MATERNAL LIFESTYLE AND PRENATAL RISK FACTORS FOR CHILDHOOD LEUKEMIA: A REVIEW OF THE EXISTING EVIDENCE.

Acute leukemia is the most common pediatric cancer, with an incidence peak at 2-5 years of age. Despite the medical advances improving survival rates, children suffer from significant side-effects of treatments as well as its high social and economic impact. The frequent prenatal origin of this developmental disease follows the two-hit carcinogenesis model established in the 70s: a first hit in prenatal life with the creation of genetic fusion lesions or aneuploidy in hematopoietic progenitor/stem cells, and usually a second hit in pediatric age that converts the preleukemic clone into clinical leukemia. Previous research has mostly focused on postnatal environmental factors triggering the second hit. There is scarce evidence on prenatal risk factors associated with the first hit. Mainly retrospective case-control studies suggested several environmental and lifestyle determinants as risk factors. If these associations could be confirmed, interventions focused on modifying prenatal factors might influence the subsequent risk of leukemia during childhood and reveal unexplored research avenues for the future. In this review, we aim to comprehensively summarize the currently available evidence on prenatal risk factors for the development of childhood leukemia.

Pulmonary vascular reactivity in growth restricted fetuses using computational modelling and machine learning analysis of fetal Doppler waveforms.

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.

Multicentre randomised trial of screening with sFlt1/PlGF and planned delivery to prevent pre-eclampsia at term: protocol of the PE37 study.

INTRODUCTION: Pre-eclampsia affects ~5%-7% of pregnancies. Although improved obstetric care has significantly diminished its associated maternal mortality, it remains a leading cause of maternal morbidity and mortality in the world. Term pre-eclampsia accounts for 70% of all cases and a large proportion of maternal-fetal morbidity related to this condition. Unlike in preterm pre-eclampsia, the prediction and prevention of term pre-eclampsia remain unsolved. Previously proposed approaches are based on combined third-trimester screening and/or prophylactic drugs, but these policies are unlikely to be widely implementable in many world settings. Recent evidence shows that the soluble fms-like tyrosine kinase-1 (s-Flt-1) to placental growth factor (PlGF) ratio measured at 35-37 weeks' gestation predicts term pre-eclampsia with an 80% detection rate. Likewise, recent studies demonstrate that induction of labour beyond 37 weeks is safe and well accepted by women. We hypothesise that a single-step universal screening for term pre-eclampsia based on sFlt1/PlGF ratio at 35-37 weeks followed by planned delivery beyond 37 weeks reduces the prevalence of term pre-eclampsia without increasing the caesarean section rates or worsening the neonatal outcomes. METHODS AND ANALYSIS: We propose an open-label randomised clinical trial to evaluate the impact of a screening of term pre-eclampsia with the sFlt-1/PlGF ratio followed by planned delivery in asymptomatic nulliparous women at 35-37 weeks. Women will be assigned 1:1 to revealed (sFlt-1/PlGF known to clinicians) versus concealed (unknown) arms. A cut-off of >90th centile is used to define the high risk of subsequent pre-eclampsia and offer planned delivery from 37 weeks. The efficacy variables will be analysed and compared between groups primarily following an intention-to-treat approach, by ORs and their 95% CI. This value will be computed using a Generalised Linear Mixed Model for binary response (study group as fixed effect and the centre as intercept random effect). ETHICS AND DISSEMINATION: The study is conducted under the principles of Good Clinical Practice. This study was accepted by the Clinical Research Ethics Committee of Hospital Clinic Barcelona on 20 November 2020. Subsequent approval by individual ethical committees and competent authorities was granted. The study results will be published in peer-reviewed journals and disseminated at international conferences. TRIAL REGISTRATION NUMBER: NCT04766866.

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.

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.

