Maternal Body Mass Index, Early-Pregnancy Metabolite Profile, and Birthweight.

CONTEXT: Maternal prepregnancy body mass index (BMI) has a strong influence on gestational metabolism, but detailed metabolic alterations are unknown. OBJECTIVE: First, to examine the associations of maternal prepregnancy BMI with maternal early-pregnancy metabolite alterations. Second, to identify an early-pregnancy metabolite profile associated with birthweight in women with a higher prepregnancy BMI that improved prediction of birthweight compared to glucose and lipid concentrations. DESIGN, SETTING, AND PARTICIPANTS: Prepregnancy BMI was obtained in a subgroup of 682 Dutch pregnant women from the Generation R prospective cohort study. MAIN OUTCOME MEASURES: Maternal nonfasting targeted amino acids, nonesterified fatty acid, phospholipid, and carnitine concentrations measured in blood serum at mean gestational age of 12.8 weeks. Birthweight was obtained from medical records. RESULTS: A higher prepregnancy BMI was associated with 72 altered amino acids, nonesterified fatty acid, phospholipid and carnitine concentrations, and 6 metabolite ratios reflecting Krebs cycle, inflammatory, oxidative stress, and lipid metabolic processes (P-values < 0.05). Using penalized regression models, a metabolite profile was selected including 15 metabolites and 4 metabolite ratios based on its association with birthweight in addition to prepregnancy BMI. The adjusted R2 of birthweight was 6.1% for prepregnancy BMI alone, 6.2% after addition of glucose and lipid concentrations, and 12.9% after addition of the metabolite profile. CONCLUSIONS: A higher maternal prepregnancy BMI was associated with altered maternal early-pregnancy amino acids, nonesterified fatty acids, phospholipids, and carnitines. Using these metabolites, we identified a maternal metabolite profile that improved prediction of birthweight in women with a higher prepregnancy BMI compared to glucose and lipid concentrations.

Altered Steroidome in Women with Gestational Diabetes Mellitus: Focus on Neuroactive and Immunomodulatory Steroids from the 24th Week of Pregnancy to Labor.

Gestational diabetes mellitus (GDM) is a complication in pregnancy, but studies focused on the steroidome in patients with GDM are not available in the public domain. This article evaluates the steroidome in GDM+ and GDM- women and its changes from 24 weeks (± of gestation) to labor. The study included GDM+ (n = 44) and GDM- women (n = 33), in weeks 24-28, 30-36 of gestation and at labor and mixed umbilical blood after delivery. Steroidomic data (101 steroids quantified by GC-MS/MS) support the concept that the increasing diabetogenic effects with the approaching term are associated with mounting progesterone levels. The GDM+ group showed lower levels of testosterone (due to reduced AKR1C3 activity), estradiol (due to a shift from the HSD17B1 towards HSD17B2 activity), 7-oxygenated androgens (competing with cortisone for HSD11B1 and shifting the balance from diabetogenic cortisol towards the inactive cortisone), reduced activities of SRD5As, and CYP17A1 in the hydroxylase but higher CYP17A1 activity in the lyase step. With the approaching term, the authors found rising activities of CYP3A7, AKR1C1, CYP17A1 in its hydroxylase step, but a decline in its lyase step, rising conjugation of neuroinhibitory and pregnancy-stabilizing steroids and weakening AKR1D1 activity.

Early postpartum abnormal glucose metabolism subtype differs according to mid-trimester lipid profile in women with gestational diabetes mellitus.

