Metabolomic Profiling of Pregnancies With Polycystic Ovary Syndrome Identifies a Unique Metabolic Signature and Potential Predictive Biomarkers of Low Birth Weight.

Background: Polycystic ovary syndrome (PCOS) is a complex syndrome with clinical features of an endocrine/metabolic disorder. Various metabolites show significant association with PCOS; however, studies comparing the metabolic profile of pregnant women with and without PCOS are lacking. In this study, metabolomics analysis of blood samples collected from PCOS women and age and BMI matched controls in the second trimester of pregnancy was performed to identify metabolic differences between the two groups and determine their association with pregnancy outcome. Methods: Sixteen PCOS and fifty-two healthy women in their second trimester underwent targeted metabolomics of plasma samples using tandem mass spectrometry with the Biocrates MxP® Quant 500 Kit. Linear regression models were used to identify the metabolic alterations associated with PCOS, followed by enrichment and Receiver Operating Characteristic (ROC) analyses to determine the best indicators of pregnancy outcomes. Results: PCOS women had lower birth weight babies compared to healthy controls. As a group, systolic blood pressure (SBP) at both second trimester and at delivery negatively correlated with birth weight. Regression models indicated significant increases in the triglycerides C20:4_C34:3 and C18:2_C38:6 in the PCOS group [false discovery rate (FDR) <0.05]. Enrichment analysis revealed significant elevations in triglycerides containing arachidonic acid, linoleic acid and palmitic acid in the PCOS group. A number of indicators of baby birth weight were identified including SBP at delivery, hexosylceramide (d18:2/24:0), ceramide (d18.0/24.1) and serine, with an AUC for all predictors combined for low birth weight (≤2500grams) of 0.88 (95%CI: 0.75-1.005, p<0.001). Conclusions: PCOS pregnancies resulted in babies with a lower birth weight, marked by a unique metabolic signature that was enriched with specific triglycerides and unsaturated fatty acids. The functional significance of these associations needs further investigation.

Characterisation of fasted state gastric and intestinal fluids collected from children.

Fundamental knowledge about the composition of intestinal fluids in paediatric populations is currently unavailable. This study aimed to characterise gastric and intestinal fluid from paediatric populations. Gastric and intestinal fluid samples were obtained during routine clinical endoscopy from paediatric patients at a large teaching hospital. These fluids were characterised to measure the pH; buffer capacity; osmolality; bile acid concentration and composition. A total of 55 children were recruited to the study aged from 11 months to 15 years of age where 53 gastric fluid samples and 40 intestinal fluid samples were obtained. pH values recorded ranged from pH 0.57 to 11.05 (median: 2.50) in gastric fluids and from 0.89 to 8.97 (median: 3.27) in intestinal fluids. The buffer capacity did not change significantly between gastric and intestinal fluids with median values of 12 mM/L/ΔpH for both fluids. Gastric fluid osmolality values ranged from 1 to 615 mOsm/kg, while intestinal fluid values ranged from 35 to 631 mOsm/kg. Gastric fluid bile acid concentrations ranged from 0.002 to 2.3 mM with a median value of 0.017 mM whilst intestinal fluid bile acid concentrations ranged from 0.0008 to 3.3 mM with a median value of 0.178 mM. Glycocholate; taurocholic acid; glycochenodeoxycholate and taurochenodeoxycholate were the most commonly identified bile acids within paediatric intestinal fluids. All compositional components were associated with large inter-individual variability. Further work is required to develop simulated paediatric media and to explore the impact of these media on drug solubility and dissolution.

DNA methylation loci in placenta associated with birthweight and expression of genes relevant for early development and adult diseases.

