Publications by authors named "Fatima Crispi"

137 Publications

Agreement between commercially available ELISA and in-house Luminex SARS-CoV-2 antibody immunoassays.

Sci Rep 2021 09 23;11(1):18984. Epub 2021 Sep 23.

ISGlobal, Hospital Clínic, Universitat de Barcelona, Barcelona, Catalonia, Spain.

Serological diagnostic of the severe respiratory distress syndrome coronavirus 2 (SARS-CoV-2) is a valuable tool for the determination of immunity and surveillance of exposure to the virus. In the context of an ongoing pandemic, it is essential to externally validate widely used tests to assure correct diagnostics and epidemiological estimations. We evaluated the performance of the COVID-19 ELISA IgG and the COVID-19 ELISA IgM/A (Vircell, S.L.) against a highly specific and sensitive in-house Luminex immunoassay in a set of samples from pregnant women and cord blood. The agreement between both assays was moderate to high for IgG but low for IgM/A. Considering seropositivity by either IgG and/or IgM/A, the technical performance of the ELISA was highly imbalanced, with 96% sensitivity at the expense of 22% specificity. As for the clinical performance, the negative predictive value reached 87% while the positive predictive value was 51%. Our results stress the need for highly specific and sensitive assays and external validation of diagnostic tests with different sets of samples to avoid the clinical, epidemiological and personal disturbances derived from serological misdiagnosis.
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http://dx.doi.org/10.1038/s41598-021-98296-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460676PMC
September 2021

Development of standard definitions and grading for Maternal and Fetal Adverse Event Terminology.

Prenat Diagn 2021 Sep 22. Epub 2021 Sep 22.

Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK.

Objective: Adverse event (AE) monitoring is central to assessing therapeutic safety. The lack of a comprehensive framework to define and grade maternal and fetal AEs in pregnancy trials severely limits understanding risks in pregnant women. We created AE terminology to improve safety monitoring for developing pregnancy drugs, devices and interventions.

Method: Existing severity grading for pregnant AEs and definitions/indicators of 'severe' and 'life-threatening' conditions relevant to maternal and fetal clinical trials were identified through a literature search. An international multidisciplinary group identified and filled gaps in definitions and severity grading using Medical Dictionary for Regulatory Activities (MedDRA) terms and severity grading criteria based on Common Terminology Criteria for Adverse Event (CTCAE) generic structure. The draft criteria underwent two rounds of a modified Delphi process with international fetal therapy, obstetric, neonatal, industry experts, patients and patient representatives.

Results: Fetal AEs were defined as being diagnosable in utero with potential to harm the fetus, and were integrated into MedDRA. AE severity was graded independently for the pregnant woman and her fetus. Maternal (n = 12) and fetal (n = 19) AE definitions and severity grading criteria were developed and ratified by consensus.

Conclusions: This Maternal and Fetal AE Terminology version 1.0 allows systematic consistent AE assessment in pregnancy trials to improve safety.
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http://dx.doi.org/10.1002/pd.6047DOI Listing
September 2021

Left myocardial performance index in monochorionic diamniotic twin pairs complicated by selective fetal growth restriction with abnormal umbilical artery Doppler.

Prenat Diagn 2021 Aug 26. Epub 2021 Aug 26.

BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Deu), IDIBAPS, University of Barcelona, and Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain.

Objective: To evaluate left myocardial performance index (MPI) and its time intervals in monochorionic diamniotic (MCDA) twin pairs complicated by selective fetal growth restriction (sFGR) with abnormal (persistent -type II- or intermittent -type III- absent or reversed end-diastolic flow) umbilical artery Doppler.

Methods: Retrospective study including 16 MCDA twin pairs with sFGR type II, 26 MCDA twin pairs with sFGR type III and 42 gestational age-matched uncomplicated MCDA twin pairs in a single tertiary center. Left isovolumetric contraction time (ICT), ejection time (ET), and isovolumetric relaxation time (IRT) were measured and MPI calculated by conventional Doppler at diagnosis of sFGR.

Results: In sFGR type II, the smaller twin had shorter ET and prolonged IRT and MPI, while the larger twin showed prolonged ICT and MPI as compared to uncomplicated MCDA twins. In sFGR type III, the smaller twin had shorter ICT and ET, while the larger twin showed prolonged ICT, IRT, and MPI in comparison to controls.

Conclusion: A differential pattern of MPI time intervals could be observed in MCDA twins with sFGR type II and III. All twins had echocardiographic signs of pressure/volume overload, except the smaller twin type III with shorter systolic times probably reflecting reduced volume load.
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http://dx.doi.org/10.1002/pd.6037DOI Listing
August 2021

SARS-CoV-2 RNA and antibody detection in breast milk from a prospective multicentre study in Spain.

Arch Dis Child Fetal Neonatal Ed 2021 Aug 20. Epub 2021 Aug 20.

Department of Biotechnology, Institute of Agrochemistry and Food Technology-National Research Council (IATA-CSIC), Paterna, Valencia, Spain

Objectives: To develop and validate a specific protocol for SARS-CoV-2 detection in breast milk matrix and to determine the impact of maternal SARS-CoV-2 infection on the presence, concentration and persistence of specific SARS-CoV-2 antibodies.

Design And Patients: This is a prospective, multicentre longitudinal study (April-December 2020) in 60 mothers with SARS-CoV-2 infection and/or who have recovered from COVID-19. A control group of 13 women before the pandemic were also included.

Setting: Seven health centres from different provinces in Spain.

Main Outcome Measures: Presence of SARS-CoV-2 RNA in breast milk, targeting the N1 region of the nucleocapsid gene and the envelope (E) gene; presence and levels of SARS-CoV-2-specific immunoglobulins (Igs)-IgA, IgG and IgM-in breast milk samples from patients with COVID-19.

Results: All breast milk samples showed negative results for presence of SARS-CoV-2 RNA. We observed high intraindividual and interindividual variability in the antibody response to the receptor-binding domain of the SARS-CoV-2 spike protein for each of the three isotypes IgA, IgM and IgG. Main Protease (MPro) domain antibodies were also detected in milk. 82.9% (58 of 70) of milk samples were positive for at least one of the three antibody isotypes, with 52.9% of these positive for all three Igs. Positivity rate for IgA was relatively stable over time (65.2%-87.5%), whereas it raised continuously for IgG (from 47.8% for the first 10 days to 87.5% from day 41 up to day 206 post-PCR confirmation).

Conclusions: Our study confirms the safety of breast feeding and highlights the relevance of virus-specific SARS-CoV-2 antibody transfer. This study provides crucial data to support official breastfeeding recommendations based on scientific evidence. NCT04768244.
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http://dx.doi.org/10.1136/archdischild-2021-322463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384494PMC
August 2021

Extracellular vesicle-associated miRNAs are an adaptive response to gestational diabetes mellitus.

J Transl Med 2021 08 20;19(1):360. Epub 2021 Aug 20.

Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women's Hospital, Faculty of Medicine, The University of Queensland, Building 71/918, Herston, QLD, 4029, Australia.

