Robot assisted Fetoscopic Laser Coagulation: Improvements in navigation, re-location and coagulation.

Fetoscopic Laser Coagulation (FLC) for Twin to Twin Transfusion Syndrome is a challenging intervention due to the working conditions: low quality images acquired from a 3 mm fetoscope inside a turbid liquid environment, local view of the placental surface, unstable surgical field and delicate tissue layers. FLC is based on locating, coagulating and reviewing anastomoses over the placenta's surface. The procedure demands the surgeons to generate a mental map of the placenta with the distribution of the anastomoses, maintaining, at the same time, precision in coagulation and protecting the placenta and amniotic sac from potential damages. This paper describes a teleoperated platform with a cognitive-based control that provides assistance to improve patient safety and surgery performance during fetoscope navigation, target re-location and coagulation processes. A comparative study between manual and teleoperated operation, executed in dry laboratory conditions, analyzes basic fetoscopic skills: fetoscope navigation and laser coagulation. Two exercises are proposed: first, fetoscope guidance and precise coagulation. Second, a resolved placenta (all anastomoses are indicated) to evaluate navigation, re-location and coagulation. The results are analyzed in terms of economy of movement, execution time, coagulation accuracy, amount of coagulated placental surface and risk of placenta puncture. In addition, new metrics, based on navigation and coagulation maps evaluate robotic performance. The results validate the developed platform, showing noticeable improvements in all the metrics.

Development and validation of a flexible fetoscope for fetoscopic laser coagulation.

PURPOSE: Fetoscopic laser coagulation for twin-to-twin transfusion syndrome is challenging for anterior placenta due to the rigidity of current tools. The capacity to keep entry port forces minimal is critical for this procedure, as is optimal coagulation distance and orientation. This work introduces technological tools to this end. METHODS: A novel fetoscope is presented with a rigid shaft and a flexible steerable segment at the distal end. The steerable segment can bend up to 90[Formula: see text] even when loaded with a laser fiber. An artificial pneumatic muscle makes such acute bending possible while allowing for a low-weight and disposable device. RESULTS: The flexible fetoscope was validated in a custom-made phantom model to measure visual range and coagulation efficacy. The flexible fetoscope shows promising results when compared to a clinical rigid curved fetoscope to reach anterior targets. The new fetoscope was then evaluated in vivo (pregnant ewe) where it successfully coagulated placental vasculature. CONCLUSION: The flexible fetoscope improved the ability to achieve optimal coagulation angle and distance on anteriorly located targets. The fetoscope also showed the potential to lead fetoscopic laser coagulation and other fetal surgical procedures toward safer and more effective interventions.

Percutaneous/mini-laparotomy fetoscopic repair of open spina bifida: a novel surgical technique.

Open spina bifida is the most common congenital anomaly of the central nervous system compatible with life. Prenatal repair of open spina bifida via open maternal-fetal surgery has been shown to improve postnatal neurologic outcomes, including reducing the need for ventriculoperitoneal shunting and improving lower neuromotor function. Fetoscopic repair of open spina bifida minimizes the maternal risks while providing similar neurosurgical outcomes to the fetus. The following 2 fetoscopic techniques are currently in use: (1) the laparotomy-assisted approach, and (2) the percutaneous approach. The laparotomy-assisted fetoscopic technique appears to be associated with a lesser risk of preterm birth than the percutaneous approach. However, the percutaneous approach avoids laparotomy and uterine exteriorization and is associated with lesser anesthesia risk and improved maternal postsurgical recovery. The purpose of this article was to describe our experience with a modified surgical approach, which we call percutaneous/mini-laparotomy fetoscopy, in which access to the uterus for one of the ports is done via a mini-laparotomy, whereas the other ports are inserted percutaneously. This technique draws on the benefits of both the laparotomy-assisted and the percutaneous techniques while minimizing their drawbacks. This surgical approach may prove invaluable in the prenatal repair of open spina bifida and other complex fetal surgical procedures.

Intraamniotic sealing of fetoscopic membrane defects in ex vivo and in vivo sheep models using an integrated semirigid bioadhesive patch.