10. Role of high dimensional technology in preeclampsia (omics in preeclampsia).

Preeclampsia is a pregnancy-specific disease that has no known precise cause. Integrative biology approach based on multi-omics has been applied to identify upstream pathways and better understand the pathophysiology of preeclampsia. At DNA level, genomics and epigenomics studies have revealed numerous genetic variants associated with preeclampsia, including those involved in regulating blood pressure and immune response. Transcriptomics analyses have revealed altered expression of genes in preeclampsia, particularly those related to inflammation and angiogenesis. At protein level, proteomics studies have identified potential biomarkers for preeclampsia diagnosis and prediction in addition to revealing the main pathophysiological pathways involved in this disease. At metabolite level, metabolomics has highlighted altered lipid and amino acid metabolisms in preeclampsia. Finally, microbiomics studies have identified dysbiosis in the gut and vaginal microbiota in pregnant women with preeclampsia. Overall, omics technologies have improved our understanding of the complex molecular mechanisms underlying preeclampsia. However, further research is warranted to fully integrate and translate these omics findings into clinical practice.

Diurnal cortisol throughout pregnancy and its association with maternal depressive symptoms and birth outcomes.

BACKGROUND: Depression during pregnancy is a common complication that can negatively affect fetal health and birth outcomes. Cortisol is believed to be a key mediator of this association. Although pregnancy entails a natural increase in cortisol levels, preclinical depression could alter its circadian rhythm, producing excessively high overall diurnal cortisol levels that might be harmful for the fetus and future offspring development. OBJECTIVES: Using a prospective longitudinal design, we aimed to study (i) trimestral cortisol circadian rhythm and its overall levels throughout pregnancy in healthy women, (ii) the extent to which maternal depressive symptoms influence both cortisol rhythmicity and overall levels, and (iii) the possible adverse consequences of elevated maternal cortisol on the offspring's weight and gestational age at birth. STUDY DESIGN: 112 healthy pregnant women from the general Spanish population were recruited before their first pregnancy. To assess cortisol circadian rhythm, participants provided four saliva samples at each trimester of pregnancy (at awakening, 30 min after awakening, before lunch and before going to bed). Overall cortisol levels were calculated with AUCg approximation. Depressive symptoms were evaluated in each trimester and defined according to EPDS cut-off values (1st trimester, EPDS ≥ 11; 2nd and 3rd trimesters, EPDS ≥ 10). At birth, the risk for low weight, prematurity and weight birth percentile was retrieved for 100 infants. Mixed models and simple effects were employed to study changes of maternal cortisol circadian rhythm and overall levels throughout pregnancy and the possible influence of maternal depressive symptoms. Finally, logistic regressions were performed to assess the associations between maternal overall cortisol levels in each trimester of pregnancy and birth anthropometrics. RESULTS: Although overall diurnal cortisol levels increase throughout pregnancy, cortisol circadian rhythm is preserved in all trimesters [1st (F(3110)= 92.565, p < .001), 2nd (F(3,85)= 46.828, p < .001) and 3rd (F(3,90)= 65.555, p < .001)]. However, women with depressive symptoms showed a flattened cortisol circadian pattern only during the second trimester, characterized by a blunted awakening peak and reduced evening decline (F(3,85)= 4.136, p = .009), but not during the first (F(3,11)= 1.676, p = .176) or the third (F(3,90)= 1.089, p = .358) trimesters. Additionally, they did not show a cortisol increase from second to third trimester (p = .636). Finally, higher maternal cortisol levels in second and third trimesters seemed to be associated with increased risk of prematurity (adjusted OR -0.371, 95% CI 0.490-0.972, p = .034) and low birth weight percentile (adjusted OR -0.612, 95% CI 0.348-0.846, p = .007) respectively. CONCLUSION: Maternal cortisol levels increased throughout pregnancy, although cortisol circadian rhythm was preserved in all trimesters of pregnancy. However, prenatal depressive symptoms were associated with flattened maternal cortisol circadian rhythm in mid-pregnancy. Therefore, it seems that women with depressive symptoms tended to increase less gradually their cortisol levels from mid to late pregnancy. Finally, higher maternal cortisol levels in mid and late-pregnancy seem to be associated with poorer birth anthropometrics Early detection of depressive symptoms in general population could help to prevent putative obstetrical and birth adverse outcomes.

