Exploratory research on first and second trimester urinary metabolic profiles and fetal growth restriction
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ABSTRACT:
ORGANISM(S): Homo Sapiens
TISSUE(S): Urine
PROVIDER: ST000573 | MetabolomicsWorkbench |
REPOSITORIES: MetabolomicsWorkbench
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Project description:Preterm birth (PB) and fetal growth restriction (FGR) convey the highest risk of perinatal mortality and morbidity, as well as increasing the chance of developing chronic disease in later life. Identifying early in pregnancy the unfavourable maternal conditions that can predict poor birth outcomes could help their prevention and management. Here we used an exploratory metabolic profiling approach (metabolomics) to investigate the association between birth outcomes and metabolites in maternal urine collected early in pregnancy as part of the prospective mother-child cohort Rhea study. Metabolomic techniques can simultaneously capture information about genotype and its interaction with the accumulated exposures experienced by an individual from their diet, environment, physical activity or disease (the exposome). As metabolic syndrome has previously been shown to be associated with PB in this cohort, we sought to gain further insight into PB-linked metabolic phenotypes and to define new predictive biomarkers.Our study was a case-control study nested within the Rhea cohort. Major metabolites (n = 34) in maternal urine samples collected at the end of the first trimester (n = 438) were measured using proton nuclear magnetic resonance spectroscopy. In addition to PB, we used FGR in weight and small for gestational age as study endpoints.We observed significant associations between FGR and decreased urinary acetate (interquartile odds ratio (IOR) = 0.18 CI 0.04 to 0.60), formate (IOR = 0.24 CI 0.07 to 0.71), tyrosine (IOR = 0.27 CI 0.08 to 0.81) and trimethylamine (IOR = 0.14 CI 0.04 to 0.40) adjusting for maternal education, maternal age, parity, and smoking during pregnancy. These metabolites were inversely correlated with blood insulin. Women with clinically induced PB (IPB) had a significant increase in a glycoprotein N-acetyl resonance (IOR = 5.84 CI 1.44 to 39.50). This resonance was positively correlated with body mass index, and stratified analysis confirmed that N-acetyl glycoprotein and IPB were significantly associated in overweight and obese women only. Spontaneous PB cases were associated with elevated urinary lysine (IOR = 2.79 CI 1.20 to 6.98) and lower formate levels (IOR = 0.42 CI 0.19 to 0.94).Urinary metabolites measured at the end of the first trimester are associated with increased risk of negative birth outcomes, and provide novel information about the possible mechanisms leading to adverse pregnancies in the Rhea cohort. This study emphasizes the potential of metabolic profiling of urine as a means to identify novel non-invasive biomarkers of PB and FGR risk.
| S-EPMC4094172 | biostudies-literature
Project description:BackgroundRoutine prenatal care fails to identify a large proportion of women at risk of fetal growth restriction (FGR). Metabolomics, the comprehensive analysis of low molecular weight molecules (metabolites) in biological samples, can provide new and earlier biomarkers of prenatal health. Recent research has suggested possible predictive first trimester urine metabolites correlating to fetal growth restriction in the third trimester. Our objective in this current study was to examine urinary metabolic profiles in the first and second trimester of pregnancy in relation to third trimester FGR in a US population from a large, multi-center cohort study of healthy pregnant women.MethodsWe conducted a nested case-control study within The Infant Development and the Environment Study (TIDES), a population-based multi-center pregnancy cohort study. We identified 53 cases of FGR based on the AUDIPOG [Neonatal growth - AUDIPOG [Internet]. [cited 29 Nov 2016]. Available from: http://www.audipog.net/courbes_morpho.php?langue=en ] formula for birthweight percentile considering maternal height, age, and prenatal weight, as well as infant sex, gestational age, and birth rank. Cases were matched to 106 controls based on study site, maternal age (± 2 years), parity, and infant sex. NMR spectroscopy was used to assess concentrations of four urinary metabolites that have been previously associated with FGR (tyrosine, acetate, formate, and trimethylamine) in first and second trimester urine samples. We fit multivariate conditional logistic regression models to estimate the odds of FGR in relation to urinary concentrations of these individual metabolites in the first and second trimesters. Exploratory analyses of custom binned spectroscopy results were run to consider other potentially related metabolites.ResultsWe found no significant association between the relative concentrations of each of the four metabolites and odds of FGR. Exploratory analyses did not reveal any significant differences in urinary metabolic profiles. Compared with controls, cases delivered earlier (38.6 vs 39.8, p < 0.001), and had lower birthweights (2527 g vs 3471 g, p < 0.001). Maternal BMI was similar between cases and controls.ConclusionsFirst and second trimester concentrations of urinary metabolites (acetate, formate, trimethylamine and tyrosine) did not predict FGR. This inconsistency with previous studies highlights the need for more rigorous investigation and data collection in this area before metabolomics can be clinically applied to obstetrics.
