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Prenatal Particulate Air Pollution and DNA Methylation in Newborns: An Epigenome-Wide Meta-Analysis.
Gruzieva, O, Xu, CJ, Yousefi, P, Relton, C, Merid, SK, Breton, CV, Gao, L, Volk, HE, Feinberg, JI, Ladd-Acosta, C, et al
Environmental health perspectives. 2019;(5):57012
Abstract
BACKGROUND Prenatal exposure to air pollution has been associated with childhood respiratory disease and other adverse outcomes. Epigenetics is a suggested link between exposures and health outcomes. OBJECTIVES We aimed to investigate associations between prenatal exposure to particulate matter (PM) with diameter [Formula: see text] ([Formula: see text]) or [Formula: see text] ([Formula: see text]) and DNA methylation in newborns and children. METHODS We meta-analyzed associations between exposure to [Formula: see text] ([Formula: see text]) and [Formula: see text] ([Formula: see text]) at maternal home addresses during pregnancy and newborn DNA methylation assessed by Illumina Infinium HumanMethylation450K BeadChip in nine European and American studies, with replication in 688 independent newborns and look-up analyses in 2,118 older children. We used two approaches, one focusing on single cytosine-phosphate-guanine (CpG) sites and another on differentially methylated regions (DMRs). We also related PM exposures to blood mRNA expression. RESULTS Six CpGs were significantly associated [false discovery rate (FDR) [Formula: see text]] with prenatal [Formula: see text] and 14 with [Formula: see text] exposure. Two of the [Formula: see text] CpGs mapped to FAM13A (cg00905156) and NOTCH4 (cg06849931) previously associated with lung function and asthma. Although these associations did not replicate in the smaller newborn sample, both CpGs were significant ([Formula: see text]) in 7- to 9-y-olds. For cg06849931, however, the direction of the association was inconsistent. Concurrent [Formula: see text] exposure was associated with a significantly higher NOTCH4 expression at age 16 y. We also identified several DMRs associated with either prenatal [Formula: see text] and or [Formula: see text] exposure, of which two [Formula: see text] DMRs, including H19 and MARCH11, replicated in newborns. CONCLUSIONS Several differentially methylated CpGs and DMRs associated with prenatal PM exposure were identified in newborns, with annotation to genes previously implicated in lung-related outcomes. https://doi.org/10.1289/EHP4522.
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[Factors associated with the prevalence of hypovitaminosis D in pregnant women and their newborns].
Blarduni, E, Arrospide, A, Galar, M, Castaño, L, Mar, J, ,
Anales de pediatria. 2019;(2):96-104
Abstract
BACKGROUND The finding of hypovitaminosis in pregnancy D has prompted the debate about its supplementation. The objective of the study was to measure the prevalence of hypovitaminosis D in mothers and newborns. METHODS A one-year observational study was conducted including the measuring of vitamin D levels in mothers and in the umbilical cord blood of newborns. An analysis was made of the variables as regards maternal characteristics, delivery and sun exposure. RESULTS Values lower than 20 ng/ml were found in 64.4% of 745 mothers and 41.3% of 560 newborns, and less than 30 ng/ml in 88.7% and 67.1%, respectively. Mean levels were higher in summer-autumn than in winter-spring (21.73 and 13.70 ng / ml in mothers and 29.04 and 20.49 ng/ml in cord), and higher in the umbilical cord than in the maternal plasma. Multiple pregnancies (OR: 6.29) and non-European origin (OR: 13.09) were risk factors for maternal hypovitaminosis, while maternal supplementation (OR: 0.19), physical activity (OR: 0.57), and sun exposure (OR: 0.46) had a preventive effect. CONCLUSIONS The high rates of hypovitaminosis support the policy of giving dietary supplements to newborns. The high level of hypovitaminosis found supports the extension of screening and supplementation to all pregnant women, and not only to those with risk factors. The greater difference between mothers and newborns in seasons of low sun exposure can be interpreted as a protective effect.
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Is cord blood hepcidin influenced by the low-grade acute-phase response occurring during delivery? A small-scale longitudinal study.
