane stitch. However, in scenarios without a placental-free window, maternal laparotomy may be used for recipient sac access. Here, we present the outcomes of our series of laparotomy-assisted FLP cases, including a trans-amniotic membrane suturing of the fetoscopic port. METHODS:Retrospective series of twin-twin transfusion syndrome or twin anemia-polycythemia sequence (TAPS) cases treated at 2 fetal centers that underwent maternal laparotomy to FLP from September 2017 to January 2023. We recorded preoperative and operative characteristics, as well as pregnancy and neonatal outcomes. RESULTS:During the study period, 9 maternal laparotomy to FLP cases were performed. Two were excluded for prior percutaneous FLP in the pregnancy. The remaining seven utilized a maternal laparotomy to trans-amniotic membrane stitch with confirmation of proper suture placement under ultrasound guidance, and all surgeries were performed with a single 10 F Check-Flo® cannula. Mean gestational age (GA) at surgery was 19.1 weeks (range 16 weeks 4 days-23 weeks 3 days), with delivery occurring at a mean GA of 35.0 weeks (range 32 weeks 0 days-37 weeks 1 day), resulting in a mean latency of 15.8 weeks, significantly longer than what is reported in the literature and our own data (mean latency for percutaneous FLP 10.2, 95% CI 9.9-10.5). Furthermore, all cases underwent iatrogenic delivery before labor onset, with the lone delivery prior to 34 weeks due to concern for post-laser TAPS. CONCLUSION/CONCLUSIONS:This case series of laparotomy to FLP with trans-amniotic stitch, demonstrated no cases of spontaneous preterm birth and a longer-than-expected latency from surgery to delivery. Larger studies are warranted to investigate this approach.

Spina bifida, known more commonly as myelomeningocele, is a neural tube defect that results in herniation of the cerebellum through the foramen magnum into the central canal as part of the Chiari II malformation. Effects stemming from the herniated cerebellum and its metabolic profile have not been extensively studied. The objective of this study is to examine the metabolic effects of this disease on the cerebellum in utero through the utilization of a retinoid acid-induced Spina bifida rat model. Analysis of this model at mid-late (day 15) and term (day 20) of gestation in comparison to both non-exposed and retinoic acid-exposed non-myelomeningocele controls, the observed metabolic changes suggest that mechanisms of oxidative stress and energy depletion are at play in this neuro tissue. These notable mechanisms are likely to result in further damage to neural tissue as the fetus grows and the compressed cerebellum develops and herniates more due to myelomeningocele.

PURPOSE/OBJECTIVE:Congenital diaphragmatic hernia (CDH) pathogenesis is poorly understood. We hypothesize that fetal CDH lungs are chronically hypoxic because of lung hypoplasia and tissue compression, affecting the cell bioenergetics as a possible explanation for abnormal lung development. METHODS:To investigate this theory, we conducted a study using the rat nitrofen model of CDH. We evaluated the bioenergetics status using H1 Nuclear magnetic resonance and studied the expression of enzymes involved in energy production, the hypoxia-inducible factor 1α, and the glucose transporter 1. RESULTS:The nitrofen-exposed lungs have increased levels of hypoxia-inducible factor 1α and the main fetal glucose transporter, more evident in the CDH lungs. We also found imbalanced AMP:ATP and ADP:ATP ratios, and a depleted energy cellular charge. Subsequent transcription levels and protein expression of the enzymes involved in bioenergetics confirm the attempt to prevent the energy collapse with the increase in lactate dehydrogenase C, pyruvate dehydrogenase kinase 1 and 2, adenosine monophosphate deaminase, AMP-activated protein kinase, calcium/calmodulin-dependent protein kinase 2, and liver kinase B1, while decreasing ATP synthase. CONCLUSION/CONCLUSIONS:Our study suggests that changes in energy production could play a role in CDH pathogenesis. If confirmed in other animal models and humans, this could lead to the development of novel therapies targeting the mitochondria to improve outcomes.

