Truncating variants in PAPSS2 gene: A cause of early prenatal onset brachyolmia?

Brachyolmia is a rare form of skeletal dysplasia characterized by a wide genetic and clinical heterogeneity. This condition is usually diagnosed postnatally, and very few cases of prenatal diagnosis have been described so far. Here, we report a case of a pregnant woman at 20 weeks' gestation referred to our center because of fetal short long bones. On targeted ultrasound, mild bowing of the femurs and fibulae and mild micrognathia were also observed. Exome sequencing analysis showed the presence in compound heterozygosity of two pathogenic variants-both truncating variants-in the 3-prime-phosphoadenosine 5-prime-phosphosulfate synthase 2 (PAPSS2) gene, known to cause brachyolmia type 4 (OMIM #612847). Of note, all of the few cases reported prenatally have indeed truncating variants. Hence, we speculate this kind of variant is likely responsible for a complete loss of function of the protein leading to an earlier and more severe phenotype.

Second trimester fetal MRI of the brain: Through the ground glass.

Fetal MRI is an important tool for the prenatal diagnosis of brain malformations and is often requested after second-trimester ultrasonography reveals a possible abnormality. Despite the immature state of the fetal brain at this early stage, early suggestive signs of the presence of brain malformations can be recognized. To differentiate between the normal dynamics of the growing brain and the developing pathological conditions can be challenging and requires extensive knowledge of normal central nervous system developmental stages and their neuroradiological counterparts at those different stages. This article reviews the second-trimester appearances of some commonly encountered brain malformations, focusing on helpful tricks and subtle signs to aid in the diagnosis of such conditions as rhombencephalosynapsis, various causes of vermian rotation, molar tooth spectrum anomalies, diencephalic-mesencephalic junction dysplasia, ganglionic eminence anomalies, and the most common malformations of cortical development.

Prenatal diagnosis of Aicardi syndrome based on a suggestive imaging pattern: A multicenter case-series.

OBJECTIVES: To characterize a suggestive prenatal imaging pattern of Aicardi syndrome using ultrasound and MR imaging. METHODS: Based on a retrospective international series of Aicardi syndrome cases from tertiary centers encountered over a 20-year period (2000-2020), we investigated the frequencies of the imaging features in order to characterize an imaging pattern highly suggestive of the diagnosis. RESULTS: Among 20 cases included, arachnoid cysts associated with a distortion of the interhemispheric fissure were constantly encountered associated with complete or partial agenesis of the corpus callosum (19/20, 95%). This triad in the presence of other CNS disorganization, such as polymicrogyria (16/17, 94%), heterotopias (15/17, 88%), ventriculomegaly (14/20, 70%), cerebral asymmetry [14/20, 70%]) and less frequently extra-CNS anomaly (ocular anomalies [7/11, 64%], costal/vertebral segmentation defect [4/20, 20%]) represent a highly suggestive pattern of Aicardi syndrome in a female patient. CONCLUSION: Despite absence of genetic test to confirm prenatal diagnosis of AS, this combination of CNS and extra-CNS fetal findings allows delineation of a characteristic imaging pattern of AS, especially when facing dysgenesis of the corpus callosum.

Consensus on Training and Assessment of Competence in Performing Chorionic Villus Sampling and Amniocentesis: An International Delphi Survey.

