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Articles publicats en revistes (BCNatal Fetal Medicine Research Center)

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    Time-course evolution of counterfactual thinking after early pregnancy loss
    (Nature Publishing Group, 2026-03-19) Mallorquí, Aida; Pauta, Montse; Cardona, Gemma; Álvarez Martín, Claudia; Paz y Miño, Fernanda; Nogué, Laura; Segú, Xavier; Ardiles-Ruesjas, Victoria; Rodríguez Fornells, Antoni; Borrell i Vilaseca, Antoni
    Counterfactual thinking (CT), the tendency to consider how events might have been different, is a common cognitive process following negative life events. This longitudinal study examines the prevalence and time-course evolution of CT immediately after early pregnancy loss. A sample of 119 women who experienced early pregnancy loss completed an online psychological assessment measuring traumatic impact, trait rumination, and CT presence, frequency, and content. The survey was administered at one week, one month, and four months post-loss. CT was highly prevalent (72%) and decreased over time. 99% of CT had an upward focus, imagining a better outcome than reality. Moreover, 91.6% were also self-referential, perceived as dependent on one’s own behaviors and emotions, frequently involving a heightened sense of personal responsibility for the loss. Rumination and traumatic impact predicted counterfactual thinking frequency over time, identifying psychological risk patterns. Findings support the idea that CT may serve an adaptive function by helping to process the loss and support future goal setting, including subsequent pregnancy. However, in individuals with high traumatic impact and rumination, CT may contribute to prolonged distress. Integrating psychological care alongside physical healthcare is essential to promoting long-term well-being after early pregnancy loss.
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    Prevalence of supratentorial anomalies assessed by magnetic resonance imaging in fetuses with open spina bifida
    (John Wiley & Sons, 2021-08-15) Trigo, Lucas; Eixarch Roca, Elisenda; Bottura, I.; Dalaqua, M.; Barbosa, A. A.; Catte, L. de; Demaerel, P.; Dymarkowski, S.; Deprest, Jan; Lapa, Denise Araújo; Aertsen, Michael; Gratacós Solsona, Eduard
    Objectives To determine the prevalence of brain anomalies at the time of preoperative magnetic resonance imaging (MRI) assessment in fetuses eligible for prenatal open spina bifida (OSB) repair, and to explore the relationship between brain abnormalities and features of the spinal defect. Methods This was a retrospective cross-sectional study, conducted in three fetal medicine centers, of fetuses eligible for OSB fetal surgery repair between January 2009 and December 2019. MRI images obtained as part of the presurgical assessment were re-evaluated by two independent observers, blinded to perinatal results, to assess: (1) the type and area of the defect and its anatomical level; (2) the presence of any structural central nervous system (CNS) anomaly and abnormal ventricular wall; and (3) fetal head and brain biometry. Binary regression analyses were performed and data were adjusted for type of defect, upper level of the lesion (ULL), gestational age (GA) at MRI and fetal medicine center. Multiple logistic regression analysis was performed in order to identify lesion characteristics and brain anomalies associated with a higher risk of presence of abnormal corpus callosum (CC) and/or heterotopia. Results Of 115 fetuses included, 91 had myelomeningocele and 24 had myeloschisis. Anatomical level of the lesion was thoracic in seven fetuses, L1–L2 in 13, L3–L5 in 68 and sacral in 27. Median GA at MRI was 24.7 (interquartile range, 23.0–25.7) weeks. Overall, 52.7% of cases had at least one additional brain anomaly. Specifically, abnormal CC was observed in 50.4% of cases and abnormality of the ventricular wall in 19.1%, of which 4.3% had nodular heterotopia. Factors associated independently with higher risk of abnormal CC and/or heterotopia were non-sacral ULL (odds ratio (OR), 0.51 (95% CI, 0.26–0.97); P = 0.043), larger ventricular width (per mm) (OR, 1.23 (95% CI, 1.07–1.43); P = 0.005) and presence of abnormal cavum septi pellucidi (OR, 3.76 (95% CI, 1.13–12.48); P = 0.031). Conclusions Half of the fetuses assessed for OSB repair had an abnormal CC and/or an abnormal ventricular wall prior to prenatal repair. The likelihood of brain abnormalities was increased in cases with a non-sacral lesion and wider lateral ventricles. These findings highlight the importance of a detailed preoperative CNS evaluation of fetuses with OSB. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
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    Towards a point of care approach for intra-amniotic infection or early delivery using minimally invasive prediction models in women with preterm labor.
    (Elsevier Inc., 2026-03-27) Cobo, Teresa; Boada, David; Burgos Artizzu, Xavier P. ; Goya, María; Vergara Gómez, Andrea; Kacerovsky, Marian; Ferrero Martinez, Sílvia ; Filella Pla, Xavier; Sellarés, Anna; González, Bernardino; Mouriz, Natalia; Mohedano, Noah; Ampurdanes, Queralt; Roldán, Eva; Barco, Ester del; Murillo Bravo, Clara; Hidalgo, Judit; Garbí, Sandra; Musilova, Ivana; Fabregat Bolufer, Aleix B. ; Palacio, Montse; Gratacós Solsona, Eduard
    Among women with preterm labor and intact membranes, those with intra-amniotic infection or inflammation represent the highest risk group of spontaneous delivery and worse adverse outcome. Identification of this group requires amniocentesis, which is perceived as too invasive by both patients and physicians. This study aimed to develop a minimally invasive prediction model for intra-amniotic infection or early delivery, thereby better stratifying patients (low or high-risk) and rationalizing the use of amniocentesis limiting the indications to the highest-risk group of spontaneous preterm delivery. We performed external validation of 4 prediction models using data from 2022-2024 of women diagnosed with preterm labor below 34 weeks admitted to the Hospital Clinic, Hospital Sant Joan de Déu, and the Hospital Vall Hebron in Barcelona (Spain), and the Hradec Kralove University Hospital, in Kradec Kralove (Czech Republic), who underwent amniocentesis to rule in/out intra-amniotic infection or inflammation. Different prediction models, including ultrasound (US) transvaginal cervical length, serum C-reactive protein (CRP), vaginal IL-6, vaginal pH, vaginal lactic acid, and vaginal Lactobacillus genus, were validated in these patients. Diagnostic performance was done in 114 women with PTL below 34 weeks, 42 (36.8%) of whom had intra-amniotic infection or spontaneous delivery within 7 days. The areas under the curve (AUC) of the different models ranged from ranging from 84 (95% confidence interval (CI) 78.8-89.2%) to 89.9% (88.4-91.4%), sensitivities ranging from 78.6 (33/42) to 90.5% (38/42). and specificities from 70.8% (51/72) to 84.7% (61/72). The most feasible and efficient model was formed by combining US cervical length, serum CRP and vaginal IL-6, showing an AUC of 84% with a sensitivity of 78.6% (33/42), specificity of 84.7% (61/72), positive predictive value of 75% (33/44), and negative predictive value of 87.1% (61/70). We developed minimally invasive models to screen women at high risk of intra-amniotic infection or early delivery and guide the selective use of amniocentesis, thereby improving both antenatal counseling and the clinical management of high-risk patients.
