Showing papers by "Elisenda Eixarch published in 2018"

Metabolic profiling and targeted lipidomics reveals a disturbed lipid profile in mothers and fetuses with intrauterine growth restriction.

Abstract: Fetal growth may be impaired by poor placental function or maternal conditions, each of which can influence the transfer of nutrients and oxygen from the mother to the developing fetus. Large-scale studies of metabolites (metabolomics) are key to understand cellular metabolism and pathophysiology of human conditions. Herein, maternal and cord blood plasma samples were used for NMR-based metabolic fingerprinting and profiling, including analysis of the enrichment of circulating lipid classes and subclasses, as well as the number of sub-fraction particles and their size. Changes in phosphatidylcholines and glycoproteins were prominent in growth-restricted fetuses indicating significant alterations in their abundance and biophysical properties. Lipoprotein profiles showed significantly lower plasma concentrations of cholesterol-intermediate density lipoprotein (IDL), triglycerides-IDL and high-density lipoprotein (HDL) in mothers of growth-restricted fetuses compared to controls (p < 0.05). In contrast, growth-restricted fetuses had significantly higher plasma concentrations of cholesterol and triglycerides transporting lipoproteins [LDL, IDL, and VLDL, (p < 0.005; all)], as well as increased VLDL particle types (large, medium and small). Significant changes in plasma concentrations of formate, histidine, isoleucine and citrate in growth-restricted fetuses were also observed. Comprehensive metabolic profiling reveals that both, mother and fetuses of pregnancies complicated with fetal growth restriction have a substantial disruption in lipid metabolism.

Genetic profile of isolated congenital diaphragmatic hernia revealed by targeted next-generation sequencing.

Abstract: BACKGROUND Congenital diaphragmatic hernia (CDH) is characterized by a defective closure of the diaphragm occurring as an isolated defect in 60% of cases. Lung size, liver herniation, and pulmonary circulation are major prognostic indices. Isolated CDH genetics is heterogeneous and poorly understood. Whether genetic lesions are also outcome determinants has never been explored. OBJECTIVES To identify isolated CDH genetic causes, to fine map the mutational burden, and to search for a correlation between the genotype and the disease severity and outcome. METHODS Targeted massively parallel sequencing of 143 human and mouse CDH causative and candidate genes in a cohort of 120 fetuses with isolated CDH and detailed outcome measures. RESULTS Pathogenic and likely pathogenic variants were identified in 10% of the cohort. These variants affect both known CDH causative genes, namely, ZFPM2, GATA4, and NR2F2, and new genes, namely, TBX1, TBX5, GATA5, and PBX1. In addition, mutation burden analysis identified LBR, CTBP2, NSD1, MMP14, MYOD1, and EYA1 as candidate genes with enrichment in rare but predicted deleterious variants. No obvious correlation between the genotype and the phenotype or short-term outcome has been found. CONCLUSION Targeted resequencing identifies a genetic cause in 10% of isolated CDH and identifies new candidate genes.

Second- to third-trimester longitudinal growth assessment for prediction of small-for-gestational age and late fetal growth restriction

