Metabolomics can provide new insights into perinatal nutrition.

Perinatal nutrition is a key factor related to the Developmental Origin of Health and Disease hypothesis, which states that each and every event that happens during the periconceptional period and pregnancy can affect the health status of an individual. Metabolomics can be a very useful tool for gathering information about the effect of perinatal nutrition on both mothers and newborn infants. This non-systematic review focuses on the main metabolites detected by this technique, with regard to gestational diabetes, intrauterine growth restriction and breast milk. Conclusion. Nutrition, metabolome and microbiome interactions are gaining interest in the scientific community.

Sardinian Infants of Diabetic Mothers: A Metabolomics Observational Study.

Gestational diabetes mellitus (GDM) is a condition characterized by glucose intolerance, with hyperglycemia of varying severity with onset during pregnancy. An uncontrolled GDM can lead to an increased risk of morbidity in the fetus and newborn, and an increased risk of obesity or developing type 2 diabetes, hypertension or neurocognitive developmental impairment in adulthood. In this study, we used nuclear magnetic resonance (NMR) spectroscopy and gas chromatography-mass spectrometry (GS-MS) to analyze the urinary metabolomic profile of newborns of diabetic mothers (NDMs) with the aim of identifying biomarkers useful for the monitoring of NDMs and for early diagnosis of predisposition to develop related chronic diseases. A total of 26 newborns were recruited: 21 children of diabetic mothers, comprising 13 in diet therapy (NDM-diet) and 8 in insulin therapy (NDM-insulin), and 5 control children of non-diabetic mothers (CTR). Urine samples were collected at five time points: at birth (T1), on the third day of life (T2), one week (T3), one month (T4) and six months postpartum (T5). At T1, variations were observed in the levels of seven potential biomarkers (acetate, lactate, glycylproline/proline, isocitrate, N,N-dimethylglycine, N-acetylglucosamine and N-carbamoyl-aspartate) in NMD-insulin infants compared to NDM-diet and CTR infants. In particular, the altered metabolites were found to be involved in several metabolic pathways such as citrate metabolism, glycine, serine and threonine metabolism, arginine and proline metabolism, amino sugar and nucleotide sugar metabolism, and pyruvate metabolism. In contrast, these changes were not visible at subsequent sampling times. The impact of early nutrition (maternal and formula milk) on the metabolomic profile was considered as a potential contributing factor to this finding.

Urinary Metabolomics Study of Patients with Bicuspid Aortic Valve Disease.

Bicuspid aortic valve (BAV) is the most common congenital heart defect responsible for valvular and aortic complications in affected patients. Causes and mechanisms of this pathology are still elusive and thus the lack of early detection biomarkers leads to challenges in its diagnosis and prevention of associated cardiovascular anomalies. The aim of this study was to explore the potential use of urine Nuclear Magnetic Resonance (NMR) metabolomics to evaluate a molecular fingerprint of BAV. Both multivariate and univariate statistical analyses were performed to compare the urinary metabolome of 20 patients with BAV with that of 24 matched controls. Orthogonal partial least squared discriminant analysis (OPLS-DA) showed statistically significant discrimination between cases and controls, suggesting seven metabolites (3-hydroxybutyrate, alanine, betaine, creatine, glycine, hippurate, and taurine) as potential biomarkers. Among these, glycine, hippurate and taurine individually displayed medium sensitivity and specificity by receiver operating characteristic (ROC) analysis. Pathway analysis indicated two metabolic pathways likely perturbed in BAV subjects. Possible contributions of gut microbiota activity and energy imbalance are also discussed. These results constitute encouraging preliminary findings in favor of the use of urine-based metabolomics for early diagnosis of BAV.

Breast Milk for Preterm Multiples: More Proteins, Less Lactose.

