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Nowadays, widespread antenatal ultrasound screenings detect congenital anomalies earlier and more frequently. This has sparked research into foetal surgery, offering treatment options for various conditions. These surgeries aim to correct anomalies or halt disease progression until after birth. Minimally invasive procedures can be conducted under local anaesthesia (with/without maternal sedation), while open mid-gestational procedures necessitate general anaesthesia. Anaesthesia serves to prevent maternal and foetal pain, to provide immobilization, and to optimize surgical conditions by ensuring uterine relaxation. As early as 12 weeks after conception, the foetus may experience pain. Thus, in procedures involving innervated foetal tissue or requiring foetal immobilization, anaesthetic drugs can be administered directly to the foetus (intramuscular or intravenous) or indirectly (transplacental) to the mother. However, animal studies have indicated that exposure to prenatal anaesthesia might impact foetal brain development, translating these findings to the clinical setting remains difficult., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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 ± standard deviation: control-group: 403 ± 39, single-exposure group: 436 ± 23 and repeated-exposure-group: 403 ± 40 neurons/mm 2 , 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: To calculate 3D-segmented total lung volume (TLV) in fetuses with thoracic anomalies using deformable slice-to-volume registration (DSVR) with comparison to 2D-manual segmentation. To establish a normogram of TLV calculated by DSVR in healthy control fetuses., Methods: A pilot study at a single regional fetal medicine referral centre included 16 magnetic resonance imaging (MRI) datasets of fetuses (22-32 weeks gestational age). Diagnosis was CDH (n = 6), CPAM (n = 2), and healthy controls (n = 8). Deformable slice-to-volume registration was used for reconstruction of 3D isotropic (0.85 mm) volumes of the fetal body followed by semi-automated lung segmentation. 3D TLV were compared to traditional 2D-based volumetry. Abnormal cases referenced to a normogram produced from 100 normal fetuses whose TLV was calculated by DSVR only., Results: Deformable slice-to-volume registration-derived TLV values have high correlation with the 2D-based measurements but with a consistently lower volume; bias -1.44 cm 3 [95% limits: -2.6 to -0.3] with improved resolution to exclude hilar structures even in cases of motion corruption or very low lung volumes., Conclusions: Deformable slice-to-volume registration for fetal lung MRI aids analysis of motion corrupted scans and does not suffer from the interpolation error inherent to 2D-segmentation. It increases information content of acquired data in terms of visualising organs in 3D space and quantification of volumes, which may improve counselling and surgical planning., (© 2022 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Background: Fetal surgery is part of modern fetal medicine, and some procedures, such as fetal spina bifida repair, are performed under general anesthesia. Fetuses are operated on in a time window when the developing brain is extremely vulnerable to external, potentially harmful factors. To date, little is known about the effect of fetal surgery on fetal brain development., Objective: This study aimed to assess the effect of fetal surgery on the developing fetal brain in the rabbit model., Study Design: This was a randomized, sham-controlled study in time-mated pregnant does at 28 days' gestation (term, 31 days), which corresponds to the start of the peak of brain development and end of the second trimester of pregnancy in humans. We included 4 different groups in this experiment: no-surgery, general anesthesia, general anesthesia+hysterotomy, and general anesthesia+fetal surgery. In 11 does, anesthesia was induced using propofol and maintained for 75 minutes with 3.6 vol% (4% is the equivalent of 1 minimum alveolar concentration) sevoflurane. Maternal blood pressure, heart rate, oxygen saturation, temperature, end-tidal CO 2 were continuously monitored. For each operated doe, 6 fetuses were part of the experiment. Randomization determined which cornual sac and what opposing third sac were assigned to fetal surgery: hysterotomy, fetal injection (atropine, fentanyl, and cisatracurium), fetal skin incision, and suturing. Only hysterotomy was performed on the opposing cornual and third amniotic sacs of the does. The fetus in these experimental sacs was used as internal unmanipulated control (general anesthesia). All fetuses (n=38) from unmanipulated does (n=4) served as external controls (no-surgery). At term, the does were delivered by cesarean delivery under ketamine-medetomidine sedation and local anesthesia. The pups underwent standardized motoric and sensory neurologic testing on day 1 followed by euthanasia and brain harvesting for histologic assessment of neurons, synapses, proliferation, and glial cells., Results: Maternal vital signs were stable during surgery. Survival was similar in the 4 groups (75%-94%), and brain-to-body weight ratio was comparable; only the no-surgery pups had a higher brain weight. On postnatal day 1, the pups in the 4 groups had a comparable neurobehavioral outcome on both motoric and sensory testing. In the prefrontal cortex, no-surgery pups had significantly higher neuron density than pups who underwent maternal surgery, but there was no difference among pups that underwent general anesthesia, hysterotomy, or fetal surgery. The measurements of proliferation had a similar outcome: a higher proliferation rate in the prefrontal cortex of no-surgery pups. Moreover, synaptic density values were higher in the no-surgery pups, but there was no difference observed among pups who underwent general anesthesia, hysterotomy, and fetal surgery. Lastly, there was no difference in gliosis among the 4 groups., Conclusion: In rabbits, fetal surgery through hysterotomy under maternal general anesthesia did not affect brain development, in addition to the effects of general anesthesia per se., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Gastroschisis (GS) is a congenital abdominal wall defect, in which the bowel eviscerates from the abdominal cavity. It is a non-lethal isolated anomaly and its pathogenesis is hypothesized to occur as a result of two hits: primary rupture of the 'physiological' umbilical hernia (congenital anomaly) followed by progressive damage of the eviscerated bowel (secondary injury). The second hit is thought to be caused by a combination of mesenteric ischemia from constriction in the abdominal wall defect and prolonged amniotic fluid exposure with resultant inflammatory damage, which eventually leads to bowel dysfunction and complications. GS can be classified as either simple or complex, with the latter being complicated by a combination of intestinal atresia, stenosis, perforation, volvulus and/or necrosis. Complex GS requires multiple neonatal surgeries and is associated with significantly greater postnatal morbidity and mortality than is simple GS. The intrauterine reduction of the eviscerated bowel before irreversible damage occurs and subsequent defect closure may diminish or potentially prevent the bowel damage and other fetal and neonatal complications associated with this condition. Serial prenatal amnioexchange has been studied in cases with GS as a potential intervention but never adopted because of its unproven benefit in terms of survival and bowel and lung function. We believe that recent advances in prenatal diagnosis and fetoscopic surgery justify reconsideration of the antenatal management of complex GS under the rubric of the criteria for fetal surgery established by the International Fetal Medicine and Surgery Society (IFMSS). Herein, we discuss how conditions for fetoscopic repair of complex GS might be favorable according to the IFMSS criteria, including an established natural history, an accurate prenatal diagnosis, absence of fully effective perinatal treatment due to prolonged need for neonatal intensive care, experimental evidence for fetoscopic repair and maternal and fetal safety of fetoscopy in expert fetal centers. Finally, we propose a research agenda that will help overcome barriers to progress and provide a pathway toward clinical implementation. © 2021 International Society of Ultrasound in Obstetrics and Gynecology., (© 2021 International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: During fetal surgery, fetuses receive medication (atropine-fentanyl-curare) to prevent fetal pain, movement and bradycardia. Although essential there has been no detailed review of potential side effects. Herein we aimed to assess the effects of this medication cocktail on fetal brain development in a rabbit model., Methods: Pregnant does underwent laparotomy at 28 days of gestation. Two pups of each horn were randomized to an ultrasound guided injection with medication (atropine-cisatracurium-fentanyl, as clinically used) or saline (sham). The third pup was used as control. At term, does were delivered by cesarean. Outcome measures were neonatal biometry, neuromotoric functioning and neuro-histology (neuron density, synaptic density and proliferation)., Results: Maternal vital parameters remained stable during surgery. Fetal heart rates did not differ before and after injection, and were comparable for the three groups. At birth, neonatal body weights and brain-to-body weight ratios were also comparable. Both motor and sensory neurobehavioral scores were comparable. There were no differences in neuron density or proliferation. Sham pups, had a lower synaptic density in the hippocampus as compared to the medication group, however there was no difference in the other brain areas., Conclusion: In the rabbit model, fetal medication does not appear to lead to short-term neurocognitive effects., (© 2021 John Wiley & Sons Ltd.)

