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1.
Fetal Serum Metabolites Are Independently Associated with Gestational Diabetes Mellitus.
Lu, YP, Reichetzeder, C, Prehn, C, von Websky, K, Slowinski, T, Chen, YP, Yin, LH, Kleuser, B, Yang, XS, Adamski, J, et al
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 2018;(2):625-638
Abstract
BACKGROUND/AIMS: Gestational diabetes (GDM) might be associated with alterations in the metabolomic profile of affected mothers and their offspring. Until now, there is a paucity of studies that investigated both, the maternal and the fetal serum metabolome in the setting of GDM. Mounting evidence suggests that the fetus is not just passively affected by gestational disease but might play an active role in it. Metabolomic studies performed in maternal blood and fetal cord blood could help to better discern distinct fetal from maternal disease interactions. METHODS At the time of birth, serum samples from mothers and newborns (cord blood samples) were collected and screened for 163 metabolites utilizing tandem mass spectrometry. The cohort consisted of 412 mother/child pairs, including 31 cases of maternal GDM. RESULTS An initial non-adjusted analysis showed that eight metabolites in the maternal blood and 54 metabolites in the cord blood were associated with GDM. After Benjamini-Hochberg (BH) procedure and adjustment for confounding factors for GDM, fetal phosphatidylcholine acyl-alkyl C 32: 1 and proline still showed an independent association with GDM. CONCLUSIONS This study found metabolites in cord blood which were associated with GDM, even after adjustment for established risk factors of GDM. To the best of our knowledge, this is the first study demonstrating an independent association between fetal serum metabolites and maternal GDM. Our findings might suggest a potential effect of the fetal metabolome on maternal GDM.
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2.
A Low Glycaemic Index Diet in Pregnancy Induces DNA Methylation Variation in Blood of Newborns: Results from the ROLO Randomised Controlled Trial.
Geraghty, AA, Sexton-Oates, A, O'Brien, EC, Alberdi, G, Fransquet, P, Saffery, R, McAuliffe, FM
Nutrients. 2018;(4)
Abstract
The epigenetic profile of the developing fetus is sensitive to environmental influence. Maternal diet has been shown to influence DNA methylation patterns in offspring, but research in humans is limited. We investigated the impact of a low glycaemic index dietary intervention during pregnancy on offspring DNA methylation patterns using a genome-wide methylation approach. Sixty neonates were selected from the ROLO (Randomised cOntrol trial of LOw glycaemic index diet to prevent macrosomia) study: 30 neonates from the low glycaemic index intervention arm and 30 from the control, whose mothers received no specific dietary advice. DNA methylation was investigated in 771,484 CpG sites in free DNA from cord blood serum. Principal component analysis and linear regression were carried out comparing the intervention and control groups. Gene clustering and pathway analysis were also explored. Widespread variation was identified in the newborns exposed to the dietary intervention, accounting for 11% of the total level of DNA methylation variation within the dataset. No association was found with maternal early-pregnancy body mass index (BMI), infant sex, or birthweight. Pathway analysis identified common influences of the intervention on gene clusters plausibly linked to pathways targeted by the intervention, including cardiac and immune functioning. Analysis in 60 additional samples from the ROLO study failed to replicate the original findings. Using a modest-sized discovery sample, we identified preliminary evidence of differential methylation in progeny of mothers exposed to a dietary intervention during pregnancy.
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3.
Effects of dietary advice on insulin-like growth factors among healthy newborns.
Bulduk, EÖ, Bulduk, S, Coşkun, BB
Archives of gynecology and obstetrics. 2018;(3):637-643
Abstract
OBJECTIVES In fetal life, insulin, insulin-like growth factor (IGF) 1, IGF 2 and IGF-binding protein (IGFBP) 3 are essential growth factors. The purpose of this study is to investigate the effects of dietary intervention on insulin-like growth factors in the cord blood of neonates. METHODS The study involved 52 pregnant women who were followed up in Gazi University Medical School Hospital at Ankara, Turkey. They were randomly divided into two groups: The experimental group was involved in nutrition education. We measured IGF 1, IGF 2 and IGFBP 3 concentrations in cord blood from 52 neonates. RESULTS In the experimental group, cord serum levels of IGF 1, IGF 2 were observed to be higher than that of control group. CONCLUSION Dietary advice had positive effects on the cord serum IGF 1 and IGF 2 concentrations. Dietary advice during pregnancy proved to be effective in fetal development.
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4.
Cord Blood Lysophosphatidylcholine 16: 1 is Positively Associated with Birth Weight.
