High-fidelity, low-cost synthetic training model for fetoscopic spina bifida repair.

BACKGROUND: Fetoscopic spina bifida repair is increasingly being practiced, but limited skill acquisition poses a barrier to widespread adoption. Extensive training in relevant models, including both ex vivo and in vivo models may help. To address this, a synthetic training model that is affordable, realistic, and that allows skill analysis would be useful. OBJECTIVE: This study aimed to create a high-fidelity model for training in the essential neurosurgical steps of fetoscopic spina bifida repair using synthetic materials. In addition, we aimed to obtain a cheap and easily reproducible model. STUDY DESIGN: We developed a 3-layered, silicon-based model that resemble the anatomic layers of a typical myelomeningocele lesion. It allows for filling of the cyst with fluid and conducting a water tightness test after repair. A compliant silicon ball mimics the uterine cavity and is fixed to a solid 3-dimensional printed base. The fetal back with the lesion (single-use) is placed inside the uterine ball, which is reusable and repairable to allow for practicing port insertion and fixation multiple times. Following cannula insertion, the uterus is insufflated and a clinical fetoscopic or robotic or prototype instruments can be used. Three skilled endoscopic surgeons each did 6 simulated fetoscopic repairs using the surgical steps of an open repair. The primary outcome was surgical success, which was determined by water tightness of the repair, operation time <180 minutes and an Objective Structured Assessment of Technical Skills score of ≥18 of 25. Skill retention was measured using a competence cumulative sum analysis of a composite binary outcome of surgical success. Secondary outcomes were cost and fabrication time of the model. RESULTS: We made a model that can be used to simulate the neurosurgical steps of spina bifida repair, including anatomic details, port insertion, placode release and descent, undermining of skin and muscular layer, and endoscopic suturing. The model was made using reusable 3-dimensional printed molds and easily accessible materials. The 1-time startup cost was €211, and each single-use, simulated myelomeningocele lesion cost €9.5 in materials and 50 minutes of working time. Two skilled endoscopic surgeons performed 6 simulated, 3-port fetoscopic repairs, whereas a third used a Da Vinci surgical robot. Operation times decreased by more than 30% from the first to the last trial. Six experiments per surgeon did not show an obvious Objective Structured Assessment of Technical Skills score improvement. Competence cumulative sum analysis confirmed competency for each surgeon. CONCLUSION: This high-fidelity, low-cost spina bifida model allows simulated dissection and closure of a myelomeningocele lesion. VIDEO ABSTRACT.

3D vs. 2D simulated fetoscopy for spina bifida repair: a quantitative motion analysis.

3D imaging technology is becoming more prominent every day. However, more validation is needed to understand the actual benefit of 3D versus conventional 2D vision. This work quantitatively investigates whether experts benefit from 3D vision during minimally invasive fetoscopic spina bifida (fSB) repair. A superiority study was designed involving one expert team ([Formula: see text] procedures prior) who performed six 2D and six 3D fSB repair simulations in a high-fidelity animal training model, using 3-port access. The 6D motion of the instruments was recorded. Among the motion metrics are total path length, smoothness, maximum speed, the modified Spectral Arc Length (SPARC), and Log Dimensionless Jerk (LDLJ). The primary clinical outcome is operation time (power 90%, 5% significance) using Sealed Envelope Ltd. 2012. Secondary clinical outcomes are water tightness of the repair, CO[Formula: see text] insufflation volume, and OSATS score. Findings show that total path length and LDLJ are considerably different. Operation time during 3D vision was found to be significantly shorter compared to 2D vision ([Formula: see text] vs. [Formula: see text] min; p [Formula: see text] 0.026). These results suggest enhanced performance with 3D vision during interrupted suturing in fetoscopic SBA repair. To confirm these results, a larger-scale follow-up study involving multiple experts and novice surgeons is recommended.

Duration of fetoscopic spina bifida repair does not affect the central nervous system in fetal lambs.