Background: Gestational diabetes mellitus (GDM) is a serious public health issue affecting 9-15% of all pregnancies worldwide. Recently, it has been suggested that extracellular vesicles (EVs) play a role throughout gestation, including mediating a placental response to hyperglycaemia. Here, we investigated the EV-associated miRNA profile across gestation in GDM, assessed their utility in developing accurate, multivariate classification models, and determined the signaling pathways in skeletal muscle proteome associated with the changes in the EV miRNA profile.

Methods: Discovery: A retrospective, case-control study design was used to identify EV-associated miRNAs that vary across pregnancy and clinical status (i.e. GDM or Normal Glucose Tolerance, NGT). EVs were isolated from maternal plasma obtained at early, mid and late gestation (n = 29) and small RNA sequencing was performed. Validation: A longitudinal study design was used to quantify expression of selected miRNAs. EV miRNAs were quantified by real-time PCR (cases = 8, control = 14, samples at three times during pregnancy) and their individual and combined classification efficiencies were evaluated. Quantitative, data-independent acquisition mass spectrometry was use to establish the protein profile in skeletal muscle biopsies from normal and GDM.

Results: A total of 2822 miRNAs were analyzed using a small RNA library, and a total of 563 miRNAs that significantly changed (p < 0.05) across gestation and 101 miRNAs were significantly changed between NGT and GDM. Analysis of the miRNA changes in NGT and GDM separately identified a total of 256 (NGT-group), and 302 (GDM-group) miRNAs that change across gestation. A multivariate classification model was developed, based on the quantitative expression of EV-associated miRNAs, and the accuracy to correctly assign samples was > 90%. We identified a set of proteins in skeletal muscle biopsies from women with GDM associated with JAK-STAT signaling which could be targeted by the miRNA-92a-3p within circulating EVs. Interestingly, overexpression of miRNA-92a-3p in primary skeletal muscle cells increase insulin-stimulated glucose uptake.

Conclusions: During early pregnancy, differently-expressed, EV-associated miRNAs may be of clinical utility in identifying presymptomatic women who will subsequently develop GDM later in gestation. We suggest that miRNA-92a-3p within EVs might be a protected mechanism to increase skeletal muscle insulin sensitivity in GDM.
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http://dx.doi.org/10.1186/s12967-021-02999-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377872PMC
August 2021

Analysis of maturation features in fetal brain ultrasound via artificial intelligence for the estimation of gestational age.

Am J Obstet Gynecol MFM 2021 Aug 14;3(6):100462. Epub 2021 Aug 14.

BCNatal, Barcelona Center for Maternal-Fetal and Neonatal Medicine, Fetal Medicine Research Center (Hospital Clínic and Hospital Sant Joan de Déu), Institut D'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain (Dr Burgos-Artizzu, Mr Coronado-Gutiérrez, and Drs Valenzuela-Alcaraz, Vellvé, Eixarch, Crispi, Bonet-Carne, Bennasar, and Gratacos); Institut D'Investigacions Biomèdiques August Pi i Sunyer, IDIBAPS, Barcelona, Spain (Drs Eixarch, Crispi, Bonet-Carne, Bennasar, and Gratacos); Center for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Madrid, Spain (Drs Eixarch, Crispi, Bonet-Carne, and Gratacos).

Background: Optimal prenatal care relies on accurate gestational age dating. After the first trimester, the accuracy of current gestational age estimation methods diminishes with increasing gestational age. Considering that, in many countries, access to first trimester crown rump length is still difficult owing to late booking, infrequent access to prenatal care, and unavailability of early ultrasound examination, the development of accurate methods for gestational age estimation in the second and third trimester of pregnancy remains an unsolved challenge in fetal medicine.

Objective: This study aimed to evaluate the performance of an artificial intelligence method based on automated analysis of fetal brain morphology on standard cranial ultrasound sections to estimate the gestational age in second and third trimester fetuses compared with the current formulas using standard fetal biometry.

Study Design: Standard transthalamic axial plane images from a total of 1394 patients undergoing routine fetal ultrasound were used to develop an artificial intelligence method to automatically estimate gestational age from the analysis of fetal brain information. We compared its performance-as stand alone or in combination with fetal biometric parameters-against 4 currently used fetal biometry formulas on a series of 3065 scans from 1992 patients undergoing second (n=1761) or third trimester (n=1298) routine ultrasound, with known gestational age estimated from crown rump length in the first trimester.

Results: Overall, 95% confidence interval of the error in gestational age estimation was 14.2 days for the artificial intelligence method alone and 11.0 when used in combination with fetal biometric parameters, compared with 12.9 days of the best method using standard biometrics alone. In the third trimester, the lower 95% confidence interval errors were 14.3 days for artificial intelligence in combination with biometric parameters and 17 days for fetal biometrics, whereas in the second trimester, the 95% confidence interval error was 6.7 and 7, respectively. The performance differences were even larger in the small-for-gestational-age fetuses group (14.8 and 18.5, respectively).

Conclusion: An automated artificial intelligence method using standard sonographic fetal planes yielded similar or lower error in gestational age estimation compared with fetal biometric parameters, especially in the third trimester. These results support further research to improve the performance of these methods in larger studies.
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http://dx.doi.org/10.1016/j.ajogmf.2021.100462DOI Listing
August 2021

Exercise Capacity in Young Adults Born Small for Gestational Age.

JAMA Cardiol 2021 Jul 21. Epub 2021 Jul 21.

Fetal Medicine Research Center, BCNatal-Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu), Institut Clínic de Ginecologia Obstetricia i Neonatologia, Universitat de Barcelona, Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain.

Importance: Being born small for gestational age (SGA), approximately 10% of all births, is associated with increased risk of cardiovascular mortality in adulthood, but mechanistic pathways are unclear. Cardiac remodeling and dysfunction occur in fetuses SGA and children born SGA, but it is uncertain whether and how these changes persist into adulthood.

Objective: To evaluate baseline cardiac function and structure and exercise capacity in young adults born SGA.

Design, Setting, And Participants: This cohort study conducted from January 2015 to January 2018 assessed a perinatal cohort born at a tertiary university hospital in Spain between 1975 and 1995. Participants included 158 randomly selected young adults aged 20 to 40 years born SGA (birth weight below the 10th centile) or with intrauterine growth within standard reference ranges (controls). Participants provided their medical history, filled out questionnaires regarding smoking and physical activity habits, and underwent incremental cardiopulmonary exercise stress testing, cardiac magnetic resonance imaging, and a physical examination, with blood pressure, glucose level, and lipid profile data collected.

Exposure: Being born SGA.

Main Outcomes And Measures: Cardiac structure and function assessed by cardiac magnetic resonance imaging, including biventricular end-diastolic shape analysis. Exercise capacity assessed by incremental exercise stress testing.

Results: This cohort study included 81 adults born SGA (median age at study, 34.4 years [IQR, 30.8-36.7 years]; 43 women [53%]) and 77 control participants (median age at study, 33.7 years [interquartile range (IQR), 31.0-37.1 years]; 33 women [43%]). All participants were of White race/ethnicity and underwent imaging, whereas 127 participants (80% of the cohort; 66 control participants and 61 adults born SGA) completed the exercise test. Cardiac shape analysis showed minor changes at rest in right ventricular geometry (DeLong test z, 2.2098; P = .02) with preserved cardiac function in individuals born SGA. However, compared with controls, adults born SGA had lower exercise capacity, with decreased maximal workload (mean [SD], 180 [62] W vs 214 [60] W; P = .006) and oxygen consumption (median, 26.0 mL/min/kg [IQR, 21.5-33.5 mL/min/kg vs 29.5 mL/min/kg [IQR, 24.0-36.0 mL/min/kg]; P = .02). Exercise capacity was significantly correlated with left ventricular mass (ρ = 0.7934; P < .001).