BACKGROUND: It is unknown whether early postpartum abnormal glucose metabolism (AGM) in women with previous gestational diabetes mellitus (GDM) is related to their mid-trimester lipid profile. The aim of this study was to characterize the mid-trimester lipid profile of women who experienced GDM and developed into different pathophysiologic subtypes of early postpartum AGM. METHODS: A retrospective cohort study of 498 women with history of GDM was conducted. A 75-g oral glucose tolerance test (OGTT) and plasma lipid measurements were performed at 24-28 weeks of gestation and 6-12 weeks of postpartum. Insulin secretion and sensitivity were estimated using early postpartum OGTT-based indices. RESULTS: Women in the mid-trimester dyslipidemia group had higher postpartum 30-min and 2-h plasma glucose, higher postpartum 2-h plasma insulin, higher postpartum triglyceride (TG), higher postpartum low density lipoprotein cholesterol (LDL-c) concentrations, lower postpartum 30-min insulinogenic index (IGI30), lower postpartum insulin sensitivity index (ISI), and lower postpartum disposition index than those in the normal lipid group (all P < 0.05). Abnormal mid-trimester TG and LDL-c concentrations were associated with postpartum AGM (adjusted odds ratio [OR] = 1.786, 95 % confidence interval [CI] = 1.142-2.425; and adjusted OR = 1.621, 95 % CI = 1.323-2.051, respectively; both P < 0.05). AGM women with low IGI30 and low ISI had higher mid-trimester total cholesterol and LDL-c concentrations, and AGM women with low ISI had higher mid-trimester TG concentrations than women with NGT or other subtypes of AGM (all P < 0.05). CONCLUSIONS: GDM women with abnormal mid-trimester TG and LDL-c were predisposed to early postpartum AGM. Postpartum AGM women who experienced GDM had heterogeneous mid-trimester lipid profile when classified according to their pathophysiologic subtype.

The significance of blood and salivary oxidative stress markers and chemerin in gestational diabetes mellitus.

OBJECTIVE: Gestational diabetes mellitus (GDM) is a medical complication of pregnancy. The aim of this study was to evaluate the correlations between the salivary and blood levels of oxidative stress markers and an adipokine chemerin, which play a role in the pathogenesis of GDM. MATERIALS AND METHODS: Study groups (Control (n = 29), GDM (n = 22)) had been assessed clinically healthy oral hygiene, according to the age range between 25 and 40 years, BMI<30 kg/m2, who were non-smokers and who were not having systemic diseases. GDM was diagnosed using a 100 g OGTT. Saliva samples were collected without stimulation between 08.30 and 10.00 a.m.. Chemerin and TrxR levels were measured by ELISA. Malondialdehyde, sulfhydryl and NO levels were determined by spectrophotometric analysis. Statistical analysis were performed by Shapiro Wilk, Mann Whitney U, Student's t test. RESULTS: Blood pressure, BMI, and plasma chemerin, salivary chemerin, fasting glucose, LDL, triglyceride, CRP levels in GDM were not different when compared to Control. There were significant differences between Plasma TrxR and HDL levels. Also, significant differences between salivary TrxR and Malondialdehyde levels were observed in GDM. CONCLUSION: It was concluded that the optimal cut-off points for oxidative stress parameters and chemerin level can be used to distinguish between healthy pregnant and GDM.

Comprehensive Profiling of Secretome Formulations from Fetal- and Perinatal Human Amniotic Fluid Stem Cells.

We previously reported that c-KIT+ human amniotic-fluid derived stem cells obtained from leftover samples of routine II trimester prenatal diagnosis (fetal hAFS) are endowed with regenerative paracrine potential driving pro-survival, anti-fibrotic and proliferative effects. hAFS may also be isolated from III trimester clinical waste samples during scheduled C-sections (perinatal hAFS), thus offering a more easily accessible alternative when compared to fetal hAFS. Nonetheless, little is known about the paracrine profile of perinatal hAFS. Here we provide a detailed characterization of the hAFS total secretome (i.e., the entirety of soluble paracrine factors released by cells in the conditioned medium, hAFS-CM) and the extracellular vesicles (hAFS-EVs) within it, from II trimester fetal- versus III trimester perinatal cells. Fetal- and perinatal hAFS were characterized and subject to hypoxic preconditioning to enhance their paracrine potential. hAFS-CM and hAFS-EV formulations were analyzed for protein and chemokine/cytokine content, and the EV cargo was further investigated by RNA sequencing. The phenotype of fetal- and perinatal hAFS, along with their corresponding secretome formulations, overlapped; yet, fetal hAFS showed immature oxidative phosphorylation activity when compared to perinatal ones. The profiling of their paracrine cargo revealed some differences according to gestational stage and hypoxic preconditioning. Both cell sources provided formulations enriched with neurotrophic, immunomodulatory, anti-fibrotic and endothelial stimulating factors, and the immature fetal hAFS secretome was defined by a more pronounced pro-vasculogenic, regenerative, pro-resolving and anti-aging profile. Small RNA profiling showed microRNA enrichment in both fetal- and perinatal hAFS-EV cargo, with a stably- expressed pro-resolving core as a reference molecular signature. Here we confirm that hAFS represents an appealing source of regenerative paracrine factors; the selection of either fetal or perinatal hAFS secretome formulations for future paracrine therapy should be evaluated considering the specific clinical scenario.

