Metabolites In Maternal Plasma Research Articles

Plasma metabolites are altered before and after diagnosis of preeclampsia or fetal growth restriction

Metabolomics is the study of small molecules (metabolites), within cells, tissues and biofluids. Maternal metabolites can provide important insight into the health and development of both mother and fetus throughout pregnancy. This study assessed metabolic profiles in the maternal circulation prior to and at the time of diagnosis of preeclampsia and fetal growth restriction. Maternal plasma samples were collected from two independent cohorts: (1) Established disease cohort: 50 participants diagnosed with early-onset preeclampsia (< 34 weeks’ gestation), 14 with early-onset fetal growth restriction, and 25 gestation-matched controls. (2) Prospective cohort, collected at 36 weeks’ gestation before diagnosis: 17 participants later developed preeclampsia, 49 delivered infants with fetal growth restriction (birthweight < 5th centile), and 72 randomly selected controls. Metabolic evaluation was performed by Metabolomics Australia on the Agilent 6545 QTOF Mass Spectrometer. In the established disease cohort, 77 metabolites were altered in circulation from participants with preeclampsia – increased l-cysteine (3.73-fold), l-cystine (3.28-fold), l-acetylcarnitine (2.57-fold), and carnitine (1.53-fold) (p < 0.05). There were 53 metabolites dysregulated in participants who delivered a fetal growth restriction infant—including increased levulinic acid, citric acid (1.93-fold), and creatine (1.14-fold) (p < 0.05). In the prospective cohort, 30 metabolites were altered in participants who later developed preeclampsia at term – reduced glutaric acid (0.85-fold), porphobilinogen (0.77-fold) and amininohippuric acid (0.82-fold) (p < 0.05) was observed. There were 5 metabolites altered in participants who later delivered a fetal growth restriction infant – including reduced 3-methoxybenzenepropanoic acid (p < 0.05). Downstream pathway analysis revealed aminoacyl-tRNA biosynthesis to be most significantly altered in the established cohort in preeclampsia (13/48 hits, p < 0.001) and fetal growth restriction (7/48 hits, p < 0.001). The predictive cohort showed no significant pathway alterations. This study observed altered metabolites in maternal plasma collected before and after diagnosis of a preeclampsia or fetal growth restriction. While a significant number of metabolites were altered with established disease, few changes were observed in the predictive cohort. Thus, metabolites measured in this study may not be useful as predictors of preeclampsia or fetal growth restriction.

Allicin in pregnancy diets modulates steroid metabolism in pregnant sows and placental sulphate metabolism promoting placental angiogenesis and foetal development

The low-birth-weight of piglets is an important factor affecting pig enterprises. The placenta, as a key organ for material exchange between mother and foetus, directly influences the growth and development of the foetus. Allicin exhibits various biological activities, including anti-inflammatory and antioxidant properties. It may also play a crucial role in enhancing sow reproductive performance and placental angiogenesis. In this study, we used 70 lactating Landrace × Yorkshire binary heterozygous sows to explore the effect of allicin on the reproductive performance of sows and placental development. The sows were randomly assigned into the Allicin group (Allicin), which was fed with a diet containing 0.25% allicin, and the negative control group, which was fed with basal feed. The experimental period lasted for 114 d from the date of mating to the end of farrowing. The results showed that the addition of allicin to the gestation diets increased the number of total born piglets, born alive piglets, and high-birth-weight piglets, reduced peripartum oxidative stress, alleviated dysregulation of glucose-lipid metabolism in sows, and increased the levels of antioxidant markers in the placenta. Differential analysis of metabolites in maternal plasma and placenta samples by non-targeted metabolomics revealed that allicin improved cholesterol metabolism, steroid biosynthesis, and increased plasma progesterone levels in sows. Allicin promoted sulphur metabolism, cysteine and methionine metabolism in placental samples and increased the hydrogen sulphide (H2S) content in the placenta. In addition, Quantitative Real-time PCR, Western blot and immunofluorescence results showed that allicin upregulated the expression of angiogenesis-related genes, VEGF-A, FLK 1 and Ang 1, in the placenta, implying that it promoted placental angiogenesis. These results indicate that supplementing the diet of pregnant sows with allicin reduces oxidative stress, alleviates dysregulation of glucose-lipid metabolism during the periparturient period, and promotes placental angiogenesis and foetal development by increasing plasma progesterone level and placental H2S content.