BACKGROUND: Prenatal spina bifida aperta repair improves neurologic outcomes yet comes with a significant risk of prematurity and uterine scar-related complications. To reduce such complications, different fetoscopic techniques, for example, with varying numbers of ports, are being explored. This has an effect on the duration of the procedure, potentially affecting central nervous system development. Both the condition and anesthesia can affect the central nervous system, particularly the hippocampus, a region crucial for prospective and episodic memory. Previous animal studies have shown the potential influence of anesthesia, premature delivery, and maternal surgery during pregnancy on this area. OBJECTIVE: This study aimed to compare the effects of 2- vs 3-port fetoscopic spina bifida aperta repair in the fetal lamb model using neuron count of the hippocampus as the primary outcome. STUDY DESIGN: Based on the hippocampal neuron count from previous lamb experiments, we calculated that we required 5 animals per group to achieve a statistical power of ≥ 80%. A spina bifida aperta defect was developed in fetal lambs at 75 days of gestation (term: 145 days). At 100 days, fetuses underwent either a 2-port or 3-port fetoscopic repair. At 143 days, all surviving fetuses were delivered by cesarean delivery, anesthetized, and transcardially perfused with a mixture of formaldehyde and gadolinium. Next, they underwent neonatal brain and spine magnetic resonance imaging after which these organs were harvested for histology. Hippocampus, frontal cortex, caudate nucleus, and cerebellum samples were immunostained to identify neurons, astrocytes, microglia, and markers associated with cell proliferation, myelination, and synapses. The degree of hindbrain herniation and the ventricular diameter were measured on magnetic resonance images and volumes of relevant brain and medulla areas were segmented. RESULTS: Both treatment groups included 5 fetuses and 9 unoperated littermates served as normal controls. The durations for both skin-to-skin (341±31 vs 287±40 minutes; P=.04) and fetal surgery (183±30 vs 128±22; P=.01) were longer for the 2-port approach than for the 3-port approach. There was no significant difference in neuron density in the hippocampus, frontal cortex, and cerebellum. In the caudate nucleus, the neuron count was higher in the 2-port group (965±156 vs 767±92 neurons/mm2; P=.04). There were neither differences in proliferation, astrogliosis, synaptophysin, or myelin. The tip of the cerebellar vermis was closer to the foramen magnum in animals undergoing the 2-port approach than in animals undergoing the 3-port approach (-0.72±0.67 vs -2.47±0.91 mm; P=.009). There was no significant difference in the ratio of the hippocampus, caudate nucleus, or cerebellar volume to body weight. For the spine, no difference was noted in spine volume-to-body weight ratio for the lower (L1-L2), middle (L3-L4), and higher (L5-L6) levels. Compared with controls, in repaired animals, the cerebellar vermis tip laid closer to the foramen magnum, parietal ventricles were enlarged, and medulla volumes were reduced. CONCLUSION: In the experimental spina bifida fetal lamb model, a 2-port repair took 40% longer than a 3-port repair. However, there was no indication of any relevant morphologic differences in the fetal brain.

Implementation and Assessment of a Laparotomy-Assisted Three-Port Fetoscopic Spina Bifida Repair Program.

Open spina bifida (OSB) is a congenital, non-lethal malformation with multifactorial etiology. Fetal therapy can be offered under certain conditions to parents after accurate prenatal diagnostic and interdisciplinary counseling. Since the advent of prenatal OSB surgery, various modifications of the original surgical techniques have evolved, including laparotomy-assisted fetoscopic repair. After a two-year preparation time, the team at the University of Giessen and Marburg (UKGM) became the first center to provide a three-port, three-layer fetoscopic repair of OSB via a laparotomy-assisted approach in the German-speaking area. We point out that under the guidance of experienced centers and by intensive multidisciplinary preparation and training, a previously described and applied technique could be transferred to a different setting.

Characterization of Suboptimal Responses to Fetoscopic Endoluminal Tracheal Occlusion in Congenital Diaphragmatic Hernia.