Exclusive breastfeeding is currently recommended until at least 6 months of postnatal age, due to maternal breast milk (BM) unique composition and beneficial properties. In fact, BM modifies itself according to gestational age (GA) at birth, adapting its composition to neonatal requests during lactation. Multiple births represent about 3% of the whole pregnancies; such neonates result more vulnerable than full-term newborns, due to lower GA and birth weight (BW) and the higher incidence of perinatal complications. Although an adequate nutrition is fundamental for twins and other multiples, studies on this topic are lacking. We collected and analyzed BM from mothers of 19 twins and 5 triplets showing GA < 33 weeks and BW < 1500 g, comparing it to a control group of 28 preterm singletons. As a result, at GA ≤ 28 weeks, we observed that protein content is higher in BM for multiples (1.53 vs. 1.29 g per 100 ml), lactose concentration is greater in BM for singletons (6.72 vs. 6.34 g per 100 ml) and GA results the most relevant factor influencing BM protein composition. BM for multiples results higher in proteins and lower in lactose, if compared with singleton's samples; this could promote and sustain growth and organ development in this vulnerable category. BM from multiples shows a trophic and immunologic role, since these neonates often show lower GA and BW instead of singletons. These findings could help in optimizing nutritional strategies and improving BM individualized fortification.

Exposure to tobacco smoke and low birth weight: from epidemiology to metabolomics.

INTRODUCTION: The exposure to tobacco smoke during pregnancy is one of the leading causes of perinatal adverse outcomes such as stillbirth, intrauterine growth restriction (IUGR), and low birth weight, but the underlying biological mechanisms are still unclear. The incidence of this phenomenon maybe largely underestimated since the evaluation is made mainly by self-assessment questionnaires rather than measuring nicotine metabolites (such as cotinine) in biological fluids. In this context metabolomics may be useful to assess the actual number of pregnant women and to highlight the pathophysiological mechanisms that lead to the abovementioned adverse outcomes. Areas covered: The aims of this review are to analyze the literature and the application of the omics sciences, such as genomics and metabolomics concerning the negative effects of smoking during pregnancy in order to give a comprehensive picture of all the study made so far and to point out the potential of metabolomics as an investigative, predictive, and diagnostic tool. Expert commentary: Metabolomics in recent years has proved an excellent tool to try to understand the problems in perinatal medicine. With the increase in the number of studies we are convinced that it can be a useful instrument of investigation in this field.

Impact of Early Postnatal Nutrition on the NMR Urinary Metabolic Profile of Infant.

NMR-based metabolomics was used to compare the metabolic urinary profiles of exclusively breast-fed term infants (n = 11) with those of a double-blinded controlled trial with 49 formula-fed term newborns randomized to receive either an infant formula enriched by functional ingredients (n = 24) or a standard formula (n = 25). Anthropometric measurements and urine samples were taken at enrollment (within the first month of life), at around 60 days of life, and at the end of study period (average age of 130 days). The metabolic profiles were examined in relation to time and diet strategy. A common age-dependent modification of the urine metabolome was observed for the three types of nutrition, mainly characterized by similar temporal trends of choline, betaine, myoinositol, taurine, and citrate. Contrariwise, differences in the metabolic profiles were identified according to the type of diet (human versus formula milk), while no significant difference was observed between the two formulas. These modifications are discussed mainly in terms of the different milk compositions. Despite the low number of enrolled infants (n = 60), these findings pointed out the potential of the metabolomics approach for neonatal nutritional science, in particular to provide important contributions to the optimization of formula milk.

Exploring the Role of Different Neonatal Nutrition Regimens during the First Week of Life by Urinary GC-MS Metabolomics.

In this study, a gas-chromatography mass spectrometry (GC-MS) metabolomics study was applied to examine urine metabolite profiles of different classes of neonates under different nutrition regimens. The study population included 35 neonates, exclusively either breastfed or formula milk fed, in a seven-day timeframe. Urine samples were collected from intrauterine growth restriction (IUGR), large for gestational age (LGA), and appropriate gestational age (AGA) neonates. At birth, IUGR and LGA neonates showed similarities in their urine metabolite profiles that differed from AGA. When neonates started milk feeding, their metabolite excretion profile was strongly characterized by the different diet regimens. After three days of formula milk nutrition, urine had higher levels of glucose, galactose, glycine and myo-inositol, while up-regulated aconitic acid, aminomalonic acid and adipic acid were found in breast milk fed neonates. At seven days, neonates fed with formula milk shared higher levels of pseudouridine with IUGR and LGA at birth. Breastfed neonates shared up-regulated pyroglutamic acid, citric acid, and homoserine, with AGA at birth. The role of most important metabolites is herein discussed.