Maternal Stress, Anxiety, Well-Being, and Sleep Quality in Pregnant Women throughout Gestation.

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 the World Health Organization Well-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.

Endothelial activation and damage as a common pathological substrate in different pathologies and cell therapy complications.

The endothelium is a biologically active interface with multiple functions, some of them common throughout the vascular tree, and others that depend on its anatomical location. Endothelial cells are continually exposed to cellular and humoral factors, and to all those elements (biological, chemical, or hemodynamic) that circulate in blood at a certain time. It can adapt to different stimuli but this capability may be lost if the stimuli are strong enough and/or persistent in time. If the endothelium loses its adaptability it may become dysfunctional, becoming a potential real danger to the host. Endothelial dysfunction is present in multiple clinical conditions, such as chronic kidney disease, obesity, major depression, pregnancy-related complications, septic syndromes, COVID-19, and thrombotic microangiopathies, among other pathologies, but also in association with cell therapies, such as hematopoietic stem cell transplantation and treatment with chimeric antigen receptor T cells. In these diverse conditions, evidence suggests that the presence and severity of endothelial dysfunction correlate with the severity of the associated disease. More importantly, endothelial dysfunction has a strong diagnostic and prognostic value for the development of critical complications that, although may differ according to the underlying disease, have a vascular background in common. Our multidisciplinary team of women has devoted many years to exploring the role of the endothelium in association with the mentioned diseases and conditions. Our research group has characterized some of the mechanisms and also proposed biomarkers of endothelial damage. A better knowledge would provide therapeutic strategies either to prevent or to treat endothelial dysfunction.

Cardiometabolic sex differences in adults born small for gestational age.

Aim: This study aimed to assess the cardiometabolic sex similarities and differences in adults born small for gestational age. Methods: This study was an ambispective cohort study from a birth registry in Barcelona, Spain, including 523 adult participants (20-40 years-old) subdivided as born small for gestational age (SGA, if birth weight <10th centile) or adequate fetal growth for gestational age (AGA). Cardiometabolic health was assessed by echocardiography, electrocardiogram, blood pressure measurement, vascular ultrasound, anthropometric measurements, and serum glycemia and lipid profile. Stratified analyses by sex were performed by estimation of adjusted absolute difference (AAD) using inverse probability weighting. Results: Compared with AGA, the stratified analyses by sex showed a more pronounced reduction in ejection fraction [AAD: female -1.73 (95% CI -3.2 to -0.28) vs. male -1.33 (-3.19 to 0.52)] and increment in heart rate [female 3.04 (0.29-5.8) vs. male 2.25 (-0.82 to 5.31)] in SGA females compared with SGA males. In contrast, a more pronounced reduction in PR interval [female -1.36 (-6.15 to 3.42) vs. male -6.61 (-11.67 to -1.54)] and an increase in systolic blood pressure [female 0.06 (-2.7 to 2.81) vs. male 2.71 (-0.48 to 5.9)] and central-to-peripheral fat ratio [female 0.05 (-0.03 to 0.12) vs. male 0.40 (0.17-0.62)] were mainly observed in SGA male compared with SGA female. Conclusions: Sex differences were observed in the effect of SGA on cardiometabolic endpoints with female being more prone to cardiac dysfunction and male to electrocardiographic, vascular, and metabolic changes. Future research including sex-stratification data is warranted.

Effects of Mediterranean diet or mindfulness-based stress reduction on fetal and neonatal brain development: a secondary analysis of a randomized clinical trial.

