Host-microbiome interactions in distinct subsets of preterm labor and birth.

Preterm birth, the leading cause of perinatal morbidity, often follows premature labor, a syndrome whose prevention remains a challenge. To better understand the relationship between premature labor and host-microbiome interactions, we conducted a mechanistic investigation using three preterm birth models. We report that intra-amniotic delivery of LPS triggers inflammatory responses in the amniotic cavity and cervico-vaginal microenvironment, causing vaginal microbiome changes and signs of active labor. Intra-amniotic IL-1α delivery causes a moderate inflammatory response in the amniotic cavity but increasing inflammation in the cervico-vaginal space, leading to vaginal microbiome disruption and signs of active labor. Conversely, progesterone action blockade by RU-486 triggers local immune responses accompanying signs of active labor without altering the vaginal microbiome. Preterm labor facilitates ascension of cervico-vaginal bacteria into the amniotic cavity, regardless of stimulus. This study provides compelling mechanistic insights into the dynamic host-microbiome interactions within the cervico-vaginal microenvironment that accompany premature labor and birth.

Blockade of IL-6R prevents preterm birth and adverse neonatal outcomes.

BACKGROUND: Preterm birth preceded by spontaneous preterm labour often occurs in the clinical setting of sterile intra-amniotic inflammation (SIAI), a condition that currently lacks treatment. METHODS: Proteomic and scRNA-seq human data were analysed to evaluate the role of IL-6 and IL-1α in SIAI. A C57BL/6 murine model of SIAI-induced preterm birth was developed by the ultrasound-guided intra-amniotic injection of IL-1α. The blockade of IL-6R by using an aIL-6R was tested as prenatal treatment for preterm birth and adverse neonatal outcomes. QUEST-MRI evaluated brain oxidative stress in utero. Targeted transcriptomic profiling assessed maternal, foetal, and neonatal inflammation. Neonatal biometrics and neurodevelopment were tested. The neonatal gut immune-microbiome was evaluated using metagenomic sequencing and immunophenotyping. FINDINGS: IL-6 plays a critical role in the human intra-amniotic inflammatory response, which is associated with elevated concentrations of the alarmin IL-1α. Intra-amniotic injection of IL-1α resembles SIAI, inducing preterm birth (7% vs. 50%, p = 0.03, Fisher's exact test) and neonatal mortality (18% vs. 56%, p = 0.02, Mann-Whitney U-test). QUEST-MRI revealed no foetal brain oxidative stress upon in utero IL-1α exposure (p > 0.05, mixed linear model). Prenatal treatment with aIL-6R abrogated IL-1α-induced preterm birth (50% vs. 7%, p = 0.03, Fisher's exact test) by dampening inflammatory processes associated with the common pathway of labour. Importantly, aIL-6R reduces neonatal mortality (56% vs. 22%, p = 0.03, Mann-Whitney U-test) by crossing from the mother to the amniotic cavity, dampening foetal organ inflammation and improving growth. Beneficial effects of prenatal IL-6R blockade carried over to neonatal life, improving survival, growth, neurodevelopment, and gut immune homeostasis. INTERPRETATION: IL-6R blockade can serve as a strategy to treat SIAI, preventing preterm birth and adverse neonatal outcomes. FUNDING: NICHD/NIH/DHHS, Contract HHSN275201300006C. WSU Perinatal Initiative in Maternal, Perinatal and Child Health.

Differential immunophenotype of circulating monocytes from pregnant women in response to viral ligands.