Conclusions And Relevance: This cohort of young adults born SGA had markedly reduced exercise capacity. These results support further research to clarify the causes of impaired exercise capacity and the potential association with increased cardiovascular mortality among adults born SGA.
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http://dx.doi.org/10.1001/jamacardio.2021.2537DOI Listing
July 2021

Paired maternal and fetal metabolomics reveal a differential fingerprint in preeclampsia versus fetal growth restriction.

Sci Rep 2021 07 13;11(1):14422. Epub 2021 Jul 13.

BCNatal|Fetal Medicine Research Center (Hospital Clínic and Hospital Sant Joan de Déu), Institut D'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.

Preeclampsia (PE) and fetal growth restriction (FGR) are both placenta-mediated disorders with unclear pathogenesis. Metabolomics of maternal and fetal pairs might help in understanding these disorders. We recruited prospectively pregnancies with normotensive FGR, PE without FGR, PE + FGR and uncomplicated pregnancies as controls. Nuclear magnetic resonance metabolomics were applied on plasma samples collected at delivery. Advanced lipoprotein, glycoprotein and choline profiling was performed using the Liposcale test. The software package Dolphin was used to quantify 24 low-molecular-weight metabolites. Statistical analysis comprised the comparison between each group of complicated pregnancies versus controls, considering 5% false discovery rate correction. Lipid profiles were altered in accordance with the clinical presentation of these disorders. Specifically, PE mothers and FGR fetuses (with or without FGR or PE, respectively) exhibited a pro-atherogenic and pro-inflammatory profile, with higher concentrations of triglycerides, remnant cholesterol (VLDL, IDL) and Glc/GalNAc-linked and lipid-associated glycoproteins compared to controls. Low-molecular-weight metabolites were extensively disturbed in preeclamptic mothers, with or without FGR. Growth restricted fetuses in the presence of PE showed changes in low-molecular-weight metabolites similar to their mothers (increased creatine and creatinine), while normotensive FGR fetuses presented scarce differences, consistent with undernutrition (lower isoleucine). Further research is warranted to clarify maternal and fetal adaptations to PE and FGR.
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http://dx.doi.org/10.1038/s41598-021-93936-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277896PMC
July 2021

Automated Pattern Recognition in Whole-Cardiac Cycle Echocardiographic Data: Capturing Functional Phenotypes with Machine Learning.

J Am Soc Echocardiogr 2021 Jul 7. Epub 2021 Jul 7.

Institute of Biomedical Research August Pi Sunyer, Barcelona, Spain; ICREA, Barcelona, Spain.

Background: Echocardiography provides complex data on cardiac function that can be integrated into patterns of dysfunction related to the severity of cardiac disease. The aim of this study was to demonstrate the feasibility of applying machine learning (ML) to automate the integration of echocardiographic data from the whole cardiac cycle and to automatically recognize patterns in velocity profiles and deformation curves, allowing the identification of functional phenotypes.

Methods: Echocardiography was performed in 189 clinically managed patients with hypertension and 97 healthy individuals without hypertension. Speckle-tracking analysis of the left ventricle and atrium was performed, and deformation curves were extracted. Aortic and mitral blood pool pulsed-wave Doppler and mitral annular tissue pulsed-wave Doppler velocity profiles were obtained. These whole-cardiac cycle deformation and velocity curves were used as ML input. Unsupervised ML was used to create a representation of patients with hypertension in a virtual space in which patients are positioned on the basis of the similarity of their integrated whole-cardiac cycle echocardiography data. Regression methods were used to explore patterns of echocardiographic traces within this virtual ML-derived space, while clustering was used to define phenogroups.

Results: The algorithm captured different patterns in tissue and blood-pool velocity and deformation profiles and integrated the findings, yielding phenotypes related to normal cardiac function and others to advanced remodeling associated with pressure overload in hypertension. The addition of individuals without hypertension into the ML-derived space confirmed the interpretation of normal and remodeled phenotypes.

Conclusions: ML-based pattern recognition is feasible from echocardiographic data obtained during the whole cardiac cycle. Automated algorithms can consistently capture patterns in velocity and deformation data and, on the basis of these patterns, group patients into interpretable, clinically comprehensive phenogroups that describe structural and functional remodeling. Automated pattern recognition may potentially aid interpretation of imaging data and diagnostic accuracy.
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http://dx.doi.org/10.1016/j.echo.2021.06.014DOI Listing
July 2021

Comprehensive assessment of myocardial remodeling in ischemic heart disease by synchrotron propagation based X-ray phase contrast imaging.

Sci Rep 2021 07 7;11(1):14020. Epub 2021 Jul 7.

University of Zagreb School of Medicine, Department of Cardiovascular Diseases, University Hospital Centre Zagreb, Kispaticeva 12, 10000, Zagreb, Croatia.

Cardiovascular research is in an ongoing quest for a superior imaging method to integrate gross-anatomical information with microanatomy, combined with quantifiable parameters of cardiac structure. In recent years, synchrotron radiation-based X-ray Phase Contrast Imaging (X-PCI) has been extensively used to characterize soft tissue in detail. The objective was to use X-PCI to comprehensively quantify ischemic remodeling of different myocardial structures, from cell to organ level, in a rat model of myocardial infarction. Myocardial infarction-induced remodeling was recreated in a well-established rodent model. Ex vivo rodent hearts were imaged by propagation based X-PCI using two configurations resulting in 5.8 µm and 0.65 µm effective pixel size images. The acquired datasets were used for a comprehensive assessment of macrostructural changes including the whole heart and vascular tree morphology, and quantification of left ventricular myocardial thickness, mass, volume, and organization. On the meso-scale, tissue characteristics were explored and compared with histopathological methods, while microstructural changes were quantified by segmentation of cardiomyocytes and calculation of cross-sectional areas. Propagation based X-PCI provides detailed visualization and quantification of morphological changes on whole organ, tissue, vascular as well as individual cellular level of the ex vivo heart, with a single, non-destructive 3D imaging modality.
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http://dx.doi.org/10.1038/s41598-021-93054-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263575PMC
July 2021

Prescriptive standards of echocardiographic morphometric and functional parameters in uncomplicated monochorionic diamniotic fetuses.

Prenat Diagn 2021 Jun 27. Epub 2021 Jun 27.

Fetal Medicine Research Center, BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Deu), Barcelona, Spain.

Objective: To create prescriptive standards of cardiac morphometric and functional parameters in a cohort of uncomplicated monochorionic diamniotic (MCDA) twins.

Method: Fetal echocardiography was performed in a cohort of uncomplicated monochorionic twin fetuses scanned longitudinally, including comprehensive morphometric and functional parameters, using 2-D imaging, M-mode and conventional Doppler. A multilevel polynomial hierarchical model adjusted by gestational age and estimated fetal weight was used to fit each cardiac parameter.