BACKGROUND: Preterm prelabor rupture of membranes is the most frequent complication of fetoscopic surgery. Strategies to seal the membrane defect created by fetoscopy have been attempted with little success. We previously developed an integrated semirigid bioadhesive patch composed of silicone and hydroxypropyl methylcellulose that achieved ex vivo sealing of membrane defects. OBJECTIVE: To evaluate the feasibility of the insertion of our integrated semirigid bioadhesive patches using a fetoscopic technique and to test the adhesion in ex vivo human membranes and in an in vivo ovine model. STUDY DESIGN: An experimental study involving 2 experiments: (1) ex vivo-human fetal membranes were mounted in a custom-designed model with saline solution simulating intraamniotic pressure. The insertion of 2 different bioadhesive patches made of silicone-hydroxypropyl methylcellulose and silicone-polyurethane-hydroxypropyl methylcellulose was performed through a 12-Fr cannula mimicking fetoscopic surgery technique. The experiment was repeated 10 times with membranes from different donors. Measures included insertion time, successful insertion, and adhesion at 5 minutes; (2) in vivo-16 patches of silicone-hydroxypropyl methylcellulose were inserted by fetoscopy in the amniotic cavity of pregnant sheep (4 bioadhesives per animal, in 4 ewes). Measures included successful insertion, adhesion at 5 minutes, and adhesion at the end of surgery. RESULTS: In the ex vivo insertion study, there was no difference in the insertion time between silicone-hydroxypropyl methylcellulose and silicone-polyurethane-hydroxypropyl methylcellulose patches (P=.49). Insertion was successful in all cases, but complete adhesion at 5 minutes was superior for silicone-hydroxypropyl methylcellulose (P=.02). In the in vivo study, insertion of silicone-hydroxypropyl methylcellulose by fetoscopy was feasible and successful in all cases, and no complications were reported. Adhesion persisted at 5 minutes and at the end of the surgery in 68.8% and 56.3% of the patches, respectively. CONCLUSION: We describe the feasibility of deploying through a fetoscopic trocar a semirigid silicone-hydroxypropyl methylcellulose patch that seals fetal membranes after an invasive fetal procedure. The results warrant further research for improving long-term adhesion and developing a clinically applicable system.

Flexible fetoscope in the treatment of twin-to-twin transfusion syndrome.

BACKGROUND: Twin-to-twin transfusion syndrome (TTTS) could be treated with fetoscopic laser photocoagulation. For patients with placenta located on the anterior wall of uterus, surgical procedures are difficult. To solve this problem, a flexible fetoscope was designed in our department. METHODS: The flexible fetoscope was made up of polyurethane, fiberglass and stainless steel coils. The specular body was soft and could bend encountering obstacles, which reduced the possibility of injury to the fetus and placenta. The distal tip of the body could curve from -180° to +270° with the control of the handweel. Three pregnant women of TTTS with anterior placenta was operated with this instrument. RESULT: All pregnant women were treated smoothly and gave live twins birth at term. Through angiography, it was demonstrated that the vascular connections on the surface had been coagulated. CONCLUSION: The flexible fetoscope was a novel instrument in treating TTTS, especially for the anterior placenta.

Pregnancy rates of day 4 and day 5 embryos after culture in an integrated time-lapse incubator.