INTRODUCTION: The aim of this study was to obtain expert consensus on the content of a curriculum for learning chorionic villus sampling (CVS) and amniocentesis (AC) and the items of an assessment tool to evaluate CVS and AC competence. METHODS: We used a 3-round iterative Delphi process. A steering committee supervised all processes. Seven international collaborators were identified to expand the breadth of the study internationally. The collaborators invited fetal medicine experts to participate as panelists. In the first round, the panelists suggested content for a CVS/AC curriculum and an assessment tool. The steering committee organized and condensed the suggested items and presented them to the panelists in round 2. In the second round, the panelists rated and commented on the suggested items. The results were processed by the steering committee and presented to the panelists in the third round, where final consensus was obtained. Consensus was defined as support by more than 80% of the panelists for an item. RESULTS: Eighty-six experts agreed to participate in the study. The panelists represented 16 countries across 4 continents. The final list of curricular content included 12 theoretical and practical items. The final assessment tool included 11 items, systematically divided into 5 categories: pre-procedure, procedure, post-procedure, nontechnical skills, and overall performance. These items were provided with behavioral scale anchors to rate performance, and an entrustment scale was used for the final overall assessment. CONCLUSION: We established consensus among international fetal medicine experts on content to be included in a CVS/AC curriculum and on an assessment tool to evaluate CVS/AC skills. These results are important to help transition current training and assessment methods from a time- and volume-based approach to a competency-based approach which is a key step in improving patient safety and outcomes for the 2 most common invasive procedures in fetal medicine.

Comprehensive Profiling of Secretome Formulations from Fetal- and Perinatal Human Amniotic Fluid Stem Cells.

We previously reported that c-KIT+ human amniotic-fluid derived stem cells obtained from leftover samples of routine II trimester prenatal diagnosis (fetal hAFS) are endowed with regenerative paracrine potential driving pro-survival, anti-fibrotic and proliferative effects. hAFS may also be isolated from III trimester clinical waste samples during scheduled C-sections (perinatal hAFS), thus offering a more easily accessible alternative when compared to fetal hAFS. Nonetheless, little is known about the paracrine profile of perinatal hAFS. Here we provide a detailed characterization of the hAFS total secretome (i.e., the entirety of soluble paracrine factors released by cells in the conditioned medium, hAFS-CM) and the extracellular vesicles (hAFS-EVs) within it, from II trimester fetal- versus III trimester perinatal cells. Fetal- and perinatal hAFS were characterized and subject to hypoxic preconditioning to enhance their paracrine potential. hAFS-CM and hAFS-EV formulations were analyzed for protein and chemokine/cytokine content, and the EV cargo was further investigated by RNA sequencing. The phenotype of fetal- and perinatal hAFS, along with their corresponding secretome formulations, overlapped; yet, fetal hAFS showed immature oxidative phosphorylation activity when compared to perinatal ones. The profiling of their paracrine cargo revealed some differences according to gestational stage and hypoxic preconditioning. Both cell sources provided formulations enriched with neurotrophic, immunomodulatory, anti-fibrotic and endothelial stimulating factors, and the immature fetal hAFS secretome was defined by a more pronounced pro-vasculogenic, regenerative, pro-resolving and anti-aging profile. Small RNA profiling showed microRNA enrichment in both fetal- and perinatal hAFS-EV cargo, with a stably- expressed pro-resolving core as a reference molecular signature. Here we confirm that hAFS represents an appealing source of regenerative paracrine factors; the selection of either fetal or perinatal hAFS secretome formulations for future paracrine therapy should be evaluated considering the specific clinical scenario.

Current Controversies in Prenatal Diagnosis 1: Should MRI be performed on all fetuses with mild ventriculomegaly?

A ventricular diameter of 10 mm correlates with more than two standard deviations of the normal and hence is qualified as ventriculomegaly. The relevance of this is dependent on whether there are associated infectious, genetic, or structural problems. The chance for neurodevelopmental delay in isolated ventriculomegaly less than 15 mm is 7.9% (4.7-11.1), and less if it is unilateral. It can be further divided in mild (10-12) or moderate (13-15), though this is not widely accepted. As part of the workup, structural assessment today may include ultrasound or magnetic resonance imaging, or both. Discussants agreed that the diagnostic performance of both methods is as good as the expertise with which the images are acquired and interpreted. Discussants agreed that when the initial neurosonogram is normal, the likelihood of finding significant findings on MRI is low. Nevertheless, some anomalies may only be picked up or better worked out by fetal MRI. In utero follow-up is advocated, as progression may indicate a poorer outcome, and some conditions are only obvious late in pregnancy. Most benefit for future patients is expected from appropriate training in prenatal neuroimaging.