BACKGROUND: Viral infections during pregnancy can have deleterious effects on mothers and their offspring. Monocytes participate in the maternal host defense against invading viruses; however, whether pregnancy alters monocyte responses is still under investigation. Herein, we undertook a comprehensive in vitro study of peripheral monocytes to characterize the differences in phenotype and interferon release driven by viral ligands between pregnant and non-pregnant women. METHODS: Peripheral blood was collected from third-trimester pregnant (n = 20) or non-pregnant (n = 20, controls) women. Peripheral blood mononuclear cells were isolated and exposed to R848 (TLR7/TLR8 agonist), Gardiquimod (TLR7 agonist), Poly(I:C) (HMW) VacciGrade™ (TLR3 agonist), Poly(I:C) (HMW) LyoVec™ (RIG-I/MDA-5 agonist), or ODN2216 (TLR9 agonist) for 24 h. Cells and supernatants were collected for monocyte phenotyping and immunoassays to detect specific interferons, respectively. RESULTS: The proportions of classical (CD14hiCD16-), intermediate (CD14hiCD16+), non-classical (CD14loCD16+), and CD14loCD16- monocytes were differentially affected between pregnant and non-pregnant women in response to TLR3 stimulation. The proportions of pregnancy-derived monocytes expressing adhesion molecules (Basigin and PSGL-1) or the chemokine receptors CCR5 and CCR2 were diminished in response to TLR7/TLR8 stimulation, while the proportions of CCR5- monocytes were increased. Such differences were found to be primarily driven by TLR8 signaling, rather than TLR7. Moreover, the proportions of monocytes expressing the chemokine receptor CXCR1 were increased during pregnancy in response to poly(I:C) stimulation through TLR3, but not RIG-I/MDA-5. By contrast, pregnancy-specific changes in the monocyte response to TLR9 stimulation were not observed. Notably, the soluble interferon response to viral stimulation by mononuclear cells was not diminished in pregnancy. CONCLUSIONS: Our data provide insight into the differential responsiveness of pregnancy-derived monocytes to ssRNA and dsRNA, mainly driven by TLR8 and membrane-bound TLR3, which may help to explain the increased susceptibility of pregnant women to adverse outcomes resulting from viral infection as observed during recent and historic pandemics.

A key role for NLRP3 signaling in preterm labor and birth driven by the alarmin S100B.

Preterm birth remains the leading cause of neonatal morbidity and mortality worldwide. A substantial number of spontaneous preterm births occur in the context of sterile intra-amniotic inflammation, a condition that has been mechanistically proven to be triggered by alarmins. However, sterile intra-amniotic inflammation still lacks treatment. The NLRP3 inflammasome has been implicated in sterile intra-amniotic inflammation; yet, its underlying mechanisms, as well as the maternal and fetal contributions to this signaling pathway, are unclear. Herein, by utilizing a translational and clinically relevant model of alarmin-induced preterm labor and birth in Nlrp3-/- mice, we investigated the role of NLRP3 signaling by using imaging and molecular biology approaches. Nlrp3 deficiency abrogated preterm birth and the resulting neonatal mortality induced by the alarmin S100B by impeding the premature activation of the common pathway of labor as well as by dampening intra-amniotic and fetal inflammation. Moreover, Nlrp3 deficiency altered leukocyte infiltration and functionality in the uterus and decidua. Last, embryo transfer revealed that maternal and fetal Nlrp3 signaling contribute to alarmin-induced preterm birth and neonatal mortality, further strengthening the concept that both individuals participate in the complex process of preterm parturition. These findings provide novel insights into sterile intra-amniotic inflammation, a common etiology of preterm labor and birth, suggesting that the adverse perinatal outcomes resulting from prematurity can be prevented by targeting NLRP3 signaling.

Machine learning-based models for gestational diabetes mellitus prediction before 24-28 weeks of pregnancy: A review.

Gestational Diabetes Mellitus (GDM) is a hyperglycemia state that impairs maternal and offspring health, short and long-term. It is usually diagnosed at 24-28 weeks of pregnancy (WP), but at that time the fetal phenotype is already altered. Machine learning (ML)-based models have emerged as an auspicious alternative to predict this pathology earlier, however, they must be validated in different populations before their implementation in routine clinical practice. This review aims to give an overview of the ML-based models that have been proposed to predict GDM before 24-28 WP, with special emphasis on their current validation state and predictive performance. Articles were searched in PubMed. Manuscripts written in English and published before January 1, 2022, were considered. 109 original research studies were selected, and categorized according to the type of variables that their models involved: medical, i.e. clinical and/or biochemical parameters; alternative, i.e. metabolites, peptides or proteins, micro-ribonucleic acid molecules, microbiota genera, or other variables that did not fit into the first category; or mixed, i.e. both medical and alternative data. Only 8.3 % of the reviewed models have had validation in independent studies, with low or moderate performance for GDM prediction. In contrast, several models that lack of independent validation have shown a very high predictive power. The evaluation of these promising models in future independent validation studies would allow to assess their performance on different populations, and continue their way towards clinical implementation. Once settled, ML-based models would help to predict GDM earlier, initiate its treatment timely and prevent its negative consequences on maternal and offspring health.