Results: The global heart dimensions including the atrial and ventricular areas, the ventricles dimensions and myocardial wall thicknesses and most of the functional parameters, such as the longitudinal myocardial motion and the biventricular cardiac output showed a positive quadratic increment throughout pregnancy. On the other hand, the left ejection fraction, shortening fraction and right fractional area change decreased with gestational age. Scatterplots for the main structural and functional parameters and ratios by gestational age, with mean, 5th, 10th, 90th, and 95th percentiles are provided. Regression equations by estimated fetal weight are also created.

Conclusion: We provide specific comprehensive echocardiographic prescriptive standards for uncomplicated MCDA twin fetuses following current standardized methodology. The implementation of these charts will potentially help to better identify abnormal cardiovascular parameters associated to monochorionic complications.
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http://dx.doi.org/10.1002/pd.5999DOI Listing
June 2021

Reliability and Concurrent and Construct Validity of a Food Frequency Questionnaire for Pregnant Women at High Risk to Develop Fetal Growth Restriction.

Nutrients 2021 May 12;13(5). Epub 2021 May 12.

Institut de Recerca Sant Joan de Déu, Endocrinology Department, Esplugues de Llobregat, 08950 Barcelona, Spain.

Accuracy of dietary assessment instruments such as food frequency questionnaire (FFQ) is crucial in the evaluation of diet-disease relationships. Test-retest reliability and concurrent and construct validity of a FFQ were evaluated in 150 pregnant women at high risk to develop fetal growth restriction randomly selected from those included in the improving mothers for better prenatal care trial Barcelona (IMPACT BCN). The FFQ and dietary records were performed at baseline and 34-36 weeks of gestation. Test-retest reliability of the FFQ for 12 food groups and 17 nutrients was moderate (ICC = 0.55) and good (ICC = 0.60), respectively. Concurrent validity between food, nutrients and a composite Mediterranean diet score (MedDiet score) and food records was fair for foods and nutrients (ρ average = 0.38 and 0.32, respectively) and moderate (r = 0.46) for the MedDiet score. Validation with biological markers ranged from poor (r = 0.07) for olives to moderate (r = 0.41) for nuts. A fair concordance between methods were found for nutrients (weighted κ = 0.22) and foods (weighted κ = 0.27). The FFQ-derived MedDiet score correlated in anticipated directions with intakes of nutrients and foods derived by food records. The FFQ showed a moderate test-retest reliability and reasonable validity to rank women according to their food and nutrient consumption and adherence to the Mediterranean diet.
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http://dx.doi.org/10.3390/nu13051629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150790PMC
May 2021

Mediterranean diet, Mindfulness-Based Stress Reduction and usual care during pregnancy for reducing fetal growth restriction and adverse perinatal outcomes: IMPACT BCN (Improving Mothers for a better PrenAtal Care Trial BarCeloNa): a study protocol for a randomized controlled trial.

Trials 2021 May 24;22(1):362. Epub 2021 May 24.

BCNatal | Fetal Medicine Research Center (Hospital Clínic and Hospital Sant Joan de Déu), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.

Background: Fetal growth restriction (FGR) affects 7-10% of all pregnancies resulting in a higher risk of perinatal morbidity and mortality, long-term disabilities, and cognitive impairment. Due to its multifactorial etiology, changes in maternal lifestyle, including suboptimal maternal diet and stress, have increasingly been associated with its prevalence. We present a protocol for the Improving Mothers for a better PrenAtal Care Trial Barcelona (IMPACT BCN), which evaluates two different maternal lifestyle strategies (improved nutrition by promoting Mediterranean diet and stress reduction program based on mindfulness techniques) on perinatal outcomes. The primary objective is to reduce the prevalence of FGR. Secondary aims are to reduce adverse perinatal outcomes and to improve neurodevelopment and cardiovascular profile in children at 2 years of age.

Methods: A randomized parallel, open-blind, single-center trial following a 1:1:1 ratio will select and randomize high-risk singleton pregnancies for FGR (N=1218), according to the criteria of the Royal College of Obstetricians and Gynaecologists (19.0-23.6 weeks' gestation), into three arms: Mediterranean diet, mindfulness-based stress reduction program, and usual care without any intervention. Compliance to the interventions will be randomly tested in 30% of participants with specific biomarkers. Maternal socio-demographic, clinical data, biological samples, and lifestyle questionnaires will be collected at enrollment and at the end of the interventions (34.0-36.6 weeks' gestation), together with a fetoplacental ultrasound and magnetic resonance. Fetoplacental biological samples and perinatal outcomes will be recorded at delivery. Postnatal follow-up is planned up to 2 years of corrected age including neurodevelopmental tests and cardiovascular assessment. Intention-to-treat and population per-protocol analysis will be performed.

Discussion: This is the first randomized study evaluating the impact of maternal lifestyle interventions during pregnancy on perinatal outcomes. The maternal lifestyle interventions (Mediterranean diet and mindfulness-based stress reduction program) are supported by scientific evidence, and their compliance will be evaluated with several biomarkers.

Trial Registration: ClinicalTrials.gov NCT03166332 . Registered on April 19, 2017.
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http://dx.doi.org/10.1186/s13063-021-05309-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147060PMC
May 2021

Diffuse trophoblast damage is the hallmark of SARS-CoV-2-associated fetal demise.

Mod Pathol 2021 09 18;34(9):1704-1709. Epub 2021 May 18.

Pathology Department, Hospital Clínic, Barcelona, Spain.

Placental pathology in SARS-CoV-2-infected pregnancies seems rather unspecific. However, the identification of the placental lesions due to SARS-CoV-2 infection would be a significant advance in order to improve the management of these pregnancies and to identify the mechanisms involved in a possible vertical transmission. The pathological findings in placentas delivered from 198 SARS-CoV-2-positive pregnant women were investigated for the presence of lesions associated with placental SARS-CoV-2 infection. SARS-CoV-2 infection was investigated in placental tissues through immunohistochemistry, and positive cases were further confirmed by in situ hybridization. SARS-CoV-2 infection was also investigated by RT-PCR in 33 cases, including all the immunohistochemically positive cases. Nine cases were SARS-CoV-2-positive by immunohistochemistry, in situ hybridization, and RT-PCR. These placentas showed lesions characterized by villous trophoblast necrosis with intervillous space collapse and variable amounts of mixed intervillous inflammatory infiltrate and perivillous fibrinoid deposition. Such lesions ranged from focal to massively widespread in five cases, resulting in intrauterine fetal death. Two of the stillborn fetuses showed some evidence of SARS-CoV-2 positivity. The remaining 189 placentas did not show similar lesions. The strong association between trophoblastic damage and placenta SARS-CoV-2 infection suggests that this lesion is a specific marker of SARS-CoV-2 infection in placenta. Diffuse trophoblastic damage, massively affecting chorionic villous tissue, can result in fetal death associated with COVID-19 disease.
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http://dx.doi.org/10.1038/s41379-021-00827-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130566PMC
September 2021

Postnatal persistence of cardiac remodeling and dysfunction in late fetal growth restriction.

