Publications by authors named "Eduard Gratacos"

291 Publications

Validation and implementation of a direct RT-qPCR method for rapid screening of SARS-CoV-2 infection by using non-invasive saliva samples.

Int J Infect Dis 2021 Jul 25. Epub 2021 Jul 25.

Institut de Recerca Sant Joan de Deu, Esplugues de Llobregat, Barcelona, Spain; Department of Medicine, Universitat Internacional de Catalunya, Barcelona, Spain; Consorcio de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; Hospital Sant Joan de Deu, Universitat de Barcelona, Esplugues de Llobregat, Barcelona, Spain. Electronic address:

Objective: To validate and implement an optimised screening method for detection of SARS-CoV-2 RNA combining use of self-collected raw saliva samples, single-step heat-treated virus inactivation and RNA extraction, and direct RT-qPCR.

Methods: 3-phased study conducted in Barcelona (Spain) in June-October, 2020, including: i) analytical validation against standard RT-qPCR in saliva samples; ii) diagnostic validation against standard RT-qPCR using paired saliva-nasopharyngeal samples obtained from asymptomatic teenagers and adults in a sports academy; and iii) pilot screening of asymptomatic health workers in a tertiary hospital.

Results: Phase i) Detection yield of the new method was comparable to that of standard RT-qPCR. Phase ii) Diagnostic sensitivity and specificity values in 303 self-collected saliva samples were 95.7% (95% CI, 79.0-99.2%) and 100.0% (95% CI, 98.6-100.0 %), respectively. Phase iii) Only 17 (0.6%) of saliva samples self-collected by 2,709 participants without supervision were invalid. Rapid analytical workflow by the new method (up to 384 batched samples processable in <2 hours) yielded 24 (0.9%) positive results in the remainder 2,692 saliva samples. Paired nasopharyngeal specimens were all positive by standard RT-qPCR..

Conclusions: Direct RT-qPCR on self-collected raw saliva is a simple, rapid, and accurate method with potential to be scaled up for enhanced SARS-CoV-2 community-wide screening.
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http://dx.doi.org/10.1016/j.ijid.2021.07.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310572PMC
July 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 Jul 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

Prenatal cerebellar growth is altered in congenital diaphragmatic hernia on ultrasound.

Prenat Diagn 2021 Jul 3. Epub 2021 Jul 3.

Department of Development and Regeneration, Cluster Woman and Child, Group Biomedical Sciences, KU Leuven University of Leuven, Leuven, Belgium.

Objective: Children with congenital diaphragmatic hernia (CDH) are at risk for neurodevelopmental delay. Herein we report on prenatal changes in biometry and brain perfusion in fetuses with isolated CDH.

Study Design: This retrospective study evaluated fetuses with isolated, left-sided CDH in three European referral centers. Abdominal circumference (AC), femur length (FL), head circumference (HC), transcerebellar diameter (TCD), middle cerebral artery (MCA) Doppler, and ventricular width (VW) were assessed during four gestational periods (<24 weeks, 25-28 weeks, 29-32 weeks, >33 weeks). Z-scores were calculated, and growth curves were created based on longitudinal data.

Results: In 367 fetuses, HC, AC and FL were within normal ranges throughout gestation. The TCD diminished with advancing gestational age to fall below the fifth percentile after 32 weeks. A less pronounced but similar trend was seen in VW. The peak systolic velocity of the MCA was consistently approximately 10% lower than normal. Disease severity was correlated to TCD (p = 0.002) and MCA doppler values (p = 0.002). There were no differences between fetuses treated with FETO and those managed expectantly.

Conclusion: Fetuses with isolated left-sided CDH have a small cerebellum and reduced MCA peak systolic velocity. Follow up studies are necessary to determine the impact of these changes on neurodevelopment.
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http://dx.doi.org/10.1002/pd.5993DOI Listing
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

Risk Factors Associated with Preterm Prelabor Rupture of Membranes after Cord Occlusion in Monochorionic Diamniotic Twins.

Fetal Diagn Ther 2021 15;48(6):457-463. Epub 2021 Jun 15.