INTRODUCTION: The aim of the study was to characterize the changes in fetal lung volume following fetoscopic endoluminal tracheal occlusion (FETO) that are associated with infant survival and need for extracorporeal membrane oxygenation (ECMO) in congenital diaphragmatic hernia (CDH). METHODS: Fetuses with CDH who underwent FETO at a single institution were included. CDH cases were reclassified by MRI metrics [observed-to-expected total lung volume (O/E TLV) and percent liver herniation]. The percent changes of MRI metrics after FETO were calculated. ROC-derived cutoffs of these changes were derived to predict infant survival to discharge. Regression analyses were done to determine the association between these cutoffs with infant survival and ECMO need, adjusted for site of CDH, gestational age at delivery, fetal sex, and CDH severity. RESULTS: Thirty CDH cases were included. ROC analysis demonstrated that post-FETO increases in O/E TLV had an area under the curve of 0.74 (p = 0.035) for the prediction of survival to hospital discharge; a cutoff of less than 10% was selected. Fetuses with a <10% post-FETO increase in O/E TLV had lower survival to hospital discharge [44.8% vs. 91.7%; p = 0.018] and higher ECMO use [61.1% vs. 16.7%; p = 0.026] compared to those with an O/E TLV increase ≥10%. Similar results were observed when the analyses were restricted to left-sided CDH cases. A post-FETO <10% increase in O/E TLV was independently associated with lower survival at hospital discharge (aOR: 0.073, 95% CI: 0.008-0.689; p = 0.022) and at 12 months of age (aOR: 0.091, 95% CI: 0.01-0.825; p = 0.036) as well as with higher ECMO use (aOR: 7.88, 95% CI: 1.31-47.04; p = 0.024). CONCLUSION: Fetuses with less than 10% increase in O/E TLV following the FETO procedure are at increased risk for requiring ECMO and for death in the postnatal period when adjusted for gestational age at delivery, CDH severity, and other confounders.

Effects of cumulative duration of repeated anaesthesia exposure on foetal brain development in the ovine model.

OBJECTIVE: Anaesthesia is required in 0.4-1% of pregnant women, and prolonged and repeated exposures to anaesthesia may be required. It is unknown whether these exposures may result in foetal neurotoxicity in humans. As sheep have a gestation comparable to that of humans, the objective of this study was to analyse the neurodevelopmental outcome of ovine foetuses that had been exposed in utero to repeated and prolonged anaesthesia. DESIGN: Randomized controlled preclinical study. SETTING: Anaesthesia for non-obstetric surgery during pregnancy. ANIMALS: Twenty-four healthy pregnant Swifter ewes. INTERVENTIONS: The ewes were randomized to no anaesthesia exposure (control-group), single exposure (at gestational age 68-70 days), or repeated exposure (at gestational age 68-70 days and 96-98 days) to 2.5 h of sevoflurane anaesthesia and maternal laparotomy. All lambs were delivered at approximately term gestation (gestational age: 140-143 days). MEASUREMENTS: The primary outcome was neuron density in the frontal cortex 24 h after birth for the control-group versus the repeated-exposure-group. Key secondary outcome was the time needed to achieve the milestone of standing. Secondary outcomes included other neurobehavioural assessments (e.g., motoric milestones) and histological parameters quantified in multiple brain regions (neuron density, total cell density, proliferation, inflammation, synaptogenesis, astrocytes and myelination). MAIN RESULTS: Neuron density in the frontal cortex did not differ between groups (mean ±â€¯standard deviation: control-group: 403 ±â€¯39, single-exposure group: 436 ±â€¯23 and repeated-exposure-group: 403 ±â€¯40 neurons/mm2, control-group versus repeated-exposure-group: p = 0.986, control-group versus single-exposure-group: p = 0.097). No significant difference was observed for the time needed to achieve the milestone of standing. Only very limited differences were observed for other histological outcome parameters and neurobehavioural assessments. CONCLUSIONS: There is no evidence for foetal neuronal injury or neurobehavioural impairments after a cumulative duration of 5 h repetitive prenatal anaesthesia in sheep.

Turner syndrome-omphalocele association: Incidence, karyotype, phenotype and fetal outcome.