Abstract: Objective Detection of fetal growth restriction (FGR) remains poor and most screening strategies rely on cross-sectional evaluation of fetal size during the third trimester. A longitudinal and individualized approach has been proposed as an alternative method of evaluation. The aim of this study was to compare second- to third-trimester longitudinal growth assessment to cross-sectional evaluation in the third trimester for the prediction of small-for-gestational age (SGA) and late FGR in low-risk singleton pregnancy. Methods This was a prospective cohort study of 2696 unselected consecutive low-risk singleton pregnancies scanned at 21 ± 2 and 32 ± 2 weeks. For cross-sectional growth assessment, abdominal circumference (AC) measurements were transformed to z-values according the 21st-INTERGROWTH standards. Longitudinal growth assessment was performed by calculating the AC z-velocity and the second- to third-trimester AC conditional growth centile. Longitudinal assessment was compared with cross-sectional assessment at 32 weeks. Association of cross-sectional and longitudinal evaluations with SGA and late FGR was assessed by logistic regression analysis. Predictive performance was determined by receiver–operating characteristics curve analysis. Result In total, 210 (7.8%) newborns were classified as SGA and 103 (3.8%) as late FGR. Neither longitudinal measurement improved the association with SGA or late FGR provided by cross-sectional evaluation of AC z-score at 32 weeks. Areas under the curves of AC z-velocity and conditional AC growth were significantly smaller than those of cross-sectional AC z-scores (P < 0.001), although AC z-velocity performed significantly better than did conditional AC growth (P < 0.001). Conclusion Longitudinal assessment of fetal growth from the second to third trimester has a low predictive capacity for SGA and late FGR in low-risk singleton pregnancy compared with cross-sectional growth evaluation. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Altered cortical development in fetuses with isolated nonsevere ventriculomegaly assessed by neurosonography

Abstract: Objectives To perform a comprehensive assessment of cortical development in fetuses with isolated nonsevere ventriculomegaly (INSVM) by neurosonography. Methods We prospectively included 40 fetuses with INSVM and 40 controls. INSVM was defined as atrial width between 10.0 and 14.9 mm without associated malformation, infection, or chromosomal abnormality. Cortical development was assessed by neurosonography at 26 and 30 weeks of gestation measuring depth of selected sulci and applying a maturation scale from 0 (no appearance) to 5 (maximally developed) of main sulci and areas. Results INSVM showed underdeveloped calcarine and parieto-occipital sulci. In addition, significant delayed maturation pattern was also observed in regions distant to ventricular system including Insula depth (controls 30.8 mm [SD 1.7] vs INSVM 31.7 mm [1.8]; P = .04), Sylvian fissure grading (>2 at 26 weeks: controls 87.5% vs INSVM 50%, P = .01), mesial area grading (>2 at 30 weeks: controls 95% vs INSVM 62.5%; P = .03), and cingulate sulcus grading (>2 at 30 weeks: controls 100% vs INSVM 80.5%; P = .01). Conclusions Fetuses with INSVM showed underdeveloped cortical maturation including also regions, where effect of ventricular dilatation is unlikely. These results suggest that in a proportion of fetuses with INSVM, ventricular dilation might be related with altered cortical architecture.

Gender-Specific Antenatal Growth Reference Charts in Monochorionic Twins.

Abstract: Objective To create antenatal gender-specific reference growth charts in uncomplicated monochorionic diamniotic twins. Materials and methods This is a prospective longitudinal study in which uncomplicated monochorionic (MC) twin pregnancies were included from 23 + 4 weeks of gestation onwards. Estimated fetal weight (EFW) and biometric parameters (biparietal diameter, head circumference, abdominal circumference, and femur length) were evaluated in both fetuses every 2 weeks using standardized methodology. Maternal and fetal complications were excluded. Charts were fitted for each biometric parameter and EFW in relation to gestational age and fetal gender using multilevel mixed models. Results The final analysis included a total of 456 ultrasound examinations in 62 MC twins, with a mean of 7 scans per pregnancy (range 5-8). The mean as well as 5th and 95th percentiles of each biometric parameter and EFW were adjusted in relation to gender and gestational age between 24 and 37 weeks of gestation. Male fetuses have higher reference values than females, and the disparity is larger in the upper centiles of the distribution. Discussion We provide gender-specific reference growth charts for MC twins. We suggest that these charts will improve prenatal MC twin assessment and surveillance, with a more accurate classification of normal or growth-restricted fetuses adjusted per sex.

Longitudinal Assessment of Abdominal Circumference versus Estimated Fetal Weight in the Detection of Late Fetal Growth Restriction.