BACKGROUND: Maternal suboptimal nutrition and high stress levels are associated with adverse fetal and infant neurodevelopment. OBJECTIVE: This study aimed to investigate if structured lifestyle interventions involving a Mediterranean diet or mindfulness-based stress reduction during pregnancy are associated with differences in fetal and neonatal brain development. STUDY DESIGN: This was a secondary analysis of the randomized clinical trial Improving Mothers for a Better Prenatal Care Trial Barcelona that was conducted in Barcelona, Spain, from 2017 to 2020. Participants with singleton pregnancies were randomly allocated into 3 groups, namely Mediterranean diet intervention, stress reduction program, or usual care. Participants in the Mediterranean diet group received monthly individual sessions and free provision of extra-virgin olive oil and walnuts. Pregnant women in the stress reduction group underwent an 8-week mindfulness-based stress reduction program adapted for pregnancy. Magnetic resonance imaging of 90 fetal brains was performed at 36 to 39 weeks of gestation and the Neonatal Neurobehavioral Assessment Scale was completed for 692 newborns at 1 to 3 months. Fetal outcomes were the total brain volume and lobular or regional volumes obtained from a 3-dimensional reconstruction and semiautomatic segmentation of magnetic resonance images. Neonatal outcomes were the 6 clusters scores of the Neonatal Neurobehavioral Assessment Scale. Multiple regression analyses were conducted to assess the association between the interventions and the fetal and neonatal outcomes. RESULTS: When compared with the usual care group, the offspring exposed to a maternal Mediterranean diet had a larger total fetal brain volume (mean, 284.11 cm3; standard deviation, 23.92 cm3 vs 294.01 cm3; standard deviation, 26.29 cm3; P=.04), corpus callosum (mean, 1.16 cm3; standard deviation, 0.19 cm3 vs 1.26 cm3; standard deviation, 0.22 cm3; P=.03), and right frontal lobe (44.20; standard deviation, 4.09 cm3 vs 46.60; standard deviation, 4.69 cm3; P=.02) volumes based on magnetic resonance imaging measures and higher scores in the Neonatal Neurobehavioral Assessment Scale clusters of autonomic stability (mean, 7.4; standard deviation, 0.9 vs 7.6; standard deviation, 0.7; P=.04), social interaction (mean, 7.5; standard deviation, 1.5 vs 7.8; standard deviation, 1.3; P=.03), and range of state (mean, 4.3; standard deviation, 1.3 vs 4.5; standard deviation, 1.0; P=.04). When compared with the usual care group, offspring from the stress reduction group had larger fetal left anterior cingulate gyri volume (1.63; standard deviation, 0.32 m3 vs 1.79; standard deviation, 0.30 cm3; P=.03) based on magnetic resonance imaging and higher scores in the Neonatal Neurobehavioral Assessment Scale for regulation of state (mean, 6.0; standard deviation, 1.8 vs 6.5; standard deviation, 1.5; P<.01). CONCLUSION: Maternal structured lifestyle interventions involving the promotion of a Mediterranean diet or stress reduction during pregnancy were associated with changes in fetal and neonatal brain development.

Similarity network fusion to identify phenotypes of small-for-gestational-age fetuses.

Fetal growth restriction (FGR) affects 5-10% of pregnancies, is the largest contributor to fetal death, and can have long-term consequences for the child. Implementation of a standard clinical classification system is hampered by the multiphenotypic spectrum of small fetuses with substantial differences in perinatal risks. Machine learning and multiomics data can potentially revolutionize clinical decision-making in FGR by identifying new phenotypes. Herein, we describe a cluster analysis of FGR based on an unbiased machine-learning method. Our results confirm the existence of two subtypes of human FGR with distinct molecular and clinical features based on multiomic analysis. In addition, we demonstrated that clusters generated by machine learning significantly outperform single data subtype analysis and biologically support the current clinical classification in predicting adverse maternal and neonatal outcomes. Our approach can aid in the refinement of clinical classification systems for FGR supported by molecular and clinical signatures.