BACKGROUND: Birthweight marks an important milestone of health across the lifespan, including cardiometabolic disease risk in later life. The placenta, a transient organ at the maternal-fetal interface, regulates fetal growth. Identifying genetic loci where DNA methylation in placenta is associated with birthweight can unravel genomic pathways that are dysregulated in aberrant fetal growth and cardiometabolic diseases in later life. RESULTS: We performed placental epigenome-wide association study (EWAS) of birthweight in an ethnic diverse cohort of pregnant women (n = 301). Methylation at 15 cytosine-(phosphate)-guanine sites (CpGs) was associated with birthweight (false discovery rate (FDR) < 0.05). Methylation at four (26.7%) CpG sites was associated with placental transcript levels of 15 genes (FDR < 0.05), including genes known to be associated with adult lipid traits, inflammation and oxidative stress. Increased methylation at cg06155341 was associated with higher birthweight and lower FOSL1 expression, and lower FOSL1 expression was correlated with higher birthweight. Given the role of the FOSL1 transcription factor in regulating developmental processes at the maternal-fetal interface, epigenetic mechanisms at this locus may regulate fetal development. We demonstrated trans-tissue portability of methylation at four genes (MLLT1, PDE9A, ASAP2, and SLC20A2) implicated in birthweight by a previous study in cord blood. We also found that methylation changes known to be related to maternal underweight, preeclampsia and adult type 2 diabetes were associated with lower birthweight in placenta. CONCLUSION: We identified novel placental DNA methylation changes associated with birthweight. Placental epigenetic mechanisms may underlie dysregulated fetal development and early origins of adult cardiometabolic diseases. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00912132.

Combined effects of ambient air pollution and home environmental factors on low birth weight.

BACKGROUND: Low birth weight (LBW) remains a major public health problem worldwide, yet its crucial environmental risk factors are still unclear. OBJECTIVE: To examine the association between LBW (term and preterm LBW) and prenatal exposure to ambient air pollution and home environmental factors as well as their combination, in order to identify critical time window for exposure and key outdoor and indoor factors in LBW development. METHODS: A cohort study of 3509 preschool children was performed in Changsha, China during the period 2011-2012. A questionnaire was conducted to survey each child's birth outcome and each mother's exposure to home environmental factors including parental smoking, new furniture, redecoration, mold/damp stains, window pane condensation, and household pets during pregnancy. Maternal exposure to inhalable particulate matter (PM10), industrial air pollutant (SO2), and traffic air pollutant (NO2) was estimated during different time windows of gestation, including conception month, three trimesters, birth month, and whole gestation. Associations of term and preterm LBW with ambient air pollutants and home environmental factors were assessed by multiple logistic regression models in terms of odds ratio (OR) with 95% confidence interval (CI). RESULTS: Term LBW (TLBW) was significantly associated with exposure to ambient PM10 during pregnancy, with OR (95% CI) = 1.47 (1.00-2.14) for per IQR increase after adjustment for the covariates and home environmental factors. Specifically, we identified the significant association in early phase of pregnancy including conception month (1.90, 1.09-3.30) and the first trimester (1.72, 1.10-2.69). We further found that TLBW was significantly related with parental smoking at home, OR (95% CI) = 2.17 (1.09-4.33). However, no association was observed for preterm LBW (PLBW). The TLBW risk of ambient air pollution and home environmental factors was independent each other and hence the combined exposure to ambient PM10 and indoor parental smoking caused the highest risk. Sensitivity analysis suggested that foetus with younger mothers were significantly more susceptible to risk of indoor parental smoking, while those with smaller house and cockroaches were more sensitive to risk of outdoor PM10 exposure. CONCLUSION: Prenatal exposure to combined outdoor and indoor air pollution, particularly in critical window(s) during early pregnancy, significantly increases the risk of term LBW.

Associated Factors with Low Birth Weight in Dire Dawa City, Eastern Ethiopia: A Cross-Sectional Study.

BACKGROUND: Low Birth Weight (LBW) is a serious public health concern in low- and middle-income countries. Globally, 20 million, an estimated 15% to 20% of babies were born with LBW, and, of these, 13% were in sub-Saharan Africa. Although the World Health Assembly targeted to reduce LBW by 30% by the end of 2025, little has been done on and known about LBW. To meet the goal successfully and efficiently, more research studies on the problem are vital. Hence, the aim of this study was to determine the prevalence and the associated factors of LBW in Dire Dawa city, eastern Ethiopia. OBJECTIVE: The purpose of this study was to assess the prevalence and the associated factors of low birth weight in Dire Dawa City, eastern Ethiopia, 2017. METHOD: A cross-sectional study designed was conducted, and using a systematic sampling technique, 431 mothers who gave birth in the public hospitals in Dire Dawa city from July 01 to August 30, 2018, were selected. Stillbirth and infants with birth defects were excluded from the study. Well-trained data collectors collected the data using a structured questionnaire which was pretested. The data were analyzed using SPSS Version 22.0. The Adjusted Odds Ratio (AOR) with 95% confidence interval (CI) was applied in multivariate logistic regression models, and p value less than 0.05 was considered as statistical significant. RESULT: The prevalence of low birth weight was 21%. Not received nutritional counseling during antenatal care (AOR = 2.03, 95% CI: 1.01, 4.06), preterm birth (AOR = 18.48, 95% CI: 6.51, 52.42), maternal smoking (AOR = 3.97, 95% CI: 1.59, 9.88), and height of the mother less than 150 cm (AOR = 3.54, 95% CI: 1.07, 11.76) were significantly associated with Low birth weight. CONCLUSION: There was a high prevalence of low birth weight in the study area. Effective dietary counseling and additional diet, implementing proven strategies to prevent preterm birth and avoid smoking during pregnancy might decrease the low birth weight and then enhance child survival.