BACKGROUND:Congenital obstructive hydrocephalus generates progressive irreversible fetal brain damage by ventricular enlargement and incremental brain tissue compression that leads to maldevelopment and poor clinical outcomes. Intrauterine treatments such as ventriculo-amniotic shunting have been unsuccessfully tried in the eighties. OBJECTIVE:To assess if prenatal endoscopic third ventriculostomy (ETV) is feasible in a large animal model and optimize this technique for ventricular decompression and potential arrest of fetal brain damage in fetal lambs. METHODS:We generated hydrocephalus in 50 fetal lambs by injecting a polymeric agent into the cisterna magna at midgestation (E85). Subsequently, 3 weeks later (E105), fetal ETV was performed using a small rigid fetoscope. The endoscopy entry point was located anterior to the coronal suture, 7 mm from the midline. RESULTS:We obtained clear visualization of the enlarged lateral ventricles by endoscopy in the hydrocephalic fetal lambs. The floor of the third ventricle was bluntly perforated and passed with the scope for a successful ETV. Total success was achieved in 32/50 cases (64%). Causes of failure were blurred vision or third ventricle obliteration by BioGlue in 10/50 (20%) cases, anatomic misdirection of the endoscope in 5 (10%) cases, 2 cases of very narrow foramen of Monro, and 1 case of choroid plexus bleeding. If we exclude the cases artificially blocked by the polymer, we had a successful performance of prenatal-ETV in 80% (32/40) of hydrocephalic fetuses. CONCLUSION:Despite the inherent difficulties arising from ovine brain anatomy, this study shows that innovative fetal ETV is technically feasible in hydrocephalic fetal lambs.

BACKGROUND:Normal saline or lactated Ringer's solutions are usually infused at the time of fetal interventions; however, the effect of these fluids on the amniotic membranes has never been assessed. Given both the significant differences between the composition of normal saline solution, lactated Ringer's solution, and amniotic fluid and the significant risk of prematurity after fetal interventions, an investigation is warranted. OBJECTIVE:This study aimed to evaluate the effect of current amnioinfusion fluids on the human amnion compared with a novel synthetic amniotic fluid. STUDY DESIGN:Amniotic epithelial cells from term placentas were isolated and cultured per protocol. A synthetic amniotic fluid was created with similar electrolyte, pH, albumin, and glucose concentrations to human amniotic fluid, termed "Amnio-well." The cultured human amniotic epithelium was exposed to normal saline solution, lactated Ringer's solution, and Amnio-well. As a control, 1 group of cells remained in culture media. Cells were evaluated for apoptosis and necrosis. A second analysis to examine if cells could be "rescued" was performed, wherein the cells were allowed to remain in the culture media for an additional 48 hours after amnioinfusion. Subsequently, tissue testing with human amniotic membrane explants was evaluated similarly. Immunofluorescent intensity studies were undertaken to evaluate reactive oxygen species-mediated cell damage. Real-time quantitative polymerase chain reaction was used to evaluate gene expression in apoptotic pathways. RESULTS:With simulated amnioinfusion, 44%, 52%, and 89% of amniotic epithelial cells were alive after exposure to normal saline solution, lactated Ringer's solution, and Amnio-well, respectively, compared with 85% in control (P<.001). After amnioinfusion and attempted cell rescue, 21%, 44%, 94%, and 88% of cells were alive after exposure to normal saline solution, lactated Ringer's solution, Amnio-well, and control, respectively (P<.001). In simulated amnioinfusion with full-thickness tissue explants, 68%, 80%, 93%, and 96% of cells were viable in normal saline solution, lactated Ringer's solution, Amnio-well, and control, respectively (P<.001). In culture, reactive oxygen species production was higher in normal saline solution, lactated Ringer's solution, and Amnio-well than in control (4.9-, 6.6-, and 1.8-fold higher, respectively, P<.001); however, this could be mitigated in Amnio-well by adding ulin-A-statin and ascorbic acid. Gene expression data revealed abnormal signaling in the p21 and BCL2/BAX pathways with normal saline solution compared with control (P=.006 and P=.041); changes were not seen with Amnio-well. CONCLUSION:In vitro, normal saline and lactated Ringer's solutions caused increased amniotic membrane reactive oxygen species and cell death. The use of a novel fluid similar to human amniotic fluid led to the normalization of cellular signaling and less cell death.