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

Introduction: Preterm prelabor rupture of membranes (PPROM) is a common complication after fetal surgeries. The aim of this study was to assess risk factors for and outcomes after PPROM following cord occlusion (CO) in monochorionic diamniotic (MCDA) pregnancies.

Methods: This was a retrospective cohort study of 188 consecutive MCDA pregnancies treated by bipolar or laser CO, either primarily because of discordant malformation (dMF) or severe selective fetal growth restriction (sFGR), or secondarily when complete bichorionization was not possible in case of twin-to-twin transfusion syndrome (TTTS) or sFGR. Intentional septostomy was performed when needed. The procedure-related PPROM was defined as rupture of membranes <32 weeks' gestation (PROM <32 weeks). Selected pre-, intra-, and early postoperative variables were analyzed by univariate and binomial logistic regression to determine they are correlated to PROM <32 weeks after CO.

Results: Between 2006 and 2017, 188 cases underwent CO. Diagnosis was TTTS in 28.2% (n = 53), severe sFGR in 49.5% (n = 93), and dMF in 22.3% (n = 42). PROM <32 weeks occurred in 21.3% (n = 40), resulting in worse perinatal outcomes, as preterm birth <32 weeks occurred in 80.7% (vs. 8.3%, p = 0.000), procedure-to-delivery interval was 47.5 days (vs. 125, p = 0.000), gestational age (GA) at birth 30.0 weeks (vs. 37.7 weeks, p = 0.000), and survival 65.0% (vs. 91.1%, p = 0.000). In univariate analysis, indication, anterior placenta, cervical length, GA at surgery, operation time, amniodistention and drainage fluid volumes, chorioamniotic membrane separation, and septostomy were selected as relevant factors to be included in the regression model. In a multivariate analysis, TTTS was the only factor associated to PROM <32 weeks (OR 3.5 CI 95% 1.5-7.9).

Conclusions: PROM <32 weeks after CO increases the risk of preterm delivery. In this cohort, the membrane rupture was more likely when CO was done in the context of TTTS.
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http://dx.doi.org/10.1159/000516513DOI Listing
June 2021

Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia.

N Engl J Med 2021 07 8;385(2):107-118. Epub 2021 Jun 8.

From the Department of Obstetrics and Gynecology, KU Leuven (J.A.D., F.M.R.) and Academic Department of Development and Regeneration, Biomedical Sciences, University Hospitals KU Leuven, Leuven, Belgium (J.A.D., B.V.C., F.M.R.); King's College Hospital (K.H.N.) and the Institute for Women's Health, University College London Hospital (J.A.D.) - both in London; Hospital Antoine-Béclère, Université Paris-Saclay, Clamart, France (A.B.); Hospital Clinic and Sant Joan de Déu, Barcelona (E.G.); Mount Sinai Hospital, Toronto (G.R.); Hospital Maggiore Policlinico, Milan (N.P.); the National Center for Child Health and Development, Tokyo (H.S.); Children's Memorial Hermann Hospital, Houston (A.J.); the Medical University of Warsaw, Warsaw, Poland (M.W.); and University Hospital Bonn, Bonn, Germany (C.B.).

Background: Observational studies have shown that fetoscopic endoluminal tracheal occlusion (FETO) has been associated with increased survival among infants with severe pulmonary hypoplasia due to isolated congenital diaphragmatic hernia on the left side, but data from randomized trials are lacking.

Methods: In this open-label trial conducted at centers with experience in FETO and other types of prenatal surgery, we randomly assigned, in a 1:1 ratio, women carrying singleton fetuses with severe isolated congenital diaphragmatic hernia on the left side to FETO at 27 to 29 weeks of gestation or expectant care. Both treatments were followed by standardized postnatal care. The primary outcome was infant survival to discharge from the neonatal intensive care unit. We used a group-sequential design with five prespecified interim analyses for superiority, with a maximum sample size of 116 women.

