Fetal–Maternal–Neonatal Metabolomics

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Integrative Metabolomics".

Deadline for manuscript submissions: closed (20 March 2023) | Viewed by 30844

Special Issue Editors


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Guest Editor
The Hospital for Sick Children Research Institute, Toronto ON M5G 0A4, Canada
Interests: one-carbon metabolism; folate, colonic absorption and the intestinal microbiome; probiotics; prebiotics; human milk and neonatal development; human milk macronutrients, micronutrients and bioactive components, metabolomics
The Hospital for Sick Children Research Institute, Toronto ON M5G 0A4, Canada
Interests: fetal and neonatal development; maternal perinatal; growth; regeneration; stem cells; metabolomics; probiotics; prebiotics

Special Issue Information

Dear Colleagues,

The maternal–fetal–neonatal axis plays a critical role in determining the risk of developing complications during pregnancy and childbirth as well as the effect of these complications on maternal and infant health outcomes. These complications include, but are not limited to: maternal preeclampsia, diabetes, intrauterine growth restriction, and preterm birth, as well as complications of prematurity in the infant such as necrotizing enterocolitis, neonatal sepsis, anemia, intraventricular hemorrhage, and patent ductus arteriosus. Early diagnosis of these complications is challenging mostly because they are complex syndromes with multiple causes and underlying mechanisms. Only limited advances in the prevention of maternal and prenatal disorders have developed in recent decades, highlighting the need to devise new approaches to improve the health of women and their children.

The metabolomics of the maternal–fetal–neonatal axis is a rapidly expanding field of research relating maternal metabolic characteristics and health before and during pregnancy, to infant and maternal health outcomes. Metabolomics, by analysis of small molecule metabolism present in biological samples taken at different stages of a pregnancy, offers a window to investigate metabolic aspects of increasingly prevalent conditions including maternal obesity, gestational diabetes, infection, fetal growth restriction, preterm birth, and environmental exposures, influencing optimal outcomes for postnatal maternal and infant health and for infant development. Current technologies applied to metabolomics include LC–MS, GC–MS, NMR, and Fourier transform infrared spectrometry (FTIR).

Dr. Susanne Aufreiter
Dr. Bo Li
Guest Editors

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Keywords

  • metabolomics
  • maternal–fetal–neonatal
  • LC–MS
  • HPLC
  • GC
  • NMR
  • FT–IR
  • urine
  • plasma
  • amniotic fluid
  • cord blood
  • human milk

Published Papers (19 papers)

