Intrauterine growth restriction and later cardiovascular function

Intrauterine growth restriction is one of the most common obstetric conditions, affecting 7-10% of fetuses. Affected fetuses are actually exposed in utero to an adverse environment during the highly critical time of development and may face life-long health consequences such as increased cardiovascular risk in adulthood. Already in utero, fetuses affected by growth restriction show remodeled hearts with signs of systolic and diastolic dysfunction. Cardiovascular remodeling persist into postnatal life, from the neonatal period to adolescence, suggesting a primary fetal cardiac programming that might explain the increased cardiovascular risk later in life. In this review we summarize the current evidence on fetal cardiovascular programming in fetuses affected by growth restriction, its consequences later and possible strategies from which they could benefit to reduce their cardiovascular risk

Long-term cardiovascular consequences of fetal growth restriction: biology, clinical implications, and opportunities for prevention of adult disease

In the modern world, cardiovascular disease is a leading cause of death for both men and women. Epidemiologic studies consistently have suggested an association between low birthweight and/or fetal growth restriction and increased rate of cardiovascular mortality in adulthood. Furthermore, experimental and clinical studies have demonstrated that sustained nutrient and oxygen restriction that are associated with fetal growth restriction activate adaptive cardiovascular changes that might explain this association. Fetal growth restriction results in metabolic programming that may increase the risk of metabolic syndrome and, consequently, of cardiovascular morbidity in the adult. In addition, fetal growth restriction is strongly associated with fetal cardiac and arterial remodeling and a subclinical state of cardiovascular dysfunction. The cardiovascular effects ocurring in fetal life, includes cardiac morphology changes, subclinical myocardial dysfunction, arterial remodeling, and impaired endothelial function, persist into childhood and adolescence. Importantly, these changes have been described in all clinical presentations of fetal growth restriction, from severe early- to milder late-onset forms. In this review we summarize the current evidence on the cardiovascular effects of fetal growth restriction, from subcellular to organ structure and function as well as from fetal to early postnatal life. Future research needs to elucidate whether and how early life cardiovascular remodeling persists into adulthood and determines the increased cardiovascular mortality rate described in epidemiologic studies

El corazón de las personas que nacieron con bajo peso podría ser distinto del de los demás

Si durante el embarazo el feto experimenta una falta de nutrientes, intentará ahorrar y engordará menos. Sin embargo, esto puede tener importantes consecuencias en su salud adulta

Nutritional intra-amniotic therapy increases survival in a rabbit model of fetal growth restriction

Objective To evaluate the perinatal effects of a prenatal therapy based on intra-amniotic nutritional supplementation in a rabbit model of intrauterine growth restriction (IUGR). Methods IUGR was surgically induced in pregnant rabbits at gestational day 25 by ligating 40-50% of uteroplacental vessels of each gestational sac. At the same time, modified-parenteral nutrition solution (containing glucose, amino acids and electrolytes) was injected into the amniotic sac of nearly half of the IUGR fetuses (IUGR-T group n = 106), whereas sham injections were performed in the rest of fetuses (IUGR group n = 118). A control group without IUGR induction but sham injection was also included (n = 115). Five days after the ligation procedure, a cesarean section was performed to evaluate fetal cardiac function, survival and birth weight. Results Survival was significantly improved in the IUGR fetuses that were treated with intra-amniotic nutritional supplementation as compared to non-treated IUGR animals (survival rate: controls 71% vs. IUGR 44% p = 0.003 and IUGR-T 63% vs. IUGR 44% p = 0.02), whereas, birth weight (controls mean 43g ± SD 9 vs. IUGR 36g ± SD 9 vs. IUGR-T 35g ± SD 8, p = 0.001) and fetal cardiac function were similar among the IUGR groups. Conclusion Intra-amniotic injection of a modified-parenteral nutrient solution appears to be a promising therapy for reducing mortality among IUGR. These results provide an opportunity to develop new intra-amniotic nutritional strategies to reach the fetus by bypassing the placental insufficienc

Prenatal adverse environment is associated with epigenetic age deceleration at birth and hypomethylation at the hypoxia-responsive EP300 gene

