Robust tracking of deformable anatomical structures with severe occlusions using deformable geometrical primitives.

BACKGROUND AND OBJECTIVE: Surgical robotics tends to develop cognitive control architectures to provide certain degree of autonomy to improve patient safety and surgery outcomes, while decreasing the required surgeons' cognitive load dedicated to low level decisions. Cognition needs workspace perception, which is an essential step towards automatic decision-making and task planning capabilities. Robust and accurate detection and tracking in minimally invasive surgery suffers from limited visibility, occlusions, anatomy deformations and camera movements. METHOD: This paper develops a robust methodology to detect and track anatomical structures in real time to be used in automatic control of robotic systems and augmented reality. The work focuses on the experimental validation in highly challenging surgery: fetoscopic repair of Open Spina Bifida. The proposed method is based on two sequential steps: first, selection of relevant points (contour) using a Convolutional Neural Network and, second, reconstruction of the anatomical shape by means of deformable geometric primitives. RESULTS: The methodology performance was validated with different scenarios. Synthetic scenario tests, designed for extreme validation conditions, demonstrate the safety margin offered by the methodology with respect to the nominal conditions during surgery. Real scenario experiments have demonstrated the validity of the method in terms of accuracy, robustness and computational efficiency. CONCLUSIONS: This paper presents a robust anatomical structure detection in present of abrupt camera movements, severe occlusions and deformations. Even though the paper focuses on a case study, Open Spina Bifida, the methodology is applicable in all anatomies which contours can be approximated by geometric primitives. The methodology is designed to provide effective inputs to cognitive robotic control and augmented reality systems that require accurate tracking of sensitive anatomies.

Evidence of brain injury in fetuses of mothers with preterm labor with intact membranes and preterm prelabor rupture of membranes.

BACKGROUND: Brain injury and poor neurodevelopment have consistently been reported in infants and adults born preterm. These changes occur at least in part prenatally and are associated with intra-amniotic inflammation. The pattern of brain changes has been partially documented by magnetic resonance imaging but not with neurosonography in combination with amniotic fluid brain injury biomarkers. OBJECTIVES: To evaluate the prenatal features of brain remodeling and injury in fetuses from patients with preterm labor with intact membranes or preterm prelabor rupture of membranes and to investigate the potential influence of intra-amniotic inflammation as a mediator of risk. STUDY DESIGN: In this prospective cohort study, fetal brain remodeling and injury was evaluated by neurosonography and amniocentesis in singleton pregnant patients with preterm labor with intact membranes or preterm prelabor rupture of membranes between 24.0-34.0 weeks, with (n=41) and without (n=54) intra-amniotic inflammation. Controls for neurosonography were outpatient pregnant patients without preterm labor or preterm prelabor rupture of membranes matched 2:1 by gestational age at ultrasound. Amniotic fluid controls were patients with an amniocentesis performed for indications other than preterm labor or preterm prelabor rupture of membranes without brain or genetic defects whose amniotic fluid was collected in our biobank for research purposes matched by gestational age at amniocentesis. The group with intra-amniotic inflammation included those with intra-amniotic infection (microbial invasion of the amniotic cavity and intra-amniotic inflammation) and those with sterile inflammation. Microbial invasion of the amniotic cavity was defined as a positive amniotic fluid culture and/or positive 16S ribosomal RNA gene. Inflammation was defined by amniotic fluid interleukin-6 >13.4 ng/ml in preterm labor and >1.43 ng/ml in preterm prelabor rupture of membranes. Neurosonography included the evaluation of brain structure biometric parameters and cortical development. As amniotic fluid brain injury biomarkers we selected neuron-specific enolase, protein S100B and glial fibrillary acidic protein. Data was adjusted for cephalic biometrics, fetal growth centile, fetal sex, non-cephalic presentation and preterm prelabor rupture of membranes at admission. RESULTS: Fetuses from mothers with preterm labor with intact membranes or preterm prelabor rupture of membranes had signs of brain remodeling and injury. First, they had a smaller cerebellum. Thus, in intra-amniotic inflammation, non- intra-amniotic inflammation and control groups, transcerebellar diameter (median (25th; 75th percentile)) was 32.7mm (29.8; 37.6), 35.3mm (31.2;39.6) and 35.0mm (31.3;38.3), respectively (p=0.019); vermian height was 16.9 mm (15.5 ;19.6), 17.2 mm (16.0;18.9) and 17.1mm (15.7;19.0), respectively (p=0.041). Second, they presented a lower corpus callosum area (0.72mm2 (0.59;0. 81), 0.71mm2 (0.63;0.82) and 0.78mm2 (0.71;0. 91), respectively (p=0.006). Third, they showed a delayed cortical maturation (Sylvian fissure depth / biparietal diameter ratio was 0.14 (0.12;0.16), 0.14 (0.13;0.16) and 0.16 (0.15;0.17), respectively (p<0.001), and right parieto-occipital sulci depth ratio was 0.09 (0.07;0.12), 0.11 (0.09;0.14) and 0.11 (0.09;0.14), respectively (p=0.012)). Finally, regarding amniotic fluid brain injury biomarkers, fetuses from mothers with preterm labor with intact membranes or preterm prelabor rupture of membranes, had higher concentrations of neuron-specific enolase (11804.6pg/ml (6213.4;21098.8), 8397.7 pg/ml (3682.1;17398.3) and 2393.7pg/ml (1717.1;3209.3), respectively (p<0.001)); protein S100B (2030.6 pg/ml (993;4883.5), 1070.3pg/ml (365.1-1463.2) and 74.8pg/ml (44.7;93.7), respectively (p<0.001)), and glial fibrillary acidic protein (1.01ng/ml (0.54;3.88), 0.965ng/ml (0.59;2.07) and 0.24mg/ml (0.20;0.28), respectively (p=0.002)). CONCLUSION: Fetuses with preterm labor with intact membranes or preterm prelabor rupture of membranes had prenatal signs of brain remodeling and injury at the time of clinical presentation. These changes were more pronounced in those with intra-amniotic inflammation.