The biomarkers of fetal growth in intrauterine growth retardation and large for gestational age cases: from adipocytokines to a metabolomic all-in-one tool.

Adipose tissue is no longer considered as inert; the literature describes the role it plays in the production of many substances, such as adiponectin, visfatin, ghrelin, S100B, apelin, TNF, IL-6 and leptin. These molecules have specific roles in humans and their potential as biomarkers useful for identifying alterations related to intrauterine growth retardation and large for gestational age neonates is emerging. Infants born in such conditions have undergone metabolic changes, such as fetal hypo- or hyperinsulinemia, which may lead to development of dysmetabolic syndrome and other chronic diseases in adulthood. In this review, these biomarkers are analyzed specifically and it is discussed how metabolomics may be an advantageous tool for detection, discrimination and prediction of metabolic alterations and diseases. Thus, a holistic approach, such as metabolomics, could help the prevention and early diagnosis of metabolic syndrome.

Nutrimetabolomics and Adipocitokines in the "Great Obstetrical Syndromes".

In neonatal medicine, nutritional research is focusing more and more on thrifty phenotype effects, in order to understand and prevent the development of long-term diseases. lschemic placental disease which brings together Gestational diabete, Preeclamptic Toxemia, and Intrauterine Growth Restriction, the "Great Obstetrical Syndromes" (GOS), originates from sugar.and lipid metabolism. Adipokines and metabolomics can be valuable tools for the diagnosis of obstetrical syndromes and addressing nutrition. Inappropriate nutrition, even in the first periods of life, can accelerate the development of chronic metabolic diseases, especially in the pediatric age. The purpose of this review is firstly to critically examine the information provided by the studies of metabolomics on GOS's and better understand their origin. Secondly, it reflects on the IUGR metabolism and on applications of metabolomics in nutrition and its "nutrimetabolomic" effects and then to discuss the principles that guide nutrition of IUGR children in the light of these.

Integrative Multiomics Approach to Skin: The Sinergy between Individualised Medicine and Futuristic Precision Skin Care?

The skin is a complex ecosystem colonized by millions of microorganisms, the skin microbiota, which are crucial in regulating not only the physiological functions of the skin but also the metabolic changes underlying the onset of skin diseases. The high microbial colonization together with a low diversity at the phylum level and a high diversity at the species level of the skin is very similar to that of the gastrointestinal tract. Moreover, there is an important communication pathway along the gut-brain-skin axis, especially associated with the modulation of neurotransmitters by the microbiota. Therefore, it is evident that the high complexity of the skin system, due not only to the genetics of the host but also to the interaction of the host with resident microbes and between microbe and microbe, requires a multi-omics approach to be deeply understood. Therefore, an integrated analysis, with high-throughput technologies, of the consequences of microbial interaction with the host through the study of gene expression (genomics and metagenomics), transcription (transcriptomics and meta-transcriptomics), and protein production (proteomics and meta-proteomics) and metabolite formation (metabolomics and lipidomics) would be useful. Although to date very few studies have integrated skin metabolomics data with at least one other 'omics' technology, in the future, this approach will be able to provide simple and fast tests that can be routinely applied in both clinical and cosmetic settings for the identification of numerous skin diseases and conditions. It will also be possible to create large archives of multi-omics data that can predict individual responses to pharmacological treatments and the efficacy of different cosmetic products on individual subjects by means of specific allotypes, with a view to increasingly tailor-made medicine. In this review, after analyzing the complexity of the skin ecosystem, we have highlighted the usefulness of this emerging integrated omics approach for the analysis of skin problems, starting with one of the latest 'omics' sciences, metabolomics, which can photograph the expression of the genome during its interaction with the environment.