Vaginal metabolic profiles during pregnancy: Changes between first and second trimester.

During pregnancy, the vaginal microbiome plays an important role in both maternal and neonatal health outcomes. Throughout pregnancy, the vaginal microbial composition undergoes significant changes, including a decrease in overall diversity and enrichment with Lactobacillus spp. In turn, the modifications in the microbial profiles are associated with shifts in the composition of vaginal metabolites. In this study, we characterized the vaginal metabolic profiles throughout pregnancy at two different gestational ages, correlating them with a microscopic evaluation of the vaginal bacterial composition. A total of 67 Caucasian pregnant women presenting to the Family Advisory Health Centres of Ravenna (Italy) were enrolled and a vaginal swab was collected at gestational ages 9-13 weeks (first trimester) and 20-24 weeks (second trimester). The composition of the vaginal microbiome was assessed by Nugent score and women were divided in 'H' (normal lactobacilli-dominated microbiota), 'I' (intermediate microbiota), and 'BV' (bacterial vaginosis) groups. Starting from the cell-free supernatants of the vaginal swabs, a metabolomic analysis was performed by means of a 1H-NMR spectroscopy. From the first to the second trimester, a greater number of women showed a normal lactobacilli-dominated microbiota, with a reduction of cases of dysbiosis. These microbial shifts were associated with profound changes in the vaginal metabolic profiles. Over the weeks, a significant reduction in the levels of BV-associated metabolites (e.g. acetate, propionate, tyramine, methylamine, putrescine) was observed. At the same time, the vaginal metabolome was characterized by higher concentrations of lactate and of several amino acids (e.g. tryptophan, threonine, isoleucine, leucine), typically found in healthy vaginal conditions. Over time, the vaginal metabolome became less diverse and more homogeneous: in the second trimester, women with BV showed metabolic profiles more similar to the healthy/intermediate groups, compared to the first trimester. Our data could help unravel the role of vaginal metabolites in the pathophysiology of pregnancy.

Residential exposure to air pollution and access to neighborhood greenspace in relation to hair cortisol concentrations during the second and third trimester of pregnancy.

BACKGROUND: Exposure to air pollution during pregnancy has been associated with adverse pregnancy outcomes in studies worldwide, other studies have described beneficial effects of residential greenspace on pregnancy outcomes. The biological mechanisms that underlie these associations are incompletely understood. A biological stress response, which implies release of cortisol, may underlie associations of air pollution exposure and access to neighborhood greenspaces with health. METHODS: We explored residential exposure to air pollution and residential access to neighborhood greenspaces in relation to hair cortisol concentrations of participants in a prospective pregnancy cohort study in Flanders, Belgium. Hair samples were collected at the end of the second pregnancy trimester (n = 133) and shortly after delivery (n = 81). Cortisol concentrations were measured in 3-cm scalp-near hair sections, to reflect second and third pregnancy trimester cortisol secretion. We estimated long-term (3 months before sampling) residential exposure to fine particulate matter (PM2.5), nitrogen dioxide (NO2) and black carbon (BC), assessed residential distance to major roads and residential access to neighborhood greenspaces (NHGS). Associations between residential exposures and hair cortisol concentrations were studied using linear regression models while adjusting for season of sampling. RESULTS: Three-month mean residential NO2 and BC concentrations were positively associated with third pregnancy trimester hair cortisol concentrations (p = 0.008 and p = 0.017). Access to a large NHGS (10 ha or more within 800 m from residence) was negatively associated with third trimester hair cortisol concentrations (p = 0.019). Access to a large NHGS significantly moderated the association between residential proximity to major roads and second trimester hair cortisol concentrations (p = 0.021). Residential distance to major roads was negatively associated with second trimester hair cortisol concentrations of participants without access to a large NHGS (p = 0.003). The association was not significant for participants with access to a large NHGS. The moderation tended towards significance in the third pregnancy trimester (p < 0.10). CONCLUSIONS: Our findings suggest a positive association between long-term residential exposure to air pollution and biological stress during pregnancy, residential access to neighborhood greenspaces may moderate the association. Further research is needed to confirm our results. TRIAL REGISTRATION: The IPANEMA study is registered under number  NCT02592005 at clinicaltrials.gov .