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

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

Diurnal cortisol throughout pregnancy and its association with maternal depressive symptoms and birth outcomes.

BACKGROUND: Depression during pregnancy is a common complication that can negatively affect fetal health and birth outcomes. Cortisol is believed to be a key mediator of this association. Although pregnancy entails a natural increase in cortisol levels, preclinical depression could alter its circadian rhythm, producing excessively high overall diurnal cortisol levels that might be harmful for the fetus and future offspring development. OBJECTIVES: Using a prospective longitudinal design, we aimed to study (i) trimestral cortisol circadian rhythm and its overall levels throughout pregnancy in healthy women, (ii) the extent to which maternal depressive symptoms influence both cortisol rhythmicity and overall levels, and (iii) the possible adverse consequences of elevated maternal cortisol on the offspring's weight and gestational age at birth. STUDY DESIGN: 112 healthy pregnant women from the general Spanish population were recruited before their first pregnancy. To assess cortisol circadian rhythm, participants provided four saliva samples at each trimester of pregnancy (at awakening, 30 min after awakening, before lunch and before going to bed). Overall cortisol levels were calculated with AUCg approximation. Depressive symptoms were evaluated in each trimester and defined according to EPDS cut-off values (1st trimester, EPDS ≥ 11; 2nd and 3rd trimesters, EPDS ≥ 10). At birth, the risk for low weight, prematurity and weight birth percentile was retrieved for 100 infants. Mixed models and simple effects were employed to study changes of maternal cortisol circadian rhythm and overall levels throughout pregnancy and the possible influence of maternal depressive symptoms. Finally, logistic regressions were performed to assess the associations between maternal overall cortisol levels in each trimester of pregnancy and birth anthropometrics. RESULTS: Although overall diurnal cortisol levels increase throughout pregnancy, cortisol circadian rhythm is preserved in all trimesters [1st (F(3110)= 92.565, p < .001), 2nd (F(3,85)= 46.828, p < .001) and 3rd (F(3,90)= 65.555, p < .001)]. However, women with depressive symptoms showed a flattened cortisol circadian pattern only during the second trimester, characterized by a blunted awakening peak and reduced evening decline (F(3,85)= 4.136, p = .009), but not during the first (F(3,11)= 1.676, p = .176) or the third (F(3,90)= 1.089, p = .358) trimesters. Additionally, they did not show a cortisol increase from second to third trimester (p = .636). Finally, higher maternal cortisol levels in second and third trimesters seemed to be associated with increased risk of prematurity (adjusted OR -0.371, 95% CI 0.490-0.972, p = .034) and low birth weight percentile (adjusted OR -0.612, 95% CI 0.348-0.846, p = .007) respectively. CONCLUSION: Maternal cortisol levels increased throughout pregnancy, although cortisol circadian rhythm was preserved in all trimesters of pregnancy. However, prenatal depressive symptoms were associated with flattened maternal cortisol circadian rhythm in mid-pregnancy. Therefore, it seems that women with depressive symptoms tended to increase less gradually their cortisol levels from mid to late pregnancy. Finally, higher maternal cortisol levels in mid and late-pregnancy seem to be associated with poorer birth anthropometrics Early detection of depressive symptoms in general population could help to prevent putative obstetrical and birth adverse outcomes.