Abstract: OBJECTIVES To perform a longitudinal assessment comparison between estimated fetal weight (EFW) and abdominal circumference (AC) in the prediction of late fetal growth restriction (FGR) as opposed to small for gestational age (SGA). PATIENTS AND METHODS A cohort of unselected singleton pregnancies scanned at 32±2 and 37±1 weeks was created. Longitudinal growth assessment by calculating the conditional AC and conditional EFW was performed, and both parameters were compared for their prediction capacity for late FGR and SGA. Conditional standards set an expected size (EFW or AC) given a first measurement performed earlier. A declining growth was defined as a conditional growth of <10th centile. RESULTS A total of 938 pregnancies were included. As expected, declining growth between 32±2 and 37±1 weeks was associated with late FGR and SGA, but the predictive capacity of both conditional AC and conditional EFW was comparably poor, with detection rates of 28% at a 10% rate of false positives for late FGR. CONCLUSIONS Longitudinal assessment of fetal growth during the third trimester has a low predictive capacity for late FGR, with no differences between conditional AC and conditional EFW.

Differential changes in myocardial performance index and its time intervals in donors and recipients of twin-to-twin transfusion syndrome before and after laser therapy.

Abstract: Objective: To evaluate left myocardial performance index (MPI) and time intervals in fetuses with twin-to-twin transfusion syndrome (TTTS) before and after laser surgery. Methods: Fifty-one fetal pairs with TTTS and 47 uncomplicated monochorionic twin pairs were included. Left ventricular isovolumetric contraction time (ICT), ejection time (ET), and isovolumetric relaxation time (IRT) were measured using conventional Doppler. Results: Recipients showed prolonged ICT (46 ± 12 vs. 31 ± 8 vs. 30 ± 5 ms; p < 0.001) and IRT (51 ± 9 vs. 43 ± 8 vs. 43 ± 5 ms; p < 0.001) and higher MPI (0.57 ± 0.12 vs. 0.47 ± 0.09 vs. 0.44 ± 0.05; p < 0.001) than donors and controls. Donors showed shorter ET than recipients and controls (157 ± 12 vs. 169 ± 10 vs. 168 ± 10 ms; p < 0.001) and higher MPI than controls (0.47 ± 0.09 vs. 0.44 ± 0.05; p = 0.006). Preoperative MPI changes were observed in all TTTS stages. Time intervals partially improved after surgery. Conclusion: Donor and recipient twins had higher MPI due to different changes in the time intervals, possibly reflecting the state of hypovolemia in the donor and hypervolemia and pressure overload in the recipient.

Fetal MRI Synthesis via Balanced Auto-Encoder Based Generative Adversarial Networks

Abstract: Machine learning approaches for image analysis require large amounts of training imaging data. As an alternative, the use of realistic synthetic data reduces the high cost associated to medical image acquisition, as well as avoiding confidentiality and privacy issues, and consequently allows the creation of public data repositories for scientific purposes. Within the context of fetal imaging, we adopt an auto-encoder based Generative Adversarial Network for synthetic fetal MRI generation. The proposed architecture features a balanced power of the discriminator against the generator during training, provides an approximate convergence measure, and enables fast and robust training to generate high-quality fetal MRI in axial, sagittal and coronal planes. We demonstrate the feasibility of the proposed approach quantitatively and qualitatively by segmenting relevant fetal structures to assess the anatomical fidelity of the simulation, and performing a clinical verisimilitude study distinguishing the simulated data from the real images. The results obtained so far are promising, which makes further investigation on this new topic worthwhile.

Preoperative Planning and Simulation Framework for Twin-to-Twin Transfusion Syndrome Fetal Surgery