Results: The trial was stopped early for efficacy after the third interim analysis. In an intention-to-treat analysis that included 80 women, 40% of infants (16 of 40) in the FETO group survived to discharge, as compared with 15% (6 of 40) in the expectant care group (relative risk, 2.67; 95% confidence interval [CI], 1.22 to 6.11; two-sided P = 0.009). Survival to 6 months of age was identical to the survival to discharge (relative risk, 2.67; 95% CI, 1.22 to 6.11). The incidence of preterm, prelabor rupture of membranes was higher among women in the FETO group than among those in the expectant care group (47% vs. 11%; relative risk, 4.51; 95% CI, 1.83 to 11.9), as was the incidence of preterm birth (75% vs. 29%; relative risk, 2.59; 95% CI, 1.59 to 4.52). One neonatal death occurred after emergency delivery for placental laceration from fetoscopic balloon removal, and one neonatal death occurred because of failed balloon removal. In an analysis that included 11 additional participants with data that were available after the trial was stopped, survival to discharge was 36% among infants in the FETO group and 14% among those in the expectant care group (relative risk, 2.65; 95% CI, 1.21 to 6.09).

Conclusions: In fetuses with isolated severe congenital diaphragmatic hernia on the left side, FETO performed at 27 to 29 weeks of gestation resulted in a significant benefit over expectant care with respect to survival to discharge, and this benefit was sustained to 6 months of age. FETO increased the risks of preterm, prelabor rupture of membranes and preterm birth. (Funded by the European Commission and others; TOTAL ClinicalTrials.gov number, NCT01240057.).
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http://dx.doi.org/10.1056/NEJMoa2027030DOI Listing
July 2021

Randomized Trial of Fetal Surgery for Moderate Left Diaphragmatic Hernia.

N Engl J Med 2021 07 8;385(2):119-129. Epub 2021 Jun 8.

From the Department of Obstetrics and Gynecology, University Hospitals KU Leuven (J.A.D., P.L.J.D.) and Academic Department of Development and Regeneration, Biomedical Sciences, KU Leuven, Leuven, Belgium (J.A.D., B.V.C., P.L.J.D.); Hospital Antoine-Béclère, Université Paris-Saclay, Clamart (A.B.), and Necker-Enfants Malades Hospital, Paris (Y.V.) - both in France; Hospital Clinic and Sant Joan de Déu, Barcelona (E.G.); Institute for Women's Health, University College London Hospital (J.A.D.) and King's College Hospital(K.H.N.) - both in London; the University Hospital Bonn, Bonn, Germany (C.B.); Hospital Maggiore Policlinico, Milan (N.P.), and Bambino Gesù Children's Hospital, Rome (F.M.) - both in Italy; Baylor College of Medicine and Texas Children's Hospital (M.B.) and Children's Memorial Hermann Hospital (A.J.) - all in Houston; Mater Mothers' Hospital, Brisbane, QLD, Australia (G.J.G.); the Medical University of Warsaw, Warsaw, Poland (M.W.); and Erasmus MC-University Medical Center Rotterdam, Rotterdam, the Netherlands (P.L.J.D.).

Background: Fetoscopic endoluminal tracheal occlusion (FETO) has been associated with increased postnatal survival among infants with severe pulmonary hypoplasia due to isolated congenital diaphragmatic hernia on the left side, but data are lacking to inform its effects in infants with moderate disease.

Methods: In this open-label trial conducted at many centers with experience in FETO and other types of prenatal surgery, we randomly assigned, in a 1:1 ratio, women carrying singleton fetuses with a moderate isolated congenital diaphragmatic hernia on the left side to FETO at 30 to 32 weeks of gestation or expectant care. Both treatments were followed by standardized postnatal care. The primary outcomes were infant survival to discharge from a neonatal intensive care unit (NICU) and survival without oxygen supplementation at 6 months of age.

Results: In an intention-to-treat analysis involving 196 women, 62 of 98 infants in the FETO group (63%) and 49 of 98 infants in the expectant care group (50%) survived to discharge (relative risk , 1.27; 95% confidence interval [CI], 0.99 to 1.63; two-sided P = 0.06). At 6 months of age, 53 of 98 infants (54%) in the FETO group and 43 of 98 infants (44%) in the expectant care group were alive without oxygen supplementation (relative risk, 1.23; 95% CI, 0.93 to 1.65). The incidence of preterm, prelabor rupture of membranes was higher among women in the FETO group than among those in the expectant care group (44% vs. 12%; relative risk, 3.79; 95% CI, 2.13 to 6.91), as was the incidence of preterm birth (64% vs. 22%, respectively; relative risk, 2.86; 95% CI, 1.94 to 4.34), but FETO was not associated with any other serious maternal complications. There were two spontaneous fetal deaths (one in each group) without obvious cause and one neonatal death that was associated with balloon removal.