3D vs. 2D simulated fetoscopy for spina bifida repair: a quantitative motion analysis.

3D imaging technology is becoming more prominent every day. However, more validation is needed to understand the actual benefit of 3D versus conventional 2D vision. This work quantitatively investigates whether experts benefit from 3D vision during minimally invasive fetoscopic spina bifida (fSB) repair. A superiority study was designed involving one expert team ([Formula: see text] procedures prior) who performed six 2D and six 3D fSB repair simulations in a high-fidelity animal training model, using 3-port access. The 6D motion of the instruments was recorded. Among the motion metrics are total path length, smoothness, maximum speed, the modified Spectral Arc Length (SPARC), and Log Dimensionless Jerk (LDLJ). The primary clinical outcome is operation time (power 90%, 5% significance) using Sealed Envelope Ltd. 2012. Secondary clinical outcomes are water tightness of the repair, CO[Formula: see text] insufflation volume, and OSATS score. Findings show that total path length and LDLJ are considerably different. Operation time during 3D vision was found to be significantly shorter compared to 2D vision ([Formula: see text] vs. [Formula: see text] min; p [Formula: see text] 0.026). These results suggest enhanced performance with 3D vision during interrupted suturing in fetoscopic SBA repair. To confirm these results, a larger-scale follow-up study involving multiple experts and novice surgeons is recommended.

Effects of Mediterranean diet or mindfulness-based stress reduction on fetal and neonatal brain development: a secondary analysis of a randomized clinical trial.