BACKGROUND: The aim of this study was to compare pregnancy rates in patients undergoing IVF/ICSI with embryo transfer after 4 and 5 days of culture in a closed incubation system with integrated time-lapse imaging. METHODS: Out of n = 2207 in vitro fertilization (IVF)/ intracytoplasmic sperm injection (ICSI) cycles performed between January 2011 and April 2016 at a tertiary referral university hospital, a total of n = 599 IVF/ICSI cycles with prolonged embryo culture in an integrated time-lapse system (EmbryoScope© (Vitrolife)) until day 4 or 5 were retrospectively analyzed with regard to embryo morphology and pregnancy rates. RESULTS: A transfer on day 5 compared to a transfer on day 4 did not result in higher implantation and clinical pregnancy rates (IR 29.4% on day 4 versus 33.0% on day 5, p = 0.310; CPR 45.2% on day 4 versus 45.7% on day 5, p = 1.0). The percentage of ideal embryos transferred on day 4 was comparable to the rate of ideal embryos transferred on day 5 (41.6% versus 44.1%, p = 0.508). However, on day 4 a significantly higher number of embryos was transferred (1.92 on day 4 versus 1.84 on day 5, p = 0.023), which did not result in higher rates of multiple pregnancies. CONCLUSIONS: Pregnancy rates in IVF/ICSI cycles with integrated time-lapse incubation and transfer on day 4 and 5 are comparable. This finding provides the clinician, IVF laboratory and patient with more flexibility. TRIAL REGISTRATION: This study was retrospectively registered by the local ethics committee of the University of Heidelberg on December 19, 2016 (registration number S-649/2016).

Medical-grade Sterilizable Target for Fluid-immersed Fetoscope Optical Distortion Calibration.

We have developed a calibration target for use with fluid-immersed endoscopes within the context of the GIFT-Surg (Guided Instrumentation for Fetal Therapy and Surgery) project. One of the aims of this project is to engineer novel, real-time image processing methods for intra-operative use in the treatment of congenital birth defects, such as spina bifida and the twin-to-twin transfusion syndrome. The developed target allows for the sterility-preserving optical distortion calibration of endoscopes within a few minutes. Good optical distortion calibration and compensation are important for mitigating undesirable effects like radial distortions, which not only hamper accurate imaging using existing endoscopic technology during fetal surgery, but also make acquired images less suitable for potentially very useful image computing applications, like real-time mosaicing. In this paper proposes a novel fabrication method to create an affordable, sterilizable calibration target suitable for use in a clinical setup. This method involves etching a calibration pattern by laser cutting a sandblasted stainless steel sheet. This target was validated using the camera calibration module provided by OpenCV, a state-of-the-art software library popular in the computer vision community.

Different effectiveness of closed embryo culture system with time-lapse imaging (EmbryoScope(TM)) in comparison to standard manual embryology in good and poor prognosis patients: a prospectively randomized pilot study.

BACKGROUND: Previously manual human embryology in many in vitro fertilization (IVF) centers is rapidly being replaced by closed embryo incubation systems with time-lapse imaging. Whether such systems perform comparably to manual embryology in different IVF patient populations has, however, never before been investigated. We, therefore, prospectively compared embryo quality following closed system culture with time-lapse photography (EmbryoScope™) and standard embryology. We performed a two-part prospectively randomized study in IVF (clinical trial # NCT92256309). Part A involved 31 infertile poor prognosis patients prospectively randomized to EmbryoScope™ and standard embryology. Part B involved embryos from 17 egg donor-recipient cycles resulting in large egg/embryo numbers, thus permitting prospectively alternative embryo assignments to EmbryoScope™ and standard embryology. We then compared pregnancy rates and embryo quality on day-3 after fertilization and embryologist time utilized per processed embryo. RESULTS: Part A revealed in poor prognosis patients no differences in day-3 embryo scores, implantation and clinical pregnancy rates between EmbryoScope™ and standard embryology. The EmbryoScope™, however, more than doubled embryology staff time (P < 0.0001). In Part B, embryos grown in the EmbyoScope™ demonstrated significantly poorer day-3 quality (depending on embryo parameter between P = 0.005 and P = 0.01). Suspicion that conical culture dishes of the EmbryoScope™ (EmbryoSlide™) may be the cause was disproven when standard culture dishes demonstrated no outcome difference in standard incubation. CONCLUSIONS: Though due to small patient numbers preliminary, this study raises concerns about the mostly uncontrolled introduction of closed incubation systems with time lapse imaging into routine clinical embryology. Appropriately designed and powered prospectively randomized studies appear urgently needed in well-defined patient populations before the uncontrolled utilization of these instruments further expands. TRIAL REGISTRATION: NCT02246309 Registered September 18, 2014.

Semiautomated analysis of embryoscope images: Using localized variance of image intensity to detect embryo developmental stages.