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    Preterm prelabor rupture of membranes: the use of amniocentesis to detect intraamniotic infection reduces maternal and neonatal duration of antibiotic exposure
    (Elsevier, 2025-11-01) Cobo Cobo, Maria Teresa; Aldecoa Bilbao, Victoria; Ferrero Martinez, Sílvia ; Balcells, Judith; Contreras, Ana Lucia; Valenzuela Rodríguez, Andrea; Pastor Lorca, María; Boada, David; Herranz Barbero, Ana; Izquierdo Renau, Montserrat; Murillo Bravo, Clara; Río, Ana del; Hernández Meneses, Marta; Fidalgo, Berta; Rodriguez Reyes, Montserrat; Figueras Retuerta, Francesc; Gratacós Solsona, Eduard; Palacio, Montse
    Current management guidelines for patients with preterm prelabor rupture of membranes at <32þ0 weeks of gestation recommend administering antibiotics, although evidence on their benefits for short- and long-term neonatal outcomes is poor. OBJECTIVE: This study aimed to evaluate whether the use of amniocentesis to detect intraamniotic infection reduces maternal and neonatal duration of antibiotic exposure. STUDY DESIGN: This was a retrospective observational cohort study (2014e2023) including patients diagnosed with preterm prelabor rupture of membranes at <32þ0 weeks of gestation who underwent amniocentesis at admission to assess the presence of intraamniotic infection. We compared 2 groups according to antenatal antibiotic management. From 2014 to 2019, patients received at least 5 days of broad-spectrum antibiotic treatment (including intravenous ampicillin and gentamicin and a single dose of oral azithromycin), regardless of intraamniotic infection status (standard management group). Beyond 2019, gentamicin was substituted for intravenous ceftriaxone and azithromycin for oral clarithromycin. Antibiotic treatment duration was optimized on the basis of amniotic fluid analysis (amniocentesis-based management): if amniotic fluid glucose concentrations were 14 mg/dL and Gram staining did not show the presence of bacteria, antibiotic treatment was discontinued at 48 hours. Otherwise, antibiotic therapy was prolonged at least until microbiological amniotic fluid results. Regardless of the management group, if intraamniotic infection was diagnosed, the type of antibiotic was individualized according to the bacteria isolated, and treatment was prolonged for 7 to 10 days unless delivery occurred earlier. There were no other differences in maternal management between the 2 periods. RESULTS: A total of 172 patients diagnosed with preterm prelabor rupture of membranes at <32þ0 weeks of gestation were included (122 in the standard management group and 50 in the amniocentesis-based management group). The prevalence of intraamniotic infection was 29% in both periods, with most cases (61%) being due to Ureaplasma species. There were no differences in maternal characteristics between the 2 groups. As expected, in the amniocentesis-based management group, maternal exposure to antibiotics was shorter (median [25th centilee75th centile] of 2 [2e3] days [amniocentesis-based management] vs 5 days [4e5] [standard management]; P<.0001). In line with the reduction of the duration of antibiotic therapy, we observed that maternal hospital stay was significantly shorter (5 [4e9] vs 11 [5e21] days; P¼.001) and outpatient management was more frequent (68% vs 47%; P¼.011) in the amniocentesis-based management group. No differences were observed in maternal morbidity. Similar results were found when neonatal outcomes were evaluated. In the amniocentesis-based management group, neonates received less antibiotic treatment at admission (odds ratio [95% confidence interval], 0.31 [0.15e0.61]; P<.001) and had less exposure to antibiotics during hospitalization (614 vs 1318 days in the standard management group; P¼.023). This did not translate into worse neonatal outcomes. CONCLUSION: Management of preterm prelabor rupture of membranes based on amniotic fluid analysis was associated with shorter maternal and neonatal antibiotic exposure and shorter maternal length of hospitalization, and allowed outpatient management without jeopardizing maternal or neonatal outcomes
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    Pulmonary vascular reactivity in growth restricted fetuses using computational modelling and machine learning analysis of fetal Doppler waveforms
    (Nature Publishing Group, 2024-03-11) Vellvé, Kilian; Garcia Canadilla, Patricia; Nogueira, Mariana; Youssef, Lina; Arranz Betegón, Angela; Nakaki, Ayako; Boada, David; Blanco Vich, Isabel; Faner, Rosa; Figueras Retuerta, Francesc; Agustí García-Navarro, Àlvar; Gratacós Solsona, Eduard; Crovetto, Francesca; Bijnens, Bart; Crispi Brillas, Fàtima
    The aim of this study was to investigate the pulmonary vasculature in baseline conditions and after maternal hyperoxygenation in growth restricted fetuses (FGR). A prospective cohort study of singleton pregnancies including 97 FGR and 111 normally grown fetuses was carried out. Ultrasound Doppler of the pulmonary vessels was obtained at 24–37 weeks of gestation and data were acquired before and after oxygen administration. After, Machine Learning (ML) and a computational model were used on the Doppler waveforms to classify individuals and estimate pulmonary vascular resistance (PVR). Our results showed lower mean velocity time integral (VTI) in the main pulmonary and intrapulmonary arteries in baseline conditions in FGR individuals. Delta changes of the main pulmonary artery VTI and intrapulmonary artery pulsatility index before and after hyperoxygenation were significantly greater in FGR when compared with controls. Also, ML identified two clusters: A (including 66% controls and 34% FGR) with similar Doppler traces over time and B (including 33% controls and 67% FGR) with changes after hyperoxygenation. The computational model estimated the ratio of PVR before and after maternal hyperoxygenation which was closer to 1 in cluster A (cluster A 0.98 ± 0.33 vs cluster B 0.78 ± 0.28, p = 0.0156). Doppler ultrasound allows the detection of significant changes in pulmonary vasculature in most FGR at baseline, and distinct responses to hyperoxygenation. Future studies are warranted to assess its potential applicability in the clinical management of FGR.