BACKGROUND: Maternal suboptimal nutrition and high stress levels are associated with adverse fetal and infant neurodevelopment. OBJECTIVE: This study aimed to investigate if structured lifestyle interventions involving a Mediterranean diet or mindfulness-based stress reduction during pregnancy are associated with differences in fetal and neonatal brain development. STUDY DESIGN: This was a secondary analysis of the randomized clinical trial Improving Mothers for a Better Prenatal Care Trial Barcelona that was conducted in Barcelona, Spain, from 2017 to 2020. Participants with singleton pregnancies were randomly allocated into 3 groups, namely Mediterranean diet intervention, stress reduction program, or usual care. Participants in the Mediterranean diet group received monthly individual sessions and free provision of extra-virgin olive oil and walnuts. Pregnant women in the stress reduction group underwent an 8-week mindfulness-based stress reduction program adapted for pregnancy. Magnetic resonance imaging of 90 fetal brains was performed at 36 to 39 weeks of gestation and the Neonatal Neurobehavioral Assessment Scale was completed for 692 newborns at 1 to 3 months. Fetal outcomes were the total brain volume and lobular or regional volumes obtained from a 3-dimensional reconstruction and semiautomatic segmentation of magnetic resonance images. Neonatal outcomes were the 6 clusters scores of the Neonatal Neurobehavioral Assessment Scale. Multiple regression analyses were conducted to assess the association between the interventions and the fetal and neonatal outcomes. RESULTS: When compared with the usual care group, the offspring exposed to a maternal Mediterranean diet had a larger total fetal brain volume (mean, 284.11 cm3; standard deviation, 23.92 cm3 vs 294.01 cm3; standard deviation, 26.29 cm3; P=.04), corpus callosum (mean, 1.16 cm3; standard deviation, 0.19 cm3 vs 1.26 cm3; standard deviation, 0.22 cm3; P=.03), and right frontal lobe (44.20; standard deviation, 4.09 cm3 vs 46.60; standard deviation, 4.69 cm3; P=.02) volumes based on magnetic resonance imaging measures and higher scores in the Neonatal Neurobehavioral Assessment Scale clusters of autonomic stability (mean, 7.4; standard deviation, 0.9 vs 7.6; standard deviation, 0.7; P=.04), social interaction (mean, 7.5; standard deviation, 1.5 vs 7.8; standard deviation, 1.3; P=.03), and range of state (mean, 4.3; standard deviation, 1.3 vs 4.5; standard deviation, 1.0; P=.04). When compared with the usual care group, offspring from the stress reduction group had larger fetal left anterior cingulate gyri volume (1.63; standard deviation, 0.32 m3 vs 1.79; standard deviation, 0.30 cm3; P=.03) based on magnetic resonance imaging and higher scores in the Neonatal Neurobehavioral Assessment Scale for regulation of state (mean, 6.0; standard deviation, 1.8 vs 6.5; standard deviation, 1.5; P<.01). CONCLUSION: Maternal structured lifestyle interventions involving the promotion of a Mediterranean diet or stress reduction during pregnancy were associated with changes in fetal and neonatal brain development.

Similarity network fusion to identify phenotypes of small-for-gestational-age fetuses.

Fetal growth restriction (FGR) affects 5-10% of pregnancies, is the largest contributor to fetal death, and can have long-term consequences for the child. Implementation of a standard clinical classification system is hampered by the multiphenotypic spectrum of small fetuses with substantial differences in perinatal risks. Machine learning and multiomics data can potentially revolutionize clinical decision-making in FGR by identifying new phenotypes. Herein, we describe a cluster analysis of FGR based on an unbiased machine-learning method. Our results confirm the existence of two subtypes of human FGR with distinct molecular and clinical features based on multiomic analysis. In addition, we demonstrated that clusters generated by machine learning significantly outperform single data subtype analysis and biologically support the current clinical classification in predicting adverse maternal and neonatal outcomes. Our approach can aid in the refinement of clinical classification systems for FGR supported by molecular and clinical signatures.

Automatic Deep Learning-Based Pipeline for Automatic Delineation and Measurement of Fetal Brain Structures in Routine Mid-Trimester Ultrasound Images.

INTRODUCTION: The aim of this study was to develop a pipeline using state-of-the-art deep learning methods to automatically delineate and measure several of the most important brain structures in fetal brain ultrasound (US) images. METHODS: The dataset was composed of 5,331 images of the fetal brain acquired during the routine mid-trimester US scan. Our proposed pipeline automatically performs the following three steps: brain plane classification (transventricular, transthalamic, or transcerebellar plane); brain structures delineation (9 different structures); and automatic measurement (from the structure delineations). The methods were trained on a subset of 4,331 images and each step was evaluated on the remaining 1,000 images. RESULTS: Plane classification reached 98.6% average class accuracy. Brain structure delineation obtained an average pixel accuracy higher than 96% and a Jaccard index higher than 70%. Automatic measurements get an absolute error below 3.5% for the four standard head biometries (head circumference, biparietal diameter, occipitofrontal diameter, and cephalic index), 9% for transcerebellar diameter, 12% for cavum septi pellucidi ratio, and 26% for Sylvian fissure operculization degree. CONCLUSIONS: The proposed pipeline shows the potential of deep learning methods to delineate fetal head and brain structures and obtain automatic measures of each anatomical standard plane acquired during routine fetal US examination.