Fetal and maternal NLRP3 signaling is required for preterm labor and birth.

Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. One of every 4 preterm neonates is born to a mother with intra-amniotic inflammation driven by invading bacteria. However, the molecular mechanisms underlying this hostile immune response remain unclear. Here, we used a translationally relevant model of preterm birth in Nlrp3-deficient and -sufficient pregnant mice to identify what we believe is a previously unknown dual role for the NLRP3 pathway in the fetal and maternal signaling required for the premature onset of the labor cascade leading to fetal injury and neonatal death. Specifically, the NLRP3 sensor molecule and/or inflammasome is essential for triggering intra-amniotic and decidual inflammation, fetal membrane activation, uterine contractility, and cervical dilation. NLRP3 also regulates the functional status of neutrophils and macrophages in the uterus and decidua, without altering their influx, as well as maternal systemic inflammation. Finally, both embryo transfer experimentation and heterozygous mating systems provided mechanistic evidence showing that NLRP3 signaling in both the fetus and the mother is required for the premature activation of the labor cascade. These data provide insights into the mechanisms of fetal-maternal dialog in the syndrome of preterm labor and indicate that targeting the NLRP3 pathway could prevent adverse perinatal outcomes.

Pregnancy imparts distinct systemic adaptive immune function.

PROBLEM: Pregnancy represents a state of systemic immune activation that is primarily driven by alterations in circulating innate immune cells. Recent studies have suggested that cellular adaptive immune components, T cells and B cells, also undergo changes throughout gestation. However, the phenotypes and functions of such adaptive immune cells are poorly understood. Herein, we utilized high-dimensional flow cytometry and functional assays to characterize T-cell and B-cell responses in pregnant and non-pregnant women. METHODS: Peripheral blood mononuclear cells from pregnant (n = 20) and non-pregnant (n = 25) women were used for phenotyping of T-cell and B-cell subsets. T-cell proliferation and B-cell activation were assessed by flow cytometry after in vitro stimulation, and lymphocyte cytotoxicity was evaluated by using a cell-based assay. Statistical comparisons were performed with linear mixed-effects models. RESULTS: Pregnancy was associated with modestly enhanced basal activation of peripheral CD4+ T cells. Both CD4+ and CD8+ T cells from pregnant women showed increased activation-induced proliferation; yet, a reduced proportion of these cells expressed activation markers compared to non-pregnant women. There were no differences in peripheral lymphocyte cytotoxicity between study groups. A greater proportion of B cells from pregnant women displayed memory-like and activated phenotypes, and such cells exhibited higher activation following stimulation. CONCLUSION: Maternal circulating T cells and B cells display distinct responses during pregnancy. The former may reflect the unique capacity of T cells to respond to potential threats without undergoing aberrant activation, thereby preventing systemic inflammatory responses that can lead to adverse perinatal consequences.

Clarithromycin prevents preterm birth and neonatal mortality by dampening alarmin-induced maternal-fetal inflammation in mice.

BACKGROUND: One of every four preterm neonates is born to a woman with sterile intra-amniotic inflammation (inflammatory process induced by alarmins); yet, this clinical condition still lacks treatment. Herein, we utilized an established murine model of sterile intra-amniotic inflammation induced by the alarmin high-mobility group box-1 (HMGB1) to evaluate whether treatment with clarithromycin prevents preterm birth and adverse neonatal outcomes by dampening maternal and fetal inflammatory responses. METHODS: Pregnant mice were intra-amniotically injected with HMGB1 under ultrasound guidance and treated with clarithromycin or vehicle control, and pregnancy and neonatal outcomes were recorded (n = 15 dams each). Additionally, amniotic fluid, placenta, uterine decidua, cervix, and fetal tissues were collected prior to preterm birth for determination of the inflammatory status (n = 7-8 dams each). RESULTS: Clarithromycin extended the gestational length, reduced the rate of preterm birth, and improved neonatal mortality induced by HMGB1. Clarithromycin prevented preterm birth by interfering with the common cascade of parturition as evidenced by dysregulated expression of contractility-associated proteins and inflammatory mediators in the intra-uterine tissues. Notably, clarithromycin improved neonatal survival by dampening inflammation in the placenta as well as in the fetal lung, intestine, liver, and spleen. CONCLUSIONS: Clarithromycin prevents preterm birth and improves neonatal survival in an animal model of sterile intra-amniotic inflammation, demonstrating the potential utility of this macrolide for treating women with this clinical condition, which currently lacks a therapeutic intervention.