Conclusions: This trial involving fetuses with moderate congenital diaphragmatic hernia on the left side did not show a significant benefit of FETO performed at 30 to 32 weeks of gestation over expectant care with respect to survival to discharge or the need for oxygen supplementation at 6 months. FETO increased the risks of preterm, prelabor rupture of membranes and preterm birth. (Funded by the European Commission and others; TOTAL ClinicalTrials.gov number, NCT00763737.).
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http://dx.doi.org/10.1056/NEJMoa2026983DOI Listing
July 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

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

Mid-trimester prediction of spontaneous preterm birth with automated cervical quantitative ultrasound texture analysis and cervical length: a prospective study.

Sci Rep 2021 Apr 2;11(1):7469. Epub 2021 Apr 2.

BCNatal - Barcelona Center for Maternal-Fetal and Neonatal Medicine, Hospital Clínic and Hospital Sant Joan de Deu, University of Barcelona, Barcelona, Spain.

The objective of this study was to evaluate a novel automated test based on ultrasound cervical texture analysis to predict spontaneous Preterm Birth (sPTB) alone and in combination with Cervical Length (CL). General population singleton pregnancies between 18 + 0 and 24 + 6 weeks' gestation were assessed prospectively at two centers. Cervical ultrasound images were evaluated and the occurrence of sPTB before weeks 37 + 0 and 34 + 0 were recorded. CL was measured on-site. The automated texture analysis test was applied offline to all images. Their performance to predict the occurrence of sPTB before 37 + 0 and 34 + 0 weeks was evaluated separately and in combination on 633 recruited patients. AUC for sPTB prediction before weeks 37 and 34 respectively were as follows: 55.5% and 65.3% for CL, 63.4% and 66.3% for texture analysis, 67.5% and 76.7% when combined. The new test improved detection rates of CL at similar low FPR. Combining the two increased detection rate compared to CL alone from 13.0 to 30.4% for sPTB < 37 and from 14.3 to 42.9% sPTB < 34. Texture analysis of cervical ultrasound improved sPTB detection rate compared to cervical length for similar FPR, and the two combined together increased significantly prediction performance. This results should be confirmed in larger cohorts.
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http://dx.doi.org/10.1038/s41598-021-86906-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018963PMC
April 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
July 2021

Transmission of SARS-CoV-2 infection among children in summer schools applying stringent control measures in Barcelona, Spain.

Clin Infect Dis 2021 Mar 12. Epub 2021 Mar 12.

NIHR Southampton Clinical Research Facility and NIHR Southampton Biomedical Research Centre, University Hospital NHS Foundation Trust; and Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, UK.

Background: Understanding the role of children in SARS-CoV-2 transmission is critical to guide decision-making for schools in the pandemic. We aimed to describe the transmission of SARS-CoV-2 among children and adult staff in summer schools.

Methods: During July 2020 we prospectively recruited children and adult staff attending summer schools in Barcelona who had SARS-CoV-2 infection. Primary SARS-CoV-2 infections were identified through: (1) surveillance program in 22 summer schools' of 1905 participants, involving weekly saliva sampling for SARS-CoV-2 RT-PCR during 2-5 weeks; (2)cases identified through the Catalonian Health Surveillance System of children diagnosed with SARS-CoV-2 infection by nasopharyngeal RT-PCR. All centres followed prevention protocols: bubble groups, hand washing, facemasks and conducting activities mostly outdoors. Contacts of a primary case within the same bubble were evaluated by nasopharyngeal RT-PCR. Secondary attack rates and effective reproduction number in summer schools(R*) were calculated.