An Artificial Placenta Experimental System in Sheep: Critical Issues for Successful Transition and Survival up to One Week.

OBJECTIVE: To describe the development of an artificial placenta (AP) system in sheep with learning curve and main bottlenecks to allow survival up to one week. METHODS: A total of 28 fetal sheep were transferred to an AP system at 110-115 days of gestation. The survival goal in the AP system was increased progressively in three consecutive study groups: 1-3 h (n = 8), 4-24 h (n = 10) and 48-168 h (n = 10). Duration of cannulation procedure, technical complications, pH, lactate, extracorporeal circulation (EC) circuit flows, fetal heart rate, and outcomes across experiments were compared. RESULTS: There was a progressive reduction in cannulation complications (75%, 50% and 0%, p = 0.004), improvement in initial pH (7.20 ± 0.06, 7.31 ± 0.04 and 7.33 ± 0.02, p = 0.161), and increment in the rate of experiments reaching survival goal (25%, 70% and 80%, p = 0.045). In the first two groups, cannulation accidents, air bubbles in the extracorporeal circuit, and thrombotic complications were the most common cause of AP system failure. CONCLUSIONS: Achieving a reproducible experimental setting for an AP system is extremely challenging, time- and effort-consuming, and requires a highly multidisciplinary team. As a result of the learning curve, we achieved reproducible transition and survival up to 7 days. Extended survival requires improving instrumentation with custom-designed devices.

Longitudinal evolution of central nervous system anomalies in fetuses with open spina bifida fetoscopic repair and correlation with neurologic outcome.

BACKGROUND: Open spina bifida is associated with central nervous system anomalies such as abnormal corpus callosum and heterotopias. However, the impact of prenatal surgery over these structures remains unclear. OBJECTIVE: This study aimed to describe longitudinal changes of central nervous system anomalies before and after prenatal open spina bifida repair and to evaluate their relationship with postnatal neurologic outcomes. STUDY DESIGN: Retrospective cohort study of fetuses with open spina bifida who underwent percutaneous fetoscopic repair from January 2009 to August 2020. All women had presurgical and postsurgical fetal magnetic resonance imaging, at an average of 1 week before and 4 weeks after surgery, respectively. We evaluated defect characteristics in the presurgical magnetic resonance images; and fetal head biometry, clivus supraocciput angle, and the presence of structural central nervous system anomalies, such as abnormalities in corpus callosum, heterotopias, ventriculomegaly, and hindbrain herniation, in both presurgical and postsurgical magnetic resonance images. Neurologic assessment was performed using the Pediatric Evaluation of Disability Inventory scale in children who were 12 months or older, covering 3 different sections, namely self-care, mobility, and social and cognitive function. RESULTS: A total of 46 fetuses were evaluated. Presurgery and postsurgery magnetic resonance imaging were performed at a median gestational age of 25.3 and 30.6 weeks, with a median interval of 0.8 weeks before surgery, and 4.0 weeks after surgery. There was a 70% reduction in hindbrain herniation (100% vs 32.6%; P<.001), and a normalization of the clivus supraocciput angle after surgery (55.3 [48.8-61.0] vs 79.9 [75.2-85.4]; P<.001). No significant increase in abnormal corpus callosum (50.0% vs 58.7%; P=.157) or heterotopia (10.8% vs 13.0%; P=.706) was observed. Ventricular dilation was higher after surgery (15.6 [12.7-18.1] vs 18.8 [13.7-22.9] mm; P<.001), with a higher proportion of severe ventricular dilation after surgery (≥15mm) (52.2% vs 67.4%; P=.020). Thirty-four children underwent neurologic assessment, with 50% presenting a global optimal Pediatric Evaluation of Disability Inventory result and 100% presenting a normal social and cognitive function. Children with optimal global Pediatric Evaluation of Disability Inventory presented a lower rate of presurgical anomalies in corpus callosum and severe ventriculomegaly. When analyzed as independent variables to global Pediatric Evaluation of Disability Inventory scale, the presence of abnormal corpus callosum and severe ventriculomegaly showed an odds ratio of 27.7 (P=.025; 95% confidence interval, 1.53-500.71) for a suboptimal result. CONCLUSION: Prenatal open spina bifida repair did not change the proportion of abnormal corpus callosum nor heterotopias after surgery. The combination of presurgical abnormal corpus callosum and severe ventricular dilation (≥15 mm) is associated with an increased risk of suboptimal neurodevelopment.