Longitudinal study on steroid hormone variations during the second trimester of gestation: a useful tool to confirm adequate foetal development.

BACKGROUND: The interaction of hormonal factors are crucial for good foetal development. During the second trimester of gestation, most of the main physiological processes of foetal development occur. Therefore, the aim of this study was to determine the variations in the physiological levels of cortisol, estriol, estrone sulphate, and progesterone during the second trimester (weeks 12-26) in order to establish normal ranges that can serve as indicators of foetal well-being and good functioning of the foetal-placental unit. METHODS: Saliva samples from 106 pregnant women were collected weekly (from week 12 to week 26 of gestation), and hormonal measurements were assayed by an enzyme immunoassay. The technique used for hormone measurements was highly sensitive and served as a non-invasive method for sample collection. RESULTS: The results revealed a statistically significant (p<0.05) difference between cortisol, progesterone, and oestrogens throughout the second trimester, with a more substantial relationship between oestrogens and progesterone [P4-E3 (r=0.427); P4-E1SO4 (r=0.419)]. By analysing these hormone concentrations, statistically significant (p<0.05) elevations in progesterone, cortisol, and estriol levels were found at the 16th [(P4 (0.78±0.088), C(1.99±0.116), E3(2.513±0.114)]; 18th [(P4 (1.116±0.144), C(3.409±0.137), E3(3.043±0.123)] and 23rd week of gestation [(P4(1.36±0.153), C(1.936±0.11), E3(2.657±0.07)]. Estrone sulphate levels appeared to increase progressively throughout the second trimester [from 1.103±0.03 to 2.244±0.09]. CONCLUSION: The 18th week of gestation seems to constitute a very important week during foetal adrenal development, and the analysis of the main hormones involved in foetal development, provided more precise information regarding the proper functioning of the foetal unit and foetal development.

Glycine, a Dispensable Amino Acid, Is Conditionally Indispensable in Late Stages of Human Pregnancy.

BACKGROUND: Recently, we showed that there are higher protein, lysine, and phenylalanine requirements in late stages of pregnancy compared with early stages. Animal studies have suggested an increased dietary need for specific dispensable amino acids in pregnancy; whether such a need exists in human pregnancies is unknown. OBJECTIVE: The objective of the current study was to examine whether healthy pregnant women at midgestation (20-29 wk) and late gestation (30-40 wk) have a dietary demand for glycine, a dispensable amino acid, using the indicator amino acid oxidation method and measurement of plasma 5-oxoproline concentrations. METHODS: Seventeen healthy women (aged 26-36 y) randomly received different test glycine intakes (range: 5-100 mg·kg-1·d-1) during each study day in midgestation (∼26 wk, n = 17 observations in 9 women) and late gestation (∼35 wk, n = 19 observations in 8 women). Diets were isocaloric with energy at 1.7 × resting energy expenditure. Protein was given as a crystalline amino acid mixture based on egg protein composition at current estimated average requirement (EAR; 0.88 g·kg-1·d-1). Breath samples were collected at baseline and isotopic steady state to measure oxidation of L-[1-13C]phenylalanine to 13CO2 (F13CO2). Plasma was collected at the sixth hour of the study day. Linear regression crossover analysis and simple linear regression were used to assess responses in F13CO2 and plasma 5-oxoproline concentrations to different glycine intakes. RESULTS: No statistically significant responses were observed in midgestation. However, in late gestation, lower glycine intakes resulted in higher rates of F13CO2 (suggesting low protein synthesis) with a breakpoint for phenylalanine oxidation at >37 mg glycine·kg-1·d-1 and higher plasma 5-oxoproline (suggesting low glycine availability) with a breakpoint >27 mg glycine·kg-1·d-1. CONCLUSIONS: The findings suggest that glycine should be considered a "conditionally" indispensable amino acid during late gestation, especially when protein intakes are at 0.88 g·kg-1·d-1, the current EAR. This trial was registered at clinicaltrials.gov as NCT02149953.