Lu, YP, Reichetzeder, C, Prehn, C, Yin, LH, Yun, C, Zeng, S, Chu, C, Adamski, J, Hocher, B
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 2018;(2):614-624
Abstract
BACKGROUND/AIMS: Impaired birth outcomes, like low birth weight, have consistently been associated with increased disease susceptibility to hypertension in later life. Alterations in the maternal or fetal metabolism might impact on fetal growth and influence birth outcomes. Discerning associations between the maternal and fetal metabolome and surrogate parameters of fetal growth could give new insight into the complex relationship between intrauterine conditions, birth outcomes, and later life disease susceptibility. METHODS Using flow injection tandem mass spectrometry, targeted metabolomics was performed in serum samples obtained from 226 mother/child pairs at delivery. Associations between neonatal birth weight and concentrations of 163 maternal and fetal metabolites were analyzed. RESULTS After FDR adjustment using the Benjamini-Hochberg procedure lysophosphatidylcholines (LPC) 14: 0, 16: 1, and 18: 1 were strongly positively correlated with birth weight. In a stepwise linear regression model corrected for established confounding factors of birth weight, LPC 16: 1 showed the strongest independent association with birth weight (CI: 93.63 - 168.94; P = 6.94×10-11 ). The association with birth weight was stronger than classical confounding factors such as offspring sex (CI: -258.81- -61.32; P = 0.002) and maternal smoking during pregnancy (CI: -298.74 - -29.51; P = 0.017). CONCLUSIONS After correction for multiple testing and adjustment for potential confounders, LPC 16: 1 showed a very strong and independent association with birth weight. The underlying molecular mechanisms linking fetal LPCs with birth weight need to be addressed in future studies.
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5.
DNA methylation in blood from neonatal screening cards and the association with BMI and insulin sensitivity in early childhood.
van Dijk, SJ, Peters, TJ, Buckley, M, Zhou, J, Jones, PA, Gibson, RA, Makrides, M, Muhlhausler, BS, Molloy, PL
International journal of obesity (2005). 2018;(1):28-35
Abstract
BACKGROUND/OBJECTIVES There is increasing evidence that metabolic diseases originate in early life, and epigenetic changes have been implicated as key drivers of this early life programming. This led to the hypothesis that epigenetic marks present at birth may predict an individual's future risk of obesity and type 2 diabetes. In this study, we assessed whether epigenetic marks in blood of newborn children were associated with body mass index (BMI) and insulin sensitivity later in childhood. SUBJECTS/METHODS DNA methylation was measured in neonatal blood spot samples of 438 children using the Illumina Infinium 450 k BeadChip. Associations were assessed between DNA methylation at birth and BMI z-scores, body fat mass, fasting plasma glucose, insulin and homeostatic model assessment of insulin resistance (HOMA-IR) at age 5 years, as well as birth weight, maternal BMI and smoking status. RESULTS No individual methylation sites at birth were associated with obesity or insulin sensitivity measures at 5 years. DNA methylation in 69 genomic regions at birth was associated with BMI z-scores at age 5 years, and in 63 regions with HOMA-IR. The methylation changes were generally small (<5%), except for a region near the non-coding RNA nc886 (VTRNA2-1) where a clear link between methylation status at birth and BMI in childhood was observed (P=0.001). Associations were also found between DNA methylation, maternal smoking and birth weight. CONCLUSIONS We identified a number of DNA methylation regions at birth that were associated with obesity or insulin sensitivity measurements in childhood. These findings support the mounting evidence on the role of epigenetics in programming of metabolic health. Whether many of these small changes in DNA methylation are causally related to the health outcomes, and of clinical relevance, remains to be determined, but the nc886 region represents a promising obesity risk marker that warrants further investigation.
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Is early cord clamping, delayed cord clamping or cord milking best?
Vatansever, B, Demirel, G, Ciler Eren, E, Erel, O, Neselioglu, S, Karavar, HN, Gundogdu, S, Ulfer, G, Bahadir, S, Tastekin, A
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 2018;(7):877-880
Abstract
PURPOSE To compare the antioxidant status of three cord clamping procedures (early clamping, delayed clamping and milking) by analyzing the thiol-disulfide balance. PATIENTS AND METHODS This randomized controlled study enrolled 189 term infants who were divided into three groups according to the cord clamping procedure: early clamping, delayed clamping and milking. Blood samples were collected from the umbilical arteries immediately after clamping, and the thiol/disulfide homeostasis was analyzed. RESULTS The native and total thiol levels were significantly (p < .05) lower in the early cord clamping group compared with the other two groups. The disulfide/total thiol ratio was significantly (p = .026) lower in the delayed cord clamping and milking groups compared with the early clamping groups. Early cord clamping causes the production of more disulfide bonds and lower thiol levels, indicating that oxidation reactions are increased in the early cord clamping procedure compared with the delayed cord clamping and milking procedures. CONCLUSION The oxidant capacity is greater with early cord clamping than with delayed clamping or cord milking. Delayed cord clamping or milking are beneficial in neonatal care, and we suggest that they be performed routinely in all deliveries.