Smoking Cessation and Pregnancy: Timing of Cessation Reduces or Eliminates the Effect on Low Birth Weight.

BACKGROUND: Women who smoke cigarettes while pregnant are at elevated risk of having low birth weight infants (LBW, < 2500 g) which increases risks of infant mortality and morbidity, including chronic conditions later in life. OBJECTIVE: Smoking cessation during pregnancy can reduce the risk of poor birth outcomes. However, the effect that timing of smoking cessation has on the reduction of poor birth outcomes in term pregnancies is unknown. STUDY DESIGN: This retrospective cohort study used birth certificate data from Missouri singleton, full-term, live births from 2010 to 2012 (N = 179,653) to examine the rates and timing of smoking cessation during pregnancy on birthweight. Smoking exposure was categorized as non-smoker, preconception cessation, first trimester cessation, second trimester cessation, and smoker. The outcome was low birth weight (LBW). Covariates included maternal race/ethnicity, age, education level, type of payment for the delivery, marital status, paternal acknowledgement, prenatal sexually transmitted infection (STI), comorbidities, and body mass index. Bivariate and multivariable analyses were used to assess relationships between smoking and LBW status. RESULTS: Preconception cessation did not have a statistically higher risk for LBW than mothers who never smoked (aOR 1.12; 95% CI 0.98, 1.28). First trimester cessation (aOR 1.26; 95% CI 1.05, 1.52), second trimester cessation (aOR 2.00; 95% CI 1.60, 2.67), and smoker (aOR 2.46; 95% CI 2.28, 2.67) had increasing odds for LBW relative to mothers who did not smoke. All covariates had significant relationships with the smoking exposure. CONCLUSION: Preconception cessation yielded LBW rates comparable to non-smokers. The risk for LBW increased as smoking continued throughout pregnancy among full term births, an important new finding in contrast with other studies.

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.

Correlation of adipokines and markers of oxidative stress in women with gestational diabetes mellitus and their newborns.

AIM: We have shown that some markers of oxidative stress were higher in women with gestational diabetes mellitus (GDM). This study examines the relationship between adipokines and oxidative stress and their potential effects in pregnant women. METHODS: Three markers of oxidative stress (malondialdehyde, 8-isoprostane and xanthine oxidase) and three adipokines (leptin, adiponectin and resistin) were measured in maternal plasma, cord plasma and placenta of 208 pregnant women. RESULTS: Among all these women, 105 were diagnosed with GDM while the other 103 were controls. Leptin, resistin, malondialdehyde, xanthine oxidase and 8-isoprostane in maternal plasma, cord plasma and placenta were significantly higher while maternal adiponectin significantly lower in women with GDM (P < 0.05). Adipokines in maternal plasma, cord plasma and placenta were positively correlated with markers of oxidative stress. Both markers of oxidative stress and adipokines were correlated inversely with homeostasis model assessment of insulin resistance whereas positively with quantitative insulin sensitivity check index (P < 0.01). Adiponectin is negatively correlated with leptin and resistin. Placental/cord leptin and cord resistin levels were higher in the macrosomia while maternal adiponectin level was lower (P < 0.05) than normal birthweight newborns. Both markers of oxidative stress and adipokines in maternal and cord plasma are negatively correlated with newborn birthweight (P < 0.05). CONCLUSION: Adipokines interact with markers of oxidative stress, both of which lead to insulin resistance, GDM and macrosomia. It has long been known that placenta involves in the development of GDM. Adipokines might participate in this process and need to be confirmed by further studies.