Abstract: Twin-to-twin transfusion syndrome (TTTS) is a complication of monochorionic twin pregnancies in which arteriovenous vascular communications in the shared placenta lead to blood transfer between the fetuses. Selective fetoscopic laser photocoagulation of abnormal blood vessel connections has become the most effective treatment. Preoperative planning is thus an essential prerequisite to increase survival rates for severe TTTS. In this work, we present the very first TTTS fetal surgery planning and simulation framework. The placenta is segmented in both magnetic resonance imaging (MRI) and 3D ultrasound (US) via novel 3D convolutional neural networks. Likewise, the umbilical cord is extracted in MRI using 3D convolutional long short-term memory units. The detection of the placenta vascular tree is carried out through a curvature-based corner detector in MRI, and the Modified Spatial Kernelized Fuzzy C-Means with a Markov random field refinement in 3D US. The proposed TTTS planning software integrates all aforementioned algorithms to explore the intrauterine environment by simulating the fetoscope camera, determine the correct entry point, train doctors’ movements ahead of surgery, and consequently, improve the success rate and reduce the operation time. The promising results indicate potential of our TTTS planner and simulator for further assessment on clinical real surgeries.

Third-Trimester Conditional Reference Values for Longitudinal Fetal Growth Assessment.

Abstract: Objectives: The aim of this study was to derive longitudinal reference values of fetal growth (estimated fetal weight [EFW] and abdominal circumference [AC]) during the third trimester and to develop coefficients for conditional growth assessment. Patients and Methods: A prospective cohort study was conducted involving consecutive singleton pregnancies in a low-risk population for a routine third-trimester scan at 30+0-34+6 weeks and follow-up at 37+0-38+6 weeks for an additional ultrasound. Statistical analysis was based on multilevel modeling using MLwiN software. Unconditional centiles were calculated from z-values at each gestational age, and conditional centiles were calculated from z-values at a given measurement (30-34 weeks) and the expected measurement (37-38 weeks). Results: At 30-34 weeks, 8 and 9.3% of the fetuses had an unconditional EFW below the 10th and above the 90th centile, respectively. At 37-38 weeks, these figures were 10.3 and 9.3%, respectively. Regarding the unconditional AC, at the first scan, 8.9 and 9.6% had values below the 10th and above the 90th centile, while at the second scan 10.5 and 10.5% had values below the 10th and above the 90th centile, respectively. The proportion with a conditional EFW below the 10th and above the 90th centile was 10.2 and 9.4% at the second scan, respectively. For conditional AC, these figures were 10.7 and 10.3%, respectively. Conclusion: We have produced reference centiles for EFW and AC growth during the third trimester as a useful tool for quantifying growth. (Less)

Revealing Regional Associations of Cortical Folding Alterations with In Utero Ventricular Dilation Using Joint Spectral Embedding.

Abstract: Fetal ventriculomegaly (VM) is a condition with dilation of one or both lateral ventricles, and is diagnosed as an atrial diameter larger than 10 mm Evidence of altered cortical folding associated with VM has been shown in the literature However, existing studies use a holistic approach (ie, ventricle as a whole) based on diagnosis or ventricular volume, thus failing to reveal the spatially-heterogeneous association patterns between cortex and ventricle To address this issue, we develop a novel method to identify spatially fine-scaled association maps between cortical development and VM by leveraging vertex-wise correlations between the growth patterns of both ventricular and cortical surfaces in terms of area expansion and curvature information Our approach comprises multiple steps In the first step, we define a joint graph Laplacian matrix using cortex-to-ventricle correlations Next, we propose a spectral embedding of the cortex-to-ventricle graph into a common underlying space where their joint growth patterns are projected More importantly, in the joint ventricle-cortex space, the vertices of associated regions from both cortical and ventricular surfaces would lie close to each other In the final step, we perform clustering in the joint embedded space to identify associated sub-regions between cortex and ventricle Using a dataset of 25 healthy fetuses and 23 fetuses with isolated non-severe VM within the age range of 26–29 gestational weeks, our results show that the proposed approach is able to reveal clinically relevant and meaningful regional associations