Embryo selection in in vitro fertilization (IVF) treatment has traditionally been done manually using microscopy at intermittent time points during embryo development. Novel technique has made it possible to monitor embryos using time lapse for long periods of time and together with the reduced cost of data storage, this has opened the door to long-term time-lapse monitoring, and large amounts of image material is now routinely gathered. However, the analysis is still to a large extent performed manually, and images are mostly used as qualitative reference. To make full use of the increased amount of microscopic image material, (semi)automated computer-aided tools are needed. An additional benefit of automation is the establishment of standardization tools for embryo selection and transfer, making decisions more transparent and less subjective. Another is the possibility to gather and analyze data in a high-throughput manner, gathering data from multiple clinics and increasing our knowledge of early human embryo development. In this study, the extraction of data to automatically select and track spatio-temporal events and features from sets of embryo images has been achieved using localized variance based on the distribution of image grey scale levels. A retrospective cohort study was performed using time-lapse imaging data derived from 39 human embryos from seven couples, covering the time from fertilization up to 6.3 days. The profile of localized variance has been used to characterize syngamy, mitotic division and stages of cleavage, compaction, and blastocoel formation. Prior to analysis, focal plane and embryo location were automatically detected, limiting precomputational user interaction to a calibration step and usable for automatic detection of region of interest (ROI) regardless of the method of analysis. The results were validated against the opinion of clinical experts. © 2015 International Society for Advancement of Cytometry.

Interventional Photoacoustic Imaging of the Human Placenta with Ultrasonic Tracking for Minimally Invasive Fetal Surgeries.

Image guidance plays a central role in minimally invasive fetal surgery such as photocoagulation of inter-twin placental anastomosing vessels to treat twin-to-twin transfusion syndrome (TTTS). Fetoscopic guidance provides insufficient sensitivity for imaging the vasculature that lies beneath the fetal placental surface due to strong light scattering in biological tissues. Incomplete photocoagulation of anastamoses is associated with postoperative complications and higher perinatal mortality. In this study, we investigated the use of multi-spectral photoacoustic (PA) imaging for better visualization of the placental vasculature. Excitation light was delivered with an optical fiber with dimensions that are compatible with the working channel of a fetoscope. Imaging was performed on an ex vivo normal term human placenta collected at Caesarean section birth. The photoacoustically-generated ultrasound signals were received by an external clinical linear array ultrasound imaging probe. A vein under illumination on the fetal placenta surface was visualized with PA imaging, and good correspondence was obtained between the measured PA spectrum and the optical absorption spectrum of deoxygenated blood. The delivery fiber had an attached fiber optic ultrasound sensor positioned directly adjacent to it, so that its spatial position could be tracked by receiving transmissions from the ultrasound imaging probe. This study provides strong indications that PA imaging in combination with ultrasonic tracking could be useful for detecting the human placental vasculature during minimally invasive fetal surgery.

Prevalence, consequence, and significance of reverse cleavage by human embryos viewed with the use of the Embryoscope time-lapse video system.

OBJECTIVE: To investigate the prevalence and potential causes of reverse cleavage (RC) by human early-cleavage embryos and its associations with embryonic development and implantation after transfer. DESIGN: Clinical retrospective cohort study. SETTING: Private fertility treatment center. PATIENT(S): A total of 126 consecutive in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) treatment cycles, with 353 IVF and 436 ICSI embryos cultured in the Embryoscope until day 3. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Embryo assessment on day 3, incidence of abnormal division, embryo morphokinetic parameters, and fetal heart beat. RESULT(S): RC, referring to either blastomere fusion or failed cytokinesis, occurred up to three times per individual embryo in 27.4% of embryos during the first three cleavage cycles. A higher incidence was associated with GnRH antagonist cycles compared with agonist cycles (odds ratio [OR] 1.683), or with ICSI compared with IVF (OR 1.600). After ICSI, sperm progressive motility was associated with RC (area under the receiver operating characteristic curve: 0.573). Compared with RC-negative embryos, a lower proportion of RC-positive embryos reached 6-cell stage or beyond by day 3 (47.7% vs. 71.7%), and were more likely to have multinucleation at the 4-cell stage (10.1% vs. 5.0%). Embryos showing RC had significantly poorer performance in both conventional grading and morphokinetic parameters, and they implanted less (0/22 vs. 29/131) than those not showing RC. CONCLUSION(S): RC significantly compromised embryo development, culminating in poor implantation potential. For each embryo, it can occur on more than one occasion at any stage during the first 3 days of culture. It is associated with factors affecting both oocyte and sperm.