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12 pages, 256 KiB  
Article
Maternal and Cord Blood Serum Metabolite Associations with Childhood Adiposity and Body Composition Outcomes
by Monica E. Bianco, My H. Vu, James R. Bain, Michael J. Muehlbauer, Olga R. Ilkayeva, Denise M. Scholtens, Jami Josefson and William L. Lowe, Jr.
Metabolites 2023, 13(6), 749; https://doi.org/10.3390/metabo13060749 - 13 Jun 2023
Cited by 1 | Viewed by 1021
Abstract
Maternal metabolites influence the size of newborns independently of maternal body mass index (BMI) and glycemia, highlighting the importance of maternal metabolism on offspring outcomes. This study examined associations of maternal metabolites during pregnancy with childhood adiposity, and cord blood metabolites with childhood [...] Read more.
Maternal metabolites influence the size of newborns independently of maternal body mass index (BMI) and glycemia, highlighting the importance of maternal metabolism on offspring outcomes. This study examined associations of maternal metabolites during pregnancy with childhood adiposity, and cord blood metabolites with childhood adiposity using phenotype and metabolomic data from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and the HAPO Follow-Up Study. The maternal metabolites analyses included 2324 mother–offspring pairs, while the cord blood metabolites analyses included 937 offspring. Multiple logistic and linear regression were used to examine associations between primary predictors, maternal or cord blood metabolites, and childhood adiposity outcomes. Multiple maternal fasting and 1 hr metabolites were significantly associated with childhood adiposity outcomes in Model 1 but were no longer significant after adjusting for maternal BMI and/or maternal glycemia. In the fully adjusted model, fasting lactose levels were negatively associated with child BMI z-scores and waist circumference, while fasting urea levels were positively associated with waist circumference. One-hour methionine was positively associated with fat-free mass. There were no significant associations between cord blood metabolites and childhood adiposity outcomes. Few metabolites were associated with childhood adiposity outcomes after adjusting for maternal BMI and glucose, suggesting that maternal BMI accounts for the association between maternal metabolites and childhood adiposity. Full article
(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)
17 pages, 1464 KiB  
Article
Effect of Genetically Reduced Maternal Myostatin on Late Gestation Maternal, Fetal, and Placental Metabolomes in Mice
by Ruth Opoku, Jenna DeCata, Charlotte L. Phillips and Laura C. Schulz
Metabolites 2023, 13(6), 719; https://doi.org/10.3390/metabo13060719 - 01 Jun 2023
Viewed by 969
Abstract
Myostatin (gene symbol: Mstn) is an autocrine and paracrine inhibitor of muscle growth. Pregnant mice with genetically reduced levels of myostatin give birth to offspring with greater adult muscle mass and bone biomechanical strength. However, maternal myostatin is not detectable in fetal [...] Read more.
Myostatin (gene symbol: Mstn) is an autocrine and paracrine inhibitor of muscle growth. Pregnant mice with genetically reduced levels of myostatin give birth to offspring with greater adult muscle mass and bone biomechanical strength. However, maternal myostatin is not detectable in fetal circulations. Fetal growth is dependent on the maternal environment, and the provisioning of nutrients and growth factors by the placenta. Thus, this study examined the effect of reduced maternal myostatin on maternal and fetal serum metabolomes, as well as the placental metabolome. Fetal and maternal serum metabolomes were highly distinct, which is consistent with the role of the placenta in creating a specific fetal nutrient environment. There was no effect from myostatin on maternal glucose tolerance or fasting insulin. In comparisons between pregnant control and Mstn+/− mice, there were more significantly different metabolite concentrations in fetal serum, at 50, than in the mother’s serum at 33, confirming the effect of maternal myostatin reduction on the fetal metabolic milieu. Polyamines, lysophospholipids, fatty acid oxidation, and vitamin C, in fetal serum, were all affected by maternal myostatin reduction. Full article
(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)
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16 pages, 3246 KiB  
Article
Development of a Urine Metabolomics Biomarker-Based Prediction Model for Preeclampsia during Early Pregnancy
by Yaqi Zhang, Karl G. Sylvester, Bo Jin, Ronald J. Wong, James Schilling, C. James Chou, Zhi Han, Ruben Y. Luo, Lu Tian, Subhashini Ladella, Lihong Mo, Ivana Marić, Yair J. Blumenfeld, Gary L. Darmstadt, Gary M. Shaw, David K. Stevenson, John C. Whitin, Harvey J. Cohen, Doff B. McElhinney and Xuefeng B. Ling
Metabolites 2023, 13(6), 715; https://doi.org/10.3390/metabo13060715 - 31 May 2023
Cited by 3 | Viewed by 1748
Abstract
Preeclampsia (PE) is a condition that poses a significant risk of maternal mortality and multiple organ failure during pregnancy. Early prediction of PE can enable timely surveillance and interventions, such as low-dose aspirin administration. In this study, conducted at Stanford Health Care, we [...] Read more.
Preeclampsia (PE) is a condition that poses a significant risk of maternal mortality and multiple organ failure during pregnancy. Early prediction of PE can enable timely surveillance and interventions, such as low-dose aspirin administration. In this study, conducted at Stanford Health Care, we examined a cohort of 60 pregnant women and collected 478 urine samples between gestational weeks 8 and 20 for comprehensive metabolomic profiling. By employing liquid chromatography mass spectrometry (LCMS/MS), we identified the structures of seven out of 26 metabolomics biomarkers detected. Utilizing the XGBoost algorithm, we developed a predictive model based on these seven metabolomics biomarkers to identify individuals at risk of developing PE. The performance of the model was evaluated using 10-fold cross-validation, yielding an area under the receiver operating characteristic curve of 0.856. Our findings suggest that measuring urinary metabolomics biomarkers offers a noninvasive approach to assess the risk of PE prior to its onset. Full article