OBJECTIVE: Omphalocele is known to be associated with genetic anomalies like trisomy 13, 18 and Beckwith-Wiedemann syndrome, but not with Turner syndrome (TS). Our aim was to assess the incidence of omphalocele in fetuses with TS, the phenotype of this association with other anomalies, their karyotype, and the fetal outcomes. METHOD: Retrospective multicenter study of fetuses with confirmed diagnosis of TS. Data were extracted from a detailed questionnaire sent to specialists in prenatal ultrasound. RESULTS: 680 fetuses with TS were included in this analysis. Incidence of small omphalocele in fetuses diagnosed ≥12 weeks was 3.1%. Including fetuses diagnosed before 12 weeks, it was 5.1%. 97.1% (34/35) of the affected fetuses had one or more associated anomalies including increased nuchal translucency (≥3 mm) and/or cystic hygroma (94.3%), hydrops/skin edema (71.1%), and cardiac anomalies (40%). The karyotype was 45,X in all fetuses. Fetal outcomes were poor with only 1 fetus born alive. CONCLUSION: TS with 45,X karyotype but not with X chromosome variants is associated with small omphalocele. Most of these fetuses have associated anomalies and a poor prognosis. Our data suggest an association of TS with omphalocele, which is evident from the first trimester.

Minimally Invasive Fetal Surgery and the Next Frontier.

Most patients with congenital anomalies do not require prenatal intervention. Furthermore, many congenital anomalies requiring surgical intervention are treated adequately after birth. However, there is a subset of patients with congenital anomalies who will die before birth, shortly after birth, or experience severe postnatal complications without fetal surgery. Fetal surgery is unique in that an operation is performed on the fetus as well as the pregnant woman who does not receive any direct benefit from the surgery but rather lends herself to risks, such as hemorrhage, abruption, and preterm labor. The maternal risks involved with fetal surgery have limited the extent to which fetal interventions may be performed but have, in turn, led to technical innovations that have significantly advanced the field. This review will examine congenital abnormalities that can be treated with minimally invasive fetal surgery and introduce the next frontier of prenatal management of fetal surgical pathology.

Local host response of commercially available dural patches for fetal repair of spina bifida aperta in rabbit model.

OBJECTIVE: Fetal surgery for spina bifida aperta (SBA) by open hysterotomy typically repairs anatomical native tissue in layers. Increasingly, fetoscopic repair is performed using a dural patch followed by skin closure. We studied the host response to selected commercially available patches currently being used in a fetal rabbit model for spina bifida repair. METHODS: SBA was surgically induced at 23-24 days of gestation (term = 31 days). Fetal rabbits were assigned to unrepaired (SBA group), or immediate repair with Duragen™ or Durepair™. Non-operated littermates served as normal controls. At term, spinal cords underwent immunohistochemical staining including Nissl and glial fibrillary acidic protein. We hypothesized that spinal cord coverage with a dural patch and skin closure would preserve motor neuron density within the non-inferiority limit of 201.65 cells/mm2 and reduce inflammation compared to unrepaired SBA fetuses. RESULTS: Motor neuron density assessed by Nissl staining was conserved both by Duragen (n = 6, 89.5; 95% CI -158.3 to -20.6) and Durepair (n = 6, 37.0; 95% CI -132.6 to -58.5), whereas density of GFAP-positive cells to quantify inflammation was lower than in unrepaired SBA-fetuses (SBA 2366.0 ± 669.7 cells/mm2 vs. Duragen 1274.0 ± 157.2 cells/mm2 ; p = 0.0002, Durepair 1069.0 ± 270.7 cells/mm2 ; p < 0.0001). CONCLUSIONS: Covering the rabbit spinal cord with either Duragen or Durepair followed by skin closure preserves motor neuron density and reduces the inflammatory response.

Arterial Embolization and Methylene Blue Injection into the Aberrant Artery in Two Infants with Intralobar Sequestration.