Results: Among the over 2000 repeatedly screened participants, 30children and 9adults were identified as primary cases. A total of 253 close contacts of these primary cases were studied (median 9 (IQR 5-10) for each primary case), among which twelve new cases (4.7%) were positive for SARS-CoV-2. The R* was 0.3, whereas the contemporary rate in the general population from the same areas in Barcelona was 1.9.

Conclusions: The transmission rate of SARS-CoV-2 infection among children attending school-like facilities under strict prevention measures was lower than that reported for the general population. This suggests that under preventive measures schools are unlikely amplifiers of SARS-CoV-2 transmission and supports current recommendations for school opening.
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http://dx.doi.org/10.1093/cid/ciab227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989514PMC
March 2021

Structural Brain Changes during the Neonatal Period in a Rabbit Model of Intrauterine Growth Restriction.

Dev Neurosci 2020 5;42(5-6):217-229. Epub 2021 Mar 5.

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

Background: Intrauterine growth restriction (IUGR) is associated with abnormal neurodevelopment, but the associated structural brain changes are poorly documented. The aim of this study was to describe in an animal model the brain changes at the cellular level in the gray and white matter induced by IUGR during the neonatal period.

Methods: The IUGR model was surgically induced in pregnant rabbits by ligating 40-50% of the uteroplacental vessels in 1 horn, whereas the uteroplacental vessels of the contralateral horn were not ligated. After 5 days, IUGR animals from the ligated horn and controls from the nonligated were delivered. On the day of delivery, perinatal data and placentas were collected. On postnatal day 1, functional changes were first evaluated, and thereafter, neuronal arborization in the frontal cortex and density of pre-oligodendrocytes, astrocytes, and microglia in the corpus callosum were evaluated.

Results: Higher stillbirth in IUGR fetuses together with a reduced birth weight as compared to controls was evidenced. IUGR animals showed poorer functional results, an altered neuronal arborization pattern, and a decrease in the pre-oligodendrocytes, with no differences in microglia and astrocyte densities.

Conclusions: Overall, in the rabbit model used, IUGR is related to functional and brain changes evidenced already at birth, including changes in the neuronal arborization and abnormal oligodendrocyte maturation.
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http://dx.doi.org/10.1159/000512948DOI Listing
March 2021

in vivo Monitoring with micro-implantable hypoxia sensor based on tissue acidosis.

Talanta 2021 May 25;226:122045. Epub 2020 Dec 25.

Centro de Investigación Biomédica en Red en Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Monforte de Lemos 3-5, Pabellón 11, 28029, Madrid, Spain; Nanobioengineering Group, Institute for Bioengineering of Catalonia (IBEC) Barcelona Institute of Science and Technology (BIST), 12 Baldiri Reixac 15-21, Barcelona, 08028, Spain; Department of Electronics and Biomedical Engineering, Universitat de Barcelona, Martí I Franquès 1, 08028, Barcelona, Spain.

Hypoxia is a common medical problem, sometimes difficult to detect and caused by different situations. Control of hypoxia is of great medical importance and early detection is essential to prevent life threatening complications. However, the few current methods are invasive, expensive, and risky. Thus, the development of reliable and accurate sensors for the continuous monitoring of hypoxia is of vital importance for clinical monitoring. Herein, we report an implantable sensor to address these needs. The developed device is a low-cost, miniaturised implantable electrochemical sensor for monitoring hypoxia in tissue by means of pH detection. This technology is based on protonation/deprotonation of polypyrrole conductive polymer. The sensor was optimized in vitro and tested in vivo intramuscularly and ex vivo in blood in adult rabbits with respiration-induced hypoxia and correlated with the standard device ePOC. The sensor demonstrated excellent sensitivity and reproducibility; 46.4 ± 0.4 mV/pH in the pH range of 4-9 and the selectivity coefficient exhibited low interference activity in vitro. The device was linear (R = 0.925) with a low dispersion of the values (n = 11) with a cut-off of 7.1 for hypoxia in vivo and ex vivo. Statistics with one-way ANOVA (α = 0.05), shows statistical differences between hypoxia and normoxia states and the good performance of the pH sensor, which demonstrated good agreement with the standard device. The sensor was stable and functional after 18 months. The excellent results demonstrated the feasibility of the sensors in real-time monitoring of intramuscular tissue and blood for medical applications.
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http://dx.doi.org/10.1016/j.talanta.2020.122045DOI Listing
May 2021

Maternal Infection and Adverse Pregnancy Outcomes among Pregnant Travellers: Results of the International Zika Virus in Pregnancy Registry.