(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)
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11 pages, 451 KiB  
Article
The Relationship between Maternal Antibodies to Fetal Brain and Prenatal Stress Exposure in Autism Spectrum Disorder
by Amy N. Costa, Bradley J. Ferguson, Emily Hawkins, Adriana Coman, Joseph Schauer, Alex Ramirez-Celis, Patrick M. Hecht, Danielle Bruce, Michael Tilley, Zohreh Talebizadeh, Judy Van de Water and David Q. Beversdorf
Metabolites 2023, 13(5), 663; https://doi.org/10.3390/metabo13050663 - 16 May 2023
Cited by 1 | Viewed by 1666
Abstract
Environmental and genetic factors contribute to the etiology of autism spectrum disorder (ASD), but their interaction is less well understood. Mothers that are genetically more stress-susceptible have been found to be at increased risk of having a child with ASD after exposure to [...] Read more.
Environmental and genetic factors contribute to the etiology of autism spectrum disorder (ASD), but their interaction is less well understood. Mothers that are genetically more stress-susceptible have been found to be at increased risk of having a child with ASD after exposure to stress during pregnancy. Additionally, the presence of maternal antibodies for the fetal brain is associated with a diagnosis of ASD in children. However, the relationship between prenatal stress exposure and maternal antibodies in the mothers of children diagnosed with ASD has not yet been addressed. This exploratory study examined the association of maternal antibody response with prenatal stress and a diagnosis of ASD in children. Blood samples from 53 mothers with at least one child diagnosed with ASD were examined by ELISA. Maternal antibody presence, perceived stress levels during pregnancy (high or low), and maternal 5-HTTLPR polymorphisms were examined for their interrelationship in ASD. While high incidences of prenatal stress and maternal antibodies were found in the sample, they were not associated with each other (p = 0.709, Cramér’s V = 0.051). Furthermore, the results revealed no significant association between maternal antibody presence and the interaction between 5-HTTLPR genotype and stress (p = 0.729, Cramér’s V = 0.157). Prenatal stress was not found to be associated with the presence of maternal antibodies in the context of ASD, at least in this initial exploratory sample. Despite the known relationship between stress and changes in immune function, these results suggest that prenatal stress and immune dysregulation are independently associated with a diagnosis of ASD in this study population, rather than acting through a convergent mechanism. However, this would need to be confirmed in a larger sample. Full article
(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)
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11 pages, 1153 KiB  
Article
Dam Body Condition Score Alters Offspring Circulating Cortisol and Energy Metabolites in Holstein Calves but Did Not Affect Neonatal Leptin Surge
by William E. Brown, Henry T. Holdorf, Sophia J. Kendall and Heather M. White
Metabolites 2023, 13(5), 631; https://doi.org/10.3390/metabo13050631 - 06 May 2023
Viewed by 1187
Abstract
The neonatal leptin surge is important for hypothalamic development, feed intake regulation, and long-term metabolic control. In sheep, the leptin surge is eliminated with maternal overnutrition and an elevated dam body condition score (BCS), but this has not been assessed in dairy cattle. [...] Read more.
The neonatal leptin surge is important for hypothalamic development, feed intake regulation, and long-term metabolic control. In sheep, the leptin surge is eliminated with maternal overnutrition and an elevated dam body condition score (BCS), but this has not been assessed in dairy cattle. The aim of this study was to characterize the neonatal profile of leptin, cortisol and other key metabolites in calves born to Holstein cows with a range of BCS. Dam BCS was determined 21 d before expected parturition. Blood was collected from calves within 4 h of birth (d 0), and on days 1, 3, 5, and 7. Serum was analyzed for concentrations of leptin, cortisol, blood urea nitrogen, β-hydroxybutyrate (BHB), free fatty acids (FFA), triglycerides, and total protein (TP). Statistical analysis was performed separately for calves sired by Holstein (HOL) or Angus (HOL-ANG) bulls. Leptin tended to decrease after birth in HOL calves, but there was no evidence of an association between leptin and BCS. For HOL calves, the cortisol level increased with an increasing dam BCS on day 0 only. Dam BCS was variably associated with the calf BHB and TP levels, depending on the sire breed and day of age. Further investigation is required to elucidate the impacts of maternal dietary and energy status during gestation on offspring metabolism and performance, in addition to the potential impact of the absence of a leptin surge on long-term feed intake regulation in dairy cattle. Full article
(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)
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15 pages, 2344 KiB  
Article
Impact of Maternal Weight Gain on the Newborn Metabolome
by Teresa Guixeres-Esteve, Francisco Ponce-Zanón, José Manuel Morales, Empar Lurbe, Julio Alvarez-Pitti and Daniel Monleón
Metabolites 2023, 13(4), 561; https://doi.org/10.3390/metabo13040561 - 15 Apr 2023
Cited by 2 | Viewed by 1376
Abstract