Minerva Obstet Gynecol 2021 Aug 5;73(4):471-481. Epub 2021 May 5.

Barcelona Center for Maternal-Fetal and Neonatal Medicine (BCNatal), Center for Biomedical Research on Rare Diseases (CIBER-ER), Instituto Clínic de Ginecología, Obstetricia y Neonatología (ICGON), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic and Hospital Sant Joan de Deu, University of Barcelona, Barcelona, Spain.

Fetal growth restriction is one of the most common obstetric complications, affecting 7-10% of all pregnancies. Affected fetuses are exposed to an adverse environment in utero during a critical time of development and may face long-term health consequences such as increased cardiovascular risk in adulthood. Growth restricted fetuses develop remodeled hearts with signs of systolic and diastolic dysfunction. Cardiac adaptations are more evident in early severe cases, but also present in late onset fetal growth restriction. Cardiovascular remodeling persists into postnatal life, from the neonatal period to adolescence, encompassing an increased susceptibility to adult disease. In this review, we summarize the current evidence on cardiovascular programming associated to fetal growth restriction, its postnatal consequences and potential strategies to reduce their cardiovascular risk.
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http://dx.doi.org/10.23736/S2724-606X.21.04823-5DOI Listing
August 2021

Strategies for intra-amniotic administration of fetal therapy in a rabbit model of intrauterine growth restriction.

Exp Biol Med (Maywood) 2021 Jul 1;246(14):1668-1679. Epub 2021 Apr 1.

BCNatal | Fetal Medicine Research Center (Hospital Clínic and Hospital Sant Joan de Déu), University of Barcelona, Barcelona 08028, Spain.

Intrauterine growth restriction affects up to 10% of all pregnancies, leading to fetal programming with detrimental consequences for lifelong health. However, no therapeutic strategies have so far been effective to ameliorate these consequences. Our previous study has demonstrated that a single dose of nutrients administered into the amniotic cavity, bypassing the often dysfunctional placenta via intra-amniotic administration, improved survival at birth but not birthweight in an intrauterine growth restriction rabbit model. The aim of this study was to further develop an effective strategy for intra-amniotic fetal therapy in an animal model. Intrauterine growth restriction was induced by selective ligation of uteroplacental vessels on one uterine horn of pregnant rabbits at gestational day 25, and fetuses were delivered by cesarean section on GD30. During the five days of intrauterine growth restriction development, three different methods of intra-amniotic administration were used: continuous intra-amniotic infusion by osmotic pump, multiple intra-amniotic injections, and single fetal intraperitoneal injection. Technical feasibility, capability to systematically reach the fetus, and survival and birthweight of the derived offspring were evaluated for each technique. Continuous intra-amniotic infusion by osmotic pump was not feasible owing to the high occurrence of catheter displacement and amnion rupture, while methods using two intra-amniotic injections and one fetal intraperitoneal injection were technically feasible but compromised fetal survival. Taking into account all the numerous factors affecting intra-amniotic fetal therapy in the intrauterine growth restriction rabbit model, we conclude that an optimal therapeutic strategy with low technical failure and positive fetal impact on both survival and birthweight still needs to be found.
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http://dx.doi.org/10.1177/15353702211003508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326435PMC
July 2021

Assessment of myocardial deformation with CMR: a comparison with ultrasound speckle tracking.

Eur Radiol 2021 Oct 31;31(10):7242-7250. Epub 2021 Mar 31.

Cardiovascular Institute, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain.

Objectives: Myocardial deformation integrated with cardiac dimensions provides a comprehensive assessment of cardiac function, which has proven useful to differentiate cardiac pathology from physiological adaptation to situations such as chronic intensive training. Feature tracking (FT) can measure myocardial deformation from cardiac magnetic resonance (CMR) cine sequences; however, its accuracy is not yet fully validated. Our aim was to compare the accuracy and reproducibility of FT with speckle tracking echocardiography (STE) in highly trained endurance athletes.

Methods: Ninety-three endurance athletes (> 12-h training/week during the last 5 years, 52% male, 35 ± 5.1 years old) and 72 age-matched controls underwent resting CMR and transthoracic echocardiography to assess biventricular exercise-induced remodeling and biventricular global longitudinal strain (GLS) by CMR-FT and STE.

Results: Strain values were significantly lower when assessed by CMR-FT compared to STE (p < 0.001), with good reproducibility for the left ventricle (bias = 3.94%, limit of agreement [LOA] = ± 4.27 %) but wider variability for right ventricle strain. Strain values by both techniques proportionally decreased with increasing ventricular volumes, potentially depicting the functional biventricular reserve that characterizes athletes' hearts.

Conclusions: Biventricular longitudinal strain values were lower when assessed by FT as compared to STE. Both methods were statistically comparable when measuring LV strain but not RV strain. These differences might be justified by the lower in-plane spatial and temporal resolution of FT, which is particularly relevant for the complex anatomy of the RV.

Key Points: • Strain values were significantly lower when assessed by FT as compared to STE, which was expected due to the lower in-plane spatial and temporal resolution of FT versus STE. • Both methods were statistically comparable when measuring LV strain but not for RV strain analysis. • Characterizing the normal ranges and reproducibility of strain metrics by FT is an important step toward its clinical applicability, since it can be assessed offline and applied to routinely acquired cine CMR images.
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http://dx.doi.org/10.1007/s00330-021-07857-2DOI Listing
October 2021

Meteorin-like/Meteorin-β protects heart against cardiac dysfunction.

J Exp Med 2021 05;218(5)

Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina, Universitat de Barcelona, Barcelona, Spain.

Meteorin-like/Meteorin-β (Metrnl/Metrnβ) is a secreted protein produced by skeletal muscle and adipose tissue that exerts metabolic actions that improve glucose metabolism. The role of Metrnβ in cardiac disease is completely unknown. Here, we show that Metrnβ-null mice exhibit asymmetrical cardiac hypertrophy, fibrosis, and enhanced signs of cardiac dysfunction in response to isoproterenol-induced cardiac hypertrophy and aging. Conversely, adeno-associated virus-mediated specific overexpression of Metrnβ in the heart prevents the development of cardiac remodeling. Furthermore, Metrnβ inhibits cardiac hypertrophy development in cardiomyocytes in vitro, indicating a direct effect on cardiac cells. Antibody-mediated blockage of Metrnβ in cardiomyocyte cell cultures indicated an autocrine action of Metrnβ on the heart, in addition to an endocrine action. Moreover, Metrnβ is highly produced in the heart, and analysis of circulating Metrnβ concentrations in a large cohort of patients reveals that it is a new biomarker of heart failure with an independent prognostic value.
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http://dx.doi.org/10.1084/jem.20201206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7923691PMC
May 2021

Impact of SARS-CoV-2 Infection on Pregnancy Outcomes: A Population-Based Study.

Clin Infect Dis 2021 Feb 8. Epub 2021 Feb 8.

Department of Maternal-Fetal Medicine, BCNatal, Barcelona Center for Maternal-Fetal and Neonatal Medicine, Hospital Sant Joan de Déu and Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.

Background: A population-based study to describe the impact of SARS-CoV-2 infection on pregnancy outcomes.