Generalisability of fetal ultrasound deep learning models to low-resource imaging settings in five African countries.

Most artificial intelligence (AI) research and innovations have concentrated in high-income countries, where imaging data, IT infrastructures and clinical expertise are plentiful. However, slower progress has been made in limited-resource environments where medical imaging is needed. For example, in Sub-Saharan Africa, the rate of perinatal mortality is very high due to limited access to antenatal screening. In these countries, AI models could be implemented to help clinicians acquire fetal ultrasound planes for the diagnosis of fetal abnormalities. So far, deep learning models have been proposed to identify standard fetal planes, but there is no evidence of their ability to generalise in centres with low resources, i.e. with limited access to high-end ultrasound equipment and ultrasound data. This work investigates for the first time different strategies to reduce the domain-shift effect arising from a fetal plane classification model trained on one clinical centre with high-resource settings and transferred to a new centre with low-resource settings. To that end, a classifier trained with 1792 patients from Spain is first evaluated on a new centre in Denmark in optimal conditions with 1008 patients and is later optimised to reach the same performance in five African centres (Egypt, Algeria, Uganda, Ghana and Malawi) with 25 patients each. The results show that a transfer learning approach for domain adaptation can be a solution to integrate small-size African samples with existing large-scale databases in developed countries. In particular, the model can be re-aligned and optimised to boost the performance on African populations by increasing the recall to [Formula: see text] and at the same time maintaining a high precision across centres. This framework shows promise for building new AI models generalisable across clinical centres with limited data acquired in challenging and heterogeneous conditions and calls for further research to develop new solutions for the usability of AI in countries with fewer resources and, consequently, in higher need of clinical support.

An automatic pipeline for atlas-based fetal and neonatal brain segmentation and analysis.

BACKGROUND AND OBJECTIVE: The automatic segmentation of perinatal brain structures in magnetic resonance imaging (MRI) is of utmost importance for the study of brain growth and related complications. While different methods exist for adult and pediatric MRI data, there is a lack for automatic tools for the analysis of perinatal imaging. METHODS: In this work, a new pipeline for fetal and neonatal segmentation has been developed. We also report the creation of two new fetal atlases, and their use within the pipeline for atlas-based segmentation, based on novel registration methods. The pipeline is also able to extract cortical and pial surfaces and compute features, such as curvature, local gyrification index, sulcal depth, and thickness. RESULTS: Results show that the introduction of the new templates together with our segmentation strategy leads to accurate results when compared to expert annotations, as well as better performances when compared to a reference pipeline (developing Human Connectome Project (dHCP)), for both early and late-onset fetal brains. CONCLUSIONS: These findings show the potential of the presented atlases and the whole pipeline for application in both fetal, neonatal, and longitudinal studies, which could lead to dramatic improvements in the understanding of perinatal brain development.

Fetal Liver Volume Assessment Using Magnetic Resonance Imaging in Fetuses With Cytomegalovirus Infection†.