Background: The US Food and Drug Administration warned that exposure of pregnant women to general anaesthetics may impair fetal brain development. This review systematically evaluates the evidence underlying this warning., Methods: PubMed, EMBASE, and Web of Science were searched from inception until April 3, 2020. Preclinical and clinical studies were eligible. Exclusion criteria included case reports, in vitro models, chronic exposures, and exposure only during delivery. Meta-analyses were performed on standardised mean differences. The primary outcome was overall effect on learning/memory. Secondary outcomes included markers of neuronal injury (apoptosis, synapse formation, neurone density, and proliferation) and subgroup analyses., Results: There were 65 preclinical studies included, whereas no clinical studies could be identified. Anaesthesia during pregnancy impaired learning and memory (standardised mean difference -1.16, 95% confidence interval -1.46 to -0.85) and resulted in neuronal injury in all experimental models, irrespective of the anaesthetic drugs and timing in pregnancy. Risk of bias was high in most studies. Rodents were the most frequently used animal species, although their brain development differs significantly from that in humans. In a minority of studies, anaesthesia was combined with surgery. Monitoring and strict control of physiological homeostasis were below preclinical and clinical standards in many studies. The duration and frequency of exposure and anaesthetic doses were often much higher than in clinical routine., Conclusion: Anaesthesia-induced neurotoxicity during pregnancy is a consistent finding in preclinical studies, but translation of these results to the clinical situation is limited by several factors. Clinical observational studies are needed., Prospero Registration Number: CRD42018115194., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Objective: We performed a systematic review to summarize the efficacy and safety of in utero stem cells application in preclinical models with myelomeningocele (MMC)., Methods: The study was registered with PROSPERO (CRD42019160399). We searched MEDLINE, Embase, Web of Science, Scopus and CENTRAL for publications articles on stem cell therapy in animal fetuses with MMC until May 2020. Publication quality was assessed by the SYRCLE's tool. Meta-analyses were pooled if studies were done in the same animal model providing similar type of stem cell used and outcome measurements. Narrative synthesis was performed for studies that could not be pooled., Results: Nineteen and seven studies were included in narrative and quantitative syntheses, respectively. Most used mesenchymal stem cells (MSCs) and primarily involved ovine and rodent models. Both intra-amniotic injection of allogeneic amniotic fluid (AF)-MSCs in rat MMC model and the application of human placental (P)-MSCs to the spinal cord during fetal surgery in MMC ovine model did not compromise fetal survival rates at term (rat model, relative risk [RR] 1.03, 95% CI 0.92-1.16; ovine model, RR 0.94, 95% CI 0.78-1.13). A single intra-amniotic injection of allogeneic AF-MSCs into rat MMC model was associated with a higher rate of complete defect coverage compared to saline injection (RR 16.35, 95% CI 3.27-81.79). The incorporation of human P-MSCs as a therapeutic adjunct to fetal surgery in the ovine MMC model significantly improved sheep locomotor rating scale after birth (mean difference 5.18, 95% CI 3.36-6.99)., Conclusions: Stem cell application during prenatal period in preclinical animal models is safe and effective., (© 2021 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Objective: Widely accepted, validated and objective measures of ultrasound competency have not been established for clinical practice. Outcomes of training curricula are often based on arbitrary thresholds, such as the number of clinical cases completed. We aimed to define metrics against which competency could be measured., Method: We undertook a prospective, observational study of obstetric sonographers at a UK University Teaching Hospital. Participants were either experienced in fetal ultrasound (n = 10, >200 ultrasound examinations) or novice operators (n = 10, <25 ultrasound examinations). We recorded probe motion data during the performance of biometry on a commercially available mid-trimester phantom., Results: We report that Dimensionless squared jerk, an assessment of deliberate hand movements, independent of movement duration, extent, spurious peaks and dimension differed significantly different between groups, 19.26 (SD 3.02) for experienced and 22.08 (SD 1.05, p = 0.01) for novice operators, respectively. Experienced operator performance, was associated with a shorter time to task completion of 176.46 s (SD 47.31) compared to 666.94 s (SD 490.36, p = 0.0004) for novice operators. Probe travel was also shorter for experienced operators 521.23 mm (SD 27.41) versus 2234.82 mm (SD 188.50, p = 0.007) when compared to novice operators., Conclusion: Our results represent progress toward an objective assessment of technical skill in obstetric ultrasound. Repeating this methodology in a clinical environment may develop insight into the generalisability of these findings into ultrasound education., (© 2020 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)

Background: Sildenafil is a phosphodiesterase-5 inhibitor considered for antenatal use for a variety of indications. We sought to assess sildenafil pharmacokinetics in the pregnant ewe and fetus and evaluate its physiological fetal effects., Methods: Twelve fetal lambs (127-133 days GA, term 145) were chronically catheterized in utero. Ewes received different doses of sildenafil, either via subcutaneous injection (1.6, 2.0 mg/kg/day) or intravenous (IV) infusion (3, 5, 7, 10, and 12 mg/kg/day). Maternal and fetal sildenafil concentrations and metabolic status (blood gas analysis) were measured at given intervals. The fetal heart rate, pulmonary blood flow, systemic and aortic pressure, and maternal uterine artery pressure were continuously monitored., Results: The transplacental sildenafil transfer was 2.9% (range: 1.4-7.8%), preventing attainment of fetal target concentrations without toxic maternal levels. IV sildenafil infusion induced an immediate, temporary, dose-dependent reduction of pulmonary vascular resistance (38-78%) and increased both pulmonary blood flow (32-132%) and heart rate (13-49%), with limited nonlinear dose-dependent effects on systemic and pulmonary pressures. Fetal and maternal blood gases and maternal uterine artery pressures were unaffected by sildenafil infusion., Conclusion: In sheep, transplacental transfer of sildenafil is extremely low. Though, minimal fetal sildenafil concentrations induce an acute transient pulmonary vasodilation, well-tolerated by the fetus and ewe., (© 2021 S. Karger AG, Basel.)