280-OR: Metabolomic Signatures of Excess Fetal Growth in Pregnancies Complicated by Type 1 Diabetes (T1D)

Background: In pregnancies complicated by T1D, glycemic control is only moderately associated with excess fetal growth, suggesting that nutrients other than glucose may be involved. Aims: We analyzed associations between metabolites in maternal and newborn plasma, and fetal growth patterns, in T1D pregnancies. Methods: We obtained maternal plasma samples in the 2nd and 3rd trimester and at delivery, and cord blood samples immediately after delivery, in 22 mother/infant dyads. We used an untargeted metabolomic platform (Broad Institute) and calculated correlation coefficients between individual metabolites and newborn growth percentiles adjusted for gestational age, sex, parity, and ethnicity (GROW percentile). We used a false discovery rate threshold of FDR&amp;lt;0.2. Large for gestational age (LGA) was defined as GROW percentile ≥90 and appropriate for gestational age (AGA) as between the 10th and 90th percentiles. Results: Forty-five percent of newborns were classified as LGA. Maternal age, BMI, diabetes duration, insulin dose and pump use did not differ between LGA vs. AGA. We identified stronger associations between GROW percentiles and metabolites in cord blood than with metabolites in maternal plasma during the 2nd or 3rd trimester. In cord blood, 29 metabolites were associated with GROW percentile (FDR&amp;lt;0.2). For 51 metabolites, the ratio between abundance in cord blood to abundance in maternal blood at delivery was associated with the GROW percentile (FDR &amp;lt;0.2). Many of the top-ranking metabolites positively associated with infant growth were long-chain glycerophosphocholines (e.g., LPC(20:3) β 0.035, p=0.0002, FDR 0.01; LPC(22:5) β 0.033, p=0.0008, FDR 0.03). Conclusion: Glycerophospholipids in cord blood were associated with excess fetal growth in T1D pregnancies, suggesting alterations in lipid metabolism. We also report associations between fetal growth and ratios of metabolites in cord blood to maternal blood, suggesting differences in placental transport. Disclosure E.M.Isganaitis: None. D.Wolfs: None. J.C.O'connell: None. G.A.Hansbury: None. S.Wolpowitz: None. C.B.Clish: None. T.James-todd: None. F.M.Brown: Other Relationship; Dexcom, Inc. Funding National Institute of Diabetes and Digestive and Kidney Diseases (P30DK036836, P30DK057521); Broad Institute

Moderate Folic Acid Supplementation in Pregnant Mice Results in Altered Methyl Metabolism and in Sex-Specific Placental Transcription Changes.

Many pregnant women have higher folic acid (FA) intake due to food fortification and increased vitamin use. It is reported that diets containing five-fold higher FA than recommended for mice (5xFASD) during pregnancy resulted in methylenetetrahydrofolate reductase (MTHFR) deficiency and altered choline/methyl metabolism, with neurobehavioral abnormalities in newborns. The goal is to determine whether these changes have their origins in the placenta during embryonic development. Female mice are fed control diet or 5xFASD for a month before mating and maintained on these diets until embryonic day 17.5. 5xFASD led to pseudo-MTHFR deficiency in maternal liver and altered choline/methyl metabolites in maternal plasma (increased methyltetrahydrofolate and decreased betaine). Methylation potential (S-adenosylmethionine:S-adenosylhomocysteine ratio) and glycerophosphocholine are decreased in placenta and embryonic liver. Folic acid supplemented diet results in sex-specific transcriptome profiles in placenta, with validation of dietary expression changes of 29 genes involved in angiogenesis, receptor biology or neurodevelopment, and altered methylation of the serotonin receptor 2A gene. Moderate increases in folate intake during pregnancy result in placental metabolic and gene expression changes, particularly in angiogenesis, which may contribute to abnormal behavior in pups. These results are relevant for determining a safe upper limit for folate intake during pregnancy.