Hoppe, M, Hulthén, L, Samuelson, G
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. 2019;(13):2166-2172
Abstract
AIM: To measure serum hepcidin in late pregnancy and in cord blood, and to analyze relationship between hepcidin, interleukin-6, and biomarkers of fetal iron status. MATERIALS AND METHODS Data from 15 uncomplicated singleton pregnancies were analyzed longitudinally in trimester 3 (T3) and at birth. RESULTS In T3, S-ferritin (median 14 µg/L) and transferrin (median 4.0 g/L) indicated low iron status, whereas the median soluble transferrin receptor (sTfR) was 4.0 mg/L, i.e. within the reference interval. Median T3 S-hepcidin was 7.8 ng/mL. Later on in cord blood, ferritin concentration (180 µg/L) were significantly higher, transferrin concentration (1.8 g/L) were significantly lower, and both sTfR (4.7 mg/L) and S-hepcidin concentrations (30.5 ng/mL) were significantly higher than maternal T3 concentrations. At the same time, cord blood interleukin-6 indicated an activated acute-phase reaction. In T3, after logarithmic transformation, there was a significant correlation between S-hepcidin and both S-ferritin (r = 0.691) and sTfR (r = -0.825). There was also a significant correlation between S-ferritin and both sTfR (r = -0.729) and transferrin (r = 0.549) in T3. CONCLUSIONS Although S-ferritin, S-hepcidin, and sTfR were correlated during pregnancy, these relationships were not apparent in umbilical cord blood. Further, cord blood interleukin-6 indicated an activated acute-phase response, and sTfR, which is known to be unaffected by inflammation, indicated a low iron status in cord blood. Thus, instead of representing an enhanced iron status, the data appear to suggest that hepcidin and ferritin in cord blood may be influenced by the low-grade acute-phase response that occurs during delivery.
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Expression network analysis reveals cord blood vitamin D-associated genes affecting risk of early life wheeze.
Mirzakhani, H, Al-Garawi, AA, Carey, VJ, Qiu, W, Litonjua, AA, Weiss, ST
Thorax. 2019;(2):200-202
Abstract
Cord blood 25-hydroxyvitamin D (25OHD) has been reported in association with risk of early life recurrent wheeze. In a subset of infants who participated in the Vitamin D Antenatal Asthma Reduction Trial, we demonstrated that higher cord blood 25OHD at birth (>31 ng/mL) was associated with a reduced risk of recurrent wheeze in the first year of life. We then identified a module of co-expressed genes associated with cord blood 25OHD levels >31 ng/mL. Genes in this module are involved in biological and immune pathways related to development and progression of asthma pathogenesis including the Notch1 and transforming growth factor-beta signalling pathways.
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Cord Blood Metabolomics: Association With Newborn Anthropometrics and C-Peptide Across Ancestries.
Kadakia, R, Talbot, O, Kuang, A, Bain, JR, Muehlbauer, MJ, Stevens, RD, Ilkayeva, OR, Lowe, LP, Metzger, BE, Newgard, CB, et al
The Journal of clinical endocrinology and metabolism. 2019;(10):4459-4472
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Abstract
CONTEXT Newborn adiposity is associated with childhood obesity. Cord blood metabolomics is one approach that can be used to understand early-life contributors to adiposity and insulin resistance. OBJECTIVE To determine the association of cord blood metabolites with newborn adiposity and hyperinsulinemia in a multiethnic cohort of newborns. DESIGN Cross-sectional, observational study. SETTING Hyperglycemia and Adverse Pregnancy Outcome study. PARTICIPANTS One thousand six hundred multiethnic mother-newborn pairs. MAIN OUTCOME MEASURE Cord blood C-peptide, birthweight, and newborn sum of skinfolds. RESULTS Meta-analyses across four ancestry groups (Afro-Caribbean, Northern European, Thai, and Mexican American) demonstrated significant associations of cord blood metabolites with cord blood C-peptide, birthweight, and newborn sum of skinfolds. Several metabolites, including branched-chain amino acids (BCAAs), medium- and long-chain acylcarnitines, nonesterified fatty acids, and triglycerides were negatively associated with cord C-peptide but positively associated with birthweight and/or sum of skinfolds. 1,5-Anhydroglucitol, an inverse marker of recent maternal glycemia, was significantly inversely associated with birthweight and sum of skinfolds. Network analyses revealed groups of interrelated amino acid, acylcarnitine, and fatty acid metabolites associated with all three newborn outcomes. CONCLUSIONS Cord blood metabolites are associated with newborn size and cord blood C-peptide levels after adjustment for maternal body mass index and glucose during pregnancy. Negative associations of metabolites with C-peptide at birth were observed. 1,5-Anhydroglucitol appears to be a marker of adiposity in newborns. BCAAs were individually associated with birthweight and demonstrated possible associations with newborn adiposity in network analyses.