Pre-pregnancy obesity and excessive gestational weight gain (GWG) appear to affect birth weight and the offspring’s risk of obesity and disease later in life. However, the identification of the mediators of this relationship, could be of clinical interest, taking into account the presence [...] Read more.
Pre-pregnancy obesity and excessive gestational weight gain (GWG) appear to affect birth weight and the offspring’s risk of obesity and disease later in life. However, the identification of the mediators of this relationship, could be of clinical interest, taking into account the presence of other confounding factors, such as genetics and other shared influences. The aim of this study was to evaluate the metabolomic profiles of infants at birth (cord blood) and 6 and 12 months after birth to identify offspring metabolites associated with maternal GWG. Nuclear Magnetic Resonance (NMR) metabolic profiles were measured in 154 plasma samples from newborns (82 cord blood samples) and in 46 and 26 of these samples at 6 months and 12 months of age, respectively. The levels of relative abundance of 73 metabolomic parameters were determined in all the samples. We performed univariate and machine-learning analysis of the association between the metabolic levels and maternal weight gain adjusted for mother‘s age, Body Mass Index (BMI), diabetes, diet adherence and infant sex. Overall, our results showed differences, both at the univariate level and in the machine-learning models, between the offspring, according to the tertiles of maternal weight gain. Some of these differences were resolved at 6 and 12 months of age, whereas some others remained. Lactate and leucine were the metabolites with the strongest and longest association with maternal weight gain during pregnancy. Leucine, as well as other significant metabolites, have been associated in the past with metabolic wellness in both general and obese populations. Our results suggest that the metabolic changes associated to excessive GWG are present in children from early life. Full article
(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)
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12 pages, 2795 KiB  
Article
Maternal High-Fat Diet Consumption in Sprague Dawley Rats Compromised the Availability and Altered the Tissue Distribution of Lutein in Neonatal Offspring
by Yanqi Zhang and Libo Tan
Metabolites 2023, 13(4), 544; https://doi.org/10.3390/metabo13040544 - 11 Apr 2023
Cited by 1 | Viewed by 1130
Abstract
Lutein, the most abundant carotenoid in the infant eye and brain, is critical for their visual and cognitive development. Due to its lipophilic nature, a high adiposity may affect the tissue distribution of lutein. The aim of the study was to determine the [...] Read more.
Lutein, the most abundant carotenoid in the infant eye and brain, is critical for their visual and cognitive development. Due to its lipophilic nature, a high adiposity may affect the tissue distribution of lutein. The aim of the study was to determine the impacts of a maternal high-fat diet (HFD) consumption on the status of lutein in the neonatal offspring. Female Sprague Dawley rats (n = 6) were fed a normal fat diet (NFD) or a HFD for 8 weeks before mating, and they were switched to an NFD or an HFD containing the same concentration of lutein ester during gestation and lactation. Rat pups (n = 7/group/time) were euthanized on postnatal day 2 (P2), P6, P11, and P20 for measuring tissue lutein concentrations. No significant difference in maternal lutein intake was found between the two groups. At both P6 and P11, a significantly lower lutein concentration was noted in the milk samples separated from the stomach of HFD pups than the concentration in the samples from the NFD pups; the HFD group showed a significantly lower lutein concentration in the liver. At P11, the HFD pups exhibited a significantly lower lutein concentration in the eye, brain, and brown adipose tissue accompanied with a significantly higher lutein concentration and mass in the visceral white adipose tissue. The study was the first to provide evidence that maternal HFD consumption resulted in a compromised availability and altered distribution of lutein in the neonatal offspring. Full article
(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)
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16 pages, 1502 KiB  
Article
The Associations of Maternal Health Characteristics, Newborn Metabolite Concentrations, and Child Body Mass Index among US Children in the ECHO Program
by Brittney M. Snyder, Tebeb Gebretsadik, Nina B. Rohrig, Pingsheng Wu, William D. Dupont, Dana M. Dabelea, Rebecca C. Fry, Susan V. Lynch, Cindy T. McEvoy, Nigel S. Paneth, Kelli K. Ryckman, James E. Gern, Tina V. Hartert and on behalf of Program Collaborators for Environmental Influences on Child Health Outcomes
Metabolites 2023, 13(4), 510; https://doi.org/10.3390/metabo13040510 - 01 Apr 2023
Cited by 1 | Viewed by 1337
Abstract
We aimed first to assess associations between maternal health characteristics and newborn metabolite concentrations and second to assess associations between metabolites associated with maternal health characteristics and child body mass index (BMI). This study included 3492 infants enrolled in three birth cohorts with [...] Read more.