Methods: Prospective, population-based study including pregnant women consecutively attended at first/second trimester or at delivery at three hospitals in Barcelona, Spain. SARS-CoV-2 antibodies (IgG and IgM/IgA) were measured in all participants and nasopharyngeal RT-PCR was performed at delivery. The primary outcome was a composite of pregnancy complications in SARS-CoV-2 positive versus negative women: miscarriage, preeclampsia, preterm delivery, perinatal death, small-for-gestational age, neonatal admission. Secondary outcomes were components of the primary outcome plus abnormal fetal growth, malformation, intrapartum fetal distress. Outcomes were also compared between positive symptomatic and positive asymptomatic SARS-CoV-2 women.

Results: Of 2,225 pregnant women, 317 (14.2%) were positive for SARS-CoV-2 antibodies (n=314, 99.1%) and/or RT-PCR (n=36, 11.4%). Among positive women, 217 (68.5%) were asymptomatic, 93 (29.3%) had mild COVID-19 and 7 (2.2%) pneumonia, of which 3 required intensive care unit admission. In women with and without SARS-CoV-2 infection, the primary outcome occurred in 43 (13.6%) and 268 (14%), respectively [risk difference -0.4%, (95% CI: -4.1% to 4.1)]. As compared with non-infected women, women with symptomatic COVID-19 had increased rates of preterm delivery (7.2% vs. 16.9%, p=0.003) and intrapartum fetal distress (9.1% vs. 19.2%, p=0.004), while asymptomatic women had similar rates to non-infected cases. Among 143 fetuses from infected mothers, none had anti-SARS-CoV-2 IgM/IgA in cord blood.

Conclusions: The overall rate of pregnancy complications in women with SARS-CoV-2 infection was similar to non-infected women. However, symptomatic COVID-19 was associated with modest increases in preterm delivery and intrapartum fetal distress.
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http://dx.doi.org/10.1093/cid/ciab104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929066PMC
February 2021

Atrioventricular plane displacement versus mitral and tricuspid annular plane systolic excursion: A comparison between cardiac magnetic resonance and M-mode echocardiography.

Clin Physiol Funct Imaging 2021 May 27;41(3):262-270. Epub 2021 Feb 27.

Clinical Physiology, Department of Clinical Sciences Lund, Lund University, Skane University Hospital, Lund, Sweden.

Introduction: Both echocardiography and CMR imaging are used to quantify longitudinal function. Inter-method variability for mitral (MAPSE) and tricuspid (TAPSE) annular plane systolic excursion, and variability between directly measured MAPSE and TAPSE and as based on atrioventricular plane displacement (AVPD) analysis by CMR, are, however, not known. This study, therefore, assessed inter-method variability and variability between annular plane systolic excursion and AVPD-based values in a healthy adult population.

Methods: Echocardiography and CMR were performed in 111 adults (35 [32-38] years). Method comparisons were assessed with Deming regression, Bland-Altman analysis and coefficient of variation. Observer reproducibility was assessed by the concordance correlation coefficient.

Results: Echocardiography and semi-automatic CMR agreed on MAPSE (17 ± 2 mm vs. 17 ± 2 mm, p = 0.1) and TAPSE (25 ± 3 mm vs. 25 ± 3 mm, p = 0.5), correlated highly between methods (fitted-slope 1.22 [95% CI 1.07-1.38] and 1.12 [95% CI 0.95-1.29]) and showed low bias (0.42 [95% CI - 2.05 to 2.88] and - 0.18 [95% CI - 4.78 to 4.43]). Intra-/inter-observer reproducibility was high for both methods for both MAPSE (echocardiography 0.96/0.86; CMR 0.87/0.85) and TAPSE (echocardiography 0.96/0.95; CMR 0.97/0.96). MAPSE (16 ± 2 mm vs. 17 ± 2 mm; p < 0.001) and TAPSE (24 ± 3 vs. 25 ± 3 mm; p < 0.001) based on AVPD were similar but statistically different compared with semi-automatic CMR.

Conclusions: Echocardiography and semi-automatic CMR have low variability and provide similar values for MAPSE and TAPSE and are thus interchangeable for follow-up studies. Lateral values based on tracked data from AVPD analysis are not clinically significantly different and could be used as a representation of annular displacement.
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http://dx.doi.org/10.1111/cpf.12693DOI Listing
May 2021

Complement and coagulation cascades activation is the main pathophysiological pathway in early-onset severe preeclampsia revealed by maternal proteomics.

Sci Rep 2021 02 4;11(1):3048. Epub 2021 Feb 4.

BCNatal | Fetal Medicine Research Center (Hospital Clínic and Hospital Sant Joan de Déu), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.

Preeclampsia is a pregnancy-specific multisystem disorder and a leading cause of maternal and perinatal morbidity and mortality. The exact pathogenesis of this multifactorial disease remains poorly defined. We applied proteomics analysis on maternal blood samples collected from 14 singleton pregnancies with early-onset severe preeclampsia and 6 uncomplicated pregnancies to investigate the pathophysiological pathways involved in this specific subgroup of preeclampsia. Maternal blood was drawn at diagnosis for cases and at matched gestational age for controls. LC-MS/MS proteomics analysis was conducted, and data were analyzed by multivariate and univariate statistical approaches with the identification of differential pathways by exploring the global human protein-protein interaction network. The unsupervised multivariate analysis (the principal component analysis) showed a clear difference between preeclamptic and uncomplicated pregnancies. The supervised multivariate analysis using orthogonal partial least square discriminant analysis resulted in a model with goodness of fit (RX = 0.99, p < 0.001) and a strong predictive ability (QY = 0.8, p < 0.001). By univariate analysis, we found 17 proteins statistically different after 5% FDR correction (q-value < 0.05). Pathway enrichment analysis revealed 5 significantly enriched pathways whereby the activation of the complement and coagulation cascades was on top (p = 3.17e-07). To validate these results, we assessed the deposits of C5b-9 complement complex and on endothelial cells that were exposed to activated plasma from an independent set of 4 cases of early-onset severe preeclampsia and 4 uncomplicated pregnancies. C5b-9 and Von Willbrand factor deposits were significantly higher in early-onset severe preeclampsia. Future studies are warranted to investigate potential therapeutic targets for early-onset severe preeclampsia within the complement and coagulation pathway.
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http://dx.doi.org/10.1038/s41598-021-82733-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862439PMC
February 2021

Low birth weight as a potential risk factor for severe COVID-19 in adults.

Sci Rep 2021 02 3;11(1):2909. Epub 2021 Feb 3.

BCNatal-Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Déu), IDIBAPS, Centre for Biomedical Research on Rare Diseases (CIBER-ER), Universitat de Barcelona, Sabino de Arana 1, 08028, Barcelona, Spain.