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    The Mediterranean Diet in Pregnancy: Implications for Maternal Brain Morphometry in a Secondary Analysis of the IMPACT BCN Randomized Clinical Trial
    (MDPI, 2024-05-24) Nakaki, Ayako; Gomez, Yvan; Castro-Barquero, Sara; Conti, Allegra; Vellvé, Kilian; Casas, Irene; Genero, Mariona; Youssef, Lina; Segalés, Laura; Benitez, Leticia; Casas Rodríguez, Rosa M.; Vieta i Pascual, Eduard, 1963-; Bargalló Alabart, Núria; Toschi, Nicola; Estruch Riba, Ramon; Crispi Brillas, Fàtima; Gratacós Solsona, Eduard; Crovetto, Francesca
    Introduction: A Mediterranean diet has positive effects on the brain in mid-older adults; however, there is scarce information on pregnant individuals. We aimed to evaluate the effect of a structured Mediterranean diet intervention on the cortical structure of the maternal brain during pregnancy. Methods: This study was a secondary analysis of the IMPACT BCN, a randomized clinical trial with 1221 high-risk pregnant women randomly allocated into three groups at 19-23 weeks of gestation: Mediterranean diet intervention, a mindfulness-based stress reduction program, or usual care. Maternal brain magnetic resonance imaging was performed during the third trimester of pregnancy in a random subgroup of participants. For this study, data from the Mediterranean diet and usual groups were analyzed. Maternal dietary intake, adherence to the Mediterranean diet and metabolite biomarkers were evaluated using a food frequency questionnaire, a 17-item dietary screener and plasma/urine samples, respectively. Results: The cluster-wise analysis showed that the Mediterranean diet group participants (n = 34) had significantly larger surface areas in the right precuneus (90%CI: <0.0001-0.0004, p < 0.001) and left superior parietal (90%CI: 0.026-0.033, p = 0.03) lobules compared to the usual care group participants (n = 37). A larger right precuneus area was associated with high improvements in adherence to the Mediterranean diet, a high intake of walnuts and high concentrations of urinary hydroxytyrosol. A larger left superior parietal area was associated with a high intake of walnuts and high concentrations of urinary hydroxytyrosol. Conclusions: The promotion of a Mediterranean diet during pregnancy has a significant effect on maternal brain structure.
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    Circulating extracellular vesicles and neutrophil extracellular traps contribute to endothelial dysfunction in preeclampsia
    (Frontiers Media, 2024-12-13) Ramos López, Alex; Youssef, Lina; Molina, Patricia; Torramade Moix, Sergi; Martínez Sánchez, Julia; Moreno Castaño, Ana Belen; Blasco, Miquel; Guillén Olmos, Elena; Moner Rafel, Blanca de; Pino, Marc; Tortajada, Marta; Camacho, Marta; Borrell, Maria; Crovetto, Francesca; Ramírez Bajo, María José; Ventura Aguiar, Pedro; Bañón Maneus, Elisenda; Rovira, Jordi; Escolar Albaladejo, Ginés; Carreras, Enric; Gratacós Solsona, Eduard; Diaz Ricart, M. Isabel; Crispi Brillas, Fàtima; Palomo, Marta
    Background: Preeclampsia (PE) is a pregnancy complication characterized by hypertension, proteinuria, endothelial dysfunction, and complement dysregulation. Placenta-derived extracellular vesicles (EVs), necessary in maternal-fetal communication, might contribute to PE pathogenesis. Moreover, neutrophil extracellular traps (NETs) play a pathogenic role in other complement-mediated pathologies, and their contribution in PE remains unexplored. Materials and methods: EVs were isolated from PE (peEVs) and normotensive pregnant women sera. NETs were obtained incubating donor-pre-activated neutrophils with PE or control sera. Microvascular (HMEC) endothelial cells (ECs) were incubated with PE or control sera with or without (depleted sera) EVs or NETs, to assess changes in VCAM-1, ICAM-1, VE-cadherin, eNOS, VWF, ROS, and C5b-9 deposits. Results were expressed as fold increase vs. control. Results: VWF, VCAM-1, and ROS expression was significantly higher in cells exposed to PE sera vs. control (12.3 ± 8.1, 3.6 ± 2.3, and 1.8 ± 0.2, respectively, p < 0.05), though significantly lower in cells exposed to depleted PE (dPE) sera (6.1 ± 2.7, 0.7 ± 0.6, and 1.2 ± 0.1, respectively, vs. control, p < 0.05). EC exposure to depleted control sera supplemented with peEVs (dC+peEVs) significantly increased VWF, VCAM-1, and ROS compared to non-supplemented sera (4.5 ± 0.3, 2.8 ± 2.0, and 1.4 ± 0.2, respectively, p < 0.05). ICAM-1, VE-cadherin, and C5b-9 did not differ among groups. ECs incubated with PE-NETs increased VWF and VCAM-1 and decreased VE-cadherin expression vs. control (4 ± 1.6, 5.9 ± 1.2, and 0.5 ± 0.1, respectively, p < 0.05), and notably increased C5b-9 deposit (7.5 ± 2.9, p < 0.05). ICAM-1 and ROS did not differ. Conclusions: Both circulating EVs and NETs from PE pregnant women exhibit a deleterious effect on ECs. Whereas EVs trigger a pro-oxidant and proinflammatory state, NETs potentiate the activation of the complement system, as already described in PE.