The third ventricle of the human fetal brain: Normative data and pathologic correlation. A 3D transvaginal neurosonography study.

OBJECTIVE: The objective of the study are to describe (a) the technical aspects and (b) the anatomical boundaries of the fetal third ventricle (3V) on the midsagittal sonographic view and to assess (c) different biometric parameters in normal and abnormal fetuses and (d) and their reproducibility. METHODS: This study included 67 normal and 50 CNS anomalies fetuses which include (1) obstructive severe ventriculomegaly (SVM; atrial width ≥ 15 mm), (2) moderate ventriculomegaly (10-14.9 mm), and (3) corpus callosum agenesis (ACC). All underwent transvaginal 3D neurosonography of the midsagittal view of the 3V. The following parameters were measured: area, perimeter, craniocaudal and anteroposterior (AP) diameters, interthalamic adhesion diameter (ITAD), wedge angle, and the ratio between the last 2 variables (ITAD/WA). Repeatability was also assessed. RESULTS: The ITAD and the ITAD/WA are significantly different between normal fetuses and the SVM (P ≤ .001). Interthalamic adhesion diameter of ≤7.1 mm is able to identify SVM with 98.6% accuracy (CI: 0.92-0.99). In ACC cases, the AP diameter is significantly shorter than both normal fetuses and ventriculomegaly. Intraobserver/interobserver reliability was good for most variables. CONCLUSIONS: Transvaginal neurosonography enables visualization of the normal and abnormal fetal third ventricle. An ITAD <7.1 identifies aqueductal stenosis as the likely etiology of severe ventriculomegaly with an accuracy of 98.6%.

Prenatal Echocardiographic Assessment of Foramen Ovale Appearance in Fetuses with D-Transposition of the Great Arteries and Impact on Neonatal Outcome.

INTRODUCTION: Neonates with D-transposition of the great arteries (dTGA) may die at birth because of the inadequate intracardiac mixing due to a misdiagnosed restrictive foramen ovale. We reviewed our experience in echocardiographic assessment and perinatal management of fetuses with dTGA searching for new features that may predict the need for urgent balloon atrial septostomy (BAS) immediately after birth. PATIENTS AND METHODS: We included fetuses diagnosed with dTGA between January 2000 and December 2014. We assessed pre- and postnatal appearance of the foramen ovale, ductus arteriosus and pulmonary veins. Both the diagnostic findings at the time of last prenatal echocardiogram and those findings deriving from a retrospective reevaluation of stored videos were considered. BAS was defined as urgent if performed in neonates with restrictive foramen ovale and severe hypoxemia. RESULTS: We reviewed 40 fetuses with dTGA. 20/40 fetuses received urgent BAS at birth. Not only the restrictive but also the hypermobile and the redundant appearance of the foramen ovale was significantly associated with urgent BAS (p < 0.0001, p = 0.002 and p = 0.0001, respectively). CONCLUSIONS: Prenatal evaluation of the foramen ovale appearance in fetuses with dTGA is still challenging. Based on our experience, also the redundant foramen ovale appearance may need urgent BAS at birth.

Azygos Vein Z Scores in Healthy Fetuses and Fetuses With Venous Malformations Related to the Azygos Vein.