The identification of factors predisposing to severe COVID-19 in young adults remains partially characterized. Low birth weight (LBW) alters cardiovascular and lung development and predisposes to adult disease. We hypothesized that LBW is a risk factor for severe COVID-19 in non-elderly subjects. We analyzed a prospective cohort of 397 patients (18-70 years) with laboratory-confirmed SARS-CoV-2 infection attended in a tertiary hospital, where 15% required admission to Intensive Care Unit (ICU). Perinatal and current potentially predictive variables were obtained from all patients and LBW was defined as birth weight ≤ 2.500 g. Age (adjusted OR (aOR) 1.04 [1-1.07], P = 0.012), male sex (aOR 3.39 [1.72-6.67], P < 0.001), hypertension (aOR 3.37 [1.69-6.72], P = 0.001), and LBW (aOR 3.61 [1.55-8.43], P = 0.003) independently predicted admission to ICU. The area under the receiver-operating characteristics curve (AUC) of this model was 0.79 [95% CI, 0.74-0.85], with positive and negative predictive values of 29.1% and 97.6% respectively. Results were reproduced in an independent cohort, from a web-based survey in 1822 subjects who self-reported laboratory-positive SARS-CoV-2 infection, where 46 patients (2.5%) needed ICU admission (AUC 0.74 [95% CI 0.68-0.81]). LBW seems to be an independent risk factor for severe COVID-19 in non-elderly adults and might improve the performance of risk stratification algorithms.
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http://dx.doi.org/10.1038/s41598-021-82389-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859212PMC
February 2021

Septal curvature as a robust and reproducible marker for basal septal hypertrophy.

J Hypertens 2021 07;39(7):1421-1428

School of Biomedical Engineering and Imaging Sciences, Kings College London, London, UK.

Background: Basal septal hypertrophy (BSH) is an asymmetric, localized thickening of the upper interventricular septum and constitutes a marker of an early remodelling in patients with hypertension. This morphological trait has been extensively researched because of its prevalence in hypertension, yet its clinical and prognostic value for individual patients remains undetermined. One of the reasons is the lack of a reliable and reproducible metric to quantify the presence and the extent of BSH. This article proposes the use of the curvature of the left ventricular endocardium as a robust feature for BSH characterization, and as an objective criterion to quantify current subjective 'visual assessment' of the presence of sigmoidal septum. The proposed marker, called average septal curvature, is defined as the inverse of the radius adjacent to each point of the endocardial contour along the basal and mid inferoseptal segments of the left ventricle.

Method: Robustness and reproducibility were assessed on a cohort of 220 patients, including 161 hypertensive patients (32 with BSH) and 59 healthy controls.

Results: The results show that compared with the conventionally used wall thickness metrics, the new marker is more reproducible (relative standard deviation of errors of 7 vs. 13%, and 8 vs. 38% for intra-observer and inter-observer variability, respectively) and better correlates to the functional parameters related to BSH, with main difference (absolute rank correlation 0.417 vs. 0.341) in local deformation changes assessed by longitudinal strain.

Conclusion: Average septal curvature is a more precisely defined and reproducible metric than thickness ratios, it can be fully automated, and better infers the functional remodelling related to hypertension.
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http://dx.doi.org/10.1097/HJH.0000000000002813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183485PMC
July 2021

Cardiac Remodeling and Hypertension in HIV-Uninfected Infants Exposed in utero to Antiretroviral Therapy.

Clin Infect Dis 2021 08;73(4):586-593

Fetal Medicine Research Center, BCNatal-Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Deu), Institut Clinic de Ginecologia, Obstetricia i Neonatologia (ICGON), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, and Centre for Biomedical Research on Rare Diseases (CIBER-ER), Barcelona, Spain.

Background: We aimed to assess the postnatal pattern of cardiovascular remodeling associated with intrauterine exposure to maternal HIV and antiretroviral treatment (ART).

Methods: Prospective cohort including 34 HIV-exposed uninfected (HEU) infants and 53 non-HIV-exposed infants were evaluated from fetal life up to 6 months postnatally. A cardiovascular evaluation was performed including echocardiography, blood pressure, and carotid intima media thickness (cIMT) measurement.

Results: ART regimens during pregnancy included 2 nucleoside reverse transcriptase inhibitors (Abacavir + Lamivudine (32.4%), Emtricitabine + Tenofovir (41.2%), and Zidovudine + Lamivudine (20.6%)). At 6 months of age, HIV-exposed uninfected infants showed thicker myocardial walls (septal wall thickness mean 5.02 mm (SD 0.85) vs 3.98 mm (0.86); P < .001), relative systolic dysfunction with decreased mitral ring displacement (8.57 mm (2.03) vs 10.34 mm (1.84); P = .002), and decreased tricuspid S' (9.71 cm/s (1.94) vs 11.54 cm/s (2.07); P = .003) together with relative diastolic dysfunction showed by prolonged left isovolumic relaxation time (58.57 ms (13.79) vs 47.94 (7.39); P < .001). Vascular assessment showed significantly higher systolic and diastolic blood pressure (102 mmHg (16.1) vs 80 mmHg (13.9); P < .001 and 64 mmHg (14.4) vs 55 mmHg (10.2); P = .045 respectively), with 50% of HIV-exposed children meeting criteria for hypertension vs 3.77% of the non-HIV-exposed group (P < .001) and thicker mean cIMT in the HIV-exposed group (0.62 µm (0.09) vs 0.51 µm (0.09); P = .015).

Conclusions: Subclinical cardiac impairment together with higher blood pressure and thicker cIMT were observed in HIV-exposed infants at 6 months of age. Half of them presented hypertension. Our findings support a possible increased cardiovascular risk in HIV uninfected infants exposed in utero to ART.
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http://dx.doi.org/10.1093/cid/ciab030DOI Listing
August 2021

Maternal proteomic profiling reveals alterations in lipid metabolism in late-onset fetal growth restriction.

Sci Rep 2020 12 3;10(1):21033. Epub 2020 Dec 3.

Department of Maternal-Fetal Medicine (ICGON), BCNatal|Fetal Medicine Research Center (Hospital Clínic and Hospital Sant Joan de Déu), Institut D'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Sabino de Arana 1, 08028, Barcelona, Spain.

Fetal growth restriction defined as the failure to achieve the fetal genetic growth potential is a major cause of perinatal morbidity and mortality. The role of maternal adaptations to placental insufficiency in this disorder is still not fully understood. We aimed to investigate the biological processes and protein-protein interactions involved in late-onset fetal growth restriction in particular. We applied 2D nano LC-MS/MS proteomics analysis on maternal blood samples collected at the time of delivery from 5 singleton pregnancies with late-onset fetal growth restriction and 5 uncomplicated pregnancies. Data were analyzed using R package "limma" and Ingenuity Pathway Analysis. 25 proteins showed significant changes in their relative abundance in late-onset fetal growth restriction (p value < 0.05). Direct protein-protein interactions network demonstrated that Neurogenic locus notch homolog protein 1 (NOTCH1) was the most significant putative upstream regulator of the observed profile. Gene ontology analysis of these proteins revealed the involvement of 14 canonical pathways. The most significant biological processes were efflux of cholesterol, efflux of phospholipids, adhesion of blood cells, fatty acid metabolism and dyslipidemia. Future studies are warranted to validate the potential role of the detected altered proteins as potential therapeutic targets in the late-onset form of fetal growth restriction.
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http://dx.doi.org/10.1038/s41598-020-78207-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713381PMC
December 2020

Uncomplicated Monochorionic Twins: Two Normal Hearts Sharing One Placenta.

J Clin Med 2020 Nov 9;9(11). Epub 2020 Nov 9.