Bronchopulmonary sequestration is a rare congenital lung dysplasia. An intralobar sequestration (ILS) is a nonfunctional mass within the lung parenchyma without bronchial communication and with aberrant systemic arterial blood supply. Surgical resection or close observation can be proposed in the management of asymptomatic and low-risk ILS, but there is a lack of consensus. Endovascular embolization before thoracoscopic resection of ILS has been described to limit perioperative bleeding. Another technique previously reported is the injection of methylene blue in the feeding artery to macroscopically mark the sequestration from the healthy lung. In that way, a nonanatomical resection can be performed instead of a lobectomy without the risk of leaving abnormal lung tissue in place. We describe the first two cases of these two techniques combined: a 3-year-old girl with an ILS in the right lower lobe with an artery originating from the abdominal aorta, and a 14-month-old girl with an ILS in the right lower lobe with an artery coming from the celiac trunk. The combination of embolization and injection of methylene blue in the aberrant artery leads to a clear macroscopic demarcation of the blue-colored ILS from the healthy lung parenchyma and allowed safe nonanatomical resection of the ILS without risk of bleeding or compromising normal lung tissue.

Natural history of posterior fetal cephaloceles and incidence of progressive cephalocele herniation.

OBJECTIVE: In utero repair of fetal posterior cephaloceles (meningocele and encephalocele) is being performed based on the premise that fetal surgery prevents progressive herniation of neural tissue and brain damage during pregnancy. However, the extent to which progressive herniation occurs during pregnancy, specifically from prenatal diagnosis to after delivery, is not well known. The objective of this study was to describe the natural history of patients with fetal cephaloceles focusing on the incidence of progressive herniation. METHODS: The authors conducted a retrospective cohort study of all patients referred to their center for posterior fetal cephalocele between 2006 and 2021. All patients underwent prenatal and postnatal MRI. Progressive herniation (primary outcome) was defined as an increase in the absolute volume of neural tissue within the cephalocele of > 5% or new herniation of a critical structure into the cephalocele. Total brain and cephalocele volumes were calculated to determine herniation progression from prenatal to postnatal MRI. Information on the presence of hydrocephalus, epilepsy, and developmental delay (secondary outcomes) was collected at 1 year of age. RESULTS: Twenty patients met all study criteria. Ten patients (50%; 95% CI 0.27-0.73) demonstrated progressive herniation from prenatal to postnatal MRI. Three patients with progressive herniation were diagnosed with a meningocele prenatally and had an encephalocele postnatally. Two patients without progression had meningocele identified prenatally that regressed and became atretic by birth. Both prenatal hindbrain herniation (p = 0.03) and prenatal microcephaly (p = 0.05) were predictive of progressive herniation. The rates of hydrocephalus (44%), epilepsy (44%), and developmental delay (63%) were not associated with the occurrence of progressive herniation in this study. CONCLUSIONS: In this study, progressive herniation was not a rare event (50%). Fetal hindbrain herniation and fetal microcephaly were associated with the occurrence of progressive herniation. These results support further investigations into why progressive herniation occurs in utero and if progressive cerebral herniation in utero plays a significant role in determining clinical outcome.

Fetoscopic insufflation of heated-humidified carbon dioxide during simulated spina bifida repair is safe under controlled anesthesia in the fetal lamb.

OBJECTIVE: To assess the safety of Partial-Amniotic-Insufflation-of-heated-humidified-CO2 (hPACI) during fetoscopic spina bifida repair (fSB-repair). METHOD: A simulated fSB-repair through an exteriorized uterus under hPACI was performed in 100-day fetal lambs (term = 145 days) under a laboratory anesthesia protocol (n = 5; group 1) which is known to induce maternal-fetal acidosis and hypercapnia. Since these may not occur clinically, we applied a clinical anesthesia protocol (n = 5; group 2), keeping maternal parameters within physiological conditions, that is, controlled maternal arterial carbon dioxide (CO2) pressure (pCO2  = 30 mmHg), blood pressure (≥67 mmHg), and temperature (37.1-39.8°C). Our superiority study used fetal pH as the primary outcome. RESULTS: Compared to group 1, controlled anesthesia normalized fetal pH (7.23 ± 0.02 vs. 7.36 ± 0.02, p < 0.001), pCO2 (70.0 ± 9.1 vs. 43.0 ± 1.0 mmHg, p = 0.011) and bicarbonate (27.8 ± 1.1 vs. 24.0 ± 0.9 mmol/L, p = 0.071) at baseline. It kept them within clinically acceptable limits (pH ≥ 7.23, pCO2  ≤ 70 mmHg, bicarbonate ≤ 30 mm/L) for ≥120 min of hPACI as opposed to ≤30 min in group one. Fetal pO2 and lactate were comparable between groups and generally within normal range. Fetal brain histology demonstrated fewer apoptotic cells and higher neuronal density in the prefrontal cortex in group two. There was no difference in fetal membrane inflammation, which was mild. CONCLUSION: Fetoscopic insufflation of heated-humidified CO2 during simulated fSB-repair through an exteriorized uterus can be done safely under controlled anesthesia.