OBJECTIVES: To establish fetal azygos vein and descending aorta sonographic Z score formulas based on femur length and gestational age and to determine the value of azygos vein diameter variation for potential use in the diagnosis of fetal venous malformations related to the azygos vein. METHODS: A total of 452 healthy singleton fetuses and 25 fetuses with venous malformations related to the azygos vein underwent prenatal sonography in this retrospective study. Azygos vein and descending aorta diameters were measured offline after spatiotemporal image correlation volume acquisition. Normal azygos vein and descending aorta Z score formulas were constructed for these measurements based on femur length by performing standard regression analysis followed by weighted regression of absolute residual values. The azygos vein-to-descending aorta ratio was calculated. Three parameters were compared between venous malformations related to the azygos vein and healthy fetuses. RESULTS: Azygos vein and descending aorta Z score formulas were constructed. Both showed a positive linear correlation with femur length (r = 0.79 and 0.90, respectively; P < .01) and gestational age (r = 0.79 and 0.91; P < .01). The azygos vein Z scores and azygos vein-to-descending aorta ratios of fetuses with malformations were significantly higher than those of healthy fetuses (P < .01). In the abnormal group, 96.0% of azygos vein Z scores (24 of 25) were greater than ±2, and 96.0% of azygos vein-to-descending aorta ratios (24 of 25) were greater than the 95% confidence interval. CONCLUSIONS: The azygos vein Z score formulas we developed can provide a quantitative basis for prenatal screening of venous malformations related to the azygos vein. Azygos vein dilatation and an abnormal azygos vein-to-descending aorta ratio may contribute to increasing the recognition of venous malformations involving the azygos vein.

Etiology of non-immune hydrops fetalis: An update.

Hydrops fetalis is an excessive fluid accumulation within the fetal extra vascular compartments and body cavities. Non-immune hydrops fetalis (NIHF), due to causes other than Rh alloimmunization, is the cause in >85% of all affected individuals. Herein we present an update of our earlier systematic literature review [Bellini et al., 2009] using all publications between 2007 and 2013. We excluded most of the initial 31,783 papers by using strict selection criteria, thus resulting in 24 relevant NIHF publications describing 1,338 individuals with NIHF. We subdivided the affected individuals into 14 classification groups based on the cause of NIHF (percentage of the total group): Cardiovascular (20.1%), Hematologic (9.3%), Chromosomal (9.0%), Syndromic (5.5%), Lymphatic Dysplasia (15.0%), Inborn Errors of Metabolism (1.3%), Infections (7.0%), Thoracic (2.3%), Urinary Tract Malformations (0.9%), Extra Thoracic Tumors (0.7%), TTTF-Placental (4.1%), Gastrointestinal (1.3%), Miscellaneous (3.6%), Idiopathic (19.8%). We discuss the results of the review. There may be some shifts in the percentages of etiological categories as compared to the previous review, but the small numbers within each category make drawing firm conclusions hazardous. We highlight the need for multi-center series of NIHF cases collected and classified using the same schemes in diagnostic work-ups to allow for comparisons of larger numbers of cases.

Ultrasound assessment of the Essure contraceptive devices: is three-dimensional ultrasound really needed?

STUDY OBJECTIVE: To evaluate the feasibility of 3-dimensional ultrasound (3DUS) for sonographic localization of Essure microinserts, comparing it with 2-dimensional ultrasound (2DUS) insofar as time to visualize the inserts and accuracy in determining their localization. DESIGN: Prospective study (Canadian Task Force classification II-2). SETTING: University clinic. PATIENTS: Twenty-seven consecutive women undergoing hysteroscopic Essure device placement. INTERVENTIONS: Essure microinserts were inserted in the outpatient hysteroscopy clinic following the manufacturer's recommendations, leaving from 3 to 8 loops of the inserts in the uterine cavity. In all patients, 2DUS and 3DUS were performed 3 months after the procedure. 2DUS was performed first; the device(s) were located, and their position was recorded. Then 3DUS scans were acquired, trying when possible to have both devices at least at a 45-degree angle with the insonation beam for optimal rendering on 3DUS. The OmniView method with volume contrast imaging was used to show the relationships of the microinserts within the uterine cavity when possible. To define the position of the Essure device in relation to the uterus and the salpinges, we used the classification developed by Legendre and colleagues. After sonographic evaluation all women underwent hysterosalpingography to assess the success of sterilization. MEASUREMENTS AND MAIN RESULTS: Hysteroscopic insertion was successful in all patients, with 2 Essure devices placed in 25 patients and 1 device in 2 patients (due to previous salpingectomy performed because of ectopic pregnancy), for a total of 52 devices. One spontaneous late (within 3 months) expulsion of the device occurred; the device had migrated almost completely into the uterine cavity. At 3-month follow-up, all 51 correctly placed devices were easily observed at 2DUS (mean [SD] duration of the procedure, 2.25 [0.8] minutes). At 3DUS in 51 cases, the device was in perfect position (1+2+3) in 21 (41.2%), in position 2+3 in 14 (27.4%), and in position +3 in 16 (31.4%). Both microinserts were observed on 3DUS reconstructed images in 31 of 35 (88.6%) 1+2+3 and 2+3 cases. However, in the 16 cases in which the devices were in position +3 (salpinx only), a single 3D sweep failed to demonstrate both devices in 10 of 16 cases (62.5%), due to substantially different angles of orientation of the inserts. This was because if 1 of the 2 devices was placed at a <30-degree angle with the insonation beam, its identification along the uterine wall was questionable because of concurrent hyperechogenicity of the bowel loops and poor visualization. Time for performance of 3DUS was 14.4 [4.8] minutes. Hysterosalpingography was performed in all patients, and confirmed tubal occlusion in all but 1 case. CONCLUSIONS: On the basis of a limited number of patients, 2DUS is more time-efficient and equivalent to 3DUS in locating Essure contraceptive microinserts. These results should be considered when planning sonographic follow-up of patients with Essure devices.

