Showing papers by "Elisenda Eixarch published in 2019"

Premature placental aging in term small-for-gestational-age and growth-restricted fetuses

Abstract: OBJECTIVE To perform a comprehensive assessment of the placental aging process in small term fetuses classified as being small-for-gestational age (SGA) or having fetal growth restriction (FGR) through analysis of senescence and apoptosis markers. METHODS This was a prospective nested case-control study of singleton pregnancies delivered at term, including 21 control pregnancies with normally grown fetuses and 36 with a small fetus classified as SGA (birth weight between the 3rd and 9th percentiles and normal fetoplacental Doppler; n = 18) or FGR (birth weight < 3rd percentile and/or abnormal cerebroplacental ratio and/or uterine artery Doppler; n = 18). Telomerase activity, telomere length (quantified by comparing the amount of amplification product for the telomere sequence (T) to that of a single copy of the gene 36B4 (S)) and RNA expression of senescence (Sirtuins 1, 3 and 6) and apoptosis (p53, p21, BAX and Caspases 3 and 9) markers (analyzed using the 2-ΔΔCt method) were determined in placental samples collected at birth and compared between the three groups. RESULTS Compared to pregnancies with a normally grown fetus, both SGA and FGR pregnancies presented signs of accelerated placental aging, including lower telomerase activity (mean ± SD, 12.8 ± 6.6% in controls vs 7.98 ± 4.2% in SGA vs 7.79 ± 4.6% in FGR; P = 0.008), shorter telomeres (mean ± SD T/S ratio, 1.20 ± 0.6 in controls vs 1.08 ± 0.9 in SGA vs 0.66 ± 0.5 in FGR; P = 0.047) and reduced Sirtuin-1 RNA expression (mean ± SD 2-ΔΔCt , 1.55 ± 0.8 in controls vs 0.91 ± 0.8 in SGA vs 0.63 ± 0.5 in FGR; P = 0.001) together with increased p53 RNA expression (median (interquartile range) 2-ΔΔCt , 1.07 (0.3-3.3) in controls vs 5.39 (0.6-15) in SGA vs 3.75 (0.9-7.8) in FGR; P = 0.040). FGR cases presented signs of apoptosis, with increased Caspase-3 RNA levels (median (interquartile range) 2-ΔΔCt , 0.94 (0.7-1.7) in controls vs 3.98 (0.9-31) in FGR; P = 0.031) and Caspase-9 RNA levels (median (interquartile range) 2-ΔΔCt , 1.21 (0.6-4.0) in controls vs 3.87 (1.5-9.0) in FGR; P = 0.037) compared with controls. In addition, Sirtuin-1 RNA expression, telomerase activity, telomere length and Caspase-3 activity showed significant linear trends across groups as severity of the condition increased. CONCLUSIONS Accelerated placental aging was observed in both clinical forms of late-onset fetal smallness (SGA and FGR), supporting a common pathophysiology and challenging the concept of SGA fetuses being constitutionally small. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Distinctive patterns of placental lesions in pre-eclampsia vs small-for-gestational age and their association with fetoplacental Doppler.

Abstract: OBJECTIVES To describe placental histopathological findings in a large cohort of pregnancies complicated by pre-eclampsia (PE) and/or small-for-gestational age (SGA), and to investigate their association with fetoplacental Doppler parameters. METHODS This was a prospective observational study of normotensive pregnancies with SGA (defined as birth weight 95th centile or MCA-PI or CPR was < 5th centile. Placental lesions were categorized as vascular (maternal or fetal side), immunoinflammatory or other, according to the 2014 Amsterdam Placental Workshop Group Consensus Statement. Comparison between the study groups was performed using univariate and multiple regression analysis, and logistic regression was used to determine the relationship between abnormal Doppler parameters and placental lesions. RESULTS Maternal-side vascular lesions were significantly more common in PE pregnancies with SGA than in the other groups (PE + SGA, 73% vs PE, 46% vs SGA, 38% vs controls, 31%; P = 0.01) and included mainly two types of lesion: developmental (PE + SGA, 13% vs PE, 5% vs SGA, 3% vs controls, 1.5%; P < 0.001) and malperfusion (PE + SGA, 70% vs PE, 39% vs SGA, 32% vs controls, 25%; P = 0.001). In contrast, the incidence of fetal-side developmental lesions was significantly higher in normotensive SGA pregnancies than in controls and PE pregnancies (PE + SGA, 0% vs PE, 3% vs SGA, 8% vs controls, 2%; P = 0.001). All cases displayed a lower prevalence of infectious lesions than did controls, with the highest prevalence of immune lesions observed in pregnancies with both PE and SGA (PE + SGA, 18% vs PE, 8% vs SGA, 10% vs controls, 9%; P = 0.001). All fetoplacental Doppler parameters evaluated were associated with maternal-side vascular lesions, mainly malperfusion (mean UtA-PI: odds ratio (OR), 2.45 (95% CI, 1.51-3.97); UA-PI: OR, 2.05 (95% CI, 1.02-4.47); MCA-PI: OR, 2.75 (95% CI, 1.40-5.42); CPR: OR, 1.75 (95% CI, 1.04-2.95)). This association was evident mainly in the normotensive SGA group, being non-significant in controls or PE pregnancies without SGA. No significant associations were observed between fetoplacental Doppler parameters and other placental lesions in any of the study groups. CONCLUSIONS PE and SGA are associated with different patterns of placental histopathological lesions in accordance with the clinical manifestation of the placental disorder (maternal vs fetal). Fetoplacental Doppler findings show an association with placental malperfusion lesions on the maternal side, supporting the use of abnormal Doppler as a surrogate for placental insufficiency. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Prenatal adverse environment is associated with epigenetic age deceleration at birth and hypomethylation at the hypoxia-responsive EP300 gene

