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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. This project has been funded by the Cellex Foundation and the Erasmus+ Programme of the European Union (Framework Agreement number: 2013-0040). This publication reflects only the authors’ views, and the Commission cannot be held responsible for any use that may be made of the information contained therein. T.M. was supported by a predoctoral grant from Erasmus Mundus FetalMed-PhD. E.E. has received funding from the Departament de Salut under grant number SLT008/18/00156.

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. ispartof: Journal of Visualized Experiments vol:2017 issue:120 ispartof: location:United States status: published

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.

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).

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. 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

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.

Our objective was to explore the feasibility of using both transvaginal endoscopy and transabdominal needle embryofetoscopy for early prenatal diagnosis. Our experience with both terminating and continuing pregnancies is presented in this report. Following the granting of informed consent, patients undergoing first-trimester terminations were invited to participate in this program. Initially, a transvaginal endoscope was used in these studies: a rigid fiberoptic endoscope 30 cm in length with a diameter of 1.5 mm. Subsequently, a specially designed 16-gauge, double-barrel needle sheath, equipped with a 0.8-mm fiberoptic endoscope and a customized 27-gauge heparinized needle were used. In either case, the endoscope was passed under ultrasound guidance into the exocelomic space, from which the anatomy of the embryo/fetus was scrutinized. For continuing pregnancies, patients were selected when at high risk for various dysmorphology syndromes. To date, we have successfully performed more than 300 transvaginal procedures, successfully visualized the fetus in 95% of cases, and verified sonographically suspected anomalies in all of the five cases studied. We have also performed 20 transabdominal procedures, 15 in terminating pregnancies and five in continuing pregnancies, without adverse effects. Our experience establishes the feasibility of first-trimester diagnostic endoscopy. This new development is expected to serve as a prelude for further studies that attempt to diagnose and treat congenital diseases in early pregnancy. Potential applications include gene and stem-cell therapy at a time when the embryo is immunologically naive.

To study the feasibility, learning curve, and safety of fetoscopy, so that fetal surgery can be confidently performed in ongoing pregnancies. Fetoscopy was performed at 12–20 weeks of gestation, in 12 women with fetal congenital malformations and/or for termination of pregnancy, under local anesthesia using fine fetoscopes ranging from 1 to 2-mm diameter. The fetal parts and placenta were examined for clarity of vision, identification, and anomalies. Fetoscopy required great skill, patience, and extensive use of ultrasound for correct orientation. Visualization was better with endoscope of 2-mm diameter. Laser coagulation of placental vessels using diode laser system was possible in the last two cases. There were no major complications. Fetal endoscopy is a feasible procedure, safe in experienced hands but has an appreciable learning curve.

OBJECTIVE: Our aim was to develop and evaluate a transabdominal endoscopic technique to visualize the embryo or fetus with thin-gauge needles and submillimetric fiberoptic endoscopes. METHODS: Under ultrasonographic guidance, an 18- or 19-gauge thin-wall needle was introduced into the uterus of 28 patients undergoing first-trimester or early second-trimester termination of pregnancy. A 0.7 mm endoscope was threaded through the lumen of the needle after removal of the stylet. Visualization of the embryo-fetus was attempted before 14 weeks' gestation ( n = 20). From 16 to 20 weeks ( n = 8), the needle and endoscope were directed to the placental insertion of the umbilical cord, and a cordocentesis was performed. RESULTS: Excellent visualization of the surface anatomy of fetuses from 7 to 13 weeks was obtained in 85% of cases (17/20). A diagnosis of Meckel-Gruber syndrome was made at 11 weeks' menstrual age by visualizing postaxial polydactyly and an occipital encephalocele. Endoscopically assisted cordocentesis allowed visualization of the lumen of the umbilical vein and of the blood flow within it. CONCLUSION: Endoscopic visualization of the embryo or fetus can be performed transabdominally in the first trimester with small needle-delivered endoscopes. This represents a clear advantage over previous endoscopic approaches to the human pregnancy. Potential applications of this technique include a precise description of fetal anatomy and physiologic features, diagnosis of anomalies, and therapeutic fetal interventions.