Metabolomics in Children Cow's Milk Protein Allergy: Possible Contribution from a System Biology Approach?

One of the most frequent triggers of food anaphylaxis in pediatric age but also among the most common, early, and complex causes of childhood food allergy is cow's milk protein allergy (CMPA). The diagnostic course and management of this allergy is defined in a complex clinical picture due to several factors. First of all, the epidemiological data are not uniform, mainly as a consequence of the diagnostic methodology used in the various studies and the different age ranges covered. In addition, there is the complexity of terminology, since although CMPA traditionally refers to immune-mediated reactions to cow's milk, it is a term encompassing numerous clinical features with different symptoms and the requirement for specific treatments. Moreover, the differential diagnosis with other very frequent diseases, especially in the first year of life, such as gastro-esophageal reflux disease or colic, is still complex. This can result in misdiagnosis and incorrect treatment, with harmful health consequences and significant economic repercussions. In this context, the combination of several omics sciences together, which have already proved useful in clarifying the allergenicity of cow's milk proteins with greater precision, could improve the diagnostic tests currently in use through the identification of new, more specific, and precise biomarkers that make it possible to improve diagnostic accuracy and predict the patient's response to the various available treatments for the recovery of tolerance.

Metabolomics and fetal-neonatal nutrition: between "not enough" and "too much".

Metabolomics is a new analytical technique defined as the study of the complex system of metabolites that is capable of describing the biochemical phenotype of a biological system. In recent years the literature has shown an increasing interest in paediatric obesity and the onset of diabetes and the metabolic syndrome in adulthood. Some studies show that fetal malnutrition, both excessive and insufficient, may permanently alter the metabolic processes of the fetus and increase the risk of future chronic pathologies. At present then, attention is being focused mainly on the formulation of new hypotheses, by means of metabolomics, concerning the biological mechanisms to departure from fetal-neonatal life that may predispose to the development of these diseases.

Metabolomics in adult and pediatric nephrology.

Metabolomics, the latest of the "omics" sciences, has a non-selective approach and can thus lead to the identification of all the metabolites (molecules < 1 kDa) in a biological system. The metabolomic profile can be considered the most predictive phenotype capable of evaluating epigenetic modifications determined by external factors. It is so close to the phenotype as to be considered the phenotype itself in its unique individuality (fingerprinting), both in health (phenome), and disease (diseasome). Urine, compared to other biological liquids, has the advantage of being a complex fluid with many components, including intermediate metabolites. Metabolomics may thus play a role in the study of different kidney diseases and overcome diagnostic difficulties. We shall present the studies that to our knowledge have been published on Nephrology and Pediatric Nephrology. Some are experimental while others are clinical. We have not considered carcinomas and transplantations. Although scarce, the data on adults and the very few ones in pediatrics are quite interesting. Further studies on kidneys are needed to determine the practical clinical impact of metabolomics in kidney renal pathologies. The "multiplatform" "omic" study of urine and namely metabolomics can contribute to improving early diagnosis and the outcome of kidney diseases.

Childhood Obesity and the Cryptic Language of the Microbiota: Metabolomics' Upgrading.

The growing obesity epidemic in childhood is increasingly concerning for the related physical and psychological consequences, with a significant impact on health care costs in both the short and the long term. Nonetheless, the scientific community has not yet completely clarified the complex metabolic mechanisms underlying body weight alterations. In only a small percentage of cases, obesity is the result of endocrine, monogenic, or syndromic causes, while in much more cases, lifestyle plays a crucial role in obesity development. In this context, the pediatric age appears to be of considerable importance as prevention strategies together with early intervention can represent important therapeutic tools not only to counteract the comorbidities that increasingly affect children but also to hinder the persistence of obesity in adulthood. Although evidence in the literature supporting the alteration of the microbiota as a critical factor in the etiology of obesity is abundant, it is not yet fully defined and understood. However, increasingly clear evidence is emerging regarding the existence of differentiated metabolic profiles in obese children, with characteristic metabolites. The identification of specific pathology-related biomarkers and the elucidation of the altered metabolic pathways would therefore be desirable in order to clarify aspects that are still poorly understood, such as the consequences of the interaction between the host, the diet, and the microbiota. In fact, metabolomics can characterize the biological behavior of a specific individual in response to external stimuli, offering not only an eventual effective screening and prevention strategy but also the possibility of evaluating adherence and response to dietary intervention.