Viruses 2021 02 22;13(2). Epub 2021 Feb 22.

School of Pharmaceutical Sciences, Geneva University and Service of Pharmacy, Lausanne University Hospital, 1011 Lausanne, Switzerland.

In this multicentre cohort study, we evaluated the risks of maternal ZIKV infections and adverse pregnancy outcomes among exposed travellers compared to women living in areas with ZIKV circulation (residents). The risk of maternal infection was lower among travellers compared to residents: 25.0% ( = 36/144) versus 42.9% ( = 309/721); aRR 0.6; 95% CI 0.5-0.8. Risk factors associated with maternal infection among travellers were travelling during the epidemic period (i.e., June 2015 to December 2016) (aOR 29.4; 95% CI 3.7-228.1), travelling to the Caribbean Islands (aOR 3.2; 95% CI 1.2-8.7) and stay duration >2 weeks (aOR 8.7; 95% CI 1.1-71.5). Adverse pregnancy outcomes were observed in 8.3% ( = 3/36) of infected travellers and 12.7% ( = 39/309) of infected residents. Overall, the risk of maternal infections is lower among travellers compared to residents and related to the presence of ongoing outbreaks and stay duration, with stays <2 weeks associated with minimal risk in the absence of ongoing outbreaks.
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http://dx.doi.org/10.3390/v13020341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926842PMC
February 2021

Quality criteria for randomized controlled studies: obstetrical journal guidelines.

Am J Obstet Gynecol MFM 2021 05 16;3(3):100334. Epub 2021 Feb 16.

Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA (Dr Berghella). Electronic address:

Background: Most retractions of obstetrics and gynecology manuscripts are because of scientific misconduct. It would be preferable to prevent randomized controlled trials with scientific misconduct from ever appearing in the peer-reviewed scientific literature, rather than to have to retract them later.

Objective: This study aimed to evaluate the policies of obstetrics and gynecology and top medical journals in their author guidelines and electronic submission systems regarding prospective randomized controlled trial registration, ethics committee approval, research protocols, Consolidated Standards of Reporting Trial guidelines, and data sharing and to detect the most common quality criteria requested for randomized controlled trials in these journals.

Study Design: Author guidelines were identified via online Google searches from the websites of selected peer-reviewed medical journals. Journals in obstetrics and gynecology were selected from the list of journals with impact factors based on the Journal Citation Report released by Clarivate Analytics on June 29, 2020, focusing on those publishing original clinical research in obstetrics, in particular randomized controlled trials. In addition, 4 of the top impact factor peer-reviewed general medical journals publishing randomized controlled trials were included. The requirements for selected quality criteria for randomized controlled trials analyzed in the author guidelines for each journal were details of 5 general issues: prospective randomized controlled trial registration (4 subcategories), ethics committee approval (4 subcategories), research protocol (3 subcategories), Consolidated Standards of Reporting Trials guidelines (3 subcategories), and data sharing (3 subcategories). To evaluate the requirements within the electronic submission system, a mock submission of a randomized controlled trial was also done for each journal, and the same criteria were assessed on the online software for submission. The primary outcome was the overall percentage for each of the quality criteria that were listed as required within the author guidelines or required in the submission system among all journals. Planned subgroup analyses were top general medicine vs obstetrics and gynecology journals and top 4 obstetrics and gynecology vs other obstetrics and gynecology journals.

Results: Most studied peer-reviewed journals listed in their author guidelines 7 specific criteria for submission of randomized controlled trials: prospective registration and registration number, statement of ethical approval with name of approving committee and statement of informed consent, statement of adherence to Consolidated Standards of Reporting Trials guidelines, and data sharing statement. For most journals, the submission software did not require these or any other criteria for submission. There were minimal differences in criteria listed for top medical journals vs other obstetrics and gynecology journals and among top vs other obstetrics and gynecology journals.