Maternal plasma metabolic markers of neonatal adiposity and associated maternal characteristics: The GUSTO study

Infant adiposity may be related to later metabolic health. Maternal metabolite profiling reflects both genetic and environmental influences and allows elucidation of metabolic pathways associated with infant adiposity. In this multi-ethnic Asian cohort, we aimed to (i) identify maternal plasma metabolites associated with infant adiposity and other birth outcomes and (ii) investigate the maternal characteristics associated with those metabolites. In 940 mother-offspring pairs, we performed gas chromatography-mass spectrometry and identified 134 metabolites in maternal fasting plasma at 26–28 weeks of gestation. At birth, neonatal triceps and subscapular skinfold thicknesses were measured by trained research personnel, while weight and length measures were abstracted from delivery records. Gestational age was estimated from first-trimester dating ultrasound. Associations were assessed by multivariable linear regression, with p-values corrected using the Benjamini-Hochberg approach. At a false discovery rate of 5%, we observed associations between 28 metabolites and neonatal sum of skinfold thicknesses (13 amino acid-related, 4 non-esterified fatty acids, 6 xenobiotics, and 5 unknown compounds). Few associations were observed with gestational duration, birth weight, or birth length. Maternal ethnicity, pre-pregnancy BMI, and diet quality during pregnancy had the strongest associations with the specific metabolome related to infant adiposity. Further studies are warranted to replicate our findings and to understand the underlying mechanisms.

Impact of maternal BMI and gestational diabetes mellitus on maternal and cord blood metabolome: results from the PREOBE cohort study.

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. 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. 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. Maternal BMI and GDM are associated with maternal and cord blood metabolites supporting the hypothesis of transgenerational cycle of obesity and diabetes.

Maternal Plasma Metabolomic Profiles in Spontaneous Preterm Birth: Preliminary Results.

Objective To profile maternal plasma metabolome in spontaneous preterm birth. Method In this retrospective case-control study, we have examined plasma of patient with preterm birth (between 22 and 36 weeks of pregnancy (n = 57)), with threatened preterm labor (between 23 and 36 weeks of pregnancy (n = 49)), and with term delivery (n = 25). Plasma samples were analysed using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-Q-TOF-MS) in positive and negative polarity modes. Results We found 168 differentially expressed metabolites that were significantly distinct between study groups. We determined 51 metabolites using publicly available databases that could be subdivided into one of the five groups: amino acids, fatty acids, lipids, hormones, and bile acids. PLS-DA models, verified by SVM classification accuracy, differentiated preterm birth and term delivery groups. Conclusions Maternal plasma metabolites are different between term and preterm parturitions. Part of them may be related with preterm labor, while others may be affected by gestational age or the beginning of labor. Metabolite profile can classify preterm or term delivery groups raising the potential of metabolome as a biomarker to identify high-risk pregnancies. Metabolomic studies are also a tool to detect individual compounds that may be further tested in targeted researches.