Tissue differences in DNA methylation changes at AHRR in full term low birth weight in maternal blood, placenta and cord blood in Chinese.

INTRODUCTION: Very few study addressed the relationship between Aryl-hydrocarbon receptor repressor (AHRR) DNA methylation and low birth weight, especially in multiple tissues of mother-infant pairs. In this study, we aimed to investigate AHRR DNA methylation modification in cord blood, placenta and maternal blood between full term low birth weight (FT-LBW) and full term normal birth weight (FT-NBW) newborns. METHODS: We enrolled 90 FT-LBW and 90 FT-NBW mother-infant pairs, of which all placenta and cord blood samples were collected while 45 maternal blood samples of each group were collected. We measured AHRR DNA methylation (Chr5: 373013-373606) using Sequenom MassARRAY, and assessed associations between AHRR DNA methylation and FT-LBW using logistic regression adjusting for maternal age, education, family income, delivery mode, and passive smoking. RESULTS: FT-LBW babies had 3% lower methylation at Chr5: 373378 (CpG 13) in cord blood, and 4-9% higher methylation levels at Chr5: 373315, 373378, 373423, 373476 and 373490/373494 (CpG 10; 13; 15; 16; 17/18 respectively) in maternal blood, comparing with FT-NBW. The methylation of Chr5: 373378 (CpG 13) remained significant association with FT-LBW both in cord blood (OR = 0.90; 95% CI: 0.82, 0.98) and maternal blood (OR = 1.14; 95% CI: 1.04, 1.25) further adjusting for each other in the same model. We observed no significant difference at any CpG sites in placenta. DISCUSSION: AHRR DNA methylation of cord and maternal blood might be independently associated with FT-LBW in different ways.

Dental Infection of Porphyromonas gingivalis Induces Preterm Birth in Mice.

BACKGROUND: Epidemiological studies have revealed a link between dental infection and preterm birth or low birth weight (PTB/LBW), however, the underlying mechanisms remain unclear. Progress in understanding the associated mechanisms has been limited in part by lack of an animal model for chronic infection-induced PTB/LBW, mimicking pregnancy under conditions of periodontitis. We aimed to establish a mouse model of chronic periodontitis in order to investigate the link between periodontitis and PTB/LBW. METHODS: To establish chronic inflammation beginning with dental infection, we surgically opened mouse (female, 8 weeks old) 1st molar pulp chambers and directly infected with w83 strain Porphyromonas gingivalis (P.g.), a keystone periodontal pathogen. Mating was initiated at 6 wks post-infection, by which time dental granuloma tissue had developed and live P.g. was cultured from extracted tooth root, which serves as a persistent source of P.g. The gestational day (gd) and birth weight were recorded during for P.g.-infected and control mice, and serum and placental tissues were collected at gd 15 to evaluate the systemic and local conditions during pregnancy. RESULTS: Dental infection with P.g. significantly increased circulating TNF-α (2.5-fold), IL-17 (2-fold), IL-6 (2-fold) and IL-1ß (2-fold). The P.g.-infected group delivered at gd 18.25 vs. gd 20.45 in the non-infected control (NC) group (p < 0.01), and pups exhibited LBW compared to controls (p < 0.01). P.g. was localized to placental tissues by immunohistochemistry and PCR, and defects in placental tissues of P.g. infected mice included premature rupture of membrane, placental detachment, degenerative changes in trophoblasts and endothelial cells, including necrotic areas. P.g. infection caused significantly increased numbers of polymorphonuclear leukocytes (PMNLs) and macrophages in placental tissues, associated with increased local expression of pro-inflammatory mediators including TNF-α and COX-2. Further placental tissue damage was indicated in P.g. infected mice by decreased CD-31 in endothelial cells, increased expression of 8OHdG, an indicator of oxidative DNA damage, and cleaved caspase-3, a marker of apoptosis. In vitro, P.g. lipopolysaccharide significantly increased expression of COX-2, IL-8 and TNF-α, in HTR-8 trophoblasts in an NF-κB-dependent fashion. CONCLUSIONS: Our novel mouse model supports previous epidemiological studies signifying dental infection as predisposing factor for PTB/LBW. We demonstrate PTB and LBW in infected mice, translocation of P.g to placental tissues, increased circulating and local pro-inflammatory markers, and the capability of P.g. LPS to directly induce cytokine production in trophoblasts, in vitro. These findings further underscore the importance of local and systemic infections and inflammation during pregnancy and suggest that prevention and/or elimination of dental infections such as marginal or periapical periodontitis before pregnancy may have a beneficial effect on PTB/LBW.