Abstract: Obstetric complications have long been retrospectively associated with a wide range of short- and long-term health consequences, including neurodevelopmental alterations such as those observed in schizophrenia and other psychiatric disorders. However, prospective studies assessing fetal well-being during pregnancy tend to focus on perinatal complications as the final outcome of interest, while there is a scarcity of postnatal follow-up studies. In this study, the cerebroplacental ratio (CPR), a hemodynamic parameter reflecting fetal adaptation to hypoxic conditions, was analyzed in a sample of monozygotic monochorionic twins (60 subjects), part of them with prenatal complications, with regard to (i) epigenetic age acceleration, and (ii) DNA methylation at genes included in the polygenic risk score (PRS) for schizophrenia, and highly expressed in placental tissue. Decreased CPR measured during the third trimester was associated with epigenetic age deceleration (β = 0.21, t = 3.362, p = 0.002). Exploration of DNA methylation at placentally expressed genes of the PRS for schizophrenia revealed methylation at cg06793497 (EP300 gene) to be associated with CPR (β = 0.021, t = 4.385; p = 0.00008, FDR-adjusted p = 0.11). This association was reinforced by means of an intrapair analysis in monozygotic twins discordant for prenatal suffering (β = 0.027, t = 3.924, p = 0.001). Prenatal adverse environment during the third trimester of pregnancy is associated with both (i) developmental immaturity in terms of epigenetic age, and (ii) decreased CpG-specific methylation in a gene involved in hypoxia response and schizophrenia genetic liability.

Fetal cortical surface atlas parcellation based on growth patterns.

Abstract: Defining anatomically and functionally meaningful parcellation maps on cortical surface atlases is of great importance in surface-based neuroimaging analysis. The conventional cortical parcellation maps are typically defined based on anatomical cortical folding landmarks in adult surface atlases. However, they are not suitable for fetal brain studies, due to dramatic differences in brain size, shape, and properties between adults and fetuses. To address this issue, we propose a novel data-driven method for parcellation of fetal cortical surface atlases into distinct regions based on the dynamic "growth patterns" of cortical properties (e.g., surface area) from a population of fetuses. Our motivation is that the growth patterns of cortical properties indicate the underlying rapid changes of microstructures, which determine the molecular and functional principles of the cortex. Thus, growth patterns are well suitable for defining distinct cortical regions in development, structure, 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 a set of reference points. Then, we nonlinearly fuse these two similarity matrices into a single one, which can better capture both their common and complementary information than by simply averaging them. Finally, based on this fused similarity matrix, we perform spectral clustering to divide the fetal cortical surface atlases into distinct regions. By applying our method on 25 normal fetuses from 26 to 29 gestational weeks, we construct age-specific fetal cortical surface atlases equipped with biologically meaningful parcellation maps based on cortical growth patterns. Importantly, our generated parcellation maps reveal spatially contiguous, hierarchical and bilaterally relatively symmetric patterns of fetal cortical surface development.

Global and Regional Changes in Cortical Development Assessed by MRI in Fetuses with Isolated Nonsevere Ventriculomegaly Correlate with Neonatal Neurobehavior.