Abstract Background: Obstetric complications have long been retrospectively associated with a wide range of short- and long-term health consequences, including neurodevelopmental alterations such as those observed in schizophrenia and other psychiatric disorders. However, prospective studies assessing fetal well-being during pregnancy tend to focus on perinatal complications as the final outcome of interest, while there is a scarcity of postnatal follow-up studies. In this study, the cerebroplacental ratio (CPR), a hemodynamic parameter reflecting fetal adaptation to hypoxic conditions, was analyzed in a sample of monozygotic monochorionic twins (60 subjects), part of them with prenatal complications, with regard to (i) epigenetic age acceleration, and (ii) DNA methylation at genes included in the polygenic risk score (PRS) for schizophrenia, and highly expressed in placental tissue. Results: Decreased CPR measured during the third trimester was associated with epigenetic age deceleration (β = 0.21, t = 3.362, p = 0.002). Exploration of DNA methylation at placentally expressed genes of the PRS for schizophrenia revealed methylation at cg06793497 (EP300 gene) to be associated with CPR (β = 0.021, t = 4.385; p = 0.00008, FDR-adjusted p = 0.11). This association was reinforced by means of an intrapair analysis in monozygotic twins discordant for prenatal suffering (β = 0.027, t = 3.924, p = 0.001). Conclusions: Prenatal adverse environment during the third trimester of pregnancy is associated with both (i) developmental immaturity in terms of epigenetic age, and (ii) decreased CpG-specific methylation in a gene involved in hypoxia response and schizophrenia genetic liability. Keywords: DNA methylation, Obstetric complications, Prenatal stress, Hypoxia, EP300 gene, Epigenetic clock, Monozygotic twins, Schizophreni

Usefulness of circulating microRNAs for the prediction of early preeclampsia at first-trimester of pregnancy

To assess the usefulness of circulating microRNAs (miRNAs) as non-invasive molecular biomarkers for early prediction of preeclampsia, a differential miRNA profiling analysis was performed in first-trimester pooled sera from 31 early preeclampsia patients, requiring delivery before 34 weeks of gestation, and 44 uncomplicated pregnancies using microfluidic arrays. Among a total of 754 miRNAs analyzed, the presence of 63 miRNAs (8%) was consistently documented in the sera from preeclampsia and control samples. Nevertheless, only 15 amplified miRNAs (2%) seemed to be differentially, although modestly, represented (fold change range: 0.4-1.4). After stem loop RT-qPCR from individual samples, the statistical analysis confirmed that none of the most consistent and differentially represented miRNAs (3 overrepresented and 4 underrepresented) were differentially abundant in serum from preeclamptic pregnancies compared with serum from normal pregnancies. Therefore, maternal serum miRNA assessment at first-trimester of pregnancy does not appear to have any predictive value for early preeclampsia

Transgenerational transmission of small for gestational age

Objective: To evaluate the transgenerational transmission of small for gestational age. Methods: Cohort study including a random sample of 2,043 offspring of deliveries occurring from 1975 to 1993. Of 623 offspring -now adults- that agreed to participate, 152 adults (72 born small-for-gestational age (SGA) and 80 with appropriate intrauterine growth) reported to have at least one child. Multiple regression analysis was used to determine the presence of SGA (defined as a birthweight < 10th percentile) or placental mediated disease (defined as the presence of SGA, preeclampsia or gestational hypertension) in the following generation. Results: Descendants from SGA adults presented lower birthweight percentile (median 26 [interquartile range 7-52] vs. 43 [19-75]; p<0.001) and higher prevalence of SGA (40.3% vs. 16.3%; p=0.001) and placental mediated disease (43.1% vs. 17.5%; p=0.001). After adjustment for confounder variables, parental SGA background was associated with an almost three-fold increased risk of subsequent SGA or any placental mediated disease in the following generation. This association was stronger in SGA mothers as compared to fathers. Conclusions: Our data provides evidence suggesting a transgenerational transmission of SGA highlighting the importance of public health strategies for preventing intrauterine growth impairment

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

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

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

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

Evaluation of deep convolutional neural networks for automatic classification of common maternal fetal ultrasound planes

The goal of this study was to evaluate the maturity of current Deep Learning classification techniques for their application in a real maternal-fetal clinical environment. A large dataset of routinely acquired maternal-fetal screening ultrasound images (which will be made publicly available) was collected from two different hospitals by several operators and ultrasound machines. All images were manually labeled by an expert maternal fetal clinician. Images were divided into 6 classes: four of the most widely used fetal anatomical planes (Abdomen, Brain, Femur and Thorax), the mother's cervix (widely used for prematurity screening) and a general category to include any other less common image plane. Fetal brain images were further categorized into the 3 most common fetal brain planes (Trans-thalamic, Trans-cerebellum, Trans-ventricular) to judge fine grain categorization performance. The final dataset is comprised of over 12,400 images from 1,792 patients, making it the largest ultrasound dataset to date. We then evaluated a wide variety of state-of-the-art deep Convolutional Neural Networks on this dataset and analyzed results in depth, comparing the computational models to research technicians, which are the ones currently performing the task daily. Results indicate for the first time that computational models have similar performance compared to humans when classifying common planes in human fetal examination. However, the dataset leaves the door open on future research to further improve results, especially on fine-grained plane categorization