Alterations to DNA methylation and expression of CXCL14 are associated with suboptimal birth outcomes.

CXCL14 is a chemokine that has previously been implicated in insulin resistance in mice. In humans, the role of CXCL14 in metabolic processes is not well established, and we sought to determine whether CXCL14 is a risk susceptibility gene important in fetal programming of metabolic disease. For this purpose, we investigated whether CXCL14 is differentially regulated in human umbilical cords of infants with varying birth weights. We found an elevated expression of CXCL14 in human low birth weight (LBW) cords, as well as in cords from nutritionally restricted Macaca fascicularis macaques. To further analyze the regulatory mechanisms underlying the expression of CXCL14, we examined CXCL14 in umbilical cord-derived mesenchymal stem cells (MSCs) that provide an in vitro cell-based system amenable to experimental manipulation. Using both whole frozen cords and MSCs, we determined that site-specific CpG methylation in the CXCL14 promoter is associated with altered expression, and that changes in methylation are evident in LBW infant-derived umbilical cords that may indicate future metabolic compromise through CXCL14.

IGF-IR signal transduction protein content and its activation by IGF-I in human placentas: relationship with gestational age and birth weight.

INTRODUCTION: The human placenta expresses the IGF-I and IGF-IR proteins and their intracellular signal components (IRS-1, AKT and mTOR). The aim of this study was to assess the IGF-IR content and activation of downstream signaling molecules in placentas from newborns who were classified by gestational age and birth weight. We studied placentas from 25 term appropriate (T-AGA), 26 term small (T-SGA), 22 preterm AGA (PT-AGA), and 20 preterm SGA (PT-SGA) newborns. The total and phosphorylated IGF-IR, IRS-1, AKT, and mTOR contents were determined by Western Blot and normalized by actin or with their respective total content. The effect of IGF-I was determined by stimulating placental explants with recombinant IGF-I 10-8 mol/L for 15, 30, and 60 minutes. RESULTS: The IGF-IR content was higher in T-SGA compared to T-AGA placentas, and the IRS-1 content was higher in PT-placentas compared with their respective T-placentas. The effect of IGF-I on the phosphorylated forms of IGF-IR was increased in T-SGA (150%) and PT-SGA (300%) compared with their respective AGA placentas. In addition, AKT serine phosphorylation was higher in PT-SGA compared to PT-AGA and T-SGA placentas (90% and 390% respectively). CONCLUSION: The higher protein content and response to IGF-I of IGF-IR, IRS-1, and AKT observed in SGA placentas may represent a compensatory mechanism in response to fetal growth restriction.

Impaired leptin gene expression and release in cultured preadipocytes isolated from individuals born with low birth weight.

Low birth weight (LBW) is associated with increased risk of the development of type 2 diabetes (T2D). The appetite-regulating hormone leptin is released from mature adipocytes, and its production may be decreased in immature preadipocytes from LBW individuals. We recruited 14 men born with LBW and 13 controls born with normal birth weight (NBW). Biopsy samples were obtained from subcutaneous abdominal fat depots, and preadipocytes were isolated and cultured. Gene expression of leptin and selected differentiation markers were analyzed during preadipocyte differentiation, and cell culture media were collected to analyze leptin secretion. DNA methylation of CpG sites in the leptin promoter was measured using pyrosequencing. We found that differentiating preadipocytes from LBW individuals showed reduced leptin gene expression and a corresponding reduced leptin release compared with NBW individuals. Mean DNA methylation of the proximal LEP promoter was increased in LBW compared with NBW individuals. The notion of impaired adipocyte maturation in LBW individuals was supported by a lower mRNA expression of the differentiation markers; fatty acid binding protein 4, peroxisome proliferator-activated receptor γ, and GLUT4. Our findings are consistent with impaired preadipocyte maturation, contributing to an increased risk of the development of T2D in LBW subjects.