Objective: The most common complication of intrauterine tracheal balloon occlusion is the preterm premature rupture of membranes (PPROM) which increases the rate of neonatal morbidity and mortality. Ultrathin fetoscopy may be a method of reducing the risk of PPROM. Materials and Methods: The operation was performed at the 27th week of gestation after sedation and relaxation of a fetus with bilateral congenital diaphragmatic hernia and with the liver lifted upwards into the thorax. An ultrathin sheath with a 1.2-mm fetoscope was used under real-time 3-D ultrasound guidance. The patient delivered in the 38th week of gestation and did not display PPROM after surgery until delivery. Conclusion: Fetal tracheal occlusion using ultrathin fetoscopic equipment in combination with real-time 3-D ultrasound may reduce the risk of PPROM.

Objective To assess outcome after fetoscopic laser coagulation (FLC) of placental vascular anastomoses with the 30° fetoscope in mid-trimester severe twin-to-twin transfusion syndrome (TTTS) with completely anterior placenta compared with the regular 0° fetoscope in TTTS with other placental locations. Methods This was a prospective study of 176 consecutive monochorionic twin pregnancies undergoing FLC for severe TTTS. Of these, 51 patients required use of the 30° fetoscope (study group) and 125 placental locations permitted use of the 0° fetoscope (controls). Results The two groups had very similar outcomes. The median gestational age at FLC in the study group vs. control group was 21.0 (range, 17.4–24.6) weeks vs. 20.6 (range, 15.9–24.6) weeks. Both fetuses survived in 58.8% (30/51) of study patients vs. 66.4% (83/125) of controls. At least one fetus survived in 84.3% (43/51) of study patients and 88.8% (111/125) of controls (P = 0.45). Study patients delivered at a median of 34.1 (range, 25.0–38.4) weeks and controls at 34.0 (range, 25.0–40.3) weeks' gestation. Conclusions Use of a 30° fetoscope for FLC in cases of technically challenging extensive anterior placentation is associated with an outcome that is very similar to that achieved when a 0° fetoscope is used in cases of more favorable placental location. Copyright © 2008 ISUOG. Published by John Wiley & Sons, Ltd.

Background/Purpose: Prenatal tracheal occlusion currently is being assessed as a treatment modality for congenital diaphragmatic hernia (CDH). The development of a totally percutaneous fetoscopic access system would help avoid the need for maternal laparotomy and reduce the morbidity rate of fetal surgical procedures for the mother. Laparoscopic radial expansion sheaths and Seldinger technique– based vascular catheters both have been advocated as means of achieving amniotic cavity access. The authors have investigated these 2 systems in an attempt to develop a reliable method for achieving safe percutaneous fetoscopic access and present the first successful attempt to deploy an intratracheal balloon using an entirely percutaneous approach through a single port in an ovine model. Methods: A number of prototype systems were evaluated sequentially over a 3-year period in an ovine model: (1) the radially expanding InnerDyne step port system, (2) a new rigid cannula with a bulbous/sharp end preloaded onto the radially expanding InnerDyne port, (3) a conical removable addition to the rigid cannula in 2, (4) a modified bulbous/ sharp ended cannula incorporating a circumferential protective insert, (5) a rigid split sheath with the radially expanding port placed through the lumen of the split sheath, (6) a flexible introducer and dilator with the split sheath (used in the Seldinger placement of central lines), and (7) a 2-needle approach using a superelastic shape-memory alloy NickelTitanium wire with the flexible dilator and sheath, incorporating a side perfusion port. For balloon tracheal occlusion, live anaesthetized time-mated pregnant ewes were used at 110 days’ gestation. Tracheobronchoscopy was achieved using a 3-mm 0° telescope, and the cutaneotracheal tract was secured by a 3.3-mm sheath incorporating a side-perfusion port. The rigid telescope was replaced by a flexible choledochoscope preloaded with a silicone balloon. The balloon was deployed 2 cm above the carina proximal to the right upper lobe bronchus. Results: The many problems encountered in the evolution of the preferred system related mainly to separation and tenting of the chorioamniotic membranes in the ovine uterus and inconsistent access to the fetal parts of interest. Each resulted in significant modifications to our approach. Furthermore, the use of rigid access devices commonly caused fetal injury. Successful access to the intrauterine cavity and cannulation of the trachea was achieved consistently with minimal trauma, irrespective of fetal position by method 7. Multiple port placement allowed visualization of the entry of all components of the system confirming minimal chorioamniotic membrane separation and tenting. Single port tracheal occlusion was undertaken first on 6 cadavers before being performed successfully on 3 live anaesthetized ewes. Fetoscopic access and cannulation of the trachea was achieved consistently in all live animals irrespective of fetal position. Conclusions: This modified Seldinger technique using the unique properties of the memory-shaped alloy wire for initial uterine access offers a safe method for the percutaneous placement of fetoscopic ports in the ovine model for prenatal intervention. Successful placement of a tracheal balloon entirely through a single percutaneously placed port represents a further advance in prenatal therapy for CDH.