Diet quality and nutrient density in pregnant women according to adherence to Mediterranean diet.

Background and aims: The dietary pattern followed during pregnancy, specifically healthy dietary patterns such as the Mediterranean diet, is a key factor in the mother's and the offspring's health. Pregnant women dietary intake is not enough to cover the micronutrient requirements of pregnancy, and higher adherence to the Mediterranean diet may improve dietary quality and nutritional density. The aim of the present study was to describe the dietary nutrient intake and diet quality during pregnancy and to evaluate whether a high adherence to Mediterranean diet was associated with a more adequate intake of micronutrients. Methods: This was a cross-sectional study with 1,356 pregnant women selected during the routine second trimester ultrasound scan (19-23 weeks' gestation). Energy and nutrient intake were calculated using a validated 151-item semi-quantitative food frequency questionnaire and nutrient density was estimated dividing the absolute nutrient intake by total energy intake. Adherence to the Mediterranean diet was evaluated with a 17-item Mediterranean diet adherence score. The criterion used for risk of inadequate nutrient intake has been set below two thirds (2/3) of the dietary reference intakes. The differences were assessed by multivariate linear regression models adjusted for confounders. Results: A significant proportion of pregnant women had an inadequate intake of macro and micronutrient that was lower in those with high adherence to the Mediterranean diet (≥12 points, n = 122, 19%), including calcium (the Mediterranean diet high adherence 2.5% vs. low adherence 26.7%, p < 0.001), magnesium (0% vs. 7.6%, p = 0.001), iron (24.5% vs. 74.1%, p < 0.001), and vitamin B9 (0% vs. 29.8%, p < 0.001), vitamin C (0% vs. 1.9%, p = 0.033), and vitamin D (61.5% vs. 92.8%, p < 0.001) intake. High adherence to Mediterranean diet was associated with higher intake of protein, monounsaturated fatty acids, fiber, vitamins (B1, B9, C, D), calcium, magnesium, iron, zinc, phosphor, potassium, essential fatty acids, and α-linolenic acid, and with a lower intake of α-linoleic acid and trans fatty acids as compared to low adherence to Mediterranean diet. Conclusion: High adherence to Mediterranean diet was associated with higher diet quality and lower proportion of inadequate micro and macronutrient intake. The Mediterranean diet promotion, particularly among pregnant women, may be a useful and public health strategy to avoid overweight and nutrient deficiencies.

A new FGF15/19-mediated gut-to-heart axis controls cardiac hypertrophy.

FGF15 and its human orthologue, FGF19, are members of the endocrine FGF family and are secreted by ileal enterocytes in response to bile acids. FGF15/19 mainly targets the liver, but recent studies indicate that it also regulates skeletal muscle mass and adipose tissue plasticity. The aim of this study was to determine the role(s) of the enterokine FGF15/19 during the development of cardiac hypertrophy. Studies in a cohort of humans suffering from heart failure showed increased circulating levels of FGF19 compared with control individuals. We found that mice lacking FGF15 did not develop cardiac hypertrophy in response to three different pathophysiological stimuli (high-fat diet, isoproterenol, or cold exposure). The heart weight/tibia length ratio and the cardiomyocyte area (as measures of cardiac hypertrophy development) under hypertrophy-inducing conditions were lower in Fgf15-null mice than in wild-type mice, whereas the levels of the cardiac damage marker atrial natriuretic factor (Nppa) were up-regulated. Echocardiographic measurements showed similar results. Moreover, the genes involved in fatty acid metabolism were down-regulated in Fgf15-null mice. Conversely, experimental increases in FGF15 induced cardiac hypertrophy in vivo, without changes in Nppa and up-regulation of metabolic genes. Finally, in vitro studies using cardiomyocytes showed that FGF19 had a direct effect on these cells promoting hypertrophy. We have identified herein an inter-organ signaling pathway that runs from the gut to the heart, acts through the enterokine FGF15/19, and is involved in cardiac hypertrophy development and regulation of fatty acid metabolism in the myocardium. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Effect of a Mediterranean Diet or Mindfulness-Based Stress Reduction During Pregnancy on Child Neurodevelopment: A Prespecified Analysis of the IMPACT BCN Randomized Clinical Trial.