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., (© 2021 S. Karger AG, Basel.)

Objective: The Management of Myelomeningocele Study (MOMS) trial demonstrated the safety and efficacy of open fetal surgery for spina bifida aperta (SBA). Recently developed alternative techniques may reduce maternal risks without compromising the fetal neuroprotective effects. The aim of this systematic review was to assess the learning curve (LC) of different fetal SBA closure techniques., Methods: MEDLINE, Web of Science, EMBASE, Scopus and Cochrane databases and the gray literature were searched to identify relevant articles on fetal surgery for SBA, without language restriction, published between January 1980 and October 2018. Identified studies were reviewed systematically and those reporting all consecutive procedures and with postnatal follow-up ≥ 12 months were selected. Studies were included only if they reported outcome variables necessary to measure the LC, as defined by fetal safety and efficacy. Two authors independently retrieved data, assessed the quality of the studies and categorized observations into blocks of 30 patients. For meta-analysis, data were pooled using a random-effects model when heterogeneous. To measure the LC, we used two complementary methods. In the group-splitting method, competency was defined when the procedure provided results comparable to those in the MOMS trial for 12 outcome variables representing the immediate surgical outcome, short-term neonatal neuroprotection and long-term neuroprotection at ≥ 12 months of age. Then, when raw patient data were available, we performed cumulative sum analysis based on a composite binary outcome defining successful surgery. The composite outcome combined four clinically relevant variables for safety (absence of extreme preterm delivery < 30 weeks, absence of fetal death ≤ 7 days after surgery) and efficacy (reversal of hindbrain herniation and absence of any neonatal treatment of dehiscence or cerebrospinal fluid leakage at the closure site)., Results: Of 6024 search results, 17 (0.3%) studies were included, all of which had low, moderate or unclear risk of bias. Fetal SBA closure was performed using standard hysterotomy (11 studies), mini-hysterotomy (one study) or fetoscopy by either exteriorized-uterus single-layer closure (one study), percutaneous single-layer closure (three studies) or percutaneous two-layer closure (one study). Only outcomes for standard hysterotomy could be meta-analyzed. Overall, outcomes improved significantly with experience. Competency was reached after 35 consecutive cases for standard hysterotomy and was predicted to be achieved after ≥ 57 cases for mini-hysterotomy and ≥ 56 for percutaneous two-layer fetoscopy. For percutaneous and exteriorized-uterus single-layer fetoscopy, competency was not reached in the 81 and 28 cases available for analysis, respectively, and LC prediction analysis could not be performed., Conclusions: The number of cases operated is correlated with the outcome of fetal SBA closure, and the number of operated cases required to reach competency ranges from 35 for standard hysterotomy to ≥ 56-57 for minimally invasive modifications. Our observations provide important information for institutions looking to establish a new fetal center, develop a new fetal surgery technique or train their team, and inform referring clinicians, potential patients and third parties. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd., (Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.)

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., (© 2019 Mac Keith Press.)

High-resolution volume reconstruction from multiple motion-corrupted stacks of 2D slices plays an increasing role for fetal brain Magnetic Resonance Imaging (MRI) studies. Currently existing reconstruction methods are time-consuming and often require user interactions to localize and extract the brain from several stacks of 2D slices. We propose a fully automatic framework for fetal brain reconstruction that consists of four stages: 1) fetal brain localization based on a coarse segmentation by a Convolutional Neural Network (CNN), 2) fine segmentation by another CNN trained with a multi-scale loss function, 3) novel, single-parameter outlier-robust super-resolution reconstruction, and 4) fast and automatic high-resolution visualization in standard anatomical space suitable for pathological brains. We validated our framework with images from fetuses with normal brains and with variable degrees of ventriculomegaly associated with open spina bifida, a congenital malformation affecting also the brain. Experiments show that each step of our proposed pipeline outperforms state-of-the-art methods in both segmentation and reconstruction comparisons including expert-reader quality assessments. The reconstruction results of our proposed method compare favorably with those obtained by manual, labor-intensive brain segmentation, which unlocks the potential use of automatic fetal brain reconstruction studies in clinical practice., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

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.

Purpose: The placenta is a vital organ for the exchange of oxygen, nutrients, and waste products between fetus and mother. The placenta may suffer from several pathologies, which affect this fetal-maternal exchange, thus the flow properties of the placenta are of interest in determining the course of pregnancy. In this work, we propose a new multiparametric model for placental tissue signal in MRI., Methods: We describe a method that separates fetal and maternal flow characteristics of the placenta using a 3-compartment model comprising fast and slowly circulating fluid pools, and a tissue pool is fitted to overlapping multiecho T2 relaxometry and diffusion MRI with low b-values. We implemented the combined model and acquisition on a standard 1.5 Tesla clinical system with acquisition taking less than 20 minutes., Results: We apply this combined acquisition in 6 control singleton placentas. Mean myometrial T2 relaxation time was 123.63 (±6.71) ms. Mean T2 relaxation time of maternal blood was 202.17 (±92.98) ms. In the placenta, mean T2 relaxation time of the fetal blood component was 144.89 (±54.42) ms. Mean ratio of maternal to fetal blood volume was 1.16 (±0.6), and mean fetal blood saturation was 72.93 (±20.11)% across all 6 cases., Conclusion: The novel acquisition in this work allows the measurement of histologically relevant physical parameters, such as the relative proportions of vascular spaces. In the placenta, this may help us to better understand the physiological properties of the tissue in disease., (© 2018 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Background and Purpose: Fetal MR imaging is part of the comprehensive prenatal assessment of fetuses with open spinal dysraphism. We aimed to assess the reliability of brain stem and posterior fossa measurements; use the reliable measurements to characterize fetuses with open spinal dysraphism versus what can be observed in healthy age-matched controls; and document changes in those within 1 week after prenatal repair., Materials and Methods: Retrospective evaluation of 349 MR imaging examinations took place, including 274 in controls and 52 in fetuses with open spinal dysraphism, of whom 23 underwent prenatal repair and had additional early postoperative MR images. We evaluated measurements of the brain stem and the posterior fossa and the ventricular width in all populations for their reliability and differences between the groups., Results: The transverse cerebellar diameter, cerebellar herniation level, clivus-supraocciput angle, transverse diameter of the posterior fossa, posterior fossa area, and ventricular width showed an acceptable intra- and interobserver reliability (intraclass correlation coefficient > 0.5). In fetuses with open spinal dysraphism, these measurements were significantly different from those of healthy fetuses (all with P < .0001). Furthermore, they also changed significantly ( P value range = .01 to < .0001) within 1 week after the fetal operation with an evolution toward normal, most evident for the clivus-supraocciput angle (65.9 ± 12.5°; 76.6 ± 10.9; P < .0001) and cerebellar herniation level (-9.9 ± 4.2 mm; -0.7 ± 5.2; P < .0001)., Conclusions: In fetuses with open spinal dysraphism, brain stem measurements varied substantially between observers. However, measurements characterizing the posterior fossa could be reliably assessed and were significantly different from normal. Following a fetal operation, these deviations from normal values changed significantly within 1 week., (© 2019 by American Journal of Neuroradiology.)