| S-EPMC5806311 | biostudies-literature
Project description:Our objective was to identify metabolites associated with fetal growth restriction (FGR) by examining early and late pregnancy differences in non-targeted urinary metabolites among FGR cases and non-FGR controls. An exploratory case-control study within LIFECODES birth cohort was performed. FGR cases (N = 30), defined as birthweight below the 10th percentile, were matched with controls (N = 30) based on maternal age, race, pre-pregnancy body mass index, and gestational age at delivery. Gas chromatography/electron-ionization mass spectrometry was performed on urine samples collected at 10 and 26 weeks of gestation. Differences in urinary metabolite levels in cases and controls at each time point and between the two time points were calculated and then changes compared across pregnancy. 137 unique urinary metabolites were annotated, and several identified that were higher in cases compared to controls. For example, urinary concentrations of benzoic acid were higher in cases compared to controls at both study visits (3.01-fold higher in cases at visit 1, p < 0.01; 3.10-fold higher in cases at visit 3, p = 0.05). However, these findings from our exploratory analysis were not robust to false-discovery-rate adjustment. In conclusion, using a high-resolution, non-targeted approach, we found specific urinary organic acids differed over pregnancy by FGR case status.
| S-EPMC7093500 | biostudies-literature
Project description:ObjectiveThe importance of the placenta in mediating the pre- and post-natal consequences of fetal growth restriction has been increasingly recognized. However, the influence of placental sexual dimorphism on driving these outcomes has received little attention. The purpose of this study was to characterize how sex contributes to the relationship between placental metabolism and fetal programming utilizing a novel rodent model of growth restriction.MethodsFetal growth restriction was induced by maternal inhalation of 0.8 ppm ozone (4 h/day) during implantation receptivity (gestation days [GDs] 5 and 6) in Long-Evans rats. Control rats were exposed to filtered air. At GD 21, placental and fetal tissues were obtained for metabolic and genomic assessments.ResultsGrowth-restricted male placentae exhibited increased mitochondrial biogenesis, increased oxygen consumption, and reduced nutrient storage. Male growth-restricted fetuses also had evidence of reduced adiposity and downregulation of hepatic metabolic signaling. In contrast, placentae from growth-restricted females had elevated markers of autophagy accompanied by an observed protection against hepatic metabolic perturbations. Despite this, growth restriction in females induced a greater number of hypothalamic gene and pathway alterations compared to growth-restricted males.ConclusionsIncreases in mitochondrial metabolism in growth-restricted male placentae likely initiates a sequela of adaptations that promote poor nutrient availability and adiposity. Divergently, the female placenta expresses protective mechanisms that may serve to increase nutrient availability to support fetal metabolic development. Collectively, this work emphasizes the importance of sex in mediating alterations in placental metabolism and fetal programming.
| S-EPMC7588867 | biostudies-literature
Project description:Fetal growth restriction (FGR) is one of the most formidable challenges in present-day antenatal care. Pathological fetal growth is a well-known factor of not only in utero demise in the third trimester, but also postnatal morbidity and unfavorable developmental outcomes, including long-term sequalae such as metabolic diseases, diabetic mellitus or hypertension. In this review, the authors present the current state of knowledge about the genetic disturbances responsible for FGR diagnosis, divided into fetal, placental and maternal causes (including preeclampsia), as well as their impact on prenatal diagnostics, with particular attention on chromosomal microarray (CMA) and noninvasive prenatal testing technique (NIPT).