We aimed first to assess associations between maternal health characteristics and newborn metabolite concentrations and second to assess associations between metabolites associated with maternal health characteristics and child body mass index (BMI). This study included 3492 infants enrolled in three birth cohorts with linked newborn screening metabolic data. Maternal health characteristics were ascertained from questionnaires, birth certificates, and medical records. Child BMI was ascertained from medical records and study visits. We used multivariate analysis of variance, followed by multivariable linear/proportional odds regression, to determine maternal health characteristic-newborn metabolite associations. Significant associations were found in discovery and replication cohorts of higher pre-pregnancy BMI with increased C0 and higher maternal age at delivery with increased C2 (C0: discovery: aβ 0.05 [95% CI 0.03, 0.07]; replication: aβ 0.04 [95% CI 0.006, 0.06]; C2: discovery: aβ 0.04 [95% CI 0.003, 0.08]; replication: aβ 0.04 [95% CI 0.02, 0.07]). Social Vulnerability Index, insurance, and residence were also associated with metabolite concentrations in a discovery cohort. Associations between metabolites associated with maternal health characteristics and child BMI were modified from 1–3 years (interaction: p < 0.05). These findings may provide insights on potential biologic pathways through which maternal health characteristics may impact fetal metabolic programming and child growth patterns. Full article
(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)
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18 pages, 2206 KiB  
Article
Association of Maternal Metabolites and Metabolite Networks with Newborn Outcomes in a Multi-Ancestry Cohort
by Brooke Gleason, Alan Kuang, James R. Bain, Michael J. Muehlbauer, Olga R. Ilkayeva, Denise M. Scholtens and William L. Lowe, Jr.
Metabolites 2023, 13(4), 505; https://doi.org/10.3390/metabo13040505 - 31 Mar 2023
Cited by 3 | Viewed by 1646
Abstract
The in utero environment is important for newborn size at birth, which is associated with childhood adiposity. We examined associations between maternal metabolite levels and newborn birthweight, sum of skinfolds (SSF), and cord C-peptide in a multinational and multi-ancestry cohort of 2337 mother–newborn [...] Read more.
The in utero environment is important for newborn size at birth, which is associated with childhood adiposity. We examined associations between maternal metabolite levels and newborn birthweight, sum of skinfolds (SSF), and cord C-peptide in a multinational and multi-ancestry cohort of 2337 mother–newborn dyads. Targeted and untargeted metabolomic assays were performed on fasting and 1 h maternal serum samples collected during an oral glucose tolerance test performed at 24–32 week gestation in women participating in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. Anthropometric measurements were obtained on newborns at birth. Following adjustment for maternal BMI and glucose, per-metabolite analyses demonstrated significant associations between maternal metabolite levels and birthweight, SSF, and cord C-peptide. In the fasting state, triglycerides were positively associated and several long-chain acylcarnitines were inversely associated with birthweight and SSF. At 1 h, additional metabolites including branched-chain amino acids, proline, and alanine were positively associated with newborn outcomes. Network analyses demonstrated distinct clusters of inter-connected metabolites significantly associated with newborn phenotypes. In conclusion, numerous maternal metabolites during pregnancy are significantly associated with newborn birthweight, SSF, and cord C-peptide independent of maternal BMI and glucose, suggesting that metabolites in addition to glucose contribute to newborn size at birth and adiposity. Full article
(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)
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14 pages, 1834 KiB  
Article
Placental Metabolomics of Fetal Growth Restriction
by Jacopo Troisi, Steven J. K. Symes, Martina Lombardi, Pierpaolo Cavallo, Angelo Colucci, Giovanni Scala, David C. Adair, Maurizio Guida and Sean M. Richards
Metabolites 2023, 13(2), 235; https://doi.org/10.3390/metabo13020235 - 04 Feb 2023
Cited by 2 | Viewed by 2736
Abstract
Fetal growth restriction is an obstetrical pathological condition that causes high neonatal mortality and morbidity. The mechanisms of its onset are not completely understood. Metabolites were extracted from 493 placentas from non-complicated pregnancies in Hamilton Country, TN (USA), and analyzed by gas chromatography–mass [...] Read more.
Fetal growth restriction is an obstetrical pathological condition that causes high neonatal mortality and morbidity. The mechanisms of its onset are not completely understood. Metabolites were extracted from 493 placentas from non-complicated pregnancies in Hamilton Country, TN (USA), and analyzed by gas chromatography–mass spectrometry (GC–MS). Newborns were classified according to raw fetal weight (low birth weight (LBW; <2500 g) and non-low birth weight (Non-LBW; >2500 g)), and according to the calculated birth weight centile as it relates to gestational age (small for gestational age (SGA), large for gestational age (LGA), and adequate for gestational age (AGA)). Mothers of LBW infants had a lower pre-pregnancy weight (66.2 ± 17.9 kg vs. 73.4 ± 21.3 kg, p < 0.0001), a lower body mass index (BMI) (25.27 ± 6.58 vs. 27.73 ± 7.83, p < 0.001), and a shorter gestation age (246.4 ± 24.0 days vs. 267.2 ± 19.4 days p < 0.001) compared with non-LBW. Marital status, tobacco use, and fetus sex affected birth weight centile classification according to gestational age. Multivariate statistical comparisons of the extracted metabolomes revealed that asparagine, aspartic acid, deoxyribose, erythritol, glycerophosphocholine, tyrosine, isoleucine, serine, and lactic acid were higher in both SGA and LBW placentas, while taurine, ethanolamine, β-hydroxybutyrate, and glycine were lower in both SGA and LBW. Several metabolic pathways are implicated in fetal growth restriction, including those related to the hypoxia response and amino-acid uptake and metabolism. Inflammatory pathways are also involved, suggesting that fetal growth restriction might share some mechanisms with preeclampsia. Full article
(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)
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15 pages, 4909 KiB  
Article
Lipidomic Analysis of Cervicovaginal Fluid for Elucidating Prognostic Biomarkers and Relevant Phospholipid and Sphingolipid Pathways in Preterm Birth