Abstract: BACKGROUND AND PURPOSE: Fetuses with isolated nonsevere ventriculomegaly (INSVM) are at risk of presenting neurodevelopmental delay. However, the currently used clinical parameters are insufficient to select cases with high risk and determine whether subtle changes in brain development are present and might be a risk factor. The aim of this study was to perform a comprehensive evaluation of cortical development in INSVM by magnetic resonance (MR) imaging and assess its association with neonatal neurobehavior. MATERIALS AND METHODS: Thirty-two INSVM fetuses and 29 healthy controls between 26–28 weeks of gestation were evaluated using MR imaging. We compared sulci and fissure depth, cortical maturation grading of specific areas and sulci and volumes of different brain regions obtained from 3D brain reconstruction of cases and controls. Neonatal outcome was assessed by using the Neonatal Behavioral Assessment Scale at a mean of 4 ± 2 weeks after birth. RESULTS: Fetuses with INSVM showed less profound and underdeveloped sulcation, including the Sylvian fissure (mean depth: controls 16.8 ± 1.9 mm, versus INSVM 16.0 ± 1.6 mm; P = .01), and reduced global cortical grading (mean score: controls 42.9 ± 10.2 mm, versus INSVM: 37.8 ± 9.9 mm; P = .01). Fetuses with isolated nonsevere ventriculomegaly showed a mean global increase of gray matter volume (controls, 276.8 ± 46.0 ×10 mm3, versus INSVM 277.5 ± 49.3 ×10 mm3, P = .01), but decreased mean cortical volume in the frontal lobe (left: controls, 53.2 ± 8.8 ×10 mm3, versus INSVM 52.4 ± 5.4 ×10 mm3; P = CONCLUSIONS: INSVM fetuses showed differences in cortical development, including regions far from the lateral ventricles, that are associated with neonatal neurobehavior. These results suggest the possible use of these parameters to identify cases at higher risk of altered neurodevelopment.

Multicenter prospective clinical study to evaluate children short-term neurodevelopmental outcome in congenital heart disease (children NEURO-HEART): study protocol

Abstract: Congenital heart disease (CHD) is the most prevalent congenital malformation affecting 1 in 100 newborns. While advances in early diagnosis and postnatal management have increased survival in CHD children, worrying long-term outcomes, particularly neurodevelopmental disability, have emerged as a key prognostic factor in the counseling of these pregnancies. Eligible participants are women presenting at 20 to < 37 weeks of gestation carrying a fetus with CHD. Maternal/neonatal recordings are performed at regular intervals, from the fetal period to 24 months of age, and include: placental and fetal hemodynamics, fetal brain magnetic resonance imaging (MRI), functional echocardiography, cerebral oxymetry, electroencephalography and serum neurological and cardiac biomarkers. Neurodevelopmental assessment is planned at 12 months of age using the ages and stages questionnaire (ASQ) and at 24 months of age with the Bayley-III test. Target recruitment is at least 150 cases classified in three groups according to three main severe CHD groups: transposition of great arteries (TGA), Tetralogy of Fallot (TOF) and Left Ventricular Outflow Tract Obstruction (LVOTO). The results of NEURO-HEART study will provide the most comprehensive knowledge until date of children’s neurologic prognosis in CHD and will have the potential for developing future clinical decisive tools and improving preventive strategies in CHD. NCT02996630 , on 4th December 2016 (retrospectively registered).

Vision Based Robot Assistance in TTTS Fetal Surgery

Abstract: This paper presents an accurate and robust tracking vision algorithm for Fetoscopic Laser Photo-coagulation (FLP) surgery for Twin-Twin Transfusion Syndrome (TTTS). The aim of the proposed method is to assist surgeons during anastomosis localization, coagulation and review using a tele-operated robotic system. The algorithm computes the relative position of the fetoscope tool tip with respect to the placenta, via local vascular structure registration.The algorithm uses image features (local superficial vascular structures of the placenta’s surface) to automatically match consecutive fetoscopic images. It is composed of three sequential steps: image processing (filtering, binarization and vascular structures segmentation); relevant Points Of Interest (POIs) seletion; and image registration between consecutive images.The algorithm has to deal with the low quality of fetoscopic images, the liquid and dirty environment inside the placenta jointly with the thin diameter of the fetoscope optics and low amount of environment light reduces the image quality. The obtained images are blurred, noisy and with very poor color components.The tracking system has been tested using real video sequences of FLP surgery for TTTS. The computational performance enables real time tracking, locally guiding the robot over the placenta’s surface with enough accuracy.

Automatic Segmentation Of the Placenta and its Peripheral Vasculature in Volumetric Ultrasound for TTTS Fetal Surgery

Abstract: Twin-to-twin transfusion syndrome is a serious condition that can affect pregnancies when identical twins share the placenta. In these cases, abnormal placental vessel connections (anastomoses) cause an uneven blood distribution between the babies. Ultrasound (US) enormously facilitates the assessment of these cases, but placenta segmentation is still a challenging task due to artifacts and high variability in its position, orientation, shape and appearance. We propose for the first time a fully-automated framework to achieve an accurate segmentation of the placenta and its peripheral vasculature in 3D US. A conditional Generative Adversarial Network is used to automatically identify the placenta. Afterwards, the entire vasculature is extracted using Modified Spatial Kernelized Fuzzy C-Means and Markov Random Fields. The method is tested on singleton and twin pregnancies from 15 to 38 gestational weeks, achieving a mean Dice coefficient of 0.75 ± 0.12 and 0.70 ± 0.14 for the placenta and its vessels.

Measurement of fetal cerebral blood flow of the lamb fetus in utero

Abstract: The feasibility of in utero measurement of cerebral blood flow diffuse correlation spectroscopy was demonstrated in lamb fetuses and compared with measurements outside the uterus.