Surgical data science - from concepts toward clinical translation.

Recent developments in data science in general and machine learning in particular have transformed the way experts envision the future of surgery. Surgical Data Science (SDS) is a new research field that aims to improve the quality of interventional healthcare through the capture, organization, analysis and modeling of data. While an increasing number of data-driven approaches and clinical applications have been studied in the fields of radiological and clinical data science, translational success stories are still lacking in surgery. In this publication, we shed light on the underlying reasons and provide a roadmap for future advances in the field. Based on an international workshop involving leading researchers in the field of SDS, we review current practice, key achievements and initiatives as well as available standards and tools for a number of topics relevant to the field, namely (1) infrastructure for data acquisition, storage and access in the presence of regulatory constraints, (2) data annotation and sharing and (3) data analytics. We further complement this technical perspective with (4) a review of currently available SDS products and the translational progress from academia and (5) a roadmap for faster clinical translation and exploitation of the full potential of SDS, based on an international multi-round Delphi process.

Validation of a high-fidelity training model for fetoscopic spina bifida surgery.

Open fetal surgery for spina bifida (SB) is safe and effective yet invasive. The growing interest in fetoscopic SB repair (fSB-repair) prompts the need for appropriate training. We aimed to develop and validate a high-fidelity training model for fSB-repair. fSB-repair was simulated in the abdominal cavity and on the stomach of adult rabbits. Laparoscopic fetal surgeons served either as novices (n = 2) or experts (n = 3) based on their experience. Technical performance was evaluated using competency Cumulative Sum (CUSUM) analysis and the group splitting method. Main outcome measure for CUSUM competency was a composite binary outcome for surgical success, i.e. watertight repair, operation time ≤ 180 min and Objective-Structured-Assessment-of-Technical-Skills (OSATS) score ≥ 18/25. Construct validity was first confirmed since competency levels of novices and experts during their six first cases using both methods were significantly different. Criterion validity was also established as 33 consecutive procedures were needed for novices to reach competency using learning curve CUSUM, which is a number comparable to that of clinical fSB-repair. Finally, we surveyed expert fetal surgeons worldwide to assess face and content validity. Respondents (26/49; 53%) confirmed it with ≥ 71% of scores for overall realism ≥ 4/7 and usefulness ≥ 3/5. We propose to use our high-fidelity model to determine and shorten the learning curve of laparoscopic fetal surgeons and retain operative skills.

Effects of Maternal Abdominal Surgery on Fetal Brain Development in the Rabbit Model.

INTRODUCTION: Anesthesia during pregnancy can impair fetal neurodevelopment, but effects of surgery remain unknown. The aim is to investigate effects of abdominal surgery on fetal brain development. Hypothesis is that surgery impairs outcome. METHODS: Pregnant rabbits were randomized at 28 days of gestation to 2 h of general anesthesia (sevoflurane group, n = 6) or to anesthesia plus laparoscopic appendectomy (surgery group, n = 13). On postnatal day 1, neurobehavior of pups was assessed and brains harvested. Primary outcome was neuron density in the frontal cortex, and secondary outcomes included neurobehavioral assessment and other histological parameters. RESULTS: Fetal survival was lower in the surgery group: 54 versus 100% litters alive at birth (p = 0.0442). In alive litters, pup survival until harvesting was 50 versus 69% (p = 0.0352). No differences were observed for primary outcome (p = 0.5114) for surviving pups. Neuron densities were significantly lower in the surgery group in the caudate nucleus (p = 0.0180), but not different in other regions. No differences were observed for secondary outcomes. Conclusions did not change after adjustment for mortality. CONCLUSION: Abdominal surgery in pregnant rabbits at a gestational age corresponding to the end of human second trimester results in limited neurohistological changes but not in neurobehavioral impairments. High intrauterine mortality limits translation to clinical scenario, where fetal mortality is close to zero.