Lipidomics and Metabolomics in Infant Atopic Dermatitis: What's the Correlation with Early Nutrition?

To date, the complex picture of atopic dermatitis (AD) has not yet been fully clarified, despite the important prevalence of this disease in the pediatric population (20%) and the possibility of persistence into adulthood, with important implications for the quality of life of those affected, as well as significant social and financial costs. The most recent scientific evidence suggests a new interpretation of AD, highlighting the important role of the environment, particularly that of nutrition in the early stages of development. In fact, the new indications seem to point out the harmful effect of elimination diets, except in rare cases, the uselessness of chrono-insertions during complementary feeding and some benefits, albeit weak, of breastfeeding in those at greater risk. In this context, metabolomics and lipidomics can be necessary for a more in-depth knowledge of the complex metabolic network underlying this pathology. In fact, an alteration of the metabolic contents in children with AD has been highlighted, especially in correlation to the intestinal microbiota. While preliminary lipidomic studies showed the usefulness of a more in-depth knowledge of the alterations of the skin barrier to improve the development of baby skin care products. Therefore, investigating the response of different allergic phenotypes could be useful for better patient management and understanding, thus providing an early intervention on dysbiosis necessary to regulate the immune response from the earliest stages of development.

Metabolomics in NEC: An Updated Review.

Necrotizing enterocolitis (NEC) represents the most common and lethal acute gastrointestinal emergency of newborns, mainly affecting those born prematurely. It can lead to severe long-term sequelae and the mortality rate is approximately 25%. Furthermore, the diagnosis is difficult, especially in the early stages, due to multifactorial pathogenesis and complex clinical pictures with mild and non-specific symptoms. In addition, the existing tests have poor diagnostic value. Thus, the scientific community has been focusing its attention on the identification of non-invasive biomarkers capable of prediction, early diagnosis and discriminating NEC from other intestinal diseases in order to intervene early and block the progression of the pathology. In this regard, the use of "omics" technologies, especially metabolomics and microbiomics, could be a fundamental synergistic strategy to study the pathophysiology of NEC. In addition, a deeper knowledge of the microbiota-host cross-talk can clarify the metabolic pathways potentially involved in the pathology, allowing for the identification of specific biomarkers. In this article, the authors analyze the state-of-the-art concerning the application of metabolomics and microbiota analysis to investigate this pathology and discuss the future possibility of the metabolomic fingerprint of patients for diagnostic purposes.

Use of Telemedicine Healthcare Systems in Pediatric Assistance at Territorial Level: Consensus Document of the Italian Society of Telemedicine (SIT), of the Italian Society of Preventive and Social Pediatrics (SIPPS), of the Italian Society of Pediatric Primary Care (SICuPP), of the Italian Federation of Pediatric Doctors (FIMP) and of the Syndicate of Family Pediatrician Doctors (SIMPeF).

Technological innovation can contribute to a reorganization of healthcare, particularly by supporting the shift in the focus of care from the hospital to the territory, through innovative citizen-centered models, and facilitating access to services in the territory. Health and social care delivery modalities, enabled by telemedicine, are crucial in this regard. The objective of this Consensus document, written by the main Italian Scientific Societies involved in the use of telemedicine in pediatrics, is to define a standard for its use at the territorial level in various declinations in the pediatric field; this paper also identifies priority areas for its application and the types of services that most require intervention and investment. The changes that are underway in digital transformation in all sectors are unstoppable, and for the digital transformation to take place in a productive sense, the contribution of not only all health professionals, but also of patients, is necessary. From this perspective, authors from different backgrounds were involved in the drafting of this Consensus and, in the future, other figures, primarily patients, are expected to be involved. In fact, this belongs to the vision of connected care, in which the citizen/patient actively participates in the treatment path so that they are assisted in a personalized, predictive and preventive way. The future scenario must be able to provide for the involvement of patients from the initial stages of planning any treatment path, even in the pediatric age, and increasing, where possible, the proximity of the health service to the families.