The immunobiology of preterm labor and birth: intra-amniotic inflammation or breakdown of maternal-fetal homeostasis.

In brief: The syndrome of preterm labor comprises multiple established and novel etiologies. This review summarizes the distinct immune mechanisms implicated in preterm labor and birth and highlights potential strategies for its prevention. Abstract: Preterm birth, the leading cause of neonatal morbidity and mortality worldwide, results from preterm labor, a syndrome that includes multiple etiologies. In this review, we have summarized the immune mechanisms implicated in intra-amniotic inflammation, the best-characterized cause of preterm labor and birth, as well as novel etiologies non-associated with intra-amniotic inflammation (i.e. formally known as idiopathic). While the intra-amniotic inflammatory responses driven by microbes (infection) or alarmins (sterile) have some overlap in the participating cellular and molecular processes, the distinct natures of these two conditions necessitate the implementation of specific approaches to prevent adverse pregnancy and neonatal outcomes. Intra-amniotic infection can be treated with the correct antibiotics, whereas sterile intra-amniotic inflammation could potentially be treated by administering a combination of anti-inflammatory drugs (e.g. betamethasone, inflammasome inhibitors, etc.). Recent evidence also supports the role of fetal T-cell activation as a newly described trigger for preterm labor and birth in a subset of cases diagnosed as idiopathic. Moreover, herein we also provide evidence of two maternally-driven immune mechanisms responsible for preterm births formerly considered to be idiopathic. First, the impairment of maternal Tregs can lead to preterm birth, likely due to the loss of immunosuppressive activity resulting in unleashed effector T-cell responses. Secondly, homeostatic macrophages were shown to be essential for maintaining pregnancy and promoting fetal development, and the adoptive transfer of homeostatic M2-polarized macrophages shows great promise for preventing inflammation-induced preterm birth. Collectively, in this review, we discuss the established and novel immune mechanisms responsible for preterm birth and highlight the potential targets for novel strategies aimed at preventing the multi-etiological syndrome of preterm labor leading to preterm birth.

Distinct Cellular Immune Responses to SARS-CoV-2 in Pregnant Women.

Pregnant women are at increased risk of adverse outcomes, including preeclampsia and preterm birth, that may result from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Pregnancy imprints specific maternal immune responses that can modulate host susceptibility to microbial infection; therefore, recent studies have focused on the humoral response against SARS-CoV-2 in pregnant women. However, the pregnancy-specific cellular immune responses triggered by SARS-CoV-2 infection are poorly understood. In this study, we undertook an extensive in vitro investigation to determine the cellular immune responses to SARS-CoV-2 particles and proteins/peptides in pregnant women. First, we show that SARS-CoV-2 particles do not alter the pregnancy-specific oxidative burst of neutrophils and monocytes. Yet, SARS-CoV-2 particles/proteins shift monocyte activation from the classical to intermediate states in pregnant, but not in nonpregnant, women. Furthermore, SARS-CoV-2 proteins, but not particles or peptide pools, mildly enhance T cell activation during pregnancy. As expected, B cell phenotypes are heavily modulated by SARS-CoV-2 particles in all women; yet, pregnancy itself further modified such responses in these adaptive immune cells. Lastly, we report that pregnancy itself governs cytokine responses in the maternal circulation, of which IFN-ß and IL-8 were diminished upon SARS-CoV-2 challenge. Collectively, these findings highlight the differential in vitro responses to SARS-CoV-2 in pregnant and nonpregnant women and shed light on the immune mechanisms implicated in coronavirus disease 2019 during pregnancy.

Pregnancy tailors endotoxin-induced monocyte and neutrophil responses in the maternal circulation.