Clinical validation of embryo culture and selection by morphokinetic analysis: a randomized, controlled trial of the EmbryoScope.

OBJECTIVE: To determine whether incubation in the integrated EmbryoScope time-lapse monitoring system (TMS) and selection supported by the use of a multivariable morphokinetic model improve reproductive outcomes in comparison with incubation in a standard incubator (SI) embryo culture and selection based exclusively on morphology. DESIGN: Prospective, randomized, double-blinded, controlled study. SETTING: University-affiliated private in vitro fertilization (IVF) clinic. PATIENT(S): Eight hundred forty-three infertile couples undergoing intracytoplasmic sperm injection (ICSI). INTERVENTION(S): No patient intervention; embryos cultured in SI with development evaluated only by morphology (control group) and embryos cultured in TMS with embryo selection was based on a multivariable model (study group). MAIN OUTCOME MEASURE(S): Rates of embryo implantation, pregnancy, ongoing pregnancy (OPR), and early pregnancy loss. RESULT(S): Analyzing per treated cycle, the ongoing pregnancy rate was statistically significantly increased 51.4% (95% CI, 46.7-56.0) for the TMS group compared with 41.7% (95% CI, 36.9-46.5) for the SI group. For pregnancy rate, differences were not statistically significant at 61.6% (95% CI, 56.9-66.0) versus 56.3% (95% CI, 51.4-61.0). The results per transfer were similar: statistically significant differences in ongoing pregnancy rate of 54.5% (95% CI, 49.6-59.2) versus 45.3% (95% CI, 40.3-50.4) and not statistically significant for pregnancy rate at 65.2% (95% CI, 60.6-69.8) versus 61.1% (95% CI, 56.2-66.1). Early pregnancy loss was statistically significantly decreased for the TMS group with 16.6% (95% CI, 12.6-21.4) versus 25.8% (95% CI, 20.6-31.9). The implantation rate was statistically significantly increased at 44.9% (95% CI, 41.4-48.4) versus 37.1% (95% CI, 33.6-40.7). CONCLUSION(S): The strategy of culturing and selecting embryos in the integrated EmbryoScope time-lapse monitoring system improves reproductive outcomes. CLINICAL TRIAL REGISTRATION NUMBER: NCT01549262.

[Time lapse (Embryoscope®) as a routine technique in the IVF laboratory: a useful tool for better embryo selection?]. / L'observation en continu du développement embryonnaire en FIV (time lapse) à l'aide de l'Embryoscope(®) : un outil d'aide à la décision ?

Among all the strategies available in order to improve success rates in IVF cycles, a lot of work has been done on embryo culture conditions and embryo quality evaluation. Most IVF centres use conventional incubators and select embryo according to punctual morphological evaluation, but this strategy has several limitations. Recently developed commercial devices associating more stable culture conditions and time lapse observation of embryo development provide new insights into early embryo development in IVF cycles. Among them, the Embryoscope(®) appears to be the most user-friendly, performing and suited for routine daily practice. The first Embryoscope(®) for France was installed in the University Hospital of Nantes in 2011. In our experience, it takes relatively a short time to get used to this system. Moreover, its integration in routine process yielded several advantages, such as better embryo selection according to kinetic parameters and observation of abnormal cleavage events, continuing education and training, quality control and flexibility. This leaded to an overall increase in success rates in IVF cycles.

Neonatal outcome using ultrathin fetoscope for laser coagulation in twin-to-twin-transfusion syndrome.