Importance: Maternal suboptimal nutrition and high stress levels are associated with adverse fetal and childhood neurodevelopment. Objective: To test the hypothesis that structured interventions based on a Mediterranean diet or mindfulness-based stress reduction (MBSR) during pregnancy improve child neurodevelopment at age 2 years. Design, Setting, and Participants: This was a prespecified analysis of the parallel-group Improving Mothers for a Better Prenatal Care Trial Barcelona (IMPACT BCN) randomized clinical trial, which was conducted at a university hospital in Barcelona, Spain, from February 2017 to March 2020. A total of 1221 singleton pregnancies (19 to 23 weeks' gestation) with high risk of delivering newborns who were small for gestational age were randomly allocated into 3 groups: a Mediterranean diet intervention, an MBSR program, or usual care. A postnatal evaluation with the Bayley Scales of Infant and Toddler Development, 3rd Edition (Bayley-III), was performed. Data were analyzed from July to November 2022. Interventions: Participants in the Mediterranean diet group received monthly individual and group educational sessions and free provision of extra virgin olive oil and walnuts. Those in the stress reduction group underwent an 8-week MBSR program adapted for pregnancy. Individuals in the usual care group received pregnancy care per institutional protocols. Main Outcomes and Measures: Neurodevelopment in children was assessed by Bayley-III at 24 months of corrected postnatal age. Results: A total of 626 children (293 [46.8%] female and 333 [53.2%] male) participated at a mean (SD) age of 24.8 (2.9) months. No differences were observed in the baseline characteristics between intervention groups. Compared with children from the usual care group, children in the Mediterranean diet group had higher scores in the cognitive domain (ß, 5.02; 95% CI, 1.52-8.53; P = .005) and social-emotional domain (ß, 5.15; 95% CI, 1.18-9.12; P = .01), whereas children from the stress reduction group had higher scores in the social-emotional domain (ß, 4.75; 95% CI, 0.54-8.85; P = .02). Conclusions and Relevance: In this prespecified analysis of a randomized clinical trial, maternal structured lifestyle interventions during pregnancy based on a Mediterranean diet or MBSR significantly improved child neurodevelopmental outcomes at age 2 years. Trial Registration: ClinicalTrials.gov Identifier: NCT03166332.

QRS-T Angles as Markers for Heart Sphericity in Subjects With Intrauterine Growth Restriction: A Simulation Study.

Changes induced by intrauterine growth restriction (IUGR) in cardiovascular anatomy and function that persist throughout life have been associated with a higher predisposition to heart disease in adulthood. Together with cardiac morphological remodelling, evaluated through the ventricular sphericity index, alterations in cardiac electrical function have been reported by characterization of the depolarization and repolarization loops, and their angular relationship, measured from the vectorcardiogram. The underlying relationship between the morphological remodelling and the angular variation of QRS and T-wave dominant vectors, if any, has not been explored. The aim of this study was to evaluate this relationship using computational models based on realistic heart and torso in which IUGR-induced morphological changes were incorporated by reducing the ventricular sphericity index. Specifically, we departed from a control model and we built eight different globular heart models by reducing the base-to-apex length and enlarging the basal ventricular diameter. We computed QRS and T-wave dominant vectors and angles from simulated pseudo-electrocardiograms and we compared them with clinical measurements. Results for the QRS to T angles follow a change trend congruent with that reported in clinical data, supporting the hypothesis that the IUGR-induced morphological remodelling could contribute to explain the observed angle changes in IUGR patients. By additionally varying the position of the ventricles with respect to the torso and the electrodes, we found that electrode displacement can impact the quantified angles and should be considered when interpreting the results.