by Se Hee Hong, Ji-Youn Lee, Sumin Seo, Bohyun Shin, Cho Hee Jeong, Eunbin Bae, Jiyu Kim, Donghee Lee, Byungchan An, Minki Shim, Jung Hoon Shin, Dong-Kyu Lee, Young Ju Kim and Sang Beom Han
Metabolites 2023, 13(2), 177; https://doi.org/10.3390/metabo13020177 - 25 Jan 2023
Cited by 2 | Viewed by 1634
Abstract
Cervicovaginal fluid (CVF) is an excellent specimen for monitoring preterm birth (PTB) as it characterizes cervical metabolites, the vaginal environment, and specific host immune responses. However, extensive lipid analysis of CVF to explain PTB has not been studied. In this study, we performed [...] Read more.
Cervicovaginal fluid (CVF) is an excellent specimen for monitoring preterm birth (PTB) as it characterizes cervical metabolites, the vaginal environment, and specific host immune responses. However, extensive lipid analysis of CVF to explain PTB has not been studied. In this study, we performed a systematic analysis combining high-throughput lipid analysis and omics to discover the unique metabolic properties of the cervix. Liquid chromatography-high resolution mass spectrometry successfully detected a total of 190 lipids in the CVF of 30 PTB and 30 term birth (TB) pregnant women. The whole lipidomics dataset analyzed by combining multivariate and univariate statistical analysis revealed 35 lipid biomarkers, including phospholipids and sphingolipids. Remarkably, sphingomyelin, which plays a physiologically essential role in sphingolipids, was significantly downregulated in PTB. Metabolic pathway study provides a close relationship between vaginal microbial organization and cell membrane formation, further supporting the robustness of our findings. Sphingolipids and phospholipids, which were determined to be important lipids for predicting PTB in our study, showed a high value of receiver operating characteristic (ROC) curve >0.7, indicating that a lipid diagnostic test and understanding the mechanism of lipids is highly related to the vaginal microbiome. Therefore, our result has high potential as a predictor of PTB. Full article
(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)
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34 pages, 3915 KiB  
Article
Optimising Fluvoxamine Maternal/Fetal Exposure during Gestation: A Pharmacokinetic Virtual Clinical Trials Study
by Khairulanwar Burhanuddin and Raj Badhan
Metabolites 2022, 12(12), 1281; https://doi.org/10.3390/metabo12121281 - 16 Dec 2022
Cited by 1 | Viewed by 1684
Abstract
Fluvoxamine plasma concentrations have been shown to decrease throughout pregnancy. CYP2D6 polymorphisms significantly influence these changes. However, knowledge of an optimum dose adjustment according to the CYP2D6 phenotype is still limited. This study implemented a physiologically based pharmacokinetic modelling approach to assess the [...] Read more.
Fluvoxamine plasma concentrations have been shown to decrease throughout pregnancy. CYP2D6 polymorphisms significantly influence these changes. However, knowledge of an optimum dose adjustment according to the CYP2D6 phenotype is still limited. This study implemented a physiologically based pharmacokinetic modelling approach to assess the gestational changes in fluvoxamine maternal and umbilical cord concentrations. The optimal dosing strategies during pregnancy were simulated, and the impact of CYP2D6 phenotypes on fluvoxamine maternal and fetal concentrations was considered. A significant decrease in fluvoxamine maternal plasma concentrations was noted during gestation. As for the fetal concentration, a substantial increase was noted for the poor metabolisers (PM), with a constant level in the ultrarapid (UM) and extensive (EM) metabolisers commencing from gestation week 20 to term. The optimum dosing regimen suggested for UM and EM reached a maximum dose of 300 mg daily at gestational weeks (GW) 15 and 35, respectively. In contrast, a stable dose of 100 mg daily throughout gestation for the PM is sufficient to maintain the fluvoxamine plasma concentration within the therapeutic window (60–230 ng/mL). Dose adjustment during pregnancy is required for fluvoxamine, particularly for UM and EM, to maintain efficacy throughout the gestational period. Full article
(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)
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13 pages, 648 KiB  
Article
Melatonin Supplementation Alters Maternal and Fetal Amino Acid Concentrations and Placental Nutrient Transporters in a Nutrient Restriction Bovine Model
by Rebecca Swanson, Zully Contreras-Correa, Thu Dinh, Heath King, Darcie Sidelinger, Derris Burnett and Caleb Lemley
Metabolites 2022, 12(12), 1208; https://doi.org/10.3390/metabo12121208 - 02 Dec 2022
Cited by 1 | Viewed by 1244
Abstract
Melatonin rescues uterine blood flow and fetal body weight in a seasonal dependent manner within a nutrient restriction bovine model. We sought to identify the effects of nutrient restriction, melatonin, and sampling time on maternal and fetal amino acids, and placental nutrient transporters. [...] Read more.
Melatonin rescues uterine blood flow and fetal body weight in a seasonal dependent manner within a nutrient restriction bovine model. We sought to identify the effects of nutrient restriction, melatonin, and sampling time on maternal and fetal amino acids, and placental nutrient transporters. Pregnant heifers received adequate or restricted nutrition, and 20 mg of melatonin or placebo from gestational days 160–240 over two seasons. On day 240 maternal and fetal blood, amnion, and placentomes were collected. Amino acid concentrations were determined by gas chromatography-mass spectrometry. Caruncle and cotyledon tissues were assessed for nutrient transporter density by qPCR. Data were analyzed using the MIXED procedure of SAS for fixed effects. In fall, melatonin rescued effects of nutrient restriction on System N, Anion, and total maternal amino acids. Furthermore, melatonin rescued effects of nutrient restriction on Systems A, N, Br, Bo, and essential amnion amino acids. In summer, melatonin rescued effects of nutrient restriction in Systems Br and Bo maternal amino acids. Furthermore, melatonin rescued effects of nutrient restriction on caruncle SLC38A10 and SLC38A2. Melatonin rescued effects of nutrient restriction in a seasonal dependent manner. These data align with previous studies suggesting melatonin is a more effective therapeutic in summer months. Full article