| S-EPMC8744929 | biostudies-literature
Project description:Fetal growth restriction (FGR) and pre-eclampsia with fetal growth restriction (PE/FGR) are high-risk perinatal diseases that may involve high levels of human chorionic gonadotropin (hCG) and mitochondrial dysfunction. However, little is known about how these factors affect placental function. We investigated how mitochondrial dysfunction and high hCG expression affected placental function in unexplained FGR and PE/FGR. We observed elevated expression of hCGβ and growth differentiation factor 15 mRNA and protein levels in the placenta with both diseases. Likewise, antiangiogenic factors, such as Ang2, IP10, sFlt1, IL8, IL1B, and TNFα, were also upregulated at the mRNA level. In addition, the expression of COXI and COXII which encoded by mitochondrial DNA were significantly decreased in both diseases, suggesting that mitochondrial translation was impaired. Treatment with hCG increased Ang2, IP10, IL8, and TNFα mRNA levels in a dose-dependent manner via the p38 and JNK pathways. Mitochondrial translation inhibitors increased hCGβ expression through stabilization of HIF1α, and increased IL8 and TNFα mRNA expression. These results revealed that high expression of hCG due to mitochondrial translational dysfunction plays an important role in the pathogenesis of FGR and PE/FGR.
| S-EPMC8904547 | biostudies-literature
Project description:The aim of this study was to identify growth-restricted fetuses using biometric parameters and to assess the validity and clinical value of individual ultrasound parameters and ratios, such as transcerebellar diameter/abdominal circumference (TCD/AC), head circumference/abdominal circumference (HC/AC), and femur length/abdominal circumference (FL/AC). In a retrospective single-center cross-sectional study, the biometric data of 9292 pregnancies between the 15th and 42nd weeks of gestation were acquired. Statistical analysis included descriptive data, quantile regression estimating the 10th and 90th percentiles, and multivariable analysis. We obtained clinically noticeable results in predicting small-for-gestational-age (SGA) and fetal growth restriction (FGR) fetuses at advanced weeks of gestation using the AC with a Youden index of 0.81 and 0.96, respectively. The other individual parameters and quotients were less suited to identifying cases of SGA and FGR. The multivariable analysis demonstrated the best results for identifying SGA and FGR fetuses with an area under the curve of 0.95 and 0.96, respectively. The individual ultrasound parameters were better suited to identifying SGA and FGR than the ratios. Amongst these, the AC was the most promising individual parameter, especially at advanced weeks of gestation. However, the highest accuracy was achieved with a multivariable model.
| S-EPMC9317726 | biostudies-literature
Project description:BackgroundAmbient air pollution may affect fetal growth restriction (FGR) through several mechanisms. However, prior studies of air pollution and small-for-gestational age (SGA), a common proxy for FGR, have reported inconsistent findings.ObjectiveWe assessed air pollution in relation to physician-diagnosed FGR and population-based SGA in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Consecutive Pregnancy Study (2002-2010).MethodsAmong 50,005 women (112,203 singleton births), FGR was captured from medical records and ICD-9 codes, and SGA determined by population standards for birthweight <10th, <5th and <3rd percentile. Community Multiscale Air Quality models estimated ambient levels of seven criteria pollutants for whole pregnancy, 3-months preconception, and 1st, 2nd and 3rd trimesters. Generalized estimating equations with robust standard errors accounted for interdependency of pregnancies within participant. Models adjusted for maternal age, race/ethnicity, pre-pregnancy body mass index, smoking, alcohol, parity, insurance, marital status, asthma and temperature.ResultsFGR was diagnosed in 1.5% of infants, and 6.7% were <10th, 2.7% <5th and 1.5% <3rd percentile for SGA. Positive associations of SO2, NO2 and PM10 and negative associations of O3 with FGR were observed throughout preconception and pregnancy. For example, an interquartile increase in whole pregnancy SO2 was associated with 16% (95% CI 8%, 25%) increased FGR risk, 17% for NO2 (95% CI 9%, 26%) and 12% for PM10 (95% CI 6%, 19%). Associations with SGA were less clear.ConclusionsChronic exposure to air pollution may be associated with FGR but not SGA in this low-risk population.