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    Maternal stress, anxiety, well-being, and sleep quality in pregnant women throughout gestation
    (MDPI, 2023-11-26) Martín Asuero, Andrés; Pascal Capdevila, Rosalia; Casas, Irene; Genero, Mariona; Nakaki, Ayako; Youssef, Lina; Larroya, Marta; Benitez, Leticia; Gomez, Yvan; Martínez-Arán, Anabel, 1971-; Morilla, Ivette; Oller-Guzmán, Teresa M.; Vieta i Pascual, Eduard, 1963-; Crispi Brillas, Fàtima; Gratacós Solsona, Eduard ; Gómez Roig, Ma. Dolores; Crovetto, Francesca
    Background: Maternal stress, anxiety, well-being, and sleep quality during pregnancy have been described as influencing factors during pregnancy. Aim: We aimed to describe maternal stress, anxiety, well-being, and sleep quality in pregnant women throughout gestation and their related factors. Methods: A prospective study including pregnant women attending BCNatal, in Barcelona, Spain (n = 630). Maternal stress and anxiety were assessed by the Perceived Stress Scale (PSS) and State-Trait Anxiety Inventory (STAI)-validated questionnaires. Maternal well-being was assessed using theWorld Health OrganizationWell-Being Index Questionnaire (WHO-5), and sleep quality was assessed using the Pittsburgh Sleep Quality Index Questionnaire (PSQI). All questionnaires were obtained twice during the second and third trimester of pregnancy. A multivariate analysis was conducted to assess factors related to higher maternal stress and anxiety and worse well-being and sleep quality. Results: High levels of maternal stress were reported in 23.1% of participants at the end of pregnancy, with maternal age <40 years (OR 2.02; 95% CI 1.08–3.81, p = 0.03), non-white ethnicity (OR 2.09; 95% CI 1.19–4.02, p = 0.01), and non-university studies (OR 1.86; 95% CI 1.08–3.19, p = 0.02) being the parameters mostly associated with it. A total of 20.7% of women had high levels of anxiety in the third trimester and the presence of psychiatric disorders (OR 3.62; 95% CI 1.34–9.78, p = 0.01) and non-university studies (OR 1.70; 95% CI 1.11–2.59, p = 0.01) provided a significant contribution to high anxiety at multivariate analysis. Poor maternal well-being was observed in 26.5% of women and a significant contribution was provided by the presence of psychiatric disorders (OR 2.96; 95% CI 1.07–8.25, p = 0.04) and non-university studies (OR 1.74; 95% CI 1.10–2.74, p = 0.02). Finally, less sleep quality was observed at the end of pregnancy (p < 0.001), with 81.1% of women reporting poor sleep quality. Conclusion: Maternal stress and anxiety, compromised maternal well-being, and sleep quality disturbances are prevalent throughout pregnancy. Anxiety and compromised sleep quality may increase over gestation. The screening of these conditions at different stages of pregnancy and awareness of the associated risk factors can help to identify women at potential risk.
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    Prenatal exposure to per- and polyfluoroalkyl substances, fetoplacental hemodynamics, and fetal growth
    (Elsevier Ltd., 2024-11-06) Cserbik, Dora; Knox, Bethany; Güil-Oumrait, Nuria; Basagaña, Xavier; Dadvand, Payam; Foraster, Maria; Galmes, Toni; Gascón, Mireia; Gómez Roig, Ma. Dolores; Gómez-Herrera, Laura; Småstuen Haug, Line; Llurba Olivé, Elisa; Márquez, Sandra; Rivas, Ioar; Sunyer, Jordi; Thomsen, Cathrine; Zanini, Maria Julia; Bustamante Pineda, Mariona; Vrijheid, Martine
    Introduction: The impact of legacy per- and polyfluoroalkyl substances (PFAS) on fetal growth has been well studied, but assessments of next-generation PFAS and PFAS mixtures are sparse and the potential role of fetoplacental hemodynamics has not been studied. We aimed to evaluate associations between prenatal PFAS exposure and fetal growth and fetoplacental hemodynamics. Methods: We included 747 pregnant women from the BiSC birth cohort (Barcelona, Spain (2018-2021)). Twenty-three PFAS were measured at 32 weeks of pregnancy in maternal plasma, of which 13 were present above detectable levels. Fetal growth was measured by ultrasound, as estimated fetal weight at 32 and 37 weeks of gestation, and weight at birth. Doppler ultrasound measurements for uterine (UtA), umbilical (UmA), and middle cerebral artery (MCA) pulsatility indices (PI), as well as the cerebroplacental ratio (CPR - ratio MCA to UmA), were obtained at 32 weeks to assess fetoplacental hemodynamics. We applied linear mixed effects models to assess the association between singular PFAS and longitudinal fetal growth and PI, and Bayesian Weighted Quantile Sum models to evaluate associations between the PFAS mixture and the aforementioned outcomes, controlled for the relevant covariates. Results: Single PFAS and the mixture tended to be associated with reduced fetal growth and CPR PI, but few associations reached statistical significance. Legacy PFAS PFOS, PFHpA, and PFDoDa were associated with statistically significant decreases in fetal weight z-score of 0.13 (95%CI (-0.22, -0.04), 0.06 (-0.10, 0.01), and 0.05 (-0.10, 0.00), respectively, per doubling of concentration. The PFAS mixture was associated with a non-statistically significant 0.09 decrease in birth weight z-score (95%CI -0.22, 0.04) per quartile increase. Conclusion: This study suggests that legacy PFAS may be associated with reduced fetal growth, but associations for next generation PFAS and for the PFAS mixture were less conclusive. Associations between PFAS and fetoplacental hemodynamics warrant further investigation.