(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)
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18 pages, 1913 KiB  
Article
Associations of Early Pregnancy Metabolite Profiles with Gestational Blood Pressure Development
by Sophia M. Blaauwendraad, Rama J. Wahab, Bas B. van Rijn, Berthold Koletzko, Vincent W. V. Jaddoe and Romy Gaillard
Metabolites 2022, 12(12), 1169; https://doi.org/10.3390/metabo12121169 - 24 Nov 2022
Viewed by 1257
Abstract
Blood pressure development plays a major role in both the etiology and prediction of gestational hypertensive disorders. Metabolomics might serve as a tool to identify underlying metabolic mechanisms in the etiology of hypertension in pregnancy and lead to the identification of novel metabolites [...] Read more.
Blood pressure development plays a major role in both the etiology and prediction of gestational hypertensive disorders. Metabolomics might serve as a tool to identify underlying metabolic mechanisms in the etiology of hypertension in pregnancy and lead to the identification of novel metabolites useful for the prediction of gestational hypertensive disorders. In a population-based, prospective cohort study among 803 pregnant women, liquid chromatography—mass spectrometry was used to determine serum concentrations of amino-acids, non-esterified fatty acids, phospholipids and carnitines in early pregnancy. Blood pressure was measured in each trimester of pregnancy. Information on gestational hypertensive disorders was obtained from medical records. Higher individual metabolite concentrations of the diacyl-phosphatidylcholines and acyl-lysophosphatidylcholines group were associated with higher systolic blood pressure throughout pregnancy (Federal Discovery Rate (FDR)-adjusted p-values < 0.05). Higher concentrations of one non-esterified fatty acid were associated with higher diastolic blood pressure throughout pregnancy (FDR-adjusted p-value < 0.05). Using penalized regression, we identified 12 individual early-pregnancy amino-acids, non-esterified fatty acids, diacyl-phosphatidylcholines and acyl-carnitines and the glutamine/glutamic acid ratio, that were jointly associated with larger changes in systolic and diastolic blood pressure from first to third trimester. These metabolites did not improve the prediction of gestational hypertensive disorders in addition to clinical markers. In conclusion, altered early pregnancy serum metabolite profiles mainly characterized by changes in non-esterified fatty acids and phospholipids metabolites are associated with higher gestational blood pressure throughout pregnancy within the physiological ranges. These findings are important from an etiological perspective and, after further replication, might improve the early identification of women at increased risk of gestational hypertensive disorders. Full article
(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)
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15 pages, 16470 KiB  
Article
Fetal Exposure to Maternal Smoking and Neonatal Metabolite Profiles
by Kim N. Cajachagua-Torres, Sophia M. Blaauwendraad, Hanan El Marroun, Hans Demmelmair, Berthold Koletzko, Romy Gaillard and Vincent W. V. Jaddoe
Metabolites 2022, 12(11), 1101; https://doi.org/10.3390/metabo12111101 - 11 Nov 2022
Cited by 3 | Viewed by 1373
Abstract
Fetal tobacco exposure has persistent effects on growth and metabolism. The underlying mechanisms of these relationships are yet unknown. We investigated the associations of fetal exposure to maternal smoking with neonatal metabolite profiles. In a population-based cohort study among 828 mother-infant pairs, we [...] Read more.
Fetal tobacco exposure has persistent effects on growth and metabolism. The underlying mechanisms of these relationships are yet unknown. We investigated the associations of fetal exposure to maternal smoking with neonatal metabolite profiles. In a population-based cohort study among 828 mother-infant pairs, we assessed maternal tobacco use by questionnaire. Metabolite concentrations of amino acids, non-esterified fatty acids, phospholipids and carnitines were determined by using LC-MS/MS in cord blood samples. Metabolite ratios reflecting metabolic pathways were computed. Compared to non-exposed neonates, those exposed to first trimester only tobacco smoking had lower neonatal mono-unsaturated acyl-alkyl-phosphatidylcholines (PC.ae) and alkyl-lysophosphatidylcholines (Lyso.PC.e) 18:0 concentrations. Neonates exposed to continued tobacco smoking during pregnancy had lower neonatal mono-unsaturated acyl-lysophosphatidylcholines (Lyso.PC.a), Lyso.PC.e.16:0 and Lyso.PC.e.18:1 concentration (False discovery rate (FDR) p-values < 0.05). Dose-response associations showed the strongest effect estimates in neonates whose mothers continued smoking ≥5 cigarettes per day (FDR p-values < 0.05). Furthermore, smoking during the first trimester only was associated with altered neonatal metabolite ratios involved in the Krebs cycle and oxidative stress, whereas continued smoking during pregnancy was associated with inflammatory, transsulfuration, and insulin resistance markers (p-value < 0.05). Thus, fetal tobacco exposure seems associated with neonatal metabolite profile adaptations. Whether these changes relate to later life metabolic health should be studied further. Full article
(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)
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Review