Role of heme oxygenase-1 in human placenta on iron supply to fetus.

INTRODUCTION: To date, details on how iron is supplied from the mother to the fetus through the placenta have remained unclear. Recently, increasing evidence has shown that heme oxygenase (HO)-1, which is an inducible isoform of the rate-limiting enzyme in the heme degradation pathway, may be involved in the effective reutilization of iron. In this study, we examined the distribution and gene expression of HO-1 in the villous tissue of human placenta at various periods of pregnancy. METHODS: Using the placenta of 38 samples for which consent was obtained, chronological changes in the localization of HO-1 protein were examined by histological examination. RT-PCR was also performed to examine the expression of HO-1, transferrin receptor-1, and ferroportin 1. Ferric iron in the tissues was analyzed by Prussian blue staining. RESULTS: Immunohistochemical studies showed that HO-1 protein was exclusively expressed in trophoblastic cells throughout gestation. In the miscarriage placenta in the first trimester, ho-1 mRNA levels were significantly higher than normal. Placenta with fetal death (miscarriage) in the first and second trimester indicate significantly higher ratio of ho-1 gene for iron production to the fpn-1 gene for iron excretion than normal. These suggest that the role of HO-1 with various physiological functions is changing throughout pregnancy. DISCUSSION: These findings suggest that HO-1 in placenta plays an important role in iron supplying system in the second trimester to support fetal development.

Association of maternal central adiposity measured by ultrasound in early mid pregnancy with infant birth size.

We sought to investigate whether early mid pregnancy visceral and subcutaneous fat depths measured by ultrasound were associated with infant birth size, independent of early pregnancy BMI. A cohort study was performed at Uppsala University Hospital, Sweden, between 2015-2018. Visceral and subcutaneous fat depths were measured at the early second-trimester anomaly scan in 2498 women, giving birth to singleton, term infants. Primary outcomes were birthweight and LGA (birthweight standard deviation score > 90th percentile in the cohort). Linear and logistic regression models were used, adjusted for BMI, age, smoking, parity, maternal country of birth, gestational age and infant sex. A 5-mm increase in visceral fat depth was associated with an increase in birthweight of 8.3 g [95% confidence interval (CI) 2.5 - 14.1 g], after adjustments, and a 6% increase in the adjusted odds of having an infant born LGA (OR 1.06, CI 1.02-1.11). There was no association between subcutaneous fat depth and birthweight or LGA after covariate adjustments. Hence, visceral fat depth measured by ultrasound in early mid pregnancy was associated with excessive fetal growth, independent of early pregnancy BMI, and may be useful in models for predicting LGA infants.

Metabolomic biomarkers in midtrimester maternal plasma can accurately predict the development of preeclampsia.

Early identification of patients at risk of developing preeclampsia (PE) would allow providers to tailor their prenatal management and adopt preventive strategies, such as low-dose aspirin. Nevertheless, no mid-trimester biomarkers have as yet been proven useful for prediction of PE. This study investigates the ability of metabolomic biomarkers in mid-trimester maternal plasma to predict PE. A case-control study was conducted including 33 pregnant women with mid-trimester maternal plasma (gestational age [GA], 16-24 weeks) who subsequently developed PE and 66 GA-matched controls with normal outcomes (mid-trimester cohort). Plasma samples were comprehensively profiled for primary metabolic and lipidomic signatures based on gas chromatography time-of-flight mass spectrometry (GC-TOF MS) and liquid chromatography Orbitrap mass spectrometry (LC-Orbitrap MS). A potential biomarker panel was computed based on binary logistic regression and evaluated using receiver operating characteristic (ROC) analysis. To evaluate whether this panel can be also used in late pregnancy, a retrospective cohort study was conducted using plasma collected from women who delivered in the late preterm period because of PE (n = 13) or other causes (n = 21) (at-delivery cohort). Metabolomic biomarkers were compared according to the indication for delivery. Performance of the metabolomic panel to identify patients with PE was compared also to a commonly used standard, the plasma soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio. In the mid-trimester cohort, a total of 329 metabolites were identified and semi-quantified in maternal plasma using GC-TOF MS and LC-Orbitrap-MS. Binary logistic regression analysis proposed a mid-trimester biomarker panel for the prediction of PE with five metabolites (SM C28:1, SM C30:1, LysoPC C19:0, LysoPE C20:0, propane-1,3-diol). This metabolomic model predicted PE better than PlGF (AUC [95% CI]: 0.868 [0.844-0.891] vs 0.604 [0.485-0.723]) and sFlt-1/PlGF ratio. Analysis of plasma from the at-delivery cohort confirmed the ability of this biomarker panel to distinguish PE from non-PE, with comparable discrimination power to that of the sFlt-1/PlGF ratio. In conclusion, an integrative metabolomic biomarker panel in mid-trimester maternal plasma can accurately predict the development of PE and showed good discriminatory power in patients with PE at delivery.