OBJECTIVE: To comprehensively characterize monocyte and neutrophil responses to E. coli and its product [lipopolysaccharide (LPS) or endotoxin] in vitro during pregnancy. MATERIAL OR SUBJECTS: Peripheral blood was collected from pregnant women during the third trimester (n = 20) and from non-pregnant women (n = 20). METHODS: The number, phagocytic activity, and reactive oxygen species (ROS) production of peripheral monocytes and neutrophils were investigated using flow cytometry. The phenotypes of peripheral monocytes and neutrophils after acute or chronic LPS stimulation were also determined using flow cytometry. Cytokine profiles were quantified for LPS-stimulated peripheral blood mononuclear cells (PBMCs) and a whole blood TruCulture® system using a multiplex immunoassay. RESULTS: Increased number, phagocytic activity, and ROS production capacity of monocytes and neutrophils were found in pregnant compared to non-pregnant women. Additionally, specific subsets of pro-inflammatory monocytes (IL-6+CD14+ or MIP-1α+CD14+ cells) and neutrophils (IL-1ß+CD15+ or MIP-1ß+CD15+ cells) were increased in pregnant women in response to acute LPS stimulation. Moreover, distinct subsets of intermediate-activated monocytes expressing CD142, IL-6, and IL-1RA were increased in pregnant women upon chronic LPS stimulation. Last, pregnant women displayed a different cytokine profile than non-pregnant women in LPS-stimulated PBMCs and in whole blood. CONCLUSIONS: Pregnancy tailors the immune responses of circulating monocytes and neutrophils to endotoxin, a Gram-negative bacterial product.

Transcriptome changes in maternal peripheral blood during term parturition mimic perturbations preceding spontaneous preterm birth†.

The complex physiologic process of parturition includes the onset of labor, which requires the orchestrated stimulation of a common pathway involving uterine contractility, cervical ripening, and chorioamniotic membrane activation. However, the labor-specific processes taking place in these tissues have limited use as predictive biomarkers unless they can be probed in non-invasive samples, such as the peripheral blood. Herein, we utilized a transcriptomic dataset to assess labor-specific changes in the peripheral blood of women who delivered at term. We identified a set of genes that were differentially expressed with labor and enriched for immunological processes, and these gene expression changes were strongly correlated with results from prior studies, providing in silico validation of our findings. We then identified significant correlations between labor-specific transcriptomic changes in the maternal circulation and those detected in the chorioamniotic membranes, myometrium, and cervix of women at term, demonstrating that tissue-specific labor signatures are partly mirrored in the peripheral blood. Finally, we demonstrated a significant overlap between the peripheral blood transcriptomic changes in term parturition and those observed in asymptomatic women, prior to the diagnosis of preterm prelabor rupture of the membranes, who ultimately delivered preterm. Collectively, we provide evidence that the normal process of labor at term is characterized by a unique immunological expression signature, which may serve as a useful tool for assessing labor status and for potentially identifying women at risk for preterm birth.

Maternal thyroid profile in first and second trimester of pregnancy is correlated with gestational diabetes mellitus through machine learning.

There is evidence about a possible relationship between thyroid abnormalities and gestational diabetes mellitus (GDM). However, there is still no conclusive data on this dependence, since no strong correlation has been proved. In this work, we used machine learning to determine whether there is a correlation between maternal thyroid profile in first and second trimester of pregnancy and GDM. Using principal component analysis, it was possible to find an evident correlation between both, which could be used as a complement for a more sensitive GDM diagnosis.

[Dyslipidemias in school-age chilean children: prevalence and associated factors]. / DISLIPIDEMIAS EN ESCOLARES CHILENOS: PREVALENCIA Y FACTORES ASOCIADOS.