Partial amniotic carbon dioxide insufflation (PACI) involves insufflating the amniotic sac with carbon dioxide (CO 2 ) and, in some cases, draining some of the amniotic fluid. The creation of a gaseous intra-amniotic compartment improves visualization, even in the presence of limited bleeding, and creates the work space required for complex fetoscopic procedures. Clinically, PACI is mostly used to perform fetoscopic myelomeningocele (MMC) repair, enabling a minimally invasive alternative to open fetal surgery. However, evidence of the fetal safety of PACI is limited. Previous animal experiments in sheep demonstrate that PACI induces fetal hypercapnia and acidosis with largely unknown short and longer term implications. In this review, we examine the literature for the physiological effects of intrauterine insufflation pressure, duration, humidity, and the role of maternal hyperventilation on fetal physiology and well-being., (© 2018 John Wiley & Sons, Ltd.)

Aim: To establish the provision of fetal surgery for myelomeningocele (MMC) worldwide., Methods: Through the International Society for Prenatal Diagnosis (ISPD) Fetal Therapy Special Interest Group and the North American Fetal Therapy Network (NAFTNet), fetal therapy centres were surveyed (September 2017-June 2018) regarding availability of fetal MMC surgical repair, patient inclusion criteria, repair techniques, number of cases, and outcome reporting. Responses were summarised on an interactive map on the ISPD website., Results: Forty-four of 59 centres responded (74.6%) of which 34 centres (77.1%) currently offered fetal surgery for MMC and seven centres (15.9%) were awaiting a first case after service set up. Patient inclusion criteria were similar and based on the Management of Myelomeningocele (MOMS) trial. Five centres (14.7%) operated beyond 26 weeks' gestational age, outside the MOMS criteria. Open fetal surgery was provided in 23 centres (67.6%), fetoscopic surgery only in five (14.7%), and six centres offered both types (17.6%). Neurosurgical closure was similar for open surgery but highly variable in fetoscopy surgery. The median number of cases per centre was 21 (range 1-253)., Conclusions: Fetal surgery for MMC is now offered globally. Two thirds of centres offer open repair via hysterotomy using criteria based on the MOMS trial., (© 2018 John Wiley & Sons, Ltd.)

Aim: Fetal skull molding is important for the adaptation of the head to the birth canal during vaginal delivery. Importantly, the fetal head must rotate around the maternal symphysis pubis. The goals of this analysis were to observe a human birth in real-time using an open magnetic resonance imaging (MRI) scanner and describe the fetal head configuration during expulsion., Methods: Real-time cinematic MRI series (TSE single-shot sequence, TR 1600 ms, TE 150 ms) were acquired from the midsagittal plane of the maternal pelvis during the active second stage of labor at 37 weeks of gestation. Frame-by-frame analyses were performed to measure the frontooccipital diameter (FOD) and distance from the vertex to the base of the fetal skull., Results: During vaginal delivery in an occiput anterior position, the initial FOD was 10.3 cm. When expulsion began, the fetal skull was deformed and elongated, with the FOD increasing to 10.8 cm and 11.2 cm at crowning. In contrast, the distance from the vertex to the base of the skull was reduced from 6.4 cm to 5.6 cm at expulsion., Conclusions: Fetal head molding is the change in the fetal head due to the forces of labor. The biomechanics of this process are poorly understood. Our visualization of the normal mechanism of late second-stage labor shows that MRI technology can for the first time help define the changes in the diameters of the fetal head during active labor.

Segmentation of the placenta from fetal MRI is challenging due to sparse acquisition, inter-slice motion, and the widely varying position and shape of the placenta between pregnant women. We propose a minimally interactive framework that combines multiple volumes acquired in different views to obtain accurate segmentation of the placenta. In the first phase, a minimally interactive slice-by-slice propagation method called Slic-Seg is used to obtain an initial segmentation from a single motion-corrupted sparse volume image. It combines high-level features, online Random Forests and Conditional Random Fields, and only needs user interactions in a single slice. In the second phase, to take advantage of the complementary resolution in multiple volumes acquired in different views, we further propose a probability-based 4D Graph Cuts method to refine the initial segmentations using inter-slice and inter-image consistency. We used our minimally interactive framework to examine the placentas of 16 mid-gestation patients from MRI acquired in axial and sagittal views respectively. The results show the proposed method has 1) a good performance even in cases where sparse scribbles provided by the user lead to poor results with the competitive propagation approaches; 2) a good interactivity with low intra- and inter-operator variability; 3) higher accuracy than state-of-the-art interactive segmentation methods; and 4) an improved accuracy due to the co-segmentation based refinement, which outperforms single volume or intensity-based Graph Cuts., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: To compare outcomes of fetoscopic spina bifida aperta repair (FSBAR) with the results of the open approach (OSBAR) as in the Management Of Myelomeningocele Study (MOMS)., Methods: This was a systematic comparison of reports on FSBAR with data from the MOMS (n = 78). Inclusion criteria were studies of spina bifida aperta patients who underwent FSBAR and were followed for ≥12 months. Primary outcome was perinatal mortality. Secondary outcomes included operative, maternal, fetal, neonatal and infant outcomes., Results: Out of 16 reports, we included 5 from 2 centers. Due to bias and heterogeneity, analysis was restricted to two overlapping case series (n = 51 and 71). In those, FSBAR was technically different from OSBAR, had comparable perinatal mortality (7.8 vs. 2.6%, p = 0.212) and shunt rate at 12 months (45 vs. 40%, p = 0.619), longer operation time (223 vs. 105 min, p < 0.001), higher preterm prelabor membrane rupture rate (84 vs. 46%, p < 0.001), earlier gestational age at birth (32.9 vs. 34.1 weeks, p = 0.03), higher postnatal reoperation rate (28 vs. 2.56%, p < 0.001) and absence of uterine thinning or dehiscence (0 vs. 36%, p < 0.001). Functional outcomes were not available., Conclusion: FSBAR utilizes a different neurosurgical technique, takes longer to complete, induces more prematurity, requires additional postnatal procedures, yet has a comparable shunt rate and is not associated with uterine thinning or dehiscence. Long-term functional data are awaited., (© 2016 S. Karger AG, Basel.)