Objective: To assess fetal liver volume (FLV) by magnetic resonance imaging (MRI) in cytomegalovirus (CMV)-infected fetuses compared to a group of healthy fetuses. Method: Most infected cases were diagnosed by the evidence of ultrasound abnormalities during routine scans and in some after maternal CMV screening. CMV-infected fetuses were considered severely or mildly affected according to prenatal brain lesions identified by ultrasound (US)/MRI. We assessed FLV, the FLV to abdominal circumference (AC) ratio (FLV/AC-ratio), and the FLV to fetal body volume (FBV) ratio (FLV/FBV-ratio). As controls, we included 33 healthy fetuses. Hepatomegaly was evaluated post-mortem in 11 cases of congenital CMV infection. Parametric trend and intraclass correlation analyses were performed. Results: There were no significant differences in FLV between infected (n = 32) and healthy fetuses. On correcting the FLV for AC and FBV, we observed a significantly higher FLV in CMV-infected fetuses. There were no significant differences in the FLV, or the FLV/AC or FLV/FBV-ratios according to the severity of brain abnormalities. There was excellent concordance between the fetal liver weight estimated by MRI and liver weight obtained post-mortem. Hepatomegaly was not detected in any CMV-infected fetus. Conclusion: In CMV-infected fetuses, FLV corrected for AC and FBV was higher compared to healthy controls, indicating relative hepatomegaly. These parameters could potentially be used as surrogate markers of liver enlargement.

Impact of Preoperative Cervical Length on Pregnancy Outcome in Twin-Twin Transfusion Syndrome.

OBJECTIVE: To evaluate the impact of preoperative cervical length on pregnancy outcome in monochorionic diamniotic twin pregnancies complicated by twin-twin transfusion syndrome that underwent laser surgery or cord occlusion. MATERIALS AND METHODS: Retrospective study of 330 patients stratified by preoperative cervical length (≥25 mm, 16-24 mm,≤15 mm). Maternal characteristics, operative data, and pregnancy outcomes were compared between the cervical length groups as well as between the subgroups of patients with a cervical length≤15 mm according to management (expectant vs. cerclage). RESULTS: A preoperative cervical length≥25 mm was observed in 82% (n=271) of cases, 16-24 mm in 9% (n=29), and≤15 mm in 9% (n=30). Patients with a preoperative cervical length≤15 mm showed shorter median procedure-to-delivery interval (5.5 weeks vs. 11.6 (16-24 mm) vs. 13.0 (≥25 mm); p<0.001); lower median gestational age at delivery (29.5 weeks vs. 34.3 (16-24 mm) vs. 33.4 (≥25 mm); p<0.001); higher rate of preterm delivery<32 weeks (78 vs. 20% (16-24 mm) vs. 31% (≥25 mm); p<0.001); and lower neonatal survival rate of at least one twin (70 vs. 88% (16-24 mm) vs. 93% (≥25 mm); p<0.001). Outcome of patients with a preoperative cervical length≤15 mm was similar regardless of management. CONCLUSION: Monochorionic diamniotic twin pregnancies complicated by twin-twin transfusion syndrome with a preoperative cervical length≤15 mm showed a higher rate of preterm delivery<32 weeks and lower neonatal survival. The role of a cervical cerclage remains unclear.

The heart after surviving twin-to-twin transfusion syndrome.