Algunas variables bioquímicas en adolescentes obesos con antecedente de bajo peso al nacer / Some biochemical variables analyzed in obese adolescents with history of low birthweight

Introducción: la malnutrición intraútero ha sido postulada con vinculación a afecciones del desarrollo embrionario que determinan el desarrollo ulterior de obesidad, diabetes mellitus tipo 2, dislipidemias, disfunción mitocondrial y aterosclerosis. Objetivo: determinar las complicaciones metabólicas en adolescentes obesos con antecedentes de bajo peso al nacer. Métodos: estudio descriptivo y de corte transversal. Se incluyeron 50 pacientes obesos, con antecedentes de bajo peso al nacer y embarazo a término, de ambos sexos, en las edades comprendidas entre 9 y 17 años de edad, que asistieron a la consulta externa del servicio de Endocrinología del Hospital Pediátrico Docente Juan Manuel Márquez, en el período comprendido de enero de 2011 a enero de 2012. Se realizaron determinaciones de colesterol, triglicéridos, aminotransferasas hepáticas, glucemia, e insulinemia en ayunas y posprandial de dos horas. Resultados: las variables bioquímicas estudiadas no mostraron diferencias entre los puntos de corte utilizados para clasificar el peso al nacer. La transaminasa glutámico pirúvica mostró valores más altos en los adolescentes entre 15 y 17 años de edad. Conclusiones: la hipertrigliceridemia fue más elevada en el sexo femenino, mientras que la hiperglucemia y la hiperinsulinemia lo fueron en el masculino

Introduction: intrauterine malnutrition has been considered as being related to embrionary development problems that determine further occurrence of obesity, diabetes mellitus type 2, dyslipidemias, mitochondrial dysfunction and atherosclerosis.Objective: to determine the metabolic complications in obese adolescents with history of low birthweight.Methods: cross-sectional descriptive study of 50 obese patients of both sexes and aged 9 to 17 years and with a history of low birthweight. They had all been attended to in the outpatient endocrinology service of Juan Manuel Marquez teaching pediatric hospital from January 2011 to January 2012. Cholesterol, triglyceride, hepatic aminotransferase, glycemia and insulinemia on fasting and postprandially after 2 hours were estimated. Results: the studied biochemical variables did not show differences among the cutoffs used to classify birthweight. Piruvic gluthamic transaminase showed higher values in 15-17 years-old adolescents.Conclusions: hypertriglyceridemia was more elevated in females whereas hyperglycemia and hyperinsulinemia were elevated in males

Alteration of cardiac glucose metabolism in association to low birth weight: experimental evidence in lambs with left ventricular hypertrophy.

OBJECTIVE: Intrauterine growth restriction that results in low birth weight (LBW) has been linked to the onset of pathological cardiac hypertrophy. An altered transition from a fetal to an adult energy metabolism phenotype, with increased reliance on glucose rather than fatty acids for energy production, could help explain this connection. We have therefore investigated cardiac metabolism in relation to left ventricular hypertrophy in LBW lambs, at 21days after birth. MATERIALS/METHODS: The expression of regulatory molecules involved in cardiac glucose and fatty acid metabolism was measured using real-time PCR and Western blotting. A section of the left ventricle was fixed for Periodic Acid Schiff staining to determine tissue glycogen content. RESULTS: There was increased abundance of insulin signalling pathway proteins (phospho-insulin receptor, insulin receptor and phospho-Akt) and the glucose transporter (GLUT)-1, but no change in GLUT-4 or glycogen content in the heart of LBW compared to ABW lambs. There was, however, increased abundance of cardiac pyruvate dehydrogenase kinase 4 (PDK-4) in LBW compared to ABW lambs. There were no significant changes in the mRNA expression of components of the peroxisome proliferator activated receptor regulatory complex or proteins involved in fatty acid metabolism. CONCLUSION: We concluded that LBW induced left ventricular hypertrophy was associated with increased GLUT-1 and PDK-4, suggesting increased glucose uptake, but decreased efficacy for the conversion of glucose to ATP. A reduced capacity for energy conversion could have significant implications for vulnerability to cardiovascular disease in adults who are born LBW.

Glial fibrillary acidic protein as a biomarker for periventricular white matter injury.