Fetal sex and maternal insulin resistance during mid-pregnancy: a retrospective cohort study.

BACKGROUND: Recent studies have suggested that fetal sex influences maternal glucose and insulin metabolism during pregnancy. We examined whether fetal sex is associated with maternal insulin resistance and the ß-cell function during mid-pregnancy. METHODS: This retrospective study included singleton pregnant women who underwent a 75-g oral glucose tolerance test (OGTT) at 24-34 weeks of gestation due to positive diabetic screening. In addition to plasma glucose (PG), we measured plasma insulin during the OGTT to obtain surrogate indices associated with insulin resistance (IR), including homeostasis assessment model (HOMA) -IR and insulin sensitivity index (IsOGTT), and ß-cell function, including insulinogenic index (II), HOMA-ß, and area under the curve of insulin response. We compared these indices between women carrying male fetuses to those carrying female fetuses. RESULTS: The study population included 617 women (mean age, 32.4 ± 4.9 years) with a mean pre-pregnancy body mass index (BMI) of 22.6±4.5. They underwent the 75g-OGTT at 29.0 ± 2.5 weeks. Two hundred fifty-eight (42%) women were diagnosed with gestational diabetes (GDM). There was no significant difference in maternal age, pre-pregnancy BMI, gestational age at OGTT, PG at OGTT, or the prevalence of GDM between women with a male fetus (n=338) (male group) and those with a female fetus (n=279) (female group). Regarding the indices of IR, IR was significantly higher and insulin sensitivity was lower in the female group than in the male group (HOMA-IR: 7.0 [5-9.6] vs. 6.2 [4.6-8.8], p< 0.05; IsOGTT: 5.86 [4.29-7.83] vs. 6.29 [4.59-8.84], p< 0.01) (median [quartile range]). These differences remained significant after adjustment for maternal age, pre-pregnancy BMI, gestational age and fasting PG at OGTT, and the diagnosis of GDM. In contrast, the ß-cell function did not differ between the two groups. CONCLUSION: Maternal IR during mid-pregnancy was significantly higher in women carrying a female fetus than in those with a male fetus. The sex of the fetus may affect maternal insulin sensitivity during mid-pregnancy.

Differences in cytochrome p450 enzyme expression and activity in fetal and adult tissues.

INTRODUCTION: Human cytochrome p450 (CYP) enzyme expression and activity is lower in the fetus as compared to the adult; however, limited quantitative data exists regarding the specific differences in magnitude or the degree of inducibility due to environmental factors. METHODS: We utilized a combination of in silico- and molecular-based approaches to profile and compare CYP expression/activity in human adult liver and fetal tissues. Using public datasets, we evaluated human CYP expression between: 1) placenta vs. adult livers; 2) fetal vs. adult livers; or 3) five compartments of the human placenta. We generated new experimental data, characterizing expression levels of nine CYPs in placenta/fetal liver vs. adult liver. In a subset of samples, we evaluated CYP3A4 activity. Finally, we summarized evidence of human fetal CYP expression/activity and environmental exposures during pregnancy. RESULTS: In silico, CYPs were predominately expressed at higher levels in the adult liver vs. fetal tissues, with a few noted exceptions. Sixty percent of CYP enzymes were expressed at nominal levels in the placenta. In wet-lab analyses, we observed significant CYP-specific differences in expression/activity between adult and fetal tissues; CYP2E1 and -3A4 were expressed significantly lower in fetal vs. adult livers, while CYP2J2 levels were similar. DISCUSSION: We provide a qualitative review of the expression of the CYP enzyme family in critical sites of xenobiotic distribution during human pregnancy and novel quantitative data regarding fetal CYP expression and activity during mid-gestation. Data outputs may be a resource for modeling predictions of chemical distribution and sensitivity.