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    Machine learning-driven blood biomarker profiling and EGCG intervention in fetal alcohol spectrum disorder
    (Elsevier España, 2025-09-04) Ramos-Triguero, Anna; Navarro Tapia, Elisabet; Vieiros, Melina; Martínez, Leopoldo; García Algar, Óscar; Andreu Fernández, Vicente
    Fetal alcohol spectrum disorders (FASD) is a complex neurodevelopmental condition caused by prenatal alcohol exposure (PAE), often underdiagnosed due to heterogeneous symptoms and diagnostic challenges. This study aimed to identify serum-based biomarkers for early FASD diagnosis and assess the potential of epigallocatechin gallate (EGCG), a natural antioxidant found in green tea, in modulating markers related to FASD. Luminex immunoassays were employed to analyze serum samples from FASD patients, identifying seven predictive biomarkers involved in neuroinflammation and immune dysregulation: IL-10, IFNγ, CCL2, NGFβ, IL-1β, CX3CL1, and CXCL16. These biomarkers reflect key disruptions in brain health, particularly in neuroinflammation, which contributes to the cognitive, behavioral, and mental health challenges frequently observed in FASD patients, including memory deficits, attention problems, and emotional dysregulation. To enhance diagnostic precision, machine learning (ML) models were trained on these biomarker datasets, with Random Forest (RF) achieving the highest accuracy (0.89), sensitivity (0.92), specificity (0.83), and ROC AUC (0.88). Additionally, an open-label pilot study in children diagnosed with FASD showed significant restoration of the levels of IFNy, CX3CL1, IL-1β, IL-10, and NGFβ after 12 months of EGCG treatment, suggesting its potential role in mitigating neuroinflammatory responses and promoting neurogenesis. These findings underscore the value of integrating serum biomarkers with ML-driven approaches to advance FASD diagnostics, while also identifying EGCG as a promising intervention for neurodevelopmental and mental health impairments associated with the disorder.
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    The frequency-following response (FFR) in late preterm neonates: a pilot study
    (Frontiers Media, 2024-05-09) Ribas-Prats, Teresa; Arenillas-Alcón, Sonia; Ferrero Martinez, Sílvia ; Gómez Roig, Ma. Dolores; Escera i Micó, Carles
    Introduction: Infants born very early preterm are at high risk of language delays. However, less is known about the consequences of late prematurity. Hence, the aim of the present study is to characterize the neural encoding of speech sounds in late preterm neonates in comparison with those born at term. Methods: The speech-evoked frequency-following response (FFR) was recorded to a consonant-vowel stimulus /da/ in 36 neonates in three different groups: 12 preterm neonates [mean gestational age (GA) 36.05 weeks], 12 “early term neonates” (mean GA 38.3 weeks), and “late term neonates” (mean GA 41.01 weeks). Results: From the FFR recordings, a delayed neural response and a weaker stimulus F0 encoding in premature neonates compared to neonates born at term was observed. No differences in the response time onset nor in stimulus F0 encoding were observed between the two groups of neonates born at term. No differences between the three groups were observed in the neural encoding of the stimulus temporal fine structure. Discussion: These results highlight alterations in the neural encoding of speech sounds related to prematurity, which were present for the stimulus F0 but not for its temporal fine structure.
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    Effects of Antioxidant Intake on Fetal Development and Maternal/Neonatal Health during Pregnancy.
    (MDPI, 2022-03-28) Sebastiani, Giorgia; Navarro Tapia, Elisabet; Almeida Toledano, Laura; Serra Delgado, Mariona; Paltrinieri, Anna Lucia; García Algar, Óscar; Andreu Fernández, Vicente
    During pregnancy, cycles of hypoxia and oxidative stress play a key role in the proper development of the fetus. Hypoxia during the first weeks is crucial for placental development, while the increase in oxygen due to the influx of maternal blood stimulates endothelial growth and angiogenesis. However, an imbalance in the number of oxidative molecules due to endogenous or exogenous factors can overwhelm defense systems and lead to excessive production of reactive oxygen species (ROS). Many pregnancy complications, generated by systemic inflammation and placental vasoconstriction, such as preeclampsia (PE), fetal growth restriction (FGR) and preterm birth (PTB), are related to this increase of ROS. Antioxidants may be a promising tool in this population. However, clinical evidence on their use, especially those of natural origin, is scarce and controversial. Following PRISMA methodology, the current review addresses the use of natural antioxidants, such as epigallocatechin gallate (EGCG), melatonin and resveratrol (RESV), as well as other classical antioxidants (vitamin C and E) during the prenatal period as treatment of the above-mentioned complications. We review the effect of antioxidant supplementation on breast milk in lactating mothers.
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    Effects of maternal drinking patterns and epigallocatechin-3-gallate treatment on behavioural and molecular outcomes in a mouse model of fetal alcohol spectrum disorders
    (Elsevier Masson SAS, 2025-05-10) Vieiros, Melina; Almeida Toledano, Laura; Serra Delgado, Mariona; Navarro Tapia, Elisabet; Ramos-Triguero, Anna; Muñoz Lozano, Concha; Martínez Martínez, Leopoldo; Marchei, Emilia; Gómez Roig, Ma. Dolores; García Algar, Óscar; Andreu Fernández, Vicente
    Prenatal alcohol exposure (PAE) impairs fetal development leading to fetal alcohol spectrum disorders (FASD). Antioxidants like epigallocatechin-3-gallate (EGCG) may mitigate alcohol-induced oxidative stress, a major contributor to FASD. This study assessed the effects of PAE on cognition and behaviour under two drinking patterns and the role of postnatal EGCG therapy in a FASD-like mouse model. C57BL/6J mice were divided into five groups: control, moderate drinking (Mod), binge drinking (Bin), Mod+EGCG, and Bin+EGCG. Cognitive and behavioural performance were assessed using Rotarod test, T-Maze, and Morris Water Maze (MWM). Western blot analyses evaluated brain and cerebellum biomarkers related to neuronal plasticity, maturation, differentiation, transport, and proliferation. PAE impaired motor coordination, significantly reducing rotarod walking time in both drinking patterns. Spatial learning and memory were also disrupted, decreasing T-maze success rate. It also decreased time in the platform area and distance travelled in MWM. Both drinking patterns affected neuronal plasticity (BDNF, DYRK1A) and maturation (NeuN), astrocyte differentiation (GFAP, s100β), neuronal transport (MBP) and proliferation (GDNF, Wnt-3) via oxidative stress (Nrf2). Our results show how EGCG treatment significantly improved behavioural tests results and restored most brain and cerebellum biomarkers, reaching levels similar to control. These findings highlight the impact of PAE on cognition and behaviour and how EGCG may counteract its effects by reducing oxidative stress and enhancing brain plasticity. Our findings open the door to future studies on the mechanism of action of this antioxidant in order to use it as a therapeutic tool in this vulnerable population.