OBJECTIVE: Periventricular white matter injury (PWMI), a precursor of cerebral palsy, traditionally is not diagnosed until 6 weeks of life by head ultrasound scanning. We sought to determine whether early neonatal glial fibrillary acidic protein (GFAP) levels could identify PWMI in low birthweight (<2500 g) infants. STUDY DESIGN: Each case with PWMI on head ultrasound scanning at 6 weeks of life from April 2009 to April 2011 was matched by gestational age and mode of delivery to 2 subsequent neonates with a normal head ultrasound scan. GFAP was measured in cord blood at birth, at neonatal intensive care unit admission, and on days 1-4 of life. RESULTS: During this 2-year period, 21 cases with PWMI with gestational age 27.4 ± 3.3 weeks were compared with 42 control infants. The incidence of cesarean delivery was 61.9% in both groups. GFAP was not significantly different in cord blood or at neonatal intensive care unit admission but was significantly elevated on day 1 (median, 5-95%; 0, 0-0.98 ng/mL cases; 0, 0-0.06 ng/mL control infants; P = .03), day 2 (0, 0-1.21 ng/mL; 0, 0-0.05 ng/mL, respectively; P = .02), day 3 (0.05, 0-0.33 ng/mL; 0, 0-0.04 ng/mL, respectively; P = .004), and day 4 (0.02, 0-1.03 ng/mL; 0, 0-0.05 ng/mL, respectively; P < .001). The odds of the development of PWMI significantly increased with increasing levels of GFAP from day 1-4 of life when adjustment was made for preeclampsia, antenatal steroid administration, and neonatal chronic lung disease. CONCLUSION: The ability to predict PWMI with a blood test for GFAP shortly after birth opens the possibility for rapid identification of infants for early intervention and provides a benchmark for the qualification of new therapies to improve neurodevelopmental outcomes.

Expression of P-selectin (CD62P) on platelets after thrombin and ADP in hypotrophic and healthy, full-term newborns.

BACKGROUND: Hypotrophic newborns in comparison with eutrophic newborns demonstrate a reduced blood platelet count and therefore may have haemostasis disorders. Expression of P-selectin (CD62P) on the surface of platelets is a marker of stimulated, activated blood platelets. The ability of platelets to react can be determined after the addition of the following activators: strong (thrombin) and weak (ADP). MATERIALS AND METHODS: We studied 48 hypotrophic newborns, 25 females and 23 males, weighing less than the 10th centile and 55 healthy, full-term newborns, 25 females and 30 males. Expression of CD62P on the surface of platelets was examined in the native state, after the addition of thrombin or ADP. RESULTS: Hypotrophic newborns exhibited almost double the percentage of platelets expressing CD62P compared with the control group, 4.21% versus 2.88%. After the addition of thrombin, the percentage was 31.5% versus 12.5%, p < 0.001, whereas after the addition of ADP, the percentage was 9.54% versus 4.5%, p = 0.002. CONCLUSIONS: Hypotrophic newborns are capable of greater platelet activation in comparison with healthy term newborns. However, gender does not affect the expression of P-selectin.

Effect of pregnancy for females born small on later life metabolic disease risk.

There is a strong inverse relationship between a females own birth weight and her subsequent risk for gestational diabetes with increased risk of developing diabetes later in life. We have shown that growth restricted females develop loss of glucose tolerance during late pregnancy with normal pancreatic function. The aim of this study was to determine whether growth restricted females develop long-term impairment of metabolic control after an adverse pregnancy adaptation. Uteroplacental insufficiency was induced by bilateral uterine vessel ligation (Restricted) or sham surgery (Control) in late pregnancy (E18) in F0 female rats. F1 Control and Restricted female offspring were mated with normal males and allowed to deliver (termed Ex-Pregnant). Age-matched Control and Restricted Virgins were also studied and glucose tolerance and insulin secretion were determined. Pancreatic morphology and hepatic glycogen and triacylglycerol content were quantified respectively. Restricted females were born lighter than Control and remained lighter at all time points studied (p<0.05). Glucose tolerance, first phase insulin secretion and liver glycogen and triacylglycerol content were not different across groups, with no changes in ß-cell mass. Second phase insulin secretion was reduced in Restricted Virgins (-34%, p<0.05) compared to Control Virgins, suggestive of enhanced peripheral insulin sensitivity but this was lost after pregnancy. Growth restriction was associated with enhanced basal hepatic insulin sensitivity, which may provide compensatory benefits to prevent adverse metabolic outcomes often associated with being born small. A prior pregnancy was associated with reduced hepatic insulin sensitivity with effects more pronounced in Controls than Restricted. Our data suggests that pregnancy ameliorates the enhanced peripheral insulin sensitivity in growth restricted females and has deleterious effects for hepatic insulin sensitivity, regardless of maternal birth weight.