Fetal cortical parcellation based on growth patterns

Abstract: Dividing the human cerebral cortex into structurally and functionally distinct regions is important in many neuroimaging studies. Although many parcellations have been created for adults, they are not applicable for fetal studies, due to dramatic differences in brain size, shape and folding between adults and fetuses, as well as dynamic growth of fetal brains. To address this issue, we propose a novel method to divide a population of fetal cortical surfaces into distinct regions based on the dynamic growth patterns of cortical properties, which indicate the underlying changes of microstructures. As microstructures determine the molecular organization and functional principles of the cortex, growth patterns enable an accurate definition of distinct regions in development, microstructure, and function. To comprehensively capture the similarities of cortical growth patterns among vertices, we construct two complementary similarity matrices. One is directly based on the growth trajectories of vertices and the other is based on the correlation profiles of vertices' growth trajectories in relation to those of reference points. Then, we nonlinearly fuse these two similarity matrices into a single one, which can better captures both their common and complementary information than by simply averaging them. Finally, based on this fused matrix, we perform spectral clustering to divide fetal cortical surfaces into distinct regions. We have applied our method on 25 normal fetuses from 26 to 29 gestational weeks and generated biologically meaningful parcellations.

71 – Neck Teratoma

Abstract: Teratomas are the most common histologic type of fetal tumors. The neck is the most common location after the sacrococcygeal area. A neck teratoma may be associated with neonatal mortality in 80% to 100% of cases if delivery is not managed properly. Prenatal diagnosis, ex utero intrapartum treatment (EXIT), and intensive neonatal care are essential to improve the management. EXIT allows adequate respiratory assistance and improves neonatal survival in cases of tracheal obstruction. Early resection is the treatment of choice.

69 – Facial Dysmorphism

Abstract: Facial dysmorphism includes all abnormalities of facial features that are usually associated with syndromic conditions. The objectives of this chapter are first to describe the systematic evaluation of the fetal face using multiplanar evaluation by ultrasound (US), and second to review the anomalies at this level and the conditions related to them. Detection is challenging considering the large phenotypic variability in human face. Thus isolated facial abnormalities must be evaluated, taking into account the facial characteristics of parents. Abnormalities that are included in this chapter are: 1. a sloping forehead that is due to a severe hypoplasia of frontal lobes that occurs in microcephaly; 2. frontal bossing, prominence of the frontal bone due to a premature closure of cranial sutures, which can be found in Apert syndrome, achondroplasia, and thanatophoric dysplasia; 3. hemifacial microsomia, an asymmetric hypoplasia of facial structures (hemifacial microsomia, cleft lip/palate, microphthalmia, external ear anomalies), mainly related to oculoauriculovertebral spectrum, which is a rare condition with poor prognosis including mental retardation and high birth mortality of 20%; and 4. otocephaly, a severe and lethal malformation characterized by an absence or hypoplasia of the mandible, aglossia, proximity of the temporal bones, and abnormal horizontal position of the ears. It can be found isolated or associated with anomalies such as holoprosencephaly, neural tube defects, cephalocele, midline proboscis, tracheoesophageal fistula, cardiac anomalies, and adrenal hypoplasia.

66 – Orbital Defects: Hypertelorism and Hypotelorism

Abstract: Orbital defects are rarely diagnosed in the fetus. However, these anomalies are highly associated with chromosomal and nonchromosomal defects. This chapter aims to describe the systematic evaluation of fetal orbits using ultrasound (US) to identify most common anomalies. Hypertelorism, which is increased interocular distance, is rarely associated with chromosomal abnormalities but is highly associated with nonchromosomal syndromes. Isolated hypertelorism is very rare; therefore an anatomic scan and karyotype analysis are necessary in order to detect malformations or chromosomal abnormalities. The prognosis depends on the underlying syndrome or associated anomalies. Hypotelorism, which is decreased interocular distance, is highly associated with chromosomal abnormalities, most commonly diagnosed is trisomy 13. In most cases it is associated with holoprosencephaly. Isolated hypotelorism is exceptional, therefore once it is diagnosed, a karyotype and anatomic scan, mainly focused on central nervous system evaluation, should be performed in order to detect holoprosencephaly or other associated malformations. General prognosis is poor due to a high mortality rate in cases associated with trisomy 13 and severe mental retardation in those cases associated with holoprosencephaly.