BACKGROUND: The persistent changes in cardiac structure and function in children who survived twin-to-twin transfusion syndrome remain a matter of concern and controversy. Current fetal echocardiographic parameters and their postnatal evolution can help improve our understanding of the subject. OBJECTIVE: To describe the echocardiographic changes of monochorionic fetuses affected by twin-to-twin transfusion syndrome, the recipient and the donor, before and after laser photocoagulation and to determine their evolution in the third trimester and during their first year of life. STUDY DESIGN: An observational study was conducted including 55 uncomplicated monochorionic diamniotic twins and 78 pairs with twin-to-twin transfusion syndrome, 44 stage I-II and 34 stage III-IV, prospectively enrolled from 2015 until 2018. Comprehensive echocardiography was performed at 4 time periods: before laser photocoagulation, at 24 to 72 hours after surgery, at 28 to 30 weeks of gestation, and at 6 to 12 months after birth. Echocardiographic parameters were transformed to z-scores or indexed for heart area, estimated fetal weight, or body mass surface. RESULTS: At diagnosis, recipients in all stages presented larger hearts (cardiothoracic ratio z-score: 2.77 [0.8] vs controls: -0.03 [0.5]; P<.001) and signs of ventricular hypertrophy (left end-diastolic ventricle wall thickness: 2.68 [0.7] vs controls -0.03 [0.7]; P<.001), along with systolic (cardiac index recipients: 317 [114] mL/min/kg vs controls: 400 [120] mL/min/kg, P<.001) and diastolic impairment (isovolumetric relaxation time z-score: 2.76 [0.6] vs controls: 0.05 [0.6]; P<.001). Donors presented smaller ventricular areas and diameters when compared with controls (left end-diastolic ventricle area z-score: -1.48 [1] vs 0.03 [0.9]; P<.001), along with decreased longitudinal motion (tricuspid annular plane systolic excursion z-score: -0.9 [1] vs controls -0.04 [1]; P<.001) and shorter ejection time z-score (-1.5 [0.7] vs controls: 0.0 [0.7]; P<.001). After surgery, an improvement in functional parameters was observed in both fetuses, whereas most morphometric changes prevailed in donors and recipients in the prenatal period. Postnatally, cardiac remodeling persisted in recipients (left relative wall thickness: 0.34 [0.02] vs controls: 0.30 [0.02]; P<.001), whereas donors mainly presented a decreased longitudinal motion in infancy (tricuspid annular plane systolic excursion z-score: -0.72 [0.7] vs controls: 0.23 [0.9]; P<.05). CONCLUSION: Cardiac remodeling is present in both fetuses at the twin-to-twin transfusion syndrome diagnosis, whereas diastolic dysfunction is only significant in the recipient. Fetal therapy improves most echocardiographic parameters, although postnatally, the echocardiographic changes persist in both fetuses.

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

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

Maternal high-dose valacyclovir and its correlation with newborn blood viral load and outcome in congenital cytomegalovirus infection.

BACKGROUND/OBJECTIVE: Currently, there is no validated treatment for fetal cytomegalovirus (CMV). Two studies suggest that high-dose maternal valacyclovir decreases fetal viral load and improves outcomes in moderately-symptomatic fetuses. We offered valacyclovir in cases of fetal infection lacking ultrasound abnormalities or with non-severe infection. Maternal tolerability, fetal outcome and newborn blood viral load were evaluated in pregnancies of mothers receiving valacyclovir. STUDY DESIGN: We performed a case series including 8 pregnancies with fetal CMV classified as unaffected/mildly-moderately affected. Mothers received valacyclovir (8 g/24h) from fetal infection diagnosis to delivery. Standard newborn evaluation was performed, and viremia was determined in the first 48 h of life and compared according to length of maternal treatment and presence/absence of prenatal anomalies. RESULTS: Valacyclovir was administered at a median gestational age of 26.5 weeks (23.8-33.1) in 3 cases without fetal abnormalities, and 5 with mild/moderate abnormalities. Three were 3 first trimester primary infections, one non-primary infection, and in 4 the type of infection was unknown. Valacyclovir was well-tolerated. Fetal features did not progress. Three newborns were asymptomatic, and one was severely affected (bilateral chorioretinitis). The median newborn viral load (IQR) was 502 IU/mL (231-191781) with lower levels when maternal treatment was administered ≥10 weeks, and in cases without fetal abnormalities [median 234 IU/mL (228-711) vs. 4061 (292-510500) p = .18; and 234 IU/mL (228-379500) vs. 711 IU/mL (292-4061) p = .65, respectively], these differences being non-significant. CONCLUSIONS: Fetal CMV lesions remained stable with high-dose maternal valacyclovir. Newborn viral load was unchanged despite treatment duration and fetal/neonatal abnormalities. SUMMARY: Fetal cytomegalovirus lesions remained stable with high-dose maternal valacyclovir. Newborn viral load was unchanged despite treatment duration and fetal/newborn abnormalities.