Tea consumption in pregnancy as a predictor of pesticide exposure and adverse birth outcomes: The MIREC Study

IntroductionPesticide residues in tea may contribute to exposure during pregnancy; however, the impact on maternal and infant health is not well understood. The aim of this study was to determine whether tea intake in the first trimester was associated with elevated concentrations of various pesticides in maternal blood or urine. Further, we examined the relationship between tea consumption and adverse birth outcomes. MethodsData from the Maternal–Infant Research on Environmental Chemicals (MIREC) Study, a pan-Canada pregnancy cohort, were used. All singleton, live births (n=1898) with available biomarkers were included in the analyses. Descriptive statistics were used to characterize the population. The geometric means (GM) of organochlorine (OC) pesticide constituents or metabolites in maternal plasma (lipid adjusted) and organophosphate (OP) pesticide metabolites (adjusted for specific gravity) in maternal urine were calculated for participants who drank regular, green or herbal tea in the first trimester and for those who did not. Differences between groups were examined using chi-square or t-tests. Associations between frequency of drinking tea and adverse birth outcomes were examined using logistic regression (preterm birth and small-for-gestational-age) or generalized linear models (birthweight decile and head circumference). ResultsThe GM of the OC pesticide constituent trans-nonachlor was 2.74mg/g lipid, and for metabolites oxychlordane and p,p′-DDE this was 1.94ng/g lipid and 55.8ng/g lipid, respectively. OP pesticide metabolite concentrations adjusted for specific gravity, were dimethylphosphate (GM: 3.19µg/L), dimethylthiophosphate (GM: 3.29µg/L), dimethyldithiophosphate (GM: 0.48µg/L), diethlphosphate (GM: 2.46), and diethylthiophosphate (GM: 0.67µg/L). There was no significant difference in mean concentrations for these OC or OP pesticide constituents or metabolites between tea drinkers — of any type — and non-tea drinkers. Further, no association was found between tea intake and adverse birth outcomes. ConclusionsPesticide concentrations did not differ by tea intake. Further, tea intake in the first trimester was not associated with adverse birth outcomes. In this study population, there was no evidence for concern about tea intake being a source of the OP or OC pesticide metabolites measured or adversely affecting birth outcomes; however, tea intake was lower than national Canadian data for women of reproductive age.

Pregnancy-Induced Metabolic Phenotype Variations in Maternal Plasma

Metabolic variations occur during normal pregnancy to provide the growing fetus with a supply of nutrients required for its development and to ensure the health of the woman during gestation. Mass spectrometry-based metabolomics was employed to study the metabolic phenotype variations in the maternal plasma that are induced by pregnancy in each of its three trimesters. Nontargeted metabolomics analysis showed that pregnancy significantly altered the profile of metabolites in maternal plasma. The levels of six metabolites were found to change significantly throughout pregnancy, with related metabolic pathway variations observed in biopterin metabolism, phospholipid metabolism, amino acid derivatives, and fatty acid oxidation. In particular, there was a pronounced elevation of dihydrobiopterin (BH₂), a compound produced in the synthesis of dopa, dopamine, norepinephrine, and epinephrine, in the second trimester, whereas it was markedly decreased in the third trimester. The turnover of BH₂ and tryptophan catabolites indicated that the fluctuations of neurotransmitters throughout pregnancy might reveal the metabolic adaption in the maternal body for the growth of the fetus. Furthermore, 11 lipid classes and 41 carnitine species were also determined and this showed variations in the presence of long-chain acylcarnitines and lysophospholipids in later pregnancy, suggesting changes of acylcarnitines and lysophospholipids to meet the energy demands in pregnant women. To our knowledge, this work is the first report of dynamic metabolic signatures and proposed related metabolic pathways in the maternal plasma for normal pregnancies and provided the basis for time-dependent metabolic trajectory against which disease-related disorders may be contrasted.