Learning-based keypoint registration for fetoscopic mosaicking.

PURPOSE: In twin-to-twin transfusion syndrome (TTTS), abnormal vascular anastomoses in the monochorionic placenta can produce uneven blood flow between the two fetuses. In the current practice, TTTS is treated surgically by closing abnormal anastomoses using laser ablation. This surgery is minimally invasive and relies on fetoscopy. Limited field of view makes anastomosis identification a challenging task for the surgeon. METHODS: To tackle this challenge, we propose a learning-based framework for in vivo fetoscopy frame registration for field-of-view expansion. The novelties of this framework rely on a learning-based keypoint proposal network and an encoding strategy to filter (i) irrelevant keypoints based on fetoscopic semantic image segmentation and (ii) inconsistent homographies. RESULTS: We validate our framework on a dataset of six intraoperative sequences from six TTTS surgeries from six different women against the most recent state-of-the-art algorithm, which relies on the segmentation of placenta vessels. CONCLUSION: The proposed framework achieves higher performance compared to the state of the art, paving the way for robust mosaicking to provide surgeons with context awareness during TTTS surgery.

Extracellular vesicles from II trimester human amniotic fluid as paracrine conveyors counteracting oxidative stress.

BACKGROUND: We previously demonstrated that the human amniotic fluid (hAF) from II trimester of gestation is a feasible source of stromal progenitors (human amniotic fluid stem cells, hAFSC), with significant paracrine potential for regenerative medicine. Extracellular vesicles (EVs) separated and concentrated from hAFSC secretome can deliver pro-survival, proliferative, anti-fibrotic and cardioprotective effects in preclinical models of skeletal and cardiac muscle injury. While hAFSC-EVs isolation can be significantly influenced by in vitro cell culture, here we profiled EVs directly concentrated from hAF as an alternative option and investigated their paracrine potential against oxidative stress. METHODS: II trimester hAF samples were obtained as leftover material from prenatal diagnostic amniocentesis following written informed consent. EVs were separated by size exclusion chromatography and concentrated by ultracentrifugation. hAF-EVs were assessed by nanoparticle tracking analysis, transmission electron microscopy, Western Blot, and flow cytometry; their metabolic activity was evaluated by oximetric and luminometric analyses and their cargo profiled by proteomics and RNA sequencing. hAF-EV paracrine potential was tested in preclinical in vitro models of oxidative stress and dysfunction on murine C2C12 cells and on 3D human cardiac microtissue. RESULTS: Our protocol resulted in a yield of 6.31 ± 0.98 × 109 EVs particles per hAF milliliter showing round cup-shaped morphology and 209.63 ± 6.10 nm average size, with relevant expression of CD81, CD63 and CD9 tetraspanin markers. hAF-EVs were enriched in CD133/1, CD326, CD24, CD29, and SSEA4 and able to produce ATP by oxygen consumption. While oxidative stress significantly reduced C2C12 survival, hAF-EV priming resulted in significant rescue of cell viability, with notable recovery of ATP synthesis and concomitant reduction of cell damage and lipid peroxidation activity. 3D human cardiac microtissues treated with hAF-EVs and experiencing H2O2 stress and TGFß stimulation showed improved survival with a remarkable decrease in the onset of fibrosis. CONCLUSIONS: Our results suggest that leftover samples of II trimester human amniotic fluid can represent a feasible source of EVs to counteract oxidative damage on target cells, thus offering a novel candidate therapeutic option to counteract skeletal and cardiac muscle injury.