INTRODUCTION: Dyslipidemias are a key cardiovascular risk factor, and are increased since early childhood. The objective of this study was to describe the prevalence, characteristics of dyslipidemias and associated factors in a population of Chilean children. METHODS: Cross-sectional study done in school-age children from Santiago, Chile (2009-2011). Parents answered questions about family medical history and children answered questions about physical activity. Anthropometry was performed and in a blood sample (12 hours fast) lipid profile, glycemia and insulinemia were measured. RESULTS: We recruited 2900 euglycemic children, 11.4 ± 0.97 years old, 52% girls. According to BMI, 22.5% were overweight and 15,3% had obesity. Considering recommended cut-off points for lipids, 69.3% were in acceptable range, 19.2% at risk and 11.5% at high cardiovascular risk. In total, 32% of the population had any clinical form of dyslipidemia: Isolated hypertriglyceridemia (9.4%), low HDL-C (7.6%), isolated hypercholesterolemia (4.9%), atherogenic dyslipidemia (6.24%) and mixed dyslipidemia (3.9%). Except for isolated hypercholesterolemia, dyslipidemias were more frequent in girls (globally 36.2% vs. 27.4%, p<0.0001). Low HDL-C was associated with sedentary lifestyle. In multiple logistic regression analysis, nutritional status was the most important associated factor, with less influence of age, sex, central obesity, insulin resistance and history of parental cardiovascular risk factors. CONCLUSIONS: In this population of Chilean school-age children, we found a high prevalence of dyslipidemia, and the principal determinant was weight excess.

Introducción: Las dislipidemias son un factor de riesgo cardiovascular clave, en aumento ya desde la niñez. El objetivo de este estudio fue describir la prevalencia, tipo de dislipidemias y factores asociados, en una población de niños chilenos. Métodos: Estudio transversal en escolares de Santiago de Chile (2009-2011). Se realizó antropometría, encuesta de antecedentes familiares a los padres y de actividad física a los niños. En muestra sanguínea de ayunas se midió perfil lipídico, glicemia e insulinemia. Resultados: Se reclutaron 2900 escolares de 11,42±0,97 años de edad, 52% mujeres, todos euglicémicos. Según IMC, 22,5% tenía sobrepeso y 15,3% obesidad. Al considerar los límites recomendados para cada lípido, 69,3% se encontraba en rango aceptable, 19,2% en riesgo y 11,5% en alto riesgo cardiovascular. En total, 32% de la población presentó alguna forma clínica de dislipidemia: Hipertrigliceridemia aislada (9,4%), Bajo C-HDL (7,6%), Hipercolesterolemia aislada (4,9%), Dislipidemia aterogénica (6,24%) y Dislipidemia mixta (3,9%). Excepto la hipercolesterolemia aislada, las demás dislipidemias fueron más frecuentes en las niñas (36,2% vs. 27,4%, p.

Dislipidemias en escolares chilenos: prevalencia y factores asociados / Dyslipidemias in school-age Chilean children: prevalence and associated factors

Introducción: Las dislipidemias son un factor de riesgo cardiovascular clave, en aumento ya desde la niñez. El objetivo de este estudio fue describir la prevalencia, tipo de dislipidemias y factores asociados, en una población de niños chilenos. Métodos: Estudio transversal en escolares de Santiago de Chile (2009-2011). Se realizó antropometría, encuesta de antecedentes familiares a los padres y de actividad física a los niños. En muestra sanguínea de ayunas se midió perfil lipídico, glicemia e insulinemia. Resultados: Se reclutaron 2900 escolares de 11,42±0,97 años de edad, 52% mujeres, todos euglicémicos. Según IMC, 22,5% tenía sobrepeso y 15,3% obesidad. Al considerar los límites recomendados para cada lípido, 69,3% se encontraba en rango aceptable, 19,2% en riesgo y 11,5% en alto riesgo cardiovascular. En total, 32% de la población presentó alguna forma clínica de dislipidemia: Hipertrigliceridemia aislada (9,4%), Bajo C-HDL (7,6%), Hipercolesterolemia aislada (4,9%), Dislipidemia aterogénica (6,24%) y Dislipidemia mixta (3,9%). Excepto la hipercolesterolemia aislada, las demás dislipidemias fueron más frecuentes en las niñas (36,2% vs. 27,4%, p<0,0001). El menor C-HDL se asoció al sedentarismo y a la menor frecuencia de actividad física. En regresión logística múltiple, el estado nutricional fue el factor asociado más gravitante, con menor influencia de: edad, sexo, obesidad central, resistencia insulínica y antecedente de factores de riesgo parental cardiovascular. Conclusiones: En esta muestra poblacional de escolares chilenos se encontró una alta prevalencia de dislipidemias asociadas principalmente al exceso de peso (AU)