Objective: We aimed to assess in vivo changes in lung and liver volumes in fetuses with isolated congenital diaphragmatic hernia, either expectantly managed or treated in utero., Method: This is a secondary analysis of prospectively collected data at two fetal therapy centers. We used archived magnetic resonance images of fetuses taken ≥7 days apart, creating paired observations in 20 expectantly managed cases, 41 with a second magnetic resonance prior to balloon reversal and 64 after balloon removal. We measured observed to expected total fetal lung volume (O/E TFLV) and liver-to-thoracic volume ratio. We calculated changes in volume as compared with the initial measurement and its rate as a function of gestational age (GA) at occlusion., Results: The liver-to-thoracic volume ratio did not change in either group. In expectantly managed fetuses, O/E TFLV did not increase with gestation. In fetuses undergoing tracheal occlusion, the measured increase in volume was 2.6 times larger with balloon in place as compared with that after its removal. GA at tracheal occlusion was an independent predictor of the O/E TFLV. The net rate seems to initially increase and plateau at a maximum of 1.5% per week by 35 to 45 days after occlusion., Conclusions: Tracheal occlusion induces a net increase in volume, its magnitude essentially dependent on the GA at occlusion., (© 2015 John Wiley & Sons, Ltd.)

Congenital diaphragmatic hernia (CDH) may be isolated or associated with other structural anomalies, the latter with poor prognosis. The defect allows viscera to herniate through the defect into the chest, competing for space with the developing lungs. At birth, pulmonary hypoplasia leads to respiratory insufficiency and persistent pulmonary hypertension that is lethal in up to 30% of patients. When isolated, survival chances can be predicted by antenatal measurement of lung size and liver herniation. Chromosomal microarrays and exome sequencing contribute to understanding genetic factors underlying isolated CDH. Prenatal intervention aims at stimulating lung development, clinically achieved by percutaneous fetal endoscopic tracheal occlusion (FETO) under local anesthesia. The Tracheal Occlusion To Accelerate Lung growth trial (www.totaltrial.eu) is an international randomized trial investigating the role of fetal therapy for severe and moderate pulmonary hypoplasia. Despite an apparent increase in survival following FETO, the search for lesser invasive and more potent prenatal interventions must continue., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objective: To prospectively determine the pattern of lung intensities and T2 values in fetuses with normally developing lungs as obtained with T2-weighted single-shot turbo spin echo magnetic resonance (TSE MR) imaging. This should serve as a reference to which images from fetuses with lung development disorders are compared., Methods: In 105 fetuses with normal lung development who were assessed at 19 to 40 weeks of gestation, MR delineation of left and right lung organs was performed on the T2-weighted images with TE of 31 ms and extrapolated to the images with echo time (TE) of 267 ms. T2 values were calculated based on the images with these two different TE. Linear regression analysis was used to assess the relationship between gestational age (GA) and T2. We compared T2 values in 11 left-sided congenital diaphragmatic hernia (CDH) to the normative ranges using the Mann-Whitney U test., Results: In fetuses with normal lungs and in CDH, there was a positive correlation between GA and T2 values in both lungs. T2 values, corrected for gestation, were lower in CDH fetuses for ipsilateral lungs as compared to normal lungs. Contralateral lungs showed no difference., Conclusions: In normally developing lungs there is a significant relation between T2 values with gestation. Ipsilateral lungs in CDH have a significant difference in intensity., (Copyright © 2011 John Wiley & Sons, Ltd.)

Objective: To document fetal stress hormone and Doppler changes after intrauterine transfusions (IUTs) in either the intrahepatic portion of the umbilical vein (IHV) or the placental cord insertion (PCI)., Method: Pregnant women scheduled for IUT for fetal anemia (N = 25) were included prospectively. Cortisol, β-endorphin and noradrenalin concentrations in fetal plasma and middle cerebral artery pulsatility index before and after transfusion were compared. Transfusions were performed through the (IHV), thus puncturing the fetus, or at the PCI., Results: There were no measurable differences between the transfusion sites., Conclusion: In anemic fetuses undergoing transfusion, Doppler changes and fetal stress hormone changes were unrelated to the site of needle insertion., (Copyright © 2011 John Wiley & Sons, Ltd.)

Objective: To assess the impact of lung perfusion by fractional moving blood volume (FMBV) for the prediction of survival in fetuses with congenital diaphragmatic hernia (CDH) treated with fetal endoscopic tracheal occlusion (FETO)., Study Design: Lung perfusion by FMBV (%) and the observed/expected lung-to-head ratio (o/e LHR) were evaluated 1 day before and 7-14 days after FETO in a cohort of 62 CDH fetuses, and their isolated and combined values to predict survival was assessed., Results: Preoperative lung perfusion did not show association with survival. However, after FETO, an increase in 30% of the preoperative lung FMBV and an increase in 50% of the LHR was significantly associated with the probability of survival. A model combining the changes in FMBV and o/e LHR after therapy allowed discrimination of cases with poor (10% survival), moderate (40-70% survival) and very good prognosis (100% survival)., Conclusion: Changes in lung tissue perfusion, evaluated by FMBV after FETO, improved the prediction of survival in fetuses with CDH., (Copyright © 2010 S. Karger AG, Basel.)

Pulmonary Doppler may play an important role in the prediction of survival and postnatal morbidity in fetuses with congenital diaphragmatic hernia treated with fetoscopic tracheal occlusion (FETO). Spectral Doppler indexes such as pulsatility index and peak early diastolic reversed flow could help to refine the selection of fetuses that might benefit from fetal therapy. When combined with lung-to-head ratio (LHR), these Doppler indices allow to discriminate cases with moderate-to-high survival rates from fetuses with extremely low chances to survive after FETO. In addition, they discriminate groups with a high or low risk of serious neonatal morbidity in surviving fetuses. After therapy, the combined evaluation of the relative increase of LHR with the increase in lung tissue perfusion by power Doppler seems to improve the prediction of fetal survival. In conclusion, while LHR remains the strongest predictive index, Doppler measurements allow to substantially improve the accuracy in the prediction of the chances of survival of fetuses with congenital diaphragmatic hernia treated with FETO., (Copyright © 2010 S. Karger AG, Basel.)