Placental vessel segmentation and registration in fetoscopy: Literature review and MICCAI FetReg2021 challenge findings.

Fetoscopy laser photocoagulation is a widely adopted procedure for treating Twin-to-Twin Transfusion Syndrome (TTTS). The procedure involves photocoagulation pathological anastomoses to restore a physiological blood exchange among twins. The procedure is particularly challenging, from the surgeon's side, due to the limited field of view, poor manoeuvrability of the fetoscope, poor visibility due to amniotic fluid turbidity, and variability in illumination. These challenges may lead to increased surgery time and incomplete ablation of pathological anastomoses, resulting in persistent TTTS. Computer-assisted intervention (CAI) can provide TTTS surgeons with decision support and context awareness by identifying key structures in the scene and expanding the fetoscopic field of view through video mosaicking. Research in this domain has been hampered by the lack of high-quality data to design, develop and test CAI algorithms. Through the Fetoscopic Placental Vessel Segmentation and Registration (FetReg2021) challenge, which was organized as part of the MICCAI2021 Endoscopic Vision (EndoVis) challenge, we released the first large-scale multi-center TTTS dataset for the development of generalized and robust semantic segmentation and video mosaicking algorithms with a focus on creating drift-free mosaics from long duration fetoscopy videos. For this challenge, we released a dataset of 2060 images, pixel-annotated for vessels, tool, fetus and background classes, from 18 in-vivo TTTS fetoscopy procedures and 18 short video clips of an average length of 411 frames for developing placental scene segmentation and frame registration for mosaicking techniques. Seven teams participated in this challenge and their model performance was assessed on an unseen test dataset of 658 pixel-annotated images from 6 fetoscopic procedures and 6 short clips. For the segmentation task, overall baseline performed was the top performing (aggregated mIoU of 0.6763) and was the best on the vessel class (mIoU of 0.5817) while team RREB was the best on the tool (mIoU of 0.6335) and fetus (mIoU of 0.5178) classes. For the registration task, overall the baseline performed better than team SANO with an overall mean 5-frame SSIM of 0.9348. Qualitatively, it was observed that team SANO performed better in planar scenarios, while baseline was better in non-planner scenarios. The detailed analysis showed that no single team outperformed on all 6 test fetoscopic videos. The challenge provided an opportunity to create generalized solutions for fetoscopic scene understanding and mosaicking. In this paper, we present the findings of the FetReg2021 challenge, alongside reporting a detailed literature review for CAI in TTTS fetoscopy. Through this challenge, its analysis and the release of multi-center fetoscopic data, we provide a benchmark for future research in this field.

Pentalogy of Cantrell: embryofetoscopic diagnosis.

Embryofetoscopy is an endoscopic technique that permits a direct visualization and morphologic study of embryos during the first and early second trimester. We report the early prenatal diagnosis of a case of Pentalogy of Cantrell combining data obtained by 2-dimensional and 3-dimensional ultrasonography and embryofetoscopy. Morphologic examination focused on a large omphalocele protruding from the anterior abdominal wall as an oval pulsating mass, measuring approximately 3 cm. The visualization of an omphalocele with ectopia cordis without other malformations confirmed the diagnosis of Pentalogy of Cantrell (class III). Currently, embryofetoscopy allows direct visualization of the embryo in vivo, enabling accurate diagnosis of developmental defects and yielding additional insights into developmental disorders in the embryo.