The Alteration of Carnitine Metabolism in Second Trimester in GDM and a Nomogram for Predicting Macrosomia.

OBJECTIVE: The metabolism of three major nutrients (sugar, lipid, and protein) will change during pregnancy, especially in the second trimester. The present study is aimed at evaluating carnitine alteration in fatty acid metabolism in the second trimester of pregnancy and the correlation between carnitine and GDM. METHODS: 450 pregnant women were recruited in the present prospective study. Metabolic profiling of 31 carnitines was detected by LC-MS/MS in these women. Correlation between carnitine metabolism and maternal and neonatal complication with GDM was analyzed. RESULTS: We found the levels of 7 carnitines increased in age > 35, BMI ≥ 30, weight gain > 20 kg, and ART pregnant groups, but the level of free carnitine (C0) decreased. Nine carnitines were specific metabolites of GDM. Prepregnancy BMI, weight gain, and carnitines (C0, C3, and C16) were independent risk factors associated with GDM and related macrosomia. C0 was negatively correlated with FBG, LDL, TG, and TC. A nomogram was developed for predicting macrosomia in GDM based on carnitine-related metabolic variables. CONCLUSION: The carnitine metabolism in the second trimester is abnormal in GDM women. The dysfunction of carnitine metabolism is closely related to the abnormality of blood lipid and glucose in GDM. Carnitine metabolism abnormality could predict macrosomia complicated with GDM.

Expression of the Insulin-like Growth Factor System in First- and Second-Trimester Human Embryonic and Fetal Gonads.

CONTEXT: Insulin-like growth factor (IGF) signaling is crucial for sex differentiation and development of Leydig and Sertoli cells in fetal mice testes. No such information is available for human embryonic and fetal testes and ovaries. OBJECTIVE: To investigate presence and activity of the IGF signaling system during human embryonic and fetal ovarian and testicular development. DESIGN: Human embryonic and fetal gonads were obtained following legal terminations of pregnancies. Gene expression was assessed by microarray and qPCR transcript analyses. Proteins of the IGF system components were detected with immunohistochemistry and immunofluorescence analyses. Specimens were included from 2010 to 2017. SETTING: University Hospital. PATIENTS/PARTICIPANTS: Ovaries and testes from a total of 124 human embryos and fetuses aged 5 to 17 postconception weeks were obtained from healthy women aged 16 to 47 years resident in Denmark or Scotland. MAIN OUTCOME MEASURES: Gene expression analysis using microarray was performed in 46 specimens and qPCR analysis in 56 specimens, both sexes included. Protein analysis included 22 specimens (11 ovaries, 11 testes). RESULTS: IGF system members were detected in embryonic and fetal testes and ovaries, both at gene transcript and protein level. A higher expression of IGF regulators was detected in testes than ovaries, with a preferred localization to Leydig cells. CONCLUSIONS: These data indicate that the IGF system is active during very early gestation, when it may have a regulatory role in Leydig cells.

Proteome profiling of gestational diabetes mellitus at 16-18 weeks revealed by LC-MS/MS.

BACKGROUND: The practices used to diagnose gestational diabetes mellitus (GDM) could only be carried out around the time of detectable symptoms, and predictive capacity is little. METHODS: LC-MS/MS was conducted to explore overview proteomics for GDM complicated pregnant woman at 16-18 gestation weeks, while normal pregnant for control. Enzyme-linked immunosorbent assay was further applied in an independent cohort of 15 GDM cases and 15 controls for verification. RESULTS: The results indicated that 24 protein expression levels were significantly changed in GDM group samples, and inflammation, oxidative stress, insulin resistance, blood coagulation, and lipid homeostasis were associated with GDM. The abnormal expression of CRP and IGFBP2 was verified in the first-trimester maternal plasma in women who subsequently developed GDM. CONCLUSIONS: This study not only identified 24 potential predictive biomarkers for GDM also provided a global overview of protein rearrangements induced by GDM.