OBJECTIVE: To improve neonatal outcome using ultrathin fetoscope for laser treatment of twin-to-twin transfusion syndrome. METHODS: Retrospective cohort study of a series of 80 cases of twin-to-twin-transfusion syndrome prior to 26-weeks' gestation subjected to laser coagulation by means of a 1.0/1.2 mm fiber fetoscope with a sheath sectional area 2.65 mm(2)/3.34 mm(2) (n=27) and a 2.0 mm classic lens fetoscope with a sheath sectional area: 6.63 mm(2)/11.27 mm(2) (n=53). RESULTS: The survival rates of at least one twin in the compared groups were 94.4% (classic optic) and 100% (ultrathin optic), for both twins: 75.5% and 83.3%, respectively. By decreasing sheath diameter a pregnancy was prolonged by an average of 21.3 days (P=0.0045), with a resulting increase in the recipient's weight of 389 g (P=0.0049) and an increase in the donor's Apgar score. However, the intervention with ultrathin optic took 11 min longer (P=0.031). CONCLUSION: The reduction of the iatrogenic damage of the amniotic membrane using ultrathin fetoscope with a small sheath, significantly improves the neonatal outcome after laser treatment of twin-to-twin-transfusion syndrome. The operator should only commence working with the 1 mm fetoscope after the learning curve has been accomplished.

A novel ultralow-illumination endoscope system.

BACKGROUND: Endoscopic surgery has become an accepted major type of minimally invasive surgery. However, complications arising from heat generated by sources of endoscopic illumination can include surgical fire or burns, and intense illumination during ob-gyn/fetoscopic surgery might damage fetal ocular development. Fiber-optic bundles for illumination within the endoscope essentially double the outer diameter of the endoscope, which is a major obstacle to miniaturization and decreasing costs. Light cables also decrease the maneuverability of the endoscope METHODS: We developed a novel endoscope with ultralow illumination to visualize dark body cavities and investigated its feasibility in vivo. An adaptor was created to connect a conventional endoscope to an ultrahigh-sensitivity camera developed by the Japan Broadcasting Corporation (NHK) for broadcasting. The ability to visualize rabbit visceral blood vessels in vivo by the new prototype and by a current endoscope under ultralow illumination provided by a standard light source was compared. In addition, the performance of the two endoscopes was compared using only an extracorporeal flashlight without any specific light source placed within body cavities. RESULTS: The new endoscope could visualize the target under ultralow illumination of approximately 100 lx. Very little could be visualized using the current endoscope, whereas the prototype generated clear images of the rabbit blood vessels under both ultralow illumination and extracorporeal illumination provided by a flashlight. CONCLUSIONS: The potential for damage caused by a light source can be minimized using our new endoscope, which results in safer and less invasive procedures. Further studies are under way to develop a nonilluminated endoscope without a light cable or source and to miniaturize the camera to decrease costs and improve the maneuverability of the entire endoscope system.

Two new approaches in intrauterine tracheal occlusion using an ultrathin fetoscope.

OBJECTIVES/HYPOTHESIS: To introduce and establish a new approach in minimal invasive fetoscopic surgery in order to reduce access trauma and the iatrogenic preterm premature rupture of the membranes (PPROM) as a major complication of intrauterine treatment of congenital diaphragmatic hernia. METHODS: In total, 27 pregnant sheep were operated on using fetoscopes with 1.2 and 1.0 mm optics. We used an elliptic sheath alone with a maximum diameter of 2.6/1.3 mm; in these cases the balloon was placed under ultrasound control. In comparison, we placed the balloon under fetoscopic control using the fetoscopic sheath and a 7F (2.3 mm) introducer. Therefore, the maximum access trauma was not bigger than the diameter of sheath of introducer. RESULTS: With this technique we successfully operated on 22 sheep. The use of real time three-dimensional ultrasound control distinctly facilitates the operation procedure. CONCLUSIONS: Our preliminary findings show that fetoscopic tracheal occlusion using ultrathin fetoscopes and reducing the access trauma on the level of 4.2 or even 2.65 mm(2) could be seen as a method of reducing the rate of PPROM.