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Higher maternal plasma folate, vitamin B12 and homocysteine levels in women with preeclampsia.
Pisal, H, Dangat, K, Randhir, K, Khaire, A, Mehendale, S, Joshi, S
Journal of human hypertension. 2019;(5):393-399
Abstract
Micronutrients like vitamin B12 and folate play an important role in nucleic acid metabolism, cell growth, and are important determinants of fetal growth. The present study examined the levels of maternal and cord plasma folate, vitamin B12, homocysteine, and their association with birth outcome in women with preeclampsia (PE). This study includes 450 normotensive control (NC) and 350 women with PE. PE women were further classified into women delivering at term (n = 224) and preterm (n = 126). Maternal and cord blood was collected at delivery. The levels of maternal vitamin B12 (p < 0.05), folate (p < 0.01), and homocysteine (p < 0.01) were higher in the PE group as compared to the NC group. Maternal folate levels were higher in both term and preterm groups, while vitamin B12 levels were higher only in the preterm group as compared to NC group. In contrast, homocysteine was higher only in the term PE group. Similar changes were also observed in the cord plasma. There was a positive association of maternal plasma homocysteine with systolic (r = 0.151, p = 0.000, n = 578) and diastolic blood pressure (r = 0.213, p = 0.000, n = 578) in the whole cohort. A negative association of maternal folate with systolic blood pressure (r = -0.105, p = 0.048, n = 352) while a positive association with baby weight in the NC group (r = 0.116, p = 0.029, n = 352). The present study suggests that maternal and cord micronutrient levels are altered in women with PE.
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The value of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) parameters in analysis with fetal malnutrition neonates.
Can, E, Can, C
Journal of perinatal medicine. 2019;(7):775-779
Abstract
Objective To assess the association between fetal malnutrition (FM) and the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) in singleton term appropriate for gestational age (AGA) neonates. Methods This cross-sectional observational study was performed with 4340 singleton, term AGA neonates without perinatal disease over a two-year period. Results A total of 4320 neonates were evaluated in this study. Those diagnosed with fetal malnutrition, 284 (6%) neonates, were compared with 150 healthy term AGA neonates. Gestational week, birth weight, birth height, head circumference, maternal age, last pregnancy weight, and status of income of the FM group were found to be lower when compared to the control group (P = 0.011). Low last pregnancy weight (P = 0.017) and low level of income (P = 0.042) were found to be factors that affect the presence of FM. The NLR and PLR were found to be significantly higher in the FM group compared with term AGA healthy controls. In correlation analyses, there was a negative correlation between the NLR and PLR with fetal nutritional status (P = 0.011 and P < 0.001, respectively). When the NLR level was taken as 4.51, the sensitivity and specificity of the test for FM were calculated as 81.2% and 80.8%, respectively [area under the receiver-operating characteristic curve (AUROC): 0.81]; when the PLR level was taken as 155.4, the sensitivity and specificity of the test for FM were calculated as 87.0% and 85.4%, respectively (AUROC 0.94). Conclusion Cord-blood NLR and PLR negatively correlate with term FM AGA neonates.
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Associations between long-chain PUFAs in maternal blood, cord blood, and breast milk and offspring body composition up to 5 years: follow-up from the INFAT study.