| S-EPMC6203640 | biostudies-literature
Project description:BackgroundFetal growth restriction is commonly defined using small for gestational age (SGA) birth (birthweight < 10th percentile) as a proxy, but this approach is problematic because most SGA infants are small but healthy. In this proof-of-concept study, we sought to develop a new approach for identifying fetal growth restriction at birth that combines information on multiple, imperfect measures of fetal growth restriction in a probabilistic manner.MethodsWe combined information on birthweight, placental weight, placental malperfusion lesions, maternal disease, and fetal acidemia using latent profile analysis to classify fetal growth in births at the Royal Victoria Hospital in Montreal, Canada, 2001-2009. We examined the clinical characteristics and health outcomes of infants classified as growth-restricted and nongrowth-restricted by our model, and among the subgroup of growth-restricted infants who had a birthweight ≥10th percentile (i.e., would have been missed by the conventional SGA proxy).ResultsAmong 26,077 births, 345 (1.3%) were classified as growth-restricted by our latent profile model. Growth-restricted infants were more likely than nongrowth-restricted infants to have an Apgar score <7 (10% vs. 2%), have hypoglycemia at birth (17% vs. 3%), require neonatal intensive care unit admission (59% vs. 6%), die in the perinatal period (3.8% vs. 0.2%), and require an emergency cesarean delivery (42% vs. 15%). Risks remained elevated in growth-restricted infants who were not SGA, suggesting our model identified at-risk infants not detected using the SGA proxy.ConclusionsLatent profile analysis is a promising strategy for classifying growth restriction at birth in fetal growth restriction research.
| S-EPMC8478298 | biostudies-literature
Project description:Background and objectivesMetabolomics is a relatively new field of "-omics" research, focusing on high-throughput identification of small molecular weight metabolites. Diet has both acute and chronic effects on metabolic profiles; however, alterations in response to dietary sodium restriction (DSR) are completely unknown. The goal of this study was to explore changes in urine metabolites in response to DSR, as well as their association with previously reported improvements in vascular function with DSR.Design, setting, participants, & measurementsUsing stored urine samples from a 10-week randomized placebo-controlled crossover study of DSR in 17 middle-aged/older adults (six men and 11 women; mean age 62±8 years) who had moderately elevated systolic BP (130-159 mmHg) and were otherwise healthy, a liquid chromatography/mass spectrometry-based analysis of 289 metabolites was performed. This study identified metabolites that were significantly altered between the typical (153±29 mmol/d) and low (70±29 mmol/d) sodium conditions, as well as their baseline (typical sodium) association with responsiveness to previously reported improvements in vascular endothelial function (brachial artery flow-mediated dilation) and large elastic artery stiffness (aortic pulse wave velocity).ResultsOf the 289 metabolites surveyed, 10 were significantly altered (nine were upregulated and one was downregulated) during the low sodium condition, and eight of these exceeded our prespecified clinically significant threshold of a >40% change. These metabolites were involved in biologic pathways broadly related to cardiovascular risk, nitric oxide production, oxidative stress, osmotic regulation, and metabolism. One metabolite, serine, was independently (positively) associated with previously reported improvements in the primary vascular outcome of brachial artery flow-mediated dilation.ConclusionsThis proof-of-concept study provides the first evidence that DSR is a stimulus that induces significant changes in urinary metabolomic profiles. Moreover, serine was independently associated with corresponding changes in vascular endothelial function after DSR. Larger follow-up studies will be required to confirm and further elucidate the metabolic pathways that are altered in response to DSR.
| S-EPMC4491302 | biostudies-literature