High-Fidelity Low-Cost Synthetic Training Model for Fetoscopic Spina Bifida Repair

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

Placental vascular alterations are associated with early neurodevelopmental and pulmonary impairment in the rabbit fetal growth restriction model

Fetal growth restriction is one of the leading causes of perinatal mortality and morbidity and has consequences that extend well beyond the neonatal period. Current management relies on timely delivery rather than improving placental function. Several prenatal strategies have failed to show benefit in clinical trials after promising results in animal models. Most of these animal models have important developmental and structural differences compared to the human and/or are insufficiently characterized. We aimed to describe placental function and structure in an FGR rabbit model, and to characterize the early brain and lung developmental morbidity using a multimodal approach. FGR was induced in time-mated rabbits at gestational day 25 by partial uteroplacental vessel ligation in one horn. Umbilical artery Doppler was measured before caesarean delivery at gestational day 30, and placentas were harvested for computed microtomography and histology. Neonates underwent neurobehavioral or pulmonary functional assessment the day after delivery, followed by brain or lung harvesting, respectively. Neuropathological assessment included multiregional quantification of neuron density, apoptosis, astrogliosis, cellular proliferation, and oligodendrocyte progenitors. Brain region volumes and diffusion metrics were obtained from ex-vivo brain magnetic resonance imaging. Lung assessment included biomechanical tests and pulmonary histology. Fetal growth restriction was associated with labyrinth alterations in the placenta, driven by fetal capillary reduction, and overall reduced vessels volume. FGR caused altered neurobehavior paralleled by regional neuropathological deficits and reduced fractional anisotropy in the cortex, white matter, and hippocampus. In addition, FGR kittens presented functional alterations in the peripheral lung and structurally underdeveloped alveoli. In conclusion, in a uteroplacental insufficiency FGR rabbit model, placental vascular alterations coincide with neurodevelopmental and pulmonary disruption

Parental attachment and depressive symptoms in pregnancies complicated by twin-twin transfusion syndrome: a cohort study

BACKGROUND: Twin-twin transfusion syndrome (TTTS) is a highly morbid condition in which treatment exists, but the pregnancy remains high-risk until delivery. It may have serious sequelae, including fetal death, and in the longer term, neurodevelopmental problems. The aim of this study is to assess antenatal and postnatal parental attachment and depressive symptoms in those with pregnancies affected by TTTS. METHODS: Couples attending for fetoscopic laser ablation treatment of TTTS were asked to complete Condon's Maternal/Paternal Antenatal/Postnatal Attachment Scale as appropriate, and the Edinburgh Depression Scale the day before ablation, 4 weeks post-ablation, and 6-10 weeks postnatally. RESULTS: 25/27 couples completed the pre-ablation questionnaire (median gestational age 19 + 3 weeks [interquartile range 18 + 2-20 + 6]). 8/18 eligible couples returned the post-ablation questionnaire. 5/17 eligible couples returned the postnatal questionnaire. There was no significant difference in parento-fetal attachment when mothers were compared to fathers at each time point, however parento-fetal attachment did increase over time in mothers (p = 0.004), but not fathers. Mothers reported more depressive symptoms antenatally compared to fathers (p < 0.02), but there was no difference postnatally. 50% women reported Edinburgh Depression Scale scores above the cut-off (≥15) 4 weeks post-ablation. Over time maternal depressive symptoms decreased (p = 0.006), however paternal depressive symptoms remained the same. CONCLUSIONS: This is the first attachment and depression study in a UK cohort of parents with pregnancies affected by TTTS. Although this was a small cohort and the questionnaires used had not been validated in these circumstances, the results suggest that centres caring for these couples should be aware of the risk of maternal and paternal antenatal depression, and screen and refer for additional psychological support. Further work is needed in larger cohorts. TRIAL REGISTRATION: ISRCTN 13114861 (retrospectively registered)

The TOTAL trial dilemma: a survey among professionals on equipoise regarding fetal therapy for severe congenital diaphragmatic hernia