A Metabonomic Approach to Analyze the Dexamethasone‐Induced Cleft Palate in Mice

Mice models are an important way to understand the relation between the fetus with cleft palate and changes of maternal biofluid. This paper aims to develop a metabonomics approach to analyze dexamethasone-induced cleft palate in pregnant C57BL/6J mice and to study the relationship between the change of endogenous small molecular metabolites in maternal plasma and the incidence of cleft palate. To do so, pregnant mice were randomly divided into two groups. The one group was injected with dexamethasone. On E17.5th day, the incident rates of cleft palate from embryos in two groups were calculated. The 1H-NMR spectra from the metabolites in plasma in two groups was collected at same time. Then the data were analyzed using metabonomics methods (PCA and SIMCA). The results showed that the data from the two groups displayed distinctive characters, and the incidence of cleft palate were significantly different (P < .005). To conclude, this study demonstrates that the metabonomics approach is a powerful and effective method in detecting the abnormal metabolites from mother in the earlier period of embryos, and supports the idea that a change from dexamethasone induced in maternal metabolites plays an important role in the incidence of cleft palate.

Levels of 24,25-dihydroxyvitamin D3, 25-hydroxyvitamin D3 and 25-hydroxyvitamin D3 3-sulphate in human plasma.

The concentrations of (24R)-24,25-dihydroxyvitamin D3[24,25(OH)2D3], 25-hydroxyvitamin D3[25(OH)D3] and its 3-sulphate [25(OH)D3(3)S] in the plasma of healthy subjects, patients with chronic renal failure, patients with climacteric syndrome, pregnant women and foetuses were determined using the enzyme-linked immunosorbent assay and high-performance liquid chromatography. 25(OH)D3(3)S was not detected in about one-third of the plasma samples from patients with chronic renal failure (n = 26). The three metabolites in maternal plasma reached the highest levels in the second trimester of pregnancy followed by a decrease to the values obtained in the first trimester. Older healthy women (age range 44-71 years) showed higher levels of 24,25(OH)2D3 and 25(OH)D3 in the plasma than did young healthy women (age range 21-29 years), whereas no clear difference was observed between the older healthy women and patients with climacteric syndrome. The level of 25(OH)D3(3)S in the plasma was higher in the latter patients than in healthy women.

Investigation of pharmacokinetics and of possible adverse effects in infants exposed to tricyclic antidepressants in breast-milk

We have studied ten breast-feeding mothers who were prescribed tricyclic antidepressant drugs and have also compared their infants' development with a similar group ( n=15) who were bottle-fed. Concentrations of tricyclic drugs in maternal plasma and urine, in fore-milk and hind-milk and in infant plasma ( n=6) and urine ( n=9) were measured by gas chromatography (GC) and by an enzyme immunoassay (EIA). The fat concentration in milk was also measured. Infants' health and development were monitored by physical examination and by the Bayley Scales of Infant Development up to 30 months. The amounts of tricyclic drugs and their principal metabolites in maternal plasma were significantly correlated with the oral dose and with the amounts in breast-milk. Drug concentrations in fore-milk, but not in hind-milk, increased in line with its fat content, which was maximal in hind-milk. Correlations between gas chromatographic and enzyme immunoassays of maternal samples were high provided that the values for amitriptyline and nortriptyline were excluded; immunoreactivities to these compounds were abnormally high, suggesting that metabolites were also being measured by EIA. The daily doses of drugs ingested by breast-fed infants were about 1% of the maternal dose/kg and the immunoassay detected very small amounts of tricyclics in infants' plasma and urine. No acute toxic effects were found in the ten medicated breast-fed infants and there was no evidence of developmental delays in comparison with bottle-fed infants. Although the number of subjects in this study is small, when taken in conjunction with other published findings, we have not found any reason to prevent mothers who are taking established tricyclic antidepressants from breast-feeding their babies if they want to do so.