Correlation of placental lesions in patients with systemic lupus erythematosus, antiphospholipid syndrome and non-criteria obstetric antiphospholipid syndrome and adverse perinatal outcomes.

INTRODUCTION: We aimed to describe the pattern of placental injuries in women with systemic lupus erythematosus (SLE), antiphospholipid antibody syndrome (APS) and non-criteria obstetric APS (NC-OAPS), and to correlate the placental findings with the occurrence of adverse perinatal outcomes. METHODS: The perinatal outcomes and placental findings of pregnancies of women with SLE, APS, and NC-OAPS and gestational-age matched healthy controls were analyzed and classified according to the 2015 Redline - Classification of placental lesions. RESULTS: 91 women with SLE, APS, and NC-OAPS and 91 controls were included. Mean values of placental weight differed between groups, being significantly lower in NC-OAPS and APS groups compared to controls. Furthermore, 14.3% of placentas in the APS group were under the 3rd percentile, which was significantly higher in comparison with other groups. Regarding histopathological placental findings, maternal-side malperfusion was significantly increased in APS (46.4%) compared to NC-OAPS (14.3%) and SLE (9.5%). Fetal-side maldevelopment was significantly increased in NC-OAPS (19.1%) compared to controls (1.1%) and SLE (2.4%). A significantly increased prevalence of adverse perinatal outcomes (APOs) was observed in all studied groups compared to healthy controls (controls 3.3%, SLE 52.4%, NC-OAPS 57.1%, APS 64.3%). Overall, both maternal (OR 6.8, 95%CI 2.1-22) and fetal-side (OR 4.1, 95%CI 1.3-13.5) lesions were significantly associated with APO. Maternal malperfusion and fetal maldevelopment were the lesions most strongly associated with APOs. DISCUSSION: Pregnant women with SLE, APS, or NC-OAPS showed a different pattern of histopathological findings. Compared to controls, SLE, APS, and NC-OAPS conferred an increased risk of APOs that was strongly associated with placental maternal-side malperfusion and fetal-side maldevelopment.

Cord blood cardiovascular biomarkers in tetralogy of fallot and D-transposition of great arteries.

Previous reports suggest that cord blood biomarkers could serve as a prognostic tool for conotruncal congenital heart defects (CHD). We aimed to describe the cord blood profile of different cardiovascular biomarkers in a prospective series of fetuses with tetralogy of Fallot (ToF) and D-transposition of great arteries (D-TGA) and to explore their correlation with fetal echocardiography and perinatal outcome. Methods: A prospective cohort study (2014-2019), including fetuses with isolated ToF and D-TGA and healthy controls, was conducted at two tertiary referral centers for CHD in Barcelona. Obstetric ultrasound and fetal echocardiography were performed in the third trimester and cord blood was obtained at delivery. Cord blood concentrations of N-terminal precursor of B-type natriuretic peptide, Troponin I, transforming growth factorß (TGFß), placental growth factor, and soluble fms-like tyrosine kinase-1 were determined. Results: Thirty-four fetuses with conotruncal-CHD (22 ToF and 12 D-TGA) and 36 controls were included. ToF-fetuses showed markedly increased cord blood TGFß (24.9 ng/ml (15.6-45.3) vs. normal heart 15.7 ng/ml (7.2-24.3) vs. D-TGA 12.6 ng/ml (8.7-37.9); P = 0.012). These results remained statistically significant even after adjusting for maternal body mass index, birth weight and mode of delivery. TGFß levels showed a negative correlation with the pulmonary valve diameter z-score at fetal echocardiography (r = -0.576, P = 0.039). No other differences were found in the rest of cord blood biomarkers among the study populations. Likewise, no other significant correlations were identified between cardiovascular biomarkers, fetal echocardiography and perinatal outcome. Conclusions: This study newly describes increased cord blood TGFß concentrations in ToF compared to D-TGA and normal fetuses. We also demonstrate that TGFß levels correlate with the severity of right ventricle outflow obstruction. These novel findings open a window of research opportunities on new prognostic and potential preventive strategies.