Fetal gene therapy is one of the possible new therapeutic strategies for congenital or perinatal diseases with high mortality or morbidity. We developed a novel delivery strategy to inject directly into the fetal mouse trachea. Intratracheal (i.t.) injection at embryonic day 18 (E18) was more efficient in targeting the fetal lung than conventional intra-amniotic (i.a.) delivery. Viral vectors derived from adeno-associated virus serotype 6.2, with tropism for the airway epithelium and not earlier tested in the fetal mouse lung, were injected into the fetal trachea. Bioluminescence (BL) imaging (BLI) was combined with magnetic resonance (MR) imaging (MRI) for noninvasive and accurate localization of transgene expression in vivo. Histological analysis for β-galactosidase (β-gal) revealed 17.5% of epithelial cells transduced in the conducting airways and 1.5% in the alveolar cells. Stable gene expression was observed up to 1 month after injection. This study demonstrates that direct injection of rAAV2/6.2 in the fetal mouse trachea is superior to i.a. delivery for transducing the lung. Second, as stable gene transfer was detected up to 1 postnatal month, this approach may be useful to evaluate fetal gene therapy for pulmonary diseases such as cystic fibrosis, requiring both substantial numbers of transduced cells as well as prolonged gene expression to obtain a stable phenotypic effect.

Objective: The aim of this study is to provide reference values for normal fetal kidney growth based on magnetic resonance (MR) volumetry. Differences in side and gender will be investigated., Method: The institute's database was reviewed for all fetal MR examinations of singleton pregnancies performed between January 2003 and December 2009. Exclusion criteria for renal volumetry were presence of urogenital anomalies, intrauterine growth retardation, polymalformative disorders, oligo- or anhydramnios and maternal diabetes. On anatomical images, renal volumetry was evaluated by delineating kidneys on all slices and combining these into one volume measurement per kidney. Polynomial regression analysis was performed to examine volume evolution over gestational age (GA)., Results: Bilateral renal volumes of 274 MR examinations in 240 fetuses with GAs between 20 and 37 weeks were calculated. The renal volumes strongly correlated with GA (polynomial regression analysis, p < 0.001). No significant difference could be observed between the left and right renal volume and between male and female (p = 0.12 and 0.68, respectively). For fetuses GA ≥ 30 weeks the right kidney was slightly larger than the left side (n = 100, p = 0.039)., Conclusion: The present study provides reference data for normal fetal renal volumes, which may enable to identify fetuses at risk to develop congenital oligonephropathy.

Objective: We sought to assess fetal cardiac function in monochorionic twins before and after therapy for twin-to-twin transfusion syndrome (TTTS) and compare it with control subjects., Study Design: We conducted prospective longitudinal assessment of fetal cardiac function in cases undergoing curative fetal therapy for TTTS (n = 39) until 4 weeks postoperatively and in uncomplicated monochorionic twins (n = 23). Fetal cardiac function was assessed by the left and right ventricular myocardial performance index, atrioventricular valve flow pattern, ductus venosus a-wave, and umbilical vein pulsations., Results: Nomograms for the myocardial performance index were constructed. Fetal cardiac function was grossly abnormal in recipient twins of TTTS when compared with control subjects (P < .001 for all indices) but normalized by 4 weeks postoperatively. The donor developed abnormal ductus venosus flow and tricuspid regurgitation postoperatively that regressed within 4 weeks., Conclusion: The cardiac dysfunction in the recipient twin of TTTS normalizes within 1 month after laser. The donor develops a transient impairment of cardiac function postoperatively.

Minimal invasive intrauterine interventions have gained their place in fetal medicine. Interventions on the placenta, umbilical cord, fetal membranes or on the fetus require special endoscopes with their respective sheaths, cannulas and additional instruments. Instruments for fetal therapy are purpose designed for the procedure of interest and most gynaecologists are therefore not familiar with them. We review the currently available instrumentation used during operations for complicated monochorionic multiple pregnancies, congenital diaphragmatic hernia, amniotic band syndrome, urinary tract obstruction and hydrothorax.

Maternal retinoid administration has beneficial effects on lung development in the nitrofen rodent toxic model of congenital diaphragmatic hernia (DH). We wanted to investigate the effects in a surgical model, where the retinoid signaling pathway is not primarily disrupted by the toxic agent. We created DH in fetal rabbits at day 23 of gestation, administrated to the does all trans-retinoic acid (ATRA) or vehicle (VHC) intramuscularly for 8 consecutive days and harvested normal and operated (DH) fetuses at 31 d (n = 7 in each group). Normal lungs exposed to ATRA had increased surfactant protein mRNA levels without change in type II pneumocyte density. There was no measurable effect on lung-to-body weight ratio and airway morphometry by ATRA. In DH lungs (DH/VHC) surfactant protein mRNA levels were increased, as well as the density of type II pneumocytes. When supplemented with ATRA (DH/ATRA) these parameters returned to normal (VHC). Cell proliferation or apoptosis were not influenced by ATRA supplementation. In conclusion, maternal ATRA supplementation does not affect gross anatomic, morphologic or proliferation indices in hypoplastic lungs related to surgically induced DH in rabbit. However, ATRA lowers surfactant protein expression and normalizes type I/II pneumocyte ratio to what is observed in normal lungs.

Purpose of Review: To look at different anesthetic approaches to different surgical techniques used in fetal procedures and the influence of maternal and fetal factors on anesthetic management., Recent Findings: Fetal surgery is evolving rapidly in the field of mainly ex-utero intrapartum treatment procedures, where new indications are found and new anesthetic techniques are developed, enabling the use of locoregional anesthesia. Further development of anesthetic techniques focuses on minimizing the risks for the mother and preserving the normal neurodevelopment of the fetus., Summary: Open fetal surgery remains a major invasive procedure for mother and fetus both, requiring general anesthesia with adequate invasive monitoring. Minimal invasive fetal procedures can be performed with local anesthesia alone or, for the more complex fetoscopic procedures, with a neuraxial locoregional technique. Fetal anesthesia and analgesia can then be provided by different routes. Ex-utero intrapartum treatment procedures are open fetal procedures, but they can be performed with locoregional anesthesia, when uterine relaxation can be achieved without volatile anesthetics with the use of intravenous nitroglycerin.

Objectives: If fetal ECG (fECG) devices could be miniaturized sufficiently, one could consider their implantation at the time of fetal surgery to allow permanent monitoring of the fetus and timely intervention in the viable period. We set up an experiment to evaluate the feasibility of in utero direct fECG monitoring and telemetric transmission using a small implantable device in a lamb model., Methods: A 2-lead miniature ECG sensor (volume 1.9 cm(3); weight 3.9 g) was subcutaneously implanted in 2 fetal lambs at 122 days gestation (range 119-125; term 145 days). The ECG sensor can continuously register and transmit fECG. The signal is captured by an external receiving antenna taped to the maternal abdominal wall. We developed dedicated software running on a commercial laptop for on-line analysis of the transmitted fECG signal. This was a noninterventional study, i.e. daily readings of the fECG signal were done without clinical consequences to the observations., Results: fECG could be successfully registered, transmitted by telemetry and analyzed from the moment of implantation till term birth in one case (24 days). In the second case, unexplained in utero fetal death occurred 12 days after implantation. In this subject, agonal fECG changes were recorded., Conclusion: An implanted miniature (<2 ml) ECG sensor can be used to retrieve, process and transmit continuously a qualitative fECG signal in third-trimester fetal lambs. The telemetric signal could be picked up by an external antenna located within a 20-cm range. In this experiment, this was achieved through taping the external receiver to the maternal abdomen. Any acquired signal could be transmitted to a commercially available laptop that could perform on-line analysis of the signal., ((c) 2008 S. Karger AG, Basel.)