OBJECTIVE: Running randomized clinical trials (RCT) in fetal therapy is challenging. This is no different for fetoscopic endoluminal tracheal occlusion (FETO) for severe left-sided Congenital Diaphragmatic Hernia (CDH). We assessed the knowledge, attitude and practice (KAP) of maternal-fetal medicine specialists toward the antenatal management of CDH, and the randomized controlled clinical (RCT) "Tracheal Occlusion To Accelerate Lung growth-trial." METHODS: A cross-sectional KAP-survey was conducted among 311 registrants of the 18th World Congress in Fetal Medicine. RESULTS: The overall knowledge of CDH and FETO was high. Remarkably only 45% considers prenatal prediction of neonatal outcome reliable. Despite, in their clinical practice they perform severity assessment (80%) and refer families for FETO either within the context of an RCT (43%) or on patient request (32%). Seventy percent perceives not offering FETO on patient demand seems as if no treatment is provided to a fetus with predicted poor outcome. Only 20% of respondents considers denying access to FETO on patient demand not as a psychological burden. CONCLUSION: Often the views of individual respondents contradicted with their clinical practice. It seems that, for severe CDH, clinicians face personal and practical dilemmas that undermine equipoise. To us, this indicates the tension between the clinical and scientific obligations physicians experience.status: accepte

Subsequent fertility, pregnancy and gynecologic outcomes after fetoscopic laser therapy for twin-twin transfusion syndrome compared to normal monochorionic twin gestations

An improved survival and quality of life for neonatal survivors after fetoscopic laser therapy (FLC) for twin-twin transfusion syndrome (TTTS) has been reported. However, little is known about the medium-term maternal effects after FLC with respect to reproductive and gynecologic outcomes.status: publishe

Neurodevelopmental outcomes in children with isolated congenital diaphragmatic hernia : A systematic review and meta-analysis

Background: Congenital diaphragmatic hernia (CDH) reportedly has neurologic consequences in childhood however little is known about the impact in isolated CDH. Aims: Herein we aimed to describe the risk of neurodevelopmental complications in children born with isolated CDH. Materials & Methods: We systematically reviewed literature for reports on the neurological outcome of infants born with isolated CDH. The primary outcome was neurodevelopmental delay. Secondary outcomes included, motor skills, intelligence, vision, hearing, language and behavior abnormalities. Results: Thirteen out of 87 (15%) studies reported on isolated CDH, including 2624 out of 24,146 children. Neurodevelopmental delay was investigated in four studies and found to be present in 16% (3-34%) of children. This was mainly attributed to motor problems in 13% (2-30%), whereas cognitive dysfunction only in 5% (0-20%) and hearing in 3% (1-7%). One study assessed the effect of fetal surgery. When both isolated and non-isolated children were included, these numbers were higher. Discussion: This systematic review demonstrates that only a minority of studies focused on isolated CDH, with neurodevelopmental delay present in 16% of children born with CDH. Conclusion: To accurately counsel patients, more research should focus on isolated CDH cases and examine children that underwent fetal surgery

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=31d). 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 GFAP. 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±270.7cells/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. This article is protected by copyright. All rights reserved

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

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

Study protocol: a core outcome set for perinatal interventions for congenital diaphragmatic hernia

Background: Congenital diaphragmatic hernia (CDH) is, depending of the severity, a birth defect associated with significant mortality and morbidity. Prenatal screening by ultrasound may detect this condition and comprehensive assessment of severity is possible, allowing for in utero referral to an experienced centre for planned delivery. In an effort to improve outcomes, prenatal interventions to stimulate lung development were proposed. Along the same lines, new postnatal management strategies are being developed. In order to enable proper comparison of novel perinatal interventions as well as outcomes, a set of uniform and relevant outcome measures is required. Core outcome sets (COS) are agreed, clearly defined sets of outcomes to be measured in a standardised manner and reported consistently. Herein we aim to describe the methodology we will use to define a COS for perinatal and neonatal outcomes of foetuses and newborns with congenital diaphragmatic hernia and to draft a dissemination and implementation plan. Methods: We will use the methodology described in the Core Outcome Measures in Effectiveness Trials (COMET) Initiative Handbook. An international steering group will be created to guide the development of the COS. We are systematically reviewing the literature to identify all potential relevant pre- and neonatal outcomes previously used in studies on perinatal interventions for CDH. We will build a consensus on these core outcomes in a stakeholder group using the Delphi method. After completion, a stakeholder meeting will decide on a final COS, using a modified Nominal Group Technique. Thereafter, we will review potential definitions and measurements of these outcomes, and again a consensus meeting will be organised, to finalise the COS before dissemination. Discussion: We have started a procedure to develop a COS for studies on perinatal interventions for congenital diaphragmatic hernia, with the purpose of improving the quality of research, guide clinical practice and improve patient care and eventual use in future clinical trials, systematic reviews and clinical practice guidelines. Trial registration: We prospectively registered this study in the International Prospective Register of Systematic Reviews (PROSPERO) (registration number: CRD42019124399) and The Core Outcome Measures in Effectiveness Trials (COMET) Initiative (registration number:1296)