Development of a Core outcome set for fetal Myelomeningocele (COSMiC): study protocol.

BACKGROUND: Open spina bifida (OSB) is one of the most common congenital central nervous system defects and leads to long-term physical and cognitive disabilities. Open fetal surgery for OSB improves neurological outcomes and reduces the need for ventriculoperitoneal shunting, compared to postnatal surgery, but is associated with a significant risk of prematurity and maternal morbidity. Fetoscopic surgery comes with less maternal morbidity, yet the question remains whether the procedure is neuroprotective and reduces prematurity. Comparison of outcomes between different treatment options is challenging due to inconsistent outcome reporting. We aim to develop and disseminate a core outcome set (COS) for fetal OSB, to ensure that outcomes relevant to all stakeholders are collected and reported in a standardised fashion in future studies. METHODS: The COS will be developed using a validated Delphi methodology. A systematic literature review will be performed to identify outcomes previously reported for prenatally diagnosed OSB. We will assess maternal (primary and subsequent pregnancies), fetal, neonatal and childhood outcomes until adolescence. In a second phase, we will conduct semi-structured interviews with stakeholders, to ensure representation of additional relevant outcomes that may not have been reported in the literature. We will include patients and parents, as well as health professionals involved in the care of these pregnancies and children (fetal medicine specialists, fetal surgeons, neonatologists/paediatricians and allied health). Subsequently, an international group of key stakeholders will rate the importance of the identified outcomes using three sequential online rounds of a modified Delphi Survey. Final agreement on outcomes to be included in the COS, their definition and measurement will be achieved through a face-to-face consensus meeting with all stakeholder groups. Dissemination of the final COS will be ensured through different media and relevant societies. DISCUSSION: Development and implementation of a COS for fetal OSB will ensure consistent outcome reporting in future clinical trials, systematic reviews and clinical practice guidelines. This will lead to higher quality research, better evidence-based clinical practice and ultimately improved maternal, fetal and long-term childhood outcomes. TRIAL REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO) CRD42018104880 . Registered on December 5, 2018. Core Outcome Measures in Effectiveness Trials (COMET): 1187.

Fetal surgical intervention for myelomeningocele: lessons learned, outcomes, and future implications.

Fetal myelomeningocele (fMMC) closure (spina bifida aperta) has become a care option for patients that meet inclusion criteria, but it is clear that fetal intervention, while improving outcomes, is not a cure. This review will: (1) focus on the rationale for fMMC surgery based on preclinical studies and observations that laid the foundation for human pilot studies and a randomized controlled trial; (2) summarize important clinical outcomes; (3) discuss the feasibility, efficacy, and safety of recent developments in fetal surgical techniques and approaches; and (4) highlight future research directions. Given the increased risk of maternal and fetal morbidity associated with prenatal intervention, accompanied by the increasing number of centres performing interventions worldwide, teams involved in the care of these patients need to proceed with caution to maintain technical expertise, competency, and patient safety. Ongoing assessment of durability of the benefits of fMMC surgery, as well as additional refinement of patient selection criteria and counselling, is needed to further improve outcomes and reduce the risks to the mother and fetus. WHAT THIS PAPER ADDS: High-quality prospective studies are needed to broaden the indication for fetal surgery in the general myelomeningocele population. Innovative minimally invasive approaches have had promising results, yet lack comprehensive and robust experimental or clinical evaluation. Important information to help families make informed decisions regarding fetal surgery for myelomeningocele is provided.