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Cord Metabolic Profiles in Obese Pregnant Women: Insights Into Offspring Growth and Body Composition.
Patel, N, Hellmuth, C, Uhl, O, Godfrey, K, Briley, A, Welsh, P, Pasupathy, D, Seed, PT, Koletzko, B, Poston, L, et al
The Journal of clinical endocrinology and metabolism. 2018;(1):346-355
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Abstract
CONTEXT Offspring exposed in utero to maternal obesity have an increased risk of later obesity; however, the underlying mechanisms remain unknown. OBJECTIVE To assess the effect of an antenatal lifestyle intervention in obese women on the offspring's cord blood metabolic profile and to examine associations of the cord blood metabolic profile with maternal clinical characteristics and offspring anthropometry at birth and age 6 months. DESIGN Randomized controlled trial and cohort study. SETTING The UK Pregnancies Better Eating and Activity Trial. PARTICIPANTS Three hundred forty-four mother-offspring pairs. INTERVENTION Antenatal behavioral lifestyle (diet and physical activity) intervention. MAIN OUTCOME MEASURES Targeted cord blood metabolic profile, including candidate hormone and metabolomic analyses. RESULTS The lifestyle intervention was not associated with change in the cord blood metabolic profile. Higher maternal glycemia, specifically fasting glucose at 28 weeks gestation, had a linear association with higher cord blood concentrations of lysophosphatidylcholines (LPCs) 16.1 (β = 0.65; 95% confidence interval: 0.03 to 0.10) and 18.1 (0.52; 0.02 to 0.80), independent of the lifestyle intervention. A principal component of cord blood phosphatidylcholines and LPCs was associated with infant z scores of birth weight (0.04; 0.02 to 0.07) and weight at age 6 months (0.05; 0.00 to 0.10). Cord blood insulin growth factor (IGF)-1 and adiponectin concentrations were positively associated with infant weight z score at birth and at 6 months. CONCLUSIONS Concentrations of LPCs and IGF-1 in cord blood are related to infant weight. These findings support the hypothesis that susceptibility to childhood obesity may be programmed in utero, but further investigation is required to establish whether these associations are causally related.
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Multifactorial analysis of the stochastic epigenetic variability in cord blood confirmed an impact of common behavioral and environmental factors but not of in vitro conception.
Gentilini, D, Somigliana, E, Pagliardini, L, Rabellotti, E, Garagnani, P, Bernardinelli, L, Papaleo, E, Candiani, M, Di Blasio, AM, Viganò, P
Clinical epigenetics. 2018;:77
Abstract
BACKGROUND An increased incidence of imprint-associated disorders has been reported in babies born from assisted reproductive technology (ART). However, previous studies supporting an association between ART and an altered DNA methylation status of the conceived babies have been often conducted on a limited number of methylation sites and without correction for critical potential confounders. Moreover, all the previous studies focused on the identification of methylation changes shared among subjects while an evaluation of stochastic differences has never been conducted. This study aims to evaluate the effect of ART and other common behavioral or environmental factors associated with pregnancy on stochastic epigenetic variability using a multivariate approach. RESULTS DNA methylation levels of cord blood from 23 in vitro and 41 naturally conceived children were analyzed using the Infinium HumanMethylation450 BeadChips. After multiple testing correction, no statistically significant difference emerged in the number of cord blood stochastic epigenetic variations or in the methylation levels between in vitro- and in vivo-conceived babies. Conversely, four multiple factor analysis dimensions summarizing common phenotypic, behavioral, or environmental factors (cord blood cell composition, pre or post conception supplementation of folates, birth percentiles, gestational age, cesarean section, pre-gestational mother's weight, parents' BMI and obesity status, presence of adverse pregnancy outcomes, mother's smoking status, and season of birth) were significantly associated with stochastic epigenetic variability. The stochastic epigenetic variation analysis allowed the identification of a rare imprinting defect in the locus GNAS in one of the babies belonging to the control population, which would not have emerged using a classical case-control association analysis. CONCLUSIONS We confirmed the effect of several common behavioral or environmental factors on the epigenome of newborns and described for the first time an epigenetic effect related to season of birth. Children born after ART did not appear to have an increased risk of genome-wide changes in DNA methylation either at specific loci or randomly scattered throughout the genome. The inability to identify differences between cases and controls suggests that the number of stochastic epigenetic variations potentially induced by ART was not greater than that naturally produced in response to maternal behavior or other common environmental factors.