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    Mortality and severe neurological morbidity in extremely preterm fetal growth-restricted fetuses
    (John Wiley & Sons, 2023-12) Mazarico Gallego, Edurne; Meler Barrabés, Eva; Mendoza Cobaleda, Manel; Herraiz, Ignacio; Llurba Olivé, Elisa; De Diego, Raúl; Comas Rovira, Montserrat; Boada, David; González Cammareri, Anna; Bonacina, Erika; Armengol Alsina, Mireia; Moline, Elisenda; Hurtado, Ivan; Torre, Núria; Gómez Roig, Ma. Dolores; Galindo Izquierdo, Alberto; Figueras, Francesc
    Objective: To develop a model for the prediction of adverse perinatal outcome in growth-restricted fetuses requiring delivery before 28 weeks in order to provide individualized patient counseling. Methods: This was a retrospective multicenter cohort study of singleton pregnancies with antenatal suspicion of fetal growth restriction requiring delivery before 28 weeks' gestation between January 2010 and January 2020 in six tertiary public hospitals in the Barcelona area, Spain. Separate predictive models for mortality only and mortality or severe neurological morbidity were created using logistic regression from variables available antenatally. For each model, predictive performance was evaluated using receiver-operating-characteristics (ROC)-curve analysis. Predictive models were validated externally in an additional cohort of growth-restricted fetuses from another public tertiary hospital with the same inclusion and exclusion criteria. Results: A total of 110 cases were included. The neonatal mortality rate was 37.3% and, among the survivors, the rate of severe neurological morbidity was 21.7%. The following factors were retained in the multivariate analysis as significant predictors of mortality: magnesium sulfate neuroprotection, gestational age at birth, estimated fetal weight, male sex and Doppler stage. This model had a significantly higher area under the ROC curve (AUC) compared with a model including only gestational age at birth (0.810 (95% CI, 0.730-0.889) vs 0.695 (95% CI, 0.594-0.795); P = 0.016). At a 20% false-positive rate, the model showed a sensitivity, negative predictive value and positive predictive value of 66%, 80% and 66%, respectively. For the prediction of the composite adverse outcome (mortality or severe neurological morbidity), the model included: gestational age at birth, male sex and Doppler stage. This model had a significantly higher AUC compared with a model including only gestational age at birth (0.810 (95% CI, 0.731-0.892) vs 0.689 (95% CI, 0.588-0.799); P = 0.017). At a 20% false-positive rate, the model showed a sensitivity, negative predictive value and positive predictive value of 55%, 63% and 74%, respectively. External validation of both models yielded similar AUCs that did not differ significantly from those obtained in the original sample. Conclusions: Estimated fetal weight, fetal sex and Doppler stage can be combined with gestational age to improve the prediction of death or severe neurological sequelae in growth-restricted fetuses requiring delivery before 28 weeks. This approach may be useful for parental counseling and decision-making. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.
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    External validation of a non-invasive vaginal tool to assess the risk of intra-amniotic inflammation in pregnant women with preterm labor and intact membranes
    (Walter de Gruyter, 2024) Cobo Cobo, Maria Teresa; Burgos Artizzu, Xavier P.; Ferrero Martinez, Sílvia ; Balcells, Judith; Bosch, Jaime; Gené, Amadeu; Murillo Bravo, Clara; Rueda, Claudia; Boada, David; Sánchez Antón, Maria Teresa; Kacerovsky, Marian; Jacobsson, Bo; Palacio, Montse
    Objectives: To prospectively validate the diagnostic performance of a non-invasive point-of-care tool (Rapid IAI System), including vaginal alpha-fetoprotein and interleukin-6, to predict the occurrence of intra-amniotic inflammation in a Spanish cohort of patients admitted with a diagnosis of preterm labor and intact membranes. Methods: From 2017 to 2022, we prospectively evaluated a cohort of pregnant women diagnosed with preterm labor and intact membranes admitted below 34+0 weeks who underwent amniocentesis to rule-in/out intra-amniotic infection and/or inflammation. Vaginal sampling was performed at the time of amniocentesis or within 24-48 h. Amniotic fluid IL-6, vaginal alpha-fetoprotein and vaginal IL-6 concentrations were measured using a point-of-care tool provided by Hologic Inc., "Rapid IAI System". We defined intra-amniotic inflammation when amniotic fluid IL-6 values were greater than 11.3 ng/mL. During recruitment, clinicians were blinded to the results of the point-of-care tool. The original prediction model proposed by Hologic Inc. to predict intra-amniotic inflammation was validated in this cohort of patients. Results: We included 151 patients diagnosed with preterm labor and intact membranes. Among these, 29 (19.2 %) had intra-amniotic inflammation. The algorithm including vaginal IL-6 and alpha-fetoprotein showed an area under curve to predict intra-amniotic inflammation of 80.3 % (±5.3 %) with a sensitivity of 72.4 %, specificity of 84.6 %, positive predictive valuve (PPV) of 52.5 %, negative predictive value (NPV) of 92.9 %, and a positive likelihood ratio (LR+) of 4.6 and negative likelihood ratio (LR-) of 0.33. Conclusions: External validation of a non-invasive rapid point-of-care tool, including vaginal alpha-fetoprotein and IL-6, showed very good diagnostic performance for predicting the absence of intra-amniotic inflammation in women with preterm labor and intact membranes.