Fetal Medicine Research Center, BCNatal-Barcelona Center for Maternal-Fetal and Neonatal Medicine (Hospital Clínic and Hospital Sant Joan de Deu), 08028 Barcelona, Spain.

Cardiovascular dysfunction has been reported in complicated monochorionic diamniotic (MCDA) pregnancies; however, little is known whether hemodynamic changes occur in uncomplicated MCDA twins. A prospective observational study was conducted including 100 uncomplicated MCDA twins matched by gestational age to 200 low-risk singletons. Echocardiography was performed at 26-30 weeks gestation and cord blood B-type natriuretic peptide (BNP) was measured at delivery. In both groups, z-scores for echocardiographic parameters were within normal ranges; however the monochorionic group had larger atrial areas (mean (standard deviation) right atria-to-heart ratio: 17.0 (2) vs. 15.9 (1); = 0.018; left atria-to-heart ratio: 17.0 (3) vs. 15.8 (2); < 0.001) and signs of concentric hypertrophy (right relative wall thickness: 0.66 (0.12) vs. 0.56 (0.11); < 0.001; left relative wall thickness: 0.69 (0.14) vs. 0.58 (0.12); < 0.001). Longitudinal function was increased in twins, leading to higher tricuspid annular plane systolic excursion (6.9 mm (0.9) vs. 5.9 mm (0.7); < 0.001) and mitral annular plane systolic excursion (4.9 mm (0.8) vs. 4.4 mm (1.1); < 0.001. BNP levels at birth were also higher in MCDA twins (median [interquartile range]: 20.81 pg/mL [16.69-34.01] vs. 13.14 pg/mL [9.17-19.84]; < 0.001). Thus, uncomplicated MCDA fetuses have normal cardiac shape and function, but signs of cardiac adaptation were identified by echocardiographic and biochemical parameters, when compared with singletons.
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http://dx.doi.org/10.3390/jcm9113602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695261PMC
November 2020

The protective effect of fibroblast growth factor-21 in alcoholic cardiomyopathy: a role in protecting cardiac mitochondrial function.

J Pathol 2021 02 26;253(2):198-208. Epub 2020 Nov 26.

Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona (IBUB) i Institut de Recerca Sant Joan de Deu (IRSJD), Universitat de Barcelona, Barcelona, Spain.

Alcoholic cardiomyopathy (ACM) resulting from chronic alcohol misuse is one of the main contributors leading to heart failure and cardiovascular mortality. Fibroblast growth factor 21 (FGF21) is a well-established cardioprotective factor. We aimed to study the role of FGF21 in experimentally induced models and clinical affected patients with cardiac damage due to chronic alcohol consumption. We found that circulating FGF21 levels and cardiac FGF21 and β-klotho protein levels were increased in subjects with chronic alcohol consumption. As an experimental model of ACM, we fed wild-type and Fgf21 knockout (Fgf21 ) mice with a 4% alcohol liquid diet for 4 and 12 weeks. FGF21 circulating levels and FGF21 expression in the myocardium were also increased in wild-type mice after chronic alcohol intake. Fgf21 mice develop a higher degree of cardiac hypertrophy, fibrosis, and cardiac dysfunction after chronic alcohol consumption than wild-type mice. Moreover, the myocardium of Fgf21 mice showed signs of metabolic deregulation, oxidative stress, and mitochondrial dysfunction after alcohol intake. Finally, human cardiac biopsies from patients with chronic alcohol consumption developing ACM presented a higher degree of oxidative stress which positively correlated with the FGF21 protein levels in the myocardium. We conclude that plasma levels and cardiac myocyte FGF21 expression were induced in response to chronic alcohol consumption. The lack of FGF21 aggravated cardiac damage produced by ACM, in association with enhanced mitochondrial and oxidative stress, thus pointing to FGF21 as a protective agent against development of alcohol-induced cardiomyopathy. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5573DOI Listing
February 2021

Rabbit neurospheres as a novel in vitro tool for studying neurodevelopmental effects induced by intrauterine growth restriction.

Stem Cells Transl Med 2021 Feb 9;10(2):209-221. Epub 2020 Oct 9.

IUF-Leibniz Research Institute for Environmental Medicine, Düsseldorf, Germany.

The aim of this study was to develop a rabbit neurosphere culture to characterize differences in basic processes of neurogenesis induced by intrauterine growth restriction (IUGR). A novel in vitro neurosphere culture has been established using fresh or frozen neural progenitor cells from newborn (PND0) rabbit brains. After surgical IUGR induction in pregnant rabbits and cesarean section 5 days later, neural progenitor cells from both control and IUGR groups were isolated and directly cultured or frozen at -80°C. These neural progenitor cells spontaneously formed neurospheres after 7 days in culture. The ability of control and IUGR neurospheres to migrate, proliferate, differentiate to neurons, astrocytes, or oligodendrocytes was compared and the possibility to modulate their responses was tested by exposure to several positive and negative controls. Neurospheres obtained from IUGR brains have a significant impairment in oligodendrocyte differentiation, whereas no significant differences are observed in other basic processes of neurogenesis. This impairment can be reverted by in vitro exposure of IUGR neurospheres to thyroid hormone, which is known to play an essential role in white matter maturation in vivo. Our new rabbit neurosphere model and the results of this study open the possibility to test several substances in vitro as neuroprotective candidates against IUGR induced neurodevelopmental damage while decreasing the number of animals and resources and allowing a more mechanistic approach at a cellular functional level.
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http://dx.doi.org/10.1002/sctm.20-0223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848321PMC
February 2021

Hemopexin and α1-microglobulin heme scavengers with differential involvement in preeclampsia and fetal growth restriction.

PLoS One 2020 11;15(9):e0239030. Epub 2020 Sep 11.

Section of Obstetrics and Gynecology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.

Hemopexin and α1-microglobulin act as scavengers to eliminate free heme-groups responsible for hemoglobin-induced oxidative stress. The present study evaluated maternal and fetal plasma concentrations of these scavengers in the different phenotypes of placenta-mediated disorders. Singleton pregnancies with normotensive fetal growth restriction [FGR] (n = 47), preeclampsia without FGR (n = 45) and preeclampsia with FGR (n = 51) were included prospectively as well as uncomplicated pregnancies (n = 49). Samples were collected at delivery and ELISA analysis was applied to measure the hemopexin and α1-microglobulin concentrations. In maternal blood in preeclampsia with and without FGR, hemopexin was significantly lower (p = 0.003 and p<0.001, respectively) and α1-microglobulin was significantly higher (p<0.001 in both) whereas no difference existed in normotensive FGR mothers compared to controls. In contrast, in fetal blood in growth restricted fetuses with and without preeclampsia, both hemopexin and α1-microglobulin were significantly lower (p<0.001 and p = 0.001 for hemopexin, p = 0.016 and p = 0.013 for α1-microglobulin, respectively) with no difference in fetuses from preeclampsia without FGR in comparison to controls. Thus, hemopexin and α1-microglobulin present significantly altered concentrations in maternal blood in the maternal disease -preeclampsia- and in cord blood in the fetal disease -FGR-, which supports their differential role in placenta-mediated disorders in accordance with the clinical presentation of these disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239030PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485876PMC
November 2020
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