Introduction: Dyslipidemias are a key cardiovascular risk factor, and are increased since early childhood. The objective of this study was to describe the prevalence, characteristics of dyslipidemias and associated factors in a population of Chilean children. Methods: Cross-sectional study done in school-age children from Santiago, Chile (2009-2011). Parents answered questions about family medical history and children answered questions about physical activity. Anthropometry was performed and in a blood sample (12 hours fast) lipid profile, glycemia and insulinemia were measured. Results: We recruited 2900 euglycemic children, 11.4±0.97 years old, 52% girls. According to BMI, 22.5% were overweight and 15,3% had obesity. Considering recommended cut-off points for lipids, 69.3% were in acceptable range, 19.2% at risk and 11.5% at high cardiovascular risk. In total, 32% of the population had any clinical form of dyslipidemia: Isolated hypertriglyceridemia (9.4%), low HDL-C (7.6%), isolated hypercholesterolemia (4.9%), atherogenic dyslipidemia (6.24%) and mixed dyslipidemia (3.9%). Except for isolated hypercholesterolemia, dyslipidemias were more frequent in girls (globally 36.2% vs. 27.4%, p<0.0001). Low HDL-C was associated with sedentary lifestyle. In multiple logistic regression analysis, nutritional status was the most important associated factor, with less influence of age, sex, central obesity, insulin resistance and history of parental cardiovascular risk factors. Conclusions: In this population of Chilean school-age children, we found a high prevalence of dyslipidemia, and the principal determinant was weight excess (AU)

Modulation of endothelial cell migration by ER stress and insulin resistance: a role during maternal obesity?

Adverse microenvironmental stimuli can trigger the endoplasmic reticulum (ER) stress pathway, which initiates the unfolded protein response (UPR), to restore protein-folding homeostasis. Several studies show induction of ER stress during obesity. Chronic UPR has been linked to different mechanisms of disease in obese and diabetic individuals, including insulin resistance (IR) and impaired angiogenesis. Endothelial cell (EC) migration is an initial step for angiogenesis, which is associated with remodeling of existing blood vessels. EC migration occurs according to the leader-follower model, involving coordinated processes of chemotaxis, haptotaxis, and mechanotaxis. Thus, a fine-tuning of EC migration is necessary to provide the right timing to form the required vessels during angiogenesis. ER stress modulates EC migration at different levels, usually impairing migration and angiogenesis, although different effects may be observed depending on the tissue and/or microenvironment. In the context of pregnancy, maternal obesity (MO) induces IR in the offspring. Interestingly, several proteins associated with obesity-induced IR are also involved in EC migration, providing a potential link with the ER stress-dependent alterations observed in obese individuals. Different signaling cascades that converge on cytoskeleton regulation directly impact EC migration, including the Akt and/or RhoA pathways. In addition, ER is the main intracellular reservoir for Ca(2+), which plays a pivotal role during EC migration. Therefore, ER stress-related alterations in Ca(2+) signaling or Ca(2+) levels might also produce distorted EC migration. However, the above findings have been studied in the context of adult obesity, and no information has been reported regarding the effect of MO on fetal EC migration. Here we summarize the state of knowledge about the possible mechanisms by which ER stress and IR might impact EC migration and angiogenesis in fetal endothelium exposed to MO during pregnancy.

Programming of fetal insulin resistance in pregnancies with maternal obesity by ER stress and inflammation.

The global epidemics of obesity during pregnancy and excessive gestational weight gain (GWG) are major public health problems worldwide. Obesity and excessive GWG are related to several maternal and fetal complications, including diabetes (pregestational and gestational diabetes) and intrauterine programming of insulin resistance (IR). Maternal obesity (MO) and neonatal IR are associated with long-term development of obesity, diabetes mellitus, and increased global cardiovascular risk in the offspring. Multiple mechanisms of insulin signaling pathway impairment have been described in obese individuals, involving complex interactions of chronically elevated inflammatory mediators, adipokines, and the critical role of the endoplasmic reticulum (ER) stress-dependent unfolded protein response (UPR). However, the underlying cellular processes linking MO and IR in the offspring have not been fully elucidated. Here, we summarize the state-of-the-art evidence supporting the possibility that adverse metabolic postnatal outcomes such as IR in the offspring of pregnancies with MO and/or excessive GWG may be related to intrauterine activation of ER stress response.