Periodontal disease and its relationship with preterm labor and/or newborns with low birth weight / A doença periodontal e sua relação com o parto prematuro e/ou recém-nascidos com baixo peso ao nascer

Objective - To establish a relationship between the periodontal disease and premature birth babies and/or low birth weight babies, to determine that the periodontal disease may be an independent risk factor for these conditions. Methods - Forty-two pregnant women who attended the prenatal visits at Cruz de Malta Assistance Center (Brazil) were enrolled in this study. Each woman was submitted to a questionnaire and to a comprehensive periodontal exam. From the periodontal exam the pregnant women were assigned into two groups. Results - The first group was composed by periodontal disease (n=18) with an average pregnancy period of 36 weeks and newborns with weight average values of 3.210 Kg ± 0.490 Kg. The second group was composed by women without periodontal disease (n=24) who presented an average pregnancy period of 35 weeks and 5 days ± 3 days and newborns with weight average values of 2.920 Kg ± 0.510 Kg. The other risk factors cited above were also evaluated. Conclusion - It was possible to conclude through this present study that the periodontal disease did not interfere in a negative way neither on the pregnancy time nor on the newborn weight. Thus it cannot be classified as an independent risk factor for preterm labors and/or newborns with low birth weight babies.

Objetivo - Estabelecer uma relação entre a doença periodontal e bebês prematuros ao nascimento e/ou bebês de baixo peso, para determinar que a doença periodontal pode ser um fator de risco independente para essas condições. Métodos - Quarenta e duas mulheres grávidas que participaram das consultas pré-natais no Centro Assistencial Cruz de Malta (Brasil) foram incluídos neste estudo. Cada mulher foi submetida a um questionário e de um exame abrangente periodontal. A partir do exame periodontal as gestantes foram divididas em dois grupos. Resultados - O primeiro grupo foi composto por doença periodontal (n=18) com um período de gestação média de 36 semanas e recém-nascidos com peso valores médios de 3,210 kg ± 0,490 kg. O segundo grupo foi composto por mulheres sem doença periodontal (n=24), que apresentou um período de gestação média de 35 semanas e 5 dias ± 3 dias e recém-nascidos com peso valores médios de 2,920 kg ± 0,510 kg. Os outros fatores de risco citados acima também foram avaliados. Conclusão - Foi possível concluir através deste estudo que a doença periodontal não interferiu de forma negativa nem sobre o tempo de gravidez, nem no peso ao nascer. Assim, não pode ser classificado como um fator de risco independente para partos pré-termo e/ou recém-nascidos com baixo peso ao nascer.

Early life precursors, epigenetics, and the development of food allergy.

Food allergy (FA), a major clinical and public health concern worldwide, is caused by a complex interplay of environmental exposures, genetic variants, gene-environment interactions, and epigenetic alterations. This review summarizes recent advances surrounding these key factors, with a particular focus on the potential role of epigenetics in the development of FA. Epidemiologic studies have reported a number of nongenetic factors that may influence the risk of FA, such as timing of food introduction and feeding pattern, diet/nutrition, exposure to environmental tobacco smoking, prematurity and low birth weight, microbial exposure, and race/ethnicity. Current studies on the genetics of FA are mainly conducted using candidate gene approaches, which have linked more than 10 genes to the genetic susceptibility of FA. Studies on gene-environment interactions of FA are very limited. Epigenetic alteration has been proposed as one of the mechanisms to mediate the influence of early life environmental exposures and gene-environment interactions on the development of diseases later in life. The role of epigenetics in the regulation of the immune system and the epigenetic effects of some FA-associated environmental exposures are discussed in this review. There is a particular lack of large-scale prospective birth cohort studies that simultaneously assess the interrelationships of early life exposures, genetic susceptibility, epigenomic alterations, and the development of FA. The identification of these key factors and their independent and joint contributions to FA will allow us to gain important insight into the biological mechanisms by which environmental exposures and genetic susceptibility affect the risk of FA and will provide essential information to develop more effective new paradigms in the diagnosis, prevention, and management of FA.