Conclusion: Prospective registration and registration number, statement of ethical approval with name of approving committee and statement of informed consent, statement of adherence to Consolidated Standards of Reporting Trials guidelines, and data sharing statement are the randomized controlled trial quality criteria requested by leading medical and obstetrics and gynecology journals. These obstetrics and gynecology journals agree to make, as much as possible, these criteria uniform and mandatory in author guidelines and also through improved submission software.
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http://dx.doi.org/10.1016/j.ajogmf.2021.100334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324065PMC
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 Feb 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

Non-invasive monitoring of pH and oxygen using miniaturized electrochemical sensors in an animal model of acute hypoxia.

J Transl Med 2021 02 4;19(1):53. Epub 2021 Feb 4.

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

Background: One of the most prevalent causes of fetal hypoxia leading to stillbirth is placental insufficiency. Hemodynamic changes evaluated with Doppler ultrasound have been used as a surrogate marker of fetal hypoxia. However, Doppler evaluation cannot be performed continuously. As a first step, the present work aimed to evaluate the performance of miniaturized electrochemical sensors in the continuous monitoring of oxygen and pH changes in a model of acute hypoxia-acidosis.

Methods: pH and oxygen electrochemical sensors were evaluated in a ventilatory hypoxia rabbit model. The ventilator hypoxia protocol included 3 differential phases: basal (100% FiO), the hypoxia-acidosis period (10% FiO) and recovery (100% FiO). Sensors were tested in blood tissue (ex vivo sensing) and in muscular tissue (in vivo sensing). pH electrochemical and oxygen sensors were evaluated on the day of insertion (short-term evaluation) and pH electrochemical sensors were also tested after 5 days of insertion (long-term evaluation). pH and oxygen sensing were registered throughout the ventilatory hypoxia protocol (basal, hypoxia-acidosis, and recovery) and were compared with blood gas metabolites results from carotid artery catheterization (obtained with the EPOC blood analyzer). Finally, histological assessment was performed on the sensor insertion site. One-way ANOVA was used for the analysis of the evolution of acid-based metabolites and electrochemical sensor signaling results; a t-test was used for pre- and post-calibration analyses; and chi-square analyses for categorical variables.

Results: At the short-term evaluation, both the pH and oxygen electrochemical sensors distinguished the basal and hypoxia-acidosis periods in both the in vivo and ex vivo sensing. However, only the ex vivo sensing detected the recovery period. In the long-term evaluation, the pH electrochemical sensor signal seemed to lose sensibility. Finally, histological assessment revealed no signs of alteration on the day of evaluation (short-term), whereas in the long-term evaluation a sub-acute inflammatory reaction adjacent to the implantation site was detected.

Conclusions: Miniaturized electrochemical sensors represent a new generation of tools for the continuous monitoring of hypoxia-acidosis, which is especially indicated in high-risk pregnancies. Further studies including more tissue-compatible material would be required in order to improve long-term electrochemical sensing.
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http://dx.doi.org/10.1186/s12967-021-02715-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863274PMC
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

Cardiac remodeling and hypertension in HIV uninfected infants exposed in utero to antiretroviral therapy.

Clin Infect Dis 2021 Jan 20. Epub 2021 Jan 20.

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 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 two 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<0.001) and relative systolic dysfunction with decreased mitral ring displacement (8.57 mm (2.03) vs 10.34 mm (1.84); p=0.002) and decreased tricuspid S' (9.71 cm/s (1.94) vs 11.54 cm/s (2.07); p=0.003) together with relative diastolic dysfunction showed by prolonged left isovolumic relaxation time (58.57 ms (13.79) vs 47.94 (7.39); p<0.001). Vascular assessment showed significantly higher systolic and diastolic blood pressure (102 mmHg (16.1) vs 80 mmHg (13.9); p<0.001 and 64 mmHg (14.4) vs 55 mmHg (10.2); p=0.045 respectively), with 50% of HIV-exposed children meeting criteria for hypertension vs 3.77% of the non-HIV-exposed group (p<0.001) and thicker mean cIMT in the HIV-exposed group (0.62 µm (0.09) vs 0.51 µm (0.09); p=0.015).