Effects of a Mediterranean Diet Intervention on Maternal Stress, Well-Being, and Sleep Quality throughout Gestation-The IMPACT-BCN Trial.

Stress and anxiety are frequent occurrences among pregnant women. We aimed to evaluate the effects of a Mediterranean diet intervention during pregnancy on maternal stress, well-being, and sleep quality throughout gestation. In a randomized clinical trial, 1221 high-risk pregnant women were randomly allocated into three groups at 19-23 weeks' gestation: a Mediterranean diet intervention, a Mindfulness-Based Stress Reduction program, or usual care. All women who provided self-reported life-style questionnaires to measure their anxiety (State Trait Anxiety Inventory (STAI), Perceived Stress Scale (PSS)), well-being (WHO Five Well Being Index (WHO-5)), and sleep quality (Pittsburgh sleep quality index (PSQI)) at enrollment and at the end of the intervention (34-36 weeks) were included. In a random subgroup of 106 women, the levels of cortisol and related metabolites were also measured. At the end of the intervention (34-36 weeks), participants in the Mediterranean diet group had significantly lower perceived stress and anxiety scores (PSS mean (SE) 15.9 (0.4) vs. 17.0 (0.4), p = 0.035; STAI-anxiety mean (SE) 13.6 (0.4) vs. 15.8 (0.5), p = 0.004) and better sleep quality (PSQI mean 7.0 ± 0.2 SE vs. 7.9 ± 0.2 SE, p = 0.001) compared to usual care. As compared to usual care, women in the Mediterranean diet group also had a more significant increase in their 24 h urinary cortisone/cortisol ratio during gestation (mean 1.7 ± SE 0.1 vs. 1.3 ± SE 0.1, p < 0.001). A Mediterranean diet intervention during pregnancy is associated with a significant reduction in maternal anxiety and stress, and improvements in sleep quality throughout gestation.

Influence of accelerated arterial aging in growth-restricted cohorts on adult-onset cardiovascular diseases.

Epidemiologists have long documented a higher risk of adult-onset cardiovascular diseases (CVDs) such as stroke, hypertension, and coronary artery disease, as well as mortality from circulatory causes in low birth-weight cohorts (poor in utero substrate supply). Utero-placental insufficiency and in utero hypoxemic state-induced alterations in arterial structure and compliance are important initiating factors for adult-onset hypertension. The mechanistic links between fetal growth restriction and CVD include decreased arterial wall elastin-to-collagen ratio, endothelial dysfunction, and heightened renin-angiotensin-aldosterone system (RAAS). Systemic arterial thickness on fetal ultrasound and vascular changes in placental histopathology in growth restricted cohorts indicate fetal/developmental origins of adult-onset circulatory diseases. Similar findings of impaired arterial compliance have been noticed across age groups (neonates through to adults). Such changes augment what occurs as "normal arterial aging," resulting in accelerated arterial aging. Data from animal models suggest that hypoxemia-associated vascular adaptations enacted in utero are region specific, reflecting long-term vascular pathology. In this review, we explore the influence of birthweight and prematurity on blood pressure and arterial stiffness, demonstrating impaired arterial dynamics in growth-restricted cohorts across age groups, explain how early arterial aging influences adult-onset CVDs, describe pathophysiology data from experimental models and finally, discuss interventions which may influence aging by way of altering various cellular and molecular mechanisms of arterial aging. Age-appropriate interventions which have noted efficacy include prolonged breastfeeding and high polyunsaturated fatty acids dietary intake. Targeting the RAAS seems a promising approach. New data indicate activation of sirtuin 1 and maternal resveratrol may have beneficial effects.