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    A Rapid Amniotic Fluid Interleukin-6 Assessment for the Identification of Intra-Amniotic Inflammation in Women with Preterm Labor and Intact Membranes
    (Karger, 2021-06-01) Cobo Cobo, Maria Teresa; Aldecoa Bilbao, Victoria; Holeckova, Magdalena; Andrys, Ctirad; Filella Pla, Xavier; Jacobsson, Bo; Kacerovsky, Marian
    Objectives: A multivariable predictive model has recently been developed with good accuracy to predict spontaneous preterm delivery within 7 days in women with preterm labor (PTL) and intact membranes. However, this model measures amniotic fluid (AF) interleukin (IL)-6 concentrations using the ELISA method, thereby limiting clinical implementation. The main objectives of this study were to validate the automated immunoassay as a quantitative method to measure AF IL-6 in women with PTL and to evaluate the diagnostic performance of AF IL-6 alone and as part of a multivariable predictive model to predict spontaneous delivery in 7 days with this automated method. Study design: This is a retrospective observational study in women with PTL below 34 weeks who underwent amniocentesis to rule out microbial invasion of the amniotic cavity. Women with clinical signs of chorioamnionitis, cervical length measurement at admission >5th centile, maternal age <18 years, and no consent to perform amniocentesis for this indication were excluded. The local Institutional Review Boards approved the study (HCB/2019/0940). Analysis of AF IL-6 Concentrations: AF IL-6 concentrations were measured using an automated Cobas e602 electrochemiluminescence immunoanalyzer and Human IL-6 Quantikine ELISA kit. Results: Of the entire study group (n = 100), 38 women spontaneously delivered within 7 days after admission. Both laboratory methods showed good agreement (intraclass correlation coefficient: 0.937 (95% confidence interval [CI] 0.908-0.957); p < 0.001). Diagnostic performance of AF IL-6 to predict spontaneous delivery within 7 days when it was included in the multivariable predictive model showed an area under the receiver operating characteristic curve of 0.894 (95% CI 0.799-0.955), sensitivity of 97%, specificity of 74%, positive predictive value of 73%, negative predictive value of 97%, positive likelihood ratio (LR) of 3.7, and negative LR of 0.045. Conclusion: While both analytical methods were comparable for measuring AF IL-6 concentrations in women with PTL, the Cobas immunoanalyzer provided rapid diagnosis of intra-amniotic inflammation within minutes. The predictive model showed a good diagnostic performance to target women at high risk of spontaneous delivery within 7 days.
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    Intra-amniotic infection and/or inflammation is associated with fetal cardiac concentric hypertrophy and diastolic dysfunction in preterm labor and preterm prelabor rupture of membranes.
    (Elsevier, 2024-01-09) Murillo Bravo, Clara; Rueda Ricarte, Claudia; Larroya Solà, Marta; Boada, David; Grau, Laia; Ponce, Júlia; Herranz Barbero, Ana; Gómez del Rincón, Olga; Ferrero Martinez, Sílvia ; Andreu Fernández, Vicente; Gratacós Solsona, Eduard; Crispi Brillas, Fàtima; Palacio, Montse; Cobo Cobo, Maria Teresa
    Background: Preterm delivery is associated with cardiovascular remodeling and dysfunction in children and adults. However, it is unknown whether these effects are caused by the neonatal consequences of preterm birth or if these are already present in utero. Objective: We evaluated fetal cardiac morphology and function in fetuses of mothers admitted for preterm labor or preterm prelabor rupture of membranes and the association of these changes with the presence of intra-amniotic infection and/or inflammation. Study design: In this prospective cohort study, fetal echocardiography and amniocentesis were performed at admission in singleton pregnant women with preterm labor and/or preterm prelabor rupture of membranes between 24.0 and 34.0 weeks' gestation with (intra-amniotic infection and/or inflammation group, n=41) and without intra-amniotic infection and/or inflammation (non-intra-amniotic infection and/or inflammation, n=54). Controls (n=48) were outpatient pregnant women without preterm labor or preterm prelabor rupture of membranes. Intra-amniotic infection was defined by a positive amniotic fluid culture or positive 16S ribosomal RNA gene. Intra-amniotic inflammation was defined by using the amniotic fluid interleukin-6 cutoff levels previously reported by our group being >1.43 ng/mL in preterm prelabor rupture of membranes and >13.4 ng/mL in preterm labor. Fetal cardiac morphology and function was evaluated using echocardiography, and troponin-I and N-terminal pro-brain natriuretic peptide concentrations were measured in amniotic fluid from women with preterm labor or preterm prelabor rupture of membranes and compared with 20 amniotic fluid Biobank samples obtained for reasons other than preterm labor or preterm prelabor rupture of membranes or cardiac pathology. The data were adjusted for the estimated fetal weight below the 10th percentile and for preterm prelabor rupture of membranes at admission and also for gestational age at amniocentesis when amniotic fluid biomarkers were compared. Results: From 2018 to 2021, 143 fetuses were included; 95 fetuses were from mothers admitted with a diagnosis of preterm labor or preterm prelabor rupture of membranes, and among those, 41 (28.7%) were in the intra-amniotic infection and/or inflammation group and 54 (37.8%) were in the non-intra-amniotic infection and/or inflammation group. A total of 48 (33.6%) fetuses were included in the control group. Fetuses with preterm labor and/or preterm prelabor rupture of membranes had signs of subclinical cardiac concentric hypertrophy (median left wall thickness of 0.93 [interquartile range, 0.72-1.16] in the intra-amniotic infection and/or inflammation group; 0.79 [0.66-0.92] in the non-intra-amniotic infection and/or inflammation group; and 0.69 [0.56-0.83] in controls; P<.001) and diastolic dysfunction (tricuspid A duration 0.23 seconds [0.21-0.25], 0.24 [0.22-0.25], and 0.21 [0.2-0.23]; P=.007). Systolic function was similar among groups. Higher values of amniotic fluid troponin I (1413 pg/mL [927-2334], 1190 [829-1636], and 841 [671-959]; P<.001) and N-terminal pro-brain natriuretic peptide were detected (35.0%, 17%, and 0%; P=.005) in fetuses with preterm labor or preterm prelabor rupture of membranes when compared with the control group. The highest N-terminal pro-brain natriuretic peptide concentrations were found in the intra-amniotic infection and/or inflammation group. Conclusion: Fetuses with preterm labor or preterm prelabor rupture of membranes showed signs of cardiac remodeling and subclinical dysfunction, which were more pronounced in those exposed to intra-amniotic infection and/or inflammation. These findings support that the cardiovascular effects observed in children and adults born preterm have, at least in part, a prenatal origin.