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
January 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

Ex-vivo mechanical sealing properties and toxicity of a bioadhesive patch as sealing system for fetal membrane iatrogenic defects.

Sci Rep 2020 10 29;10(1):18608. Epub 2020 Oct 29.

BCNatal | Fetal Medicine Research Center (Hospital Clínic and Hospital Sant Joan de Déu), University of Barcelona, Building Helios 2, Sabino Arana Street, 1, 08028, Barcelona, Spain.

Preterm prelabor rupture of membranes (PPROM) is the most frequent complication of fetal surgery. Strategies to seal the membrane defect created by fetoscopy aiming to reduce the occurrence of PPROM have been attempted with little success. The objective of this study was to evaluate the ex-vivo mechanical sealing properties and toxicity of four different bioadhesives integrated in semi-rigid patches for fetal membranes. We performed and ex-vivo study using term human fetal membranes to compare the four integrated patches composed of silicone or silicone-polyurethane combined with dopaminated-hyaluronic acid or hydroxypropyl methylcellulose (HPMC). For mechanical sealing properties, membranes were mounted in a multiaxial inflation device with saline, perforated and sealed with the 4 combinations. We measured bursting pressure and maximum pressure free of leakage (n = 8). For toxicity, an organ culture of membranes sealed with the patches was used to measure pyknotic index (PI) and lactate dehydrogenase (LDH) concentration (n = 5). All bioadhesives achieved appropriate bursting pressures, but only HPMC forms achieved high maximum pressures free of leakage. Concerning toxicity, bioadhesives showed low PI and LDH levels, suggesting no cell toxicity. We conclude that a semi-rigid patch coated with HPMC achieved ex-vivo sealing of iatrogenic defects in fetal membranes with no signs of cell toxicity. These results warrant further research addressing long-term adhesiveness and feasibility as a sealing system for fetoscopy.
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http://dx.doi.org/10.1038/s41598-020-75242-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596722PMC
October 2020

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

Segmentation of the placenta and its vascular tree in Doppler ultrasound for fetal surgery planning.

Int J Comput Assist Radiol Surg 2020 Nov 19;15(11):1869-1879. Epub 2020 Sep 19.

Department of Information and Communication Technologies, Universitat Pompeu Fabra, Barcelona, Spain.

Purpose: Twin-to-twin transfusion syndrome (TTTS) is a serious condition that occurs in about 10-15% of monochorionic twin pregnancies. In most instances, the blood flow is unevenly distributed throughout the placenta anastomoses leading to the death of both fetuses if no surgical procedure is performed. Fetoscopic laser coagulation is the optimal therapy to considerably improve co-twin prognosis by clogging the abnormal anastomoses. Notwithstanding progress in recent years, TTTS surgery is highly risky. Computer-assisted planning of the intervention can thus improve the outcome.

Methods: In this work, we implement a GPU-accelerated random walker (RW) algorithm to detect the placenta, both umbilical cord insertions and the placental vasculature from Doppler ultrasound (US). Placenta and background seeds are manually initialized in 10-20 slices (out of 245). Vessels are automatically initialized in the same slices by means of Otsu thresholding. The RW finds the boundaries of the placenta and reconstructs the vasculature.

Results: We evaluate our semiautomatic method in 5 monochorionic and 24 singleton pregnancies. Although satisfactory performance is achieved on placenta segmentation (Dice ≥ 84.0%), some vascular connections are still neglected due to the presence of US reverberation artifacts (Dice ≥ 56.9%). We also compared inter-user variability and obtained Dice coefficients of ≥ 76.8% and ≥ 97.42% for placenta and vasculature, respectively. After a 3-min manual initialization, our GPU approach speeds the computation 10.6 times compared to the CPU.

Conclusions: Our semiautomatic method provides a near real-time user experience and requires short training without compromising the segmentation accuracy. A powerful approach is thus presented to rapidly plan the fetoscope insertion point ahead of TTTS surgery.
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http://dx.doi.org/10.1007/s11548-020-02256-2DOI Listing
November 2020

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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