Today, modern ultrasound equipment and the wide implementation of screening programmes allow the timely diagnosis of many congenital anomalies. For some of these, fetal surgery may be a life-saving option. In Europe, open fetal surgery became poorly accepted because of its invasiveness and the high incidence of postoperative premature labour and rupture of the fetal membranes. In the 1990s, the merger of fetoscopy and advanced video-endoscopic surgery formed the basis for endoscopic fetal surgery. We review the current applications of fetal surgery via both methods of access. The first clinical fetoscopic surgeries were interventions on the umbilical cord and the placenta, often referred to as obstetrical endoscopy. The outcome of a randomized clinical trial demonstrating that fetoscopic laser coagulation of chorionic plate vessels is the most effective treatment for twin-twin transfusion syndrome (TTTS) has revived interest in endoscopic fetal therapy. Operating on the fetus is another more challenging enterprise. Clinical fetal surgery programmes were virtually non-existent in Europe until minimally invasive fetoscopic surgery made such operations clinically possible as well as maternally acceptable. At present, most experience has been gathered with fetal tracheal occlusion as a therapy for severe congenital diaphragmatic hernia. As in other fields, minimally invasive surgery has pushed back boundaries and now allows safe operations to be performed on the fetal patient. Whereas minimal access seems to solve the problem of preterm labour, all procedures remain invasive, and carry a risk to the mother and a substantial risk of preterm prelabour rupture of the membranes (PPROM). The latter problem may prove to be a bottleneck for further developments, although treatment modalities are currently being evaluated.

Twin-to-twin transfusion syndrome (TTTS) is a severe complication in monochorionic twin pregnancies that results from a hemodynamical imbalance of placentar vascular anstomoses that connect the circulation of both fetuses. In TTTS, a poly/oligohydramnios sequence with high fetal morbidity and mortality rates occurs. Fetoscopic laser coagulation of the placentar anastomoses can limit or prevent fetal injury. The purpose of this report is to present and discuss fetal magnetic resonance imaging as a postoperative imaging tool after fetoscopic laser coagulation.

In recent years, fetal stress and analgesia draw more and more attention. Evidence that fetuses show a significant endocrinological and hemodynamical response to invasive stimuli, and that these responses can be blocked by analgesia, suggests that fetuses experience a stress response, even if this does not signify they experience "pain". Moreover, it is becoming increasingly clear that experiences of pain of a fetus will be "remembered" by the developing nervous system, perhaps for the entire life of the individual, which can probably lead to abnormal behavioural patterns or altered nociception. But up to now, the entire mechanism of fetal stress response and the optimal analgesic drug, dose and route of administration is not so clear.

Background/purpose: Endoscopic fetal surgery could help avoid many of the problems associated with open fetal surgery, but the use of multiple ports may be too traumatic to the membranes. The authors describe a single-port technique of tracheoscopic surgery in the fetus., Methods: Time-dated pregnant ewes (95 to 105 days; term, 145 days) underwent midline laparotomy under general halothane anesthesia. A 5-mm-diameter balloon-tipped cannula was introduced in the uterus by Seldinger technique. A 1.2-mm semirigid mini-endoscope, fitted inside a 9F, 20 degrees curved sheath, was introduced under continuous, low-pressure irrigation, inside the fetus' mouth, and advanced into the trachea., Results: Endotracheal procedures, including temporary (n = 11) and permanent balloon tracheal occlusion (n = 30) and placement of a barbed guide wire for endotracheal occlusion device insertion (n = 12), were performed by introducing a 1-mm diameter instrument alongside the telescope. These were successfully performed in 52 of the 53 fetuses. The rigidity of the telescope allowed controlled access to the pharynx; its curve allowed full tracheobronchial endoscopy with the fetus in utero., Conclusions: The present technique marries the control and optical quality of a rigid endoscope with the physiological curve only a flexible instrument could offer until now. The types of procedures performed with this technique illustrate its potential as a research tool; the size (1.2-mm diameter), shape, and optical qualities of the telescope should make clinical applications possible.

Nd: YAG laser coagulation is used to treat severe twin-to-twin transfusion syndrome (TTS). Success of the technique depends on visualization of the placenta, the fetal membranes and the targeted vessels, as well as obtaining an optimal inclination angle for laser coagulation. In the rare case of an extensive anterior placenta, it may be difficult to achieve these conditions using the percutaneous approach. Here, we propose an alternative to the percutaneous procedure. Modifications involve an open access and the use of a flexible cannula and bent scope. An extraplacental area, usually at the fundus, is identified by B-mode and color Doppler imaging. A mini-laparotomy is made under general anesthesia. The viscera are retracted and the cannula is inserted under direct view and ultrasound control by the Seldinger technique. The curved fiberscope is passed through the flexible cannula, allowing adequate inspection of the placenta, and target vessels can be coagulated at an angle close to 90 degrees. After the procedure, the uterus is closed primarily to prevent postoperative leakage of amniotic fluid or hemorrhage. This technique has been successfully used in six patients with TTS and a completely anterior placenta, with a gestational age between 18.5 and 22.0 weeks. In all patients, the amniotic cavity was accessed without hemorrhage. The outcomes are similar to those published previously for laser coagulation. The mean interval from intervention until delivery was 10.5 weeks. All 12 fetuses were live born but four died from complications of extreme prematurity. No maternal complications occurred.

In a limited number of conditions in utero surgery may be life-saving, such as some cases of congenital diaphragmatic hernia, cystic adenomatoid malformation of the lung, sacrococcygeal teratoma and lower urinary tract obstruction. Postoperative premature labour and its extreme invasiveness have been major drawbacks for open fetal surgery. More recently the merger of fetoscopy and advanced video-endoscopic surgery has been the basis of the concept of endoscopic fetal surgery. In order to evaluate the opportunities of 'fetendo' surgery, animal models have been developed to test the safety of the endoscopic approach, and the feasibility of surgical manipulations on the fetus. In the non-human primate, a lesser invasiveness of endoscopy over open surgical approach was demonstrated, by a significant decrease in uterine activity in comparison with hysterotomy. The main application of fetoscopy today is the surgical treatment of complicated or abnormal monochorionic twin gestations. Fetoscopic laser coagulation of chorionic plate vessels is suggested as a causal therapy for severe feto-fetal transfusion syndrome. Survival rates are around 55 per cent with an incidence of five per cent of neurological morbidity. Fetoscopic cord ligation is associated with a 66 per cent survival rate, but unfortunately also with a risk of 30 per cent for PPROM prior to 32 weeks. Although still in its early experimental phase, endoscopy seems to offer new hope for surgical fetal therapy. Though conceptually very tempting, the development of endoscopic fetal surgery should follow the formal guidelines, as earlier formulated for open surgery by the International Fetal Medicine and Surgery Society. The prospective registration of worldwide experience is advocated and a randomized trial of laser therapy versus amniodrainage is announced.