All-Trans-Retinoic Acid in Maternal Plasma and Teratogenicity in Rats and Rabbits

The teratogenicity of all-trans-retinoic acid, 13-cis-retinoic acid, and retinol was investigated in pregnant Wistar rats given a single oral dose on Day 10 of gestation. External malformations showed dose-dependent increases and the order of potency was all-trans-retinoic acid > retinol > 13-cis-retinoic acid. The metabolites in maternal plasma were determined following a single oral dose on Day 10 of gestation. Equipotent teratogenic doses of all-trans-retinoic acid and 13-cis-retinoic acid had similar plasma levels of all-trans-retinoic acid; however, retinol teratogenicity could not be accounted for by circulating all-trans-retinoic acid or its metabolites. The teratogenicity and maternal pharmacokinetics of all-trans-retinoic were compared in pregnant Wistar rats when given as a single dose (50 mg/kg) and as three equal doses (16.66 mg/kg) over 6 hr. Divided doses were of slightly greater potency than the single dose but the maximum observed concentration (Cmax) and area under the plasma concentration–time curve (AUC) values for the second and third doses were greatly attenuated compared with the first dose; in consequence, both the total AUC andCmaxwere reduced compared with the single dose. The altered profile could not be explained by increased formation of all-trans-retinoic acid glucuronide or increased isomerisation to 13-cis-retinoic acid. The maternal plasma levels of all-trans-retinoic acid in pregnant rabbits were reduced by a dose given 24 hr earlier. These data show that all-trans-retinoic acid in maternal plasma is a poor indicator of fetal exposure to teratogenic risk.

Caffeine and its dimethylxanthines and fetal cerebral development in rat

The relationship between the distribution and pharmacokinetic behavior of caffeine and its dimethylxanthines in pregnant rats and fetuses and fetal cerebral development was compared in four groups with different modes of oral caffeine ingestion by the mothers. During the premating period and pregnancy, female Wistar rats were divided into 0.04% caffeine (C) and water (W) groups, respectively. When the groups are expressed as W or C before mating-W or C during pregnancy, the fetal body weight was low in the three caffeine-treated groups (W-C, C-W and C-C) and the fetal cerebral weight was the lowest in the W-C group. The mean concentration of caffeine or metabolites in maternal plasma, maternal liver, placenta and fetal cerebrum on gestational day (g d) 21 was increased in the W-C group compared to in the C-C group. The concentration of caffeine in fetal cerebrum was increased but that of metabolites was not, compared to the concentration of caffeine or metabolites in the placenta. Radioactivity in fetal cerebrum after intraperitoneal injection of 14C-caffeine was higher in the W-C group than in the other three groups. After intravenous injection of caffeine the apparent volume of distribution of caffeine in maternal plasma was markedly decreased in the W-C group, and the plasma molar concentration ratio of theophylline to caffeine was significantly increased in both the W-C and C-C groups. The adverse effect of maternal caffeine ingestion on the fetal cerebrum may be associated with the decreased apparent volume of distribution of caffeine in maternal plasma and the high caffeine content of fetal cerebrum.

DHEA-S-loading test in cases of intrauterine growth retardation: relationship between the pattern of the maternal plasma metabolites and the fetoplacental dysfunction.

Dehydroepiandrosterone sulfate loading tests (DLT) have been performed in 17 cases of clinically suspected intrauterine fetal growth retardation. At birth, 9 babies had adequate birth weights for gestational age (AGA) and 8 infants were small for gestational age (SGA). In both groups, plasma levels of dehydroepiandrosterone sulfate (DHEA-S), unconjugated DHEA, delta4-adrostenedione (delta4-A), testosterone (T), unconjugated estrone (E1) and estradiol (E2) were measured seven times from 15 min to 4 h after the intravenous injection of 50 mg DHEA-S. Several differences appear between the AGA group and the SGA group: (1) in the latter group, the rate of disappearance of the injected DHEA-S is decreased; (2) plasma levels of delta4-A and T are significantly increased and remain elevated for 2-3 h, whereas in the AGA group these values are increased only for a short period of time just after the injection. E1 and E2 patterns are similar in both groups. It has previously been demonstrated that an impaired response to DLT reflects a reduced uteroplacental blood flow. In addition, our results suggests a concomitant impairment of the aromatizing activity which reduces the placental metabolization of neutral steroids to estrogens.