Obesidad en el embarazo: razones para volver a preocuparse de la nutrición materna / Obesity in pregnancy: why we must be concerned about maternal nutrition again

Las causas de la transición nutricional en nuestro país provienen por un lado de la reducción significativa del número de personas con desnutrición, y por otro del aumento explosivo de la proporción de sobrepeso y obesidad en todos los grupos etarios. No es de extrañar que más de la mitad de las mujeres embarazadas chilenas presenten sobrepeso y obesidad al iniciar el control prenatal y con ello, una tendencia prácticamente inevitable a tener una ganancia de peso gestacional excesiva. El objetivo de este trabajo es revisar los efectos adversos del exceso de peso materno sobre la mujer y su descendencia, así como los potenciales beneficios de las intervenciones orientadas al control nutricional en este ámbito. Múltiples estudios poblacionales y experimentales han evidenciado un riesgo dos a tres veces mayor de presentar complicaciones maternas y perinatales en las embarazadas con sobrepeso y obesidad en comparación a las mujeres con estado nutricional normal. Dado que el período gestacional es considerado una etapa crítica para el desarrollo de un individuo, las alteraciones metabólicas identificadas a nivel de nutrientes, hormonas y mediadores inflamatorios podrían explicar muchos de los resultados adversos descritos a mediano y largo plazo en los hijos de madres con exceso de peso durante el embarazo. Las distintas estrategias de intervención planteadas no han demostrado efectos significativos sobre el peso al nacer. Sin embargo, tanto las intervenciones dietéticas como aquellas que incluyen actividad física controlada durante el embarazo han comprobado que es posible restringir la ganancia de peso gestacional total. Esto permite sostener que es factible seguir evaluando potenciales diferencias clínicamente significativas, tanto a nivel de mecanismos de daño metabólico materno-fetal durante el embarazo, como en la vida posterior de las mujeres y sus niños.

The causes of the nutritional transition in our country can be accounted for by the reduction in the number of malnourished people, on the one hand, and the explosive increase in the proportion of overweight and obesity in all age groups, on the other. It comes as no surprise then that more than half of Chilean pregnant women are overweight and obese at their first prenatal visit and thus have an almost inevitable tendency to gain excess gestational weight. The purpose of this article is to review the adverse effects of maternal overweight on women and their offspring, and the potential benefits of nutritional interventions in this area. Multiple population and experimental studies have demonstrated a two to three times greater likelihood of developing maternal and perinatal complications in pregnant women with overweight and obesity compared to women with normal nutritional status. Since the gestational period is critical for the development of an individual, metabolic changes in nutrients, hormones and inflammatory mediators could explain many of the adverse outcomes described in the medium and long term in children of mothers with excess weight during pregnancy. No significant effects on birth weight have been seen after employing various interventional strategies. However, both dietary interventions and those involving controlled physical activity during pregnancy have been found to limit total gestational weight gain. In consequence, it appears to be feasible to further evaluate potentially clinically significant differences, both at the maternal-fetal metabolic injury level during pregnancy, as well as later on in life in mothers and their offspring.

Cesárea electiva versus parto vaginal / Elective Caesarean section versus vaginal delivery

Se revisan aspectos actuales de la operación cesárea en términos de su incremento en todos los países del mundo, especialmente en Chile. Se analizan frecuencias, causas e indicaciones, así como las recomendaciones vigentes en términos de frecuencia esperada. Se recuerdan los indicadores chilenos de salud materno-infantil y se analizan, de acuerdo a la mejor evidencia disponible, las ventajas y desventajas de ambas vías de parto: operación cesárea versus parto vaginal. Finalmente se presentan recomendaciones generales que podrían contribuir a reducir la alta tasa de cesáreas.

This article reviews current aspects of Cesarean section considering increasing rate in all countries of the world, with special emphasis on Chile. Frequencies, causes and indications, as well as recent recommendations in terms of expected frequencies are analyzed. Chilean child and maternal health indicators are reminded and, in accordance to the best evidence available, the advantages and disadvantages of both delivery modes are analyzed, i.e. C-section versus vaginal delivery. Finally, general recommendations are given that could contribute to reducing the high rate of Cesarean section.