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    Acupuncture before planned admission for induction of labor (ACUPUNT study): a randomized controlled trial
    (Elsevier Inc., 2024-08-17) Zamora Brito, Montserrat; Migliorelli, Federico; Pérez Guervós, Raquel; Solans Oliva, Rosa; Arranz Betegón, Ángela; Palacio, Montse
    Background: The increase in the use of induction of labor is a worldwide phenomenon in the current management of labor and delivery in Western societies, with approximately one out of every 4 pregnancies undergoing this procedure This has led women to seek various methods for stimulation of the onset of labor. Some data suggest that the use of acupuncture for favoring spontaneous labor onset could reduce the number of inductions of labor procedures. However, good quality evidence in this respect is not yet available. Objective: The aim of this study was to evaluate the effectiveness of acupuncture using a filiform needle to induce spontaneous onset of labor in women with a scheduled induction of labor date and assess the safety and satisfaction of women undergoing acupuncture. Study design: We conducted a multicenter, randomized, controlled, parallel-arm, unmasked trial in 3 hospitals in Spain. Eligible participants were women older than 18 years with a singleton pregnancy and a cephalic presentation, scheduled for induction of labor following center-specific protocols. Participants were randomly allocated to one of 2 groups: the intervention group, which underwent acupuncture sessions for a maximum of 4 days prior to the scheduled induction of labor, or the control group, which received no specific prelabor intervention. The primary study outcome was the proportion of women admitted because of spontaneous onset of labor or premature rupture of membranes before or the day of the scheduled induction of labor. Results: Between November 2017 and June 2023, 212 women were recruited and included in the analysis (106 in the acupuncture group and 106 in the control group). There were no significant differences between the 2 groups in the baseline demographic characteristics. Regarding the primary outcome, 65.1% (69/106) of women in the acupuncture group and 39.6% (42/106) in the control group were admitted for spontaneous onset of labor or premature rupture of membranes (P<.001). Overall, women in the intervention group were admitted 1.25 days before (SD 1.4) their scheduled induction of labor date compared to 0.67 days (SD 1.15) for those in the control group (P=.001). The median time from recruitment to hospitalization was 4.48 days for the acupuncture group and 5.33 days for the control group (HR 0.52, 95% CI 0.35-0.77, P=.001). There were no significant differences between the 2 groups regarding the time from admission to delivery or the cesarean delivery rate. Nor were there differences in the rates of maternal or neonatal outcomes, and no maternal or fetal deaths occurred in either group. Conclusion: Acupuncture with filiform needles, administered 4 days prior to scheduled induction of labor increased admission for spontaneous onset of labor and premature rupture of membranes before the induction of labor date.
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    in vivo Monitoring with micro-implantable hypoxia sensor based on tissue acidosis
    (Elsevier B.V., 2021-05-01) Dulay, Samuel; Rivas, Lourdes; Miserere, Sandrine; Pla, Laura; Berdún, Sergio; Parra, Johanna; Eixarch Roca, Elisenda; Gratacós Solsona, Eduard; Illa, Míriam; Mir Llorente, Mònica; Samitier i Martí, Josep
    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 ePOCTM. 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 (R2 = 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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    Longitudinal evolution of central nervous system anomalies in fetuses with open spina bifida fetoscopic repair and correlation with neurologic outcome
    (2023-06-01) Trigo, Lucas; Eixarch Roca, Elisenda; Faig Leite, Fernanda; Gómez Chiari, Marta; Rebollo Polo, Mónica; Dalaqua, Mariana; Gratacós Solsona, Eduard; Lapa, Denise Araújo
    Background: Open spina bifida is associated with central nervous system anomalies such as abnormal corpus callosum and heterotopias. However, the impact of prenatal surgery over these structures remains unclear. Objective: This study aimed to describe longitudinal changes of central nervous system anomalies before and after prenatal open spina bifida repair and to evaluate their relationship with postnatal neurologic outcomes. Study design: Retrospective cohort study of fetuses with open spina bifida who underwent percutaneous fetoscopic repair from January 2009 to August 2020. All women had presurgical and postsurgical fetal magnetic resonance imaging, at an average of 1 week before and 4 weeks after surgery, respectively. We evaluated defect characteristics in the presurgical magnetic resonance images; and fetal head biometry, clivus supraocciput angle, and the presence of structural central nervous system anomalies, such as abnormalities in corpus callosum, heterotopias, ventriculomegaly, and hindbrain herniation, in both presurgical and postsurgical magnetic resonance images. Neurologic assessment was performed using the Pediatric Evaluation of Disability Inventory scale in children who were 12 months or older, covering 3 different sections, namely self-care, mobility, and social and cognitive function. Results: A total of 46 fetuses were evaluated. Presurgery and postsurgery magnetic resonance imaging were performed at a median gestational age of 25.3 and 30.6 weeks, with a median interval of 0.8 weeks before surgery, and 4.0 weeks after surgery. There was a 70% reduction in hindbrain herniation (100% vs 32.6%; P<.001), and a normalization of the clivus supraocciput angle after surgery (55.3 [48.8-61.0] vs 79.9 [75.2-85.4]; P<.001). No significant increase in abnormal corpus callosum (50.0% vs 58.7%; P=.157) or heterotopia (10.8% vs 13.0%; P=.706) was observed. Ventricular dilation was higher after surgery (15.6 [12.7-18.1] vs 18.8 [13.7-22.9] mm; P<.001), with a higher proportion of severe ventricular dilation after surgery (≥15mm) (52.2% vs 67.4%; P=.020). Thirty-four children underwent neurologic assessment, with 50% presenting a global optimal Pediatric Evaluation of Disability Inventory result and 100% presenting a normal social and cognitive function. Children with optimal global Pediatric Evaluation of Disability Inventory presented a lower rate of presurgical anomalies in corpus callosum and severe ventriculomegaly. When analyzed as independent variables to global Pediatric Evaluation of Disability Inventory scale, the presence of abnormal corpus callosum and severe ventriculomegaly showed an odds ratio of 27.7 (P=.025; 95% confidence interval, 1.53-500.71) for a suboptimal result. Conclusion: Prenatal open spina bifida repair did not change the proportion of abnormal corpus callosum nor heterotopias after surgery. The combination of presurgical abnormal corpus callosum and severe ventricular dilation (≥15 mm) is associated with an increased risk of suboptimal neurodevelopment.