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.

Background Shortening the prenatal disease course of severe aortic and pulmonary stenoses by balloon valvuloplasty may diminish their postnatal expression. The purpose of this study in fetal sheep was to assess the feasibility of fetoscopic and open transumbilical fetal cardiac catheterization guided by fetal transesophageal echocardiography to provide alternative approaches for human fetal cardiac intervention. Methods and Results We studied a total of nine fetal sheep (95 to 103 days of gestation; term=145 to 150 days) and performed transumbilical fetal cardiac catheterization by a minimally invasive fetoscopic (n=6) or an open fetal surgical approach (n=3). Monitored by fetal transesophageal echocardiography, with an 8F or 10F, 10-MHz intravascular ultrasound catheter we placed guidewires and interventional catheters via the umbilical arterial route into the fetal heart. In three of the fetuses, we created supravalvar pulmonary artery stenosis by open fetal cardiac surgery. After fetal and maternal recovery, we exteriorized these fetuses and performed open transumbilical fetal cardiac catheterization with successful pulmonary arterial angioplasty in two. Three fetuses survived fetoscopic transumbilical catheterization for 1 or 2 days and died most likely of blood loss after sheath dislodgment (n=1) or removal (n=2). By securing the sheath insertion site with a suture, we prevented sheath dislodgment and minimized bleeding during sheath removal in three fetuses. These fetuses then survived fetoscopic transumbilical fetal cardiac catheterization for 1 to 2 weeks before being killed. Conclusions This study in fetal sheep demonstrates that fetoscopic and open transumbilical fetal cardiac catheterization are feasible and, guided by fetal transesophageal echocardiography, provide potential alternative approaches for human fetal cardiac intervention.

The ability of ultrasound to diagnose fetal anomalies is limited in the early stages of gestation. We describe a microendoscope that can be used with an 18-gauge needle at the time of amniocentesis to provide more precise diagnostic information when the first-trimester ultrasound examination suggests a problem.

Our objective was to explore the feasibility of using both transvaginal endoscopy and transabdominal needle embryofetoscopy for early prenatal diagnosis. Our experience with both terminating and continuing pregnancies is presented in this report. Following the granting of informed consent, patients undergoing first-trimester terminations were invited to participate in this program. Initially, a transvaginal endoscope was used in these studies: a rigid fiberoptic endoscope 30 cm in length with a diameter of 1.5 mm. Subsequently, a specially designed 16-gauge, double-barrel needle sheath, equipped with a 0.8-mm fiberoptic endoscope and a customized 27-gauge heparinized needle were used. In either case, the endoscope was passed under ultrasound guidance into the exocelomic space, from which the anatomy of the embryo/fetus was scrutinized. For continuing pregnancies, patients were selected when at high risk for various dysmorphology syndromes. To date, we have successfully performed more than 300 transvaginal procedures, successfully visualized the fetus in 95% of cases, and verified sonographically suspected anomalies in all of the five cases studied. We have also performed 20 transabdominal procedures, 15 in terminating pregnancies and five in continuing pregnancies, without adverse effects. Our experience establishes the feasibility of first-trimester diagnostic endoscopy. This new development is expected to serve as a prelude for further studies that attempt to diagnose and treat congenital diseases in early pregnancy. Potential applications include gene and stem-cell therapy at a time when the embryo is immunologically naive.