In this study, we have investigated the maternal effects of distending the uterine cavity with Hartmann's solution in 2nd trimester equivalent pregnant sheep. In 7 pregnant ewes, double endoscopic cannulation of the amniotic cavity was performed under general anesthesia, and 1 liter of Hartmann's solution at 38 degrees C, radiolabeled with 99mTc-red blood cells, was infused. Maternal central venous pressure, hematocrit, serum and amniotic fluid osmolarity, and amniotic fluid volume were measured at nine time points within a 2-hour period. Over this time interval, no significant fluid shift to the maternal compartment was observed. We detected no adsorption of radioactivity to the fetus or membranes, and no diffusion of radioactivity to maternal or fetal tissues was noticed. We conclude from these experiments that following double cannulation and intra-amniotic infusion of Hartmann's solution into the 2nd-trimester pregnant ovine uterus, no significant shift of fluid to the maternal compartment was observed over a 2-hour time period.

Objective: Our purpose was to evaluate the feasibility of intrauterine endoscopic fetal surgery in a fetal lamb model by creating a urinary tract obstruction., Study Design: Lower urinary tract obstruction was created by ligation of the urethra and urachus in 21 fetal lambs, eight at 95 to 105 days' gestation (term 145 days) and 13 at 70 to 75 days. The endoscopic approach consisted of a 0-degree 5 mm telescope, three 5 mm cannulas, uterine distention by amnioinfusion, and adapted instrumentation. Intrauterine fetal monitoring included temperature and pulse oximetry registration., Results: In 20 cases the urachus could be identified and ligated inside the umbilical cord. The urethra was ligated in the anterior abdominal wall (n = 7) or obstructed at the level of the penis (n = 13). Mean fetal heart rate was 147 +/- 35 beats/min, and fetal temperature at the end of intervention was 38.14 degrees +/- 2.1 degrees C. The overall postoperative survival rate was 76%., Conclusion: Urinary tract obstruction can be created endoscopically in the fetal lamb. This operation can serve as a model for endoscopic fetal surgery.

Video-endoscopic technology may offer new hope for the future of fetal surgery. Ten time-dated pregnant ewes (95 to 105 days; term, 145 days) were used to develop a model of fetal surgery through intrauterine endoscopy. Special 5-mm ports were designed with short, flexible, balloon-tipped shafts. The cannulas were inserted through purse-stringed hysterostomies. Amnioinfusion of warmed physiological fluid (Hartmann) was used as the work medium. Fetal heart rate and oxygen saturation (pulse oximetry), temperature, and amniotic pressure were monitored continuously through endoscopically placed sensors. Surgical procedures included subcutaneous dissection of the abdominal wall and ligation of the urethra in the male fetus (n = 7), ligation of the urachus within the umbilical cord (n = 8), and endoscopy of the fetal esophagus and trachea (n = 6). Bloodless surgery was achieved with a novel coagulation device that allows bipolar cutting and coagulation in an electrolyte-rich fluid medium. The mean fetal operative time was 147 minutes (range, 130 to 195). The intraamniotic temperature was maintained between 38.0 +/- 0.9 degrees C and 41.7 +/- 1.7 degrees C throughout the procedure. Oxygen saturation ranged from 51 +/- 20% to 72 +/- 14%, and fetal heart rate from 120 to 140 beats per minute. In conclusion, intrauterine endoscopy in a fluid medium allows fully monitored surgical procedures, lasting more than 2 hours, to be performed on the fetal lamb.

Recently developed techniques of video-endoscopic surgery may offer new hope for the future of fetal surgery. To allow this approach, the amniotic cavity has to be temporarily enlarged, either by carbon dioxide (CO2) insufflation or by amnioinfusion. In 6 anesthetized ewes, CO2 insufflation of the amniotic cavity produced severe fetal hypercapnia (from 57.6 +/- 1.6 to 87.0 +/- 7.0 torr) and acidosis (from 7.22 +/- 0.03 to 7.11 +/- 0.08) despite normal maternal CO2 pressure and pH. CO2 pneumoamnios does not therefore appear to be an ideal working medium. Fetal endoscopic surgery through amnioinfusion of physiologic fluid may be a safer alternative.

Background: Abnormal intracranial findings are often detected at mid-trimester ultrasound (US) in fetuses with myelomeningocele (MMC). It is unclear whether these findings constitute a spectrum of the disease or are an independent finding, which should contraindicate fetal surgery.Objective: To ascertain the spectrum and frequency of US-detected cranial findings in fetuses with MMC.Search Strategy: MEDLINE, Embase, Web of Science and CENTRAL were searched from January 2000 to June 2020.Selection Criteria: Study reporting incidence of cranial US findings in consecutive cases of second-trimester fetuses with MMC.Data Collection and Analysis: Publication quality was assessed by Newcastle-Ottawa Scale (NOS) and modified NOS. Meta-analysis could not be performed as a result of high clinical diversity and study heterogeneity.Main Results: Fourteen cranial US findings were reported in 15 studies. Findings in classic Chiari II malformation (CIIM) spectrum included posterior fossa funnelling (96%), small transcerebellar diameter (82-96%), 'banana' sign (50-100%), beaked tectum (65%) and 'lemon' sign (53-100%). Additional cranial findings were small biparietal diameter (BPD) and head circumference (HC) (<5th centile; 53 and 71%, respectively), ventriculomegaly (45-89%), abnormal pointed shape of the occipital horn (77-78%), thinning of the posterior cerebrum, perinodular heterotopia (11%), abnormal gyration (3%), corpus callosum disorders (60%) and midline interhemispheric cyst (42%).Conclusions: We identified 14 cranial findings by second-trimester US in fetuses with MMC. The relatively high incidence of these findings and their unclear prognostic significance might not contraindicate fetal surgery in the case of normal fetal genetic testing. Some cranial findings may independently affect postnatal outcome, however. Long-term detailed follow-up is required to investigate this.Tweetable Abstract: A high rate of cranial abnormalities found on second-trimester ultrasound in fetuses with myelomeningocele. [ABSTRACT FROM AUTHOR]