Jump to: Research, Other

26 pages, 1296 KiB  
Review
Made in the Womb: Maternal Programming of Offspring Cardiovascular Function by an Obesogenic Womb
by Mariana S. Diniz, Luís F. Grilo, Carolina Tocantins, Inês Falcão-Pires and Susana P. Pereira
Metabolites 2023, 13(7), 845; https://doi.org/10.3390/metabo13070845 - 13 Jul 2023
Cited by 4 | Viewed by 1648
Abstract
Obesity incidence has been increasing at an alarming rate, especially in women of reproductive age. It is estimated that 50% of pregnancies occur in overweight or obese women. It has been described that maternal obesity (MO) predisposes the offspring to an increased risk [...] Read more.
Obesity incidence has been increasing at an alarming rate, especially in women of reproductive age. It is estimated that 50% of pregnancies occur in overweight or obese women. It has been described that maternal obesity (MO) predisposes the offspring to an increased risk of developing many chronic diseases in an early stage of life, including obesity, type 2 diabetes, and cardiovascular disease (CVD). CVD is the main cause of death worldwide among men and women, and it is manifested in a sex-divergent way. Maternal nutrition and MO during gestation could prompt CVD development in the offspring through adaptations of the offspring’s cardiovascular system in the womb, including cardiac epigenetic and persistent metabolic programming of signaling pathways and modulation of mitochondrial metabolic function. Currently, despite diet supplementation, effective therapeutical solutions to prevent the deleterious cardiac offspring function programming by an obesogenic womb are lacking. In this review, we discuss the mechanisms by which an obesogenic intrauterine environment could program the offspring’s cardiovascular metabolism in a sex-divergent way, with a special focus on cardiac mitochondrial function, and debate possible strategies to implement during MO pregnancy that could ameliorate, revert, or even prevent deleterious effects of MO on the offspring’s cardiovascular system. The impact of maternal physical exercise during an obesogenic pregnancy, nutritional interventions, and supplementation on offspring’s cardiac metabolism are discussed, highlighting changes that may be favorable to MO offspring’s cardiovascular health, which might result in the attenuation or even prevention of the development of CVD in MO offspring. The objectives of this manuscript are to comprehensively examine the various aspects of MO during pregnancy and explore the underlying mechanisms that contribute to an increased CVD risk in the offspring. We review the current literature on MO and its impact on the offspring’s cardiometabolic health. Furthermore, we discuss the potential long-term consequences for the offspring. Understanding the multifaceted effects of MO on the offspring’s health is crucial for healthcare providers, researchers, and policymakers to develop effective strategies for prevention and intervention to improve care. Full article
(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)
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20 pages, 877 KiB  
Review
Maternal and Child Health, Non-Communicable Diseases and Metabolites
by Marlon E. Cerf
Metabolites 2023, 13(6), 756; https://doi.org/10.3390/metabo13060756 - 15 Jun 2023
Cited by 2 | Viewed by 1644
Abstract
Mothers influence the health and disease trajectories of their children, particularly during the critical developmental windows of fetal and neonatal life reflecting the gestational–fetal and lactational–neonatal phases. As children grow and develop, they are exposed to various stimuli and insults, such as metabolites, [...] Read more.
Mothers influence the health and disease trajectories of their children, particularly during the critical developmental windows of fetal and neonatal life reflecting the gestational–fetal and lactational–neonatal phases. As children grow and develop, they are exposed to various stimuli and insults, such as metabolites, that shape their physiology and metabolism to impact their health. Non-communicable diseases, such as diabetes, cardiovascular disease, cancer and mental illness, have high global prevalence and are increasing in incidence. Non-communicable diseases often overlap with maternal and child health. The maternal milieu shapes progeny outcomes, and some diseases, such as gestational diabetes and preeclampsia, have gestational origins. Metabolite aberrations occur from diets and physiological changes. Differential metabolite profiles can predict the onset of non-communicable diseases and therefore inform prevention and/or better treatment. In mothers and children, understanding the metabolite influence on health and disease can provide insights for maintaining maternal physiology and sustaining optimal progeny health over the life course. The role and interplay of metabolites on physiological systems and signaling pathways in shaping health and disease present opportunities for biomarker discovery and identifying novel therapeutic agents, particularly in the context of maternal and child health, and non-communicable diseases. Full article
(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)
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22 pages, 5040 KiB  
Review
Iodine and Thyroid Maternal and Fetal Metabolism during Pregnancy
by Charles Mégier, Grégoire Dumery and Dominique Luton
Metabolites 2023, 13(5), 633; https://doi.org/10.3390/metabo13050633 - 06 May 2023
Cited by 10 | Viewed by 2701
Abstract
Thyroid hormones and iodine are required to increase basal metabolic rate and to regulate protein synthesis, long bone growth and neuronal maturation. They are also essential for protein, fat and carbohydrate metabolism regulation. Imbalances in thyroid and iodine metabolism can negatively affect these [...] Read more.
Thyroid hormones and iodine are required to increase basal metabolic rate and to regulate protein synthesis, long bone growth and neuronal maturation. They are also essential for protein, fat and carbohydrate metabolism regulation. Imbalances in thyroid and iodine metabolism can negatively affect these vital functions. Pregnant women are at risk of hypo or hyperthyroidism, in relation to or regardless of their medical history, with potential dramatic outcomes. Fetal development highly relies on thyroid and iodine metabolism and can be compromised if they malfunction. As the interface between the fetus and the mother, the placenta plays a crucial role in thyroid and iodine metabolism during pregnancy. This narrative review aims to provide an update on current knowledge of thyroid and iodine metabolism in normal and pathological pregnancies. After a brief description of general thyroid and iodine metabolism, their main modifications during normal pregnancies and the placental molecular actors are described. We then discuss the most frequent pathologies to illustrate the upmost importance of iodine and thyroid for both the mother and the fetus. Full article
(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)
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Other

Jump to: Research, Review

12 pages, 819 KiB  
Hypothesis
Metabolic Inheritance and the Competition for Calories between Mother and Fetus
by Edward Archer, Carl J. Lavie, Urska Dobersek and James O. Hill
Metabolites 2023, 13(4), 545; https://doi.org/10.3390/metabo13040545 - 11 Apr 2023
Cited by 1 | Viewed by 1337
Abstract
During the prenatal period, maternal and fetal cells compete for calories and nutrients. To ensure the survival of the mother and development of the fetus, the prenatal hormonal milieu alters the competitive environment via metabolic perturbations (e.g., insulin resistance). These perturbations increase maternal [...] Read more.
During the prenatal period, maternal and fetal cells compete for calories and nutrients. To ensure the survival of the mother and development of the fetus, the prenatal hormonal milieu alters the competitive environment via metabolic perturbations (e.g., insulin resistance). These perturbations increase maternal caloric consumption and engender increments in both maternal fat mass and the number of calories captured by the fetus. However, a mother’s metabolic and behavioral phenotypes (e.g., physical activity levels) and her external environment (e.g., food availability) can asymmetrically impact the competitive milieu, leading to irreversible changes in pre- and post-natal development—as exhibited by stunting and obesity. Therefore, the interaction of maternal metabolism, behavior, and environment impact the competition for calories—which in turn creates a continuum of health trajectories in offspring. In sum, the inheritance of metabolic phenotypes offers a comprehensive and consilient explanation for much of the increase in obesity and T2DM over the past 50 years in human and non-human mammals. Full article
(This article belongs to the Special Issue Fetal–Maternal–Neonatal Metabolomics)
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