Toward a navigation framework for fetoscopy.

PURPOSE: Fetoscopic laser photocoagulation of placental anastomoses is the most effective treatment for twin-to-twin transfusion syndrome (TTTS). A robust mosaic of placenta and its vascular network could support surgeons' exploration of the placenta by enlarging the fetoscope field-of-view. In this work, we propose a learning-based framework for field-of-view expansion from intra-operative video frames. METHODS: While current state of the art for fetoscopic mosaicking builds upon the registration of anatomical landmarks which may not always be visible, our framework relies on learning-based features and keypoints, as well as robust transformer-based image-feature matching, without requiring any anatomical priors. We further address the problem of occlusion recovery and frame relocalization, relying on the computed features and their descriptors. RESULTS: Experiments were conducted on 10 in-vivo TTTS videos from two different fetal surgery centers. The proposed framework was compared with several state-of-the-art approaches, achieving higher [Formula: see text] on 7 out of 10 videos and a success rate of [Formula: see text] in occlusion recovery. CONCLUSION: This work introduces a learning-based framework for placental mosaicking with occlusion recovery from intra-operative videos using a keypoint-based strategy and features. The proposed framework can compute the placental panorama and recover even in case of camera tracking loss where other methods fail. The results suggest that the proposed framework has large potential to pave the way to creating a surgical navigation system for TTTS by providing robust field-of-view expansion.

Vein of Galen aneurysmal malformation in newborns: a retrospective study to describe a paradigm of treatment and identify risk factors of adverse outcome in a referral center.

Background: Vein of Galen aneurysmal malformation (VGAM) is a rare cerebral vascular malformation associated with significant morbidity and mortality. Newborns with VGAM without adequate treatment may develop rapidly deteriorating high output heart failure (HOHF) and are at risk for severe neurological outcomes. Objective: To describe the clinical course and management of newborns with VGAM, and identify which echocardiographic and neuroradiologic factors may be associated with severe heart failure at birth and adverse short term outcomes. Methods: This is a single center retrospective cohort study including all consecutive newborns with VGAM admitted to Gaslini Children's Hospital between 2009 and 2022. We reviewed clinical data, intensive care support, fetal and neonatal cardiologic and neuroradiologic findings and we studied the association with severe HOHF, endovascular complications and death. Results: Out of 40 newborns, 17 (42.5%) developed severe HOHF requiring early endovascular procedures. Medical treatment was focused on the main components of HOHF by providing inotropic support and peripheral vasodilation. Pulmonary vasodilators were avoided to reduce the negative effects of pulmonary overflow and prevent vascular remodeling. Reduction of the obligatory left to right shunt through the VGAM was possible only through endovascular treatment. Fetal cardiothoracic ratio was significantly associated with severe HOHF at birth and death. Cardiologic parameters of right ventricular overload, pulmonary hypertension and systemic steal were the leading findings associated with haemodynamic compromise at birth. The mediolateral diameter of the straight or falcine sinus at its shortest section (SS-MD), and arterial pseudofeeders were significantly associated with severe HOHF at birth in prenatal and postnatal assessments. None of the postnatal echocardiographic and MRI variables, nor a higher inotropic support were associated with major periprocedural complications or death. Mortality was due to palliation for congenital severe brain damage (4/40, 10%), or major periprocedural complications (3/40, 7.5%). None of the patients died due to HOHF and multiorgan failure. Overall survival at discharge was 82.5% (33/40). Conclusions: The complexity of neonatal VGAM pathophysiology requires a multidisciplinary approach, specialized intensive care management, and early endovascular treatment to reduce mortality and optimize clinical outcomes. Cardiologic and neuroradiologic parameters are key to define risk stratification and treatment strategies.