Meyer, DM, Brei, C, Stecher, L, Much, D, Brunner, S, Hauner, H
European journal of clinical nutrition. 2019;(3):458-464
Abstract
BACKGROUND/OBJECTIVES Limited research suggests that exposure to long-chain PUFAs (LCPUFAs) during perinatal development can influence adipose tissue expansion later in life. In previous analyses, we observed that maternal LCPUFAs in late gestation promote offspring gestational growth, whereas breast milk n-3 LCPUFAS promote adipogenesis in infants up to 1 year. This follow-up analysis examines these relationships in offspring up to 5 years. SUBJECTS/METHODS In this observational study of 169 children, relationships between n-3, n-6 LCPUFAs, and the n-6/n-3 LCPUFA ratio in maternal blood at 32 weeks' gestation, cord blood, and breast milk, and anthropometry in offspring from 2 to 5 years were investigated. Body composition was assessed with indirect (i.e., body weight, BMI percentiles, sum of four skinfold thicknesses) and direct (i.e., ultrasonography, magnetic resonance imaging in a subgroup) measurement tools. RESULTS Maternal and cord blood LCPUFAs were largely not shown to be related to offspring body composition. Breast milk n-3 LCPUFAs were significantly positively related to several measurements of child anthropometry at 2 and 4 y, but only a positive relationship between n-3 LCPUFAs and lean body mass remained statistically significant at 5 y. Breast milk n-6/n-3 LCPUFA ratio was inversely related to weight and BMI percentiles at 2 y, and lean body mass at 4 and 5 y. CONCLUSIONS Results from this follow-up do not provide sufficient evidence that LCPUFAs in maternal blood, cord blood, and breast milk predict offspring adiposity in children up to 5 years.
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Impact of maternal BMI and gestational diabetes mellitus on maternal and cord blood metabolome: results from the PREOBE cohort study.
Shokry, E, Marchioro, L, Uhl, O, Bermúdez, MG, García-Santos, JA, Segura, MT, Campoy, C, Koletzko, B
Acta diabetologica. 2019;(4):421-430
Abstract
AIMS: Maternal obesity and gestational diabetes mellitus (GDM) were frequently reported to be risk factors for obesity and diabetes in offspring. Our goal was to study the impact of maternal prepregnancy BMI (pBMI) and GDM on both maternal and cord blood metabolic profiles. METHODS We used LC-MS/MS to measure 201 metabolites comprising phospholipids (PL), amino acids, non-esterified fatty acids (NEFA), organic acids, acyl carnitines (AC), and Krebs cycle metabolites in maternal plasma at delivery and cord plasma obtained from 325 PREOBE study participants. RESULTS Several metabolites were associated with pBMI/GDM in both maternal and cord blood (p < 0.05), while others were specific to either blood sources. BMI was positively associated with leucine, isoleucine, and inflammation markers in both mother and offspring, while β-hydroxybutyric acid was positively associated only in cord blood. GDM showed elevated levels of sum of hexoses, a characteristic finding in both maternal and cord blood. Uniquely in cord blood of offspring born to GDM mothers, free carnitine was significantly lower with the same tendency observed for AC, long-chain NEFA, PL, specific Krebs cycle metabolites, and β-oxidation markers. CONCLUSIONS Maternal BMI and GDM are associated with maternal and cord blood metabolites supporting the hypothesis of transgenerational cycle of obesity and diabetes.
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Cord Blood Erythropoietin and Hepcidin Reflect Lower Newborn Iron Stores due to Maternal Obesity during Pregnancy.
Korlesky, C, Kling, PJ, Pham, DQD, Ovasapyan, AA, Leyns, CEG, Weber, MB, Coe, CL
American journal of perinatology. 2019;(5):511-516
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Abstract
OBJECTIVE Obesity during pregnancy impedes fetal iron endowment. In adults, both iron depletion and hypoxia stimulate erythropoietin (Epo) production, while hepcidin, the primary iron regulator, is inhibited by Epo and stimulated by obesity. To understand this relationship in fetuses, we investigated obesity, inflammation, and fetal iron status on fetal Epo and hepcidin levels. STUDY DESIGN Epo, hepcidin, C-reactive protein (CRP), and ferritin levels were measured in 201 newborns of 35 to 40 weeks' gestation with historical risk factors for a low fetal iron endowment, including half with maternal obesity. RESULTS Epo was unrelated to fetal size, but Epo was directly related to maternal body mass index (BMI; kg/m2) (p < 0.03) and CRP (p < 0.0005) at delivery. Epo levels were twice as likely to be elevated (≥50 IU/L) while comparing the lowest quartile of ferritin with the upper three quartiles (p < 0.01). Hepcidin was directly related to ferritin (p < 0.001) and indirectly related to maternal BMI (p < 0.015), but BMI became nonsignificant when undergoing multivariate analysis. Hepcidin was unrelated to Epo. CONCLUSION Although some of the fetal responses involving Epo were similar to adults, we did not find a hepcidin-Epo relationship like that of adults, where fetal liver is the site of both hepcidin and Epo production.