Use of Telemedicine Healthcare Systems in Children and Adolescents with Chronic Disease or in Transition Stages of Life: Consensus Document of the Italian Society of Telemedicine (SIT), of the Italian Society of Preventive and Social Pediatrics (SIPPS), of the Italian Society of Pediatric Primary Care (SICuPP), of the Italian Federation of Pediatric Doctors (FIMP) and of the Syndicate of Family Pediatrician Doctors (SIMPeF).

Telemedicine is considered an excellent tool to support the daily and traditional practice of the health profession, especially when referring to the care and management of chronic patients. In a panorama in which chronic pathologies with childhood onset are constantly increasing and the improvement of treatments has allowed survival for them into adulthood, telemedicine and remote assistance are today considered effective and convenient solutions both for the chronic patient, who thus receives personalized and timely assistance, and for the doctors, who reduce the need for direct intervention, hospitalizations and consequent management costs. This Consensus document, written by the main Italian Scientific Societies involved in the use of telemedicine in pediatrics, has the objectives to propose an organizational model based on the relationships between the actors who participate in the provision of a telemedicine service aimed at minors with chronic pathologies, identifying specific project links between the areas of telemedicine in the developmental age from the first 1000 days of life to the age adult. The future scenario will have to be able to integrate digital innovation in order to offer the best care to patients and citizens. It will have to be able to provide the involvement of patients from the very beginning of the design of any care pathway, increasing where possible the proximity of the health service to citizens.

Information and Training on the Use of Telemedicine in Pediatric Population: Consensus Document of the Italian Society of Telemedicine (SIT), of the Italian Society of Preventive and Social Pediatrics (SIPPS), of the Italian Society of Pediatric Primary Care (SICuPP), of the Italian Federation of Pediatric Doctors (FIMP), and of the Syndicate of Family Pediatrician Doctors (SIMPeF).

Telemedicine has entered the daily lives of doctors, although the digital skills of healthcare professionals still remain a goal to be achieved. For the purpose of a large-scale development of telemedicine, it is necessary to create trust in the services it can offer and to favor their acceptance by healthcare professionals and patients. In this context, information for the patient regarding the use of telemedicine, the benefits that can be derived from it, and the training of healthcare professionals and patients for the use of new technologies are fundamental aspects. This consensus document is a commentary that has the aim of defining the information on and training aspects of telemedicine for pediatric patients and their caregivers, as well as pediatricians and other health professionals who deal with minors. For the present and the future of digital healthcare, there is a need for a growth in the skills of professionals and a lifelong learning approach throughout the professional life. Therefore, information and training actions are important to guarantee the necessary professionalism and knowledge of the tools, as well as a good understanding of the interactive context in which they are used. Furthermore, medical skills can also be integrated with the skills of various professionals (engineers, physicists, statisticians, and mathematicians) to birth a new category of health professionals responsible for building new semiotics, identifying criteria for predictive models to be integrated into clinical practice, standardizing clinical and research databases, and defining the boundaries of social networks and new communication technologies within health services.

Isolated 'sign of the horns': a simple, pathognomonic, prenatal sonographic marker of Crisponi syndrome.

The case of a patient presenting with Crisponi syndrome recently hospitalized at our institution is described. During pregnancy a diagnosis of this syndrome was hypothesized following sonographic observation of the fetus with the hands showing 'the sign of the horns'. Such a finding, if isolated, as in our case, may represent a simple, pathognomonic sonographic marker of Crisponi syndrome.