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[Effect of oxytocin on the levels of malondialdehyde, nitric oxide, and s100b protein in newborns].
Condori-Merma, D, Moreno-Loaiza, O, Paz-Aliaga, A, Barrionuevo-Rodríguez, J
Revista peruana de medicina experimental y salud publica. 2018;(3):449-455
Abstract
OBJECTIVES To assess the effects of the administration of oxytocin during labor management on the levels of malondialdehyde (MDA), nitric oxide (NO), and S100B protein in newborns. MATERIALS AND METHODS We selected 80 term pregnant women without obstetric and fetal pathology, forming two groups: pregnant women with normal delivery and pregnant women conducted with oxytocin. Blood was collected immediately after delivery from the umbilical cord vein to measure MDA, ON and from the artery for protein S100B. The concentration of MDA and ON was quantified by spectroscopic methods and the protein S100B by ELISA. RESULTS Values of 3.4 uMol/L and 3.6 uMol/L of MDA and 1.4 uMol/L and 1.8 uMol/L of NO were obtained in the oxytocin and control group, respectively, without significant difference; S100B levels were higher in the oxytocin managed group, with a median of 1.36 μg/L compared to the normal delivery group 1.11 μg/L (p=0.03). There was no relationship between the dose of oxytocin administered and the levels of MDA, ON, and S100B. CONCLUSIONS There is no difference between MDA and NO levels between pregnant women undergoing a normal or managed birth. There is a significant difference in S100B protein levels in newborns born via an oxytocin-managed delivery. There is no relationship between oxytocin dose and levels of oxidative stress and S100B protein.
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The maternal-fetal gradient of free and esterified phytosterols at the time of delivery in humans.
Correani, A, Visentin, S, Cosmi, E, Ponchia, E, D'Aronco, S, Simonato, M, Vedovelli, L, Cogo, P, Carnielli, VP
Clinical nutrition (Edinburgh, Scotland). 2018;(6 Pt A):2107-2112
Abstract
BACKGROUND High dietary intakes of phytosterols (Phyto), such as those consumed by vegans and vegetarians, are not recommended for cholesterol-lowering in pregnant women (PW) because the safety of their use during pregnancy has not been fully established [1]. Information on Phyto in pregnancy is very limited. OBJECTIVE To characterize the maternal-fetal gradient of free and esterified Phyto at the time of delivery in humans. DESIGN PW who had a term delivery at the Obstetrics and Gynecology Unit of the University Hospital of Padua (Padua, Italy), between November 2016 and March 2017, participated in the study. Fatty acids (FA), cholesterol (Chol), Chol metabolites (7-dehydrocholesterol, 7-DHChol; lathosterol, Latho; 7α-hydroxycholesterol, 7α-OHChol), and Phyto (campesterol, Camp; stigmasterol, Stigma; sitosterol, Sito) were measured in both maternal (MB) and cord blood (CB) at the time of delivery. Non-pregnant adult volunteers (Ref-NA) served as a reference. RESULTS Thirty-four term PW and 12 Ref-NA signed informed consent and were studied. Plasma total Phyto concentrations in CB were up to 20-fold lower than in MB (p < 0.05). Positive and significant correlations were found between total Phyto of MB-CB pairs (p < 0.01), and between total FA and Camp of MB (p < 0.05). Interestingly, free Chol to Chol ester ratio of CB did not differ from that of MB, and free Phyto to Phyto ester ratios were higher in CB than in MB (p < 0.001). No differences were found between Phyto concentrations of MB and Ref-NA. However, free Chol to Chol ester ratio, and free Phyto to Phyto ester ratios were higher in MB than in Ref-NA (p < 0.05). Chol synthesis, as indicated by 7-DHChol to 7α-OHChol, Latho to 7α-OHChol, and Latho to Sito ratios, was greatest in CB and lowest in Ref-NA. CONCLUSION Our data suggest that free Phyto cross the human placenta more easily than Phyto ester. An elevated Stigma to Chol ratio in CB than in MB was also described for the first time. The impact of these findings on the neonatal outcomes remains to be elucidated.