INTERVENCIÓN QUIRÚRGICA FETAL PARA MIELOMENINGOCELE: LECCIONES APRENDIDAS, RESULTADOS E IMPLICACIONES FUTURAS: El cierre del mielomeningocele fetal (fMMC) (espina bífida) se ha convertido en una opción de atención para pacientes que cumplen con los criterios de inclusión, pero está claro que la intervención fetal mientras se mejoran los resultados no es una cura. Esta revisión: (1) se centrará en la justificación de la cirugía fMMC basada en estudios preclínicos y observaciones que sentaron las bases para estudios piloto humanos y un ensayo controlado aleatorio; (2) resumir resultados clínicos importantes; (3) discutir la viabilidad, eficacia y seguridad de los desarrollos recientes en técnicas y enfoques de cirugía fetal; y (4) resaltar futuras direcciones de investigación. Dado el mayor riesgo de morbilidad materna y fetal asociada con la intervención prenatal, acompañado por el creciente número de centros que realizan intervenciones en todo el mundo, los equipos involucrados en la atención de estos pacientes deben proceder con precaución para mantener la experiencia técnica, la competencia y la seguridad del paciente. Se necesita una evaluación continua de la durabilidad de los beneficios de la cirugía fMMC, así como un refinamiento adicional de los criterios de selección de pacientes y asesoramiento, para mejorar aún más los resultados y reducir los riesgos para la madre y el feto.

INTERVENÇÃO CIRÚRGICA FETAL PARA MIELOMENINGOCELE: LIÇÕES APRENDIDAS, RESULTADOS E IMPLICAÇÕES FUTURAS: O fechamento fetal da mielomeningocele (fFMM), ou espinha bífida aberta, se tornou uma opção de cuidado para pacientes que atendem aos critérios de inclusão, mas está claro que, embora melhore os resultados, a intervenção fetal não representa cura. Esta revisão irá: 1) focar nos princípios da cirurgia de fFMM com base em estudos pré-clínicos e observações que basearam estudos pilotos com humanos e um estudo randomizado controlado; 2) sintetizar resultados clínicos importantes; 3) discutir a viabilidade, eficácia e segurança dos desenvolvimentos recentes em técnicas e abordagens de cirurgia fetal; e 4) destacar direções para futuras pesquisas. Dado o risco aumentado de morbidade maternal e fetal associado com a intervenção pré-natal, acompanhado pelo aumento no número de centros que realizam a intervenção no mundo, equipes envolvidas no cuidado destes pacientes precisam proceder com cautela para manter a especialidade técnica, competência e segurança dos pacientes. Contínua avaliação da durabilidade dos benefícios da fFMMM, assim como refinamento adicional dos critérios de seleção de pacientes e aconselhamento, são necessários para melhorar os resultados e reduzir os riscos para mãe e feto.

Validation of the Fetal Lamb Model of Spina Bifida.

A randomized trial demonstrated that fetal spina bifida (SB) repair is safe and effective yet invasive. New less invasive techniques are proposed but are not supported by adequate experimental studies. A validated animal model is needed to bridge the translational gap to the clinic and should mimic the human condition. Introducing a standardized method, we comprehensively and reliably characterize the SB phenotype in two lamb surgical models with and without myelotomy as compared to normal lambs. Hindbrain herniation measured on brain magnetic resonance imaging (MRI) was the primary outcome. Secondary outcomes included gross examination with cerebrospinal fluid (CSF) leakage test, neurological examination with locomotor assessment, whole-body MRI, motor and somatosensory evoked potentials; brain, spinal cord, hindlimb muscles, bladder and rectum histology and/or immunohistochemistry. We show that the myelotomy model best phenocopies the anatomy, etiopathophysiology and symptomatology of non-cystic SB. This encompasses hindbrain herniation, ventriculomegaly, posterior fossa anomalies, loss of brain neurons; lumbar CSF leakage, hindlimb somatosensory-motor deficit with absence of motor and somatosensory evoked potentials due to loss of spinal cord neurons, astroglial cells and myelin; urinary incontinence. This model obtains the highest validity score for SB animal models and is adequate to assess the efficacy of novel fetal therapies.