Untargeted Metabolomics Screen of Mid-pregnancy Maternal Serum and Autism in Offspring.

Discovering pathophysiologic networks in a blood-based approach may help to generate valuable tools for early treatment or preventive measures in autism. To date targeted or untargeted metabolomics approaches to identify metabolic features and pathways affecting fetal neurodevelopment have rarely been applied to pregnancy samples, that is, an early period potentially relevant for the development of autism spectrum disorders (ASD). We conducted a population-based study relying on autism diagnoses retrieved from California Department of Developmental Services record. After linking cases to and sampling controls from birth certificates, we retrieved stored maternal mid-pregnancy serum samples collected as part of the California Prenatal Screening Program from the California Biobank for children born 2004 to 2010 in the central valley of California. We retrieved serum for 52 mothers whose children developed autism and 62 population controls originally selected from all eligible children matched by birth year and child's sex. Also, we required that these mothers were relatively low or unexposed to air pollution and select pesticides during early pregnancy. We identified differences in metabolite levels in several metabolic pathways, including glycosphingolipid biosynthesis and metabolism, N-glycan and pyrimidine metabolism, bile acid pathways and, importantly, C21-steroid hormone biosynthesis and metabolism. Disturbances in these pathways have been shown to be relevant for neurodevelopment in rare genetic syndromes or implicated in previous studies of autism. This study provides new insight into maternal mid-pregnancy metabolic features possibly related to the development of autism and an incentive to explore whether these pathways and metabolites are useful for early diagnosis, treatment, or prevention. LAY SUMMARY: This study found that in mid-pregnancy the blood of mothers who give birth to a child that develops autism has some characteristic features that are different from those of blood samples taken from control mothers. These features are related to biologic mechanisms that can affect fetal brain development. In the future, these insights may help identify biomarkers for early autism diagnosis and treatment or preventive measures. Autism Res 2020, 13: 1258-1269. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

Non-invasive measurement of biochemical profiles in the healthy fetal brain.

Proton magnetic resonance spectroscopy (1H-MRS) of the fetal brain can be used to study emerging metabolite profiles in the developing brain. Identifying early deviations in brain metabolic profiles in high-risk fetuses may offer important adjunct clinical information to improve surveillance and management during pregnancy. OBJECTIVE: To investigate the normative trajectory of the fetal brain metabolites during the second half of gestation, and to determine the impact of using different Cramer-Rao Lower Bounds (CRLB) threshold on metabolite measurements using magnetic resonance spectroscopy. STUDY DESIGN: We prospectively enrolled 219 pregnant women with normal fetal ultrasound and biometric measures. We performed a total of 331 fetal 1H-MRS studies with gestational age in the rage of 18-39 weeks with 112 of the enrolled participants scanned twice. All the spectra in this study were acquired on a GE 1.5 T scanner using long echo-time of 144 â€‹ms and analyzed in LCModel. RESULTS: We successfully acquired and analyzed fetal 1H-MRS with a success rate of 93%. We observed increases in total NAA, total creatine, total choline, scyllo inositol and total NAA-to-total choline ratio with advancing GA. Our results also showed faster increases in total NAA and total NAA-to-total choline ratio during the third trimester compared to the second trimester. We also observed faster increases in total choline and total NAA in female fetuses. Increasing the Cramer-Rao lower bounds threshold progressively from 100% to 40%-20% increased the mean metabolite concentrations and decreased the number of observations available for analysis. CONCLUSION: We report serial fetal brain biochemical profiles in a large cohort of health fetuses studied twice in gestation with a high success rate in the second and third trimester of pregnancy. We present normative in-vivo fetal brain metabolite trajectories over a 21-week gestational period which can be used to non-invasively measure and monitor brain biochemistry in the healthy and high-risk fetus.

Mid-trimester amniotic fluid proteome's association with spontaneous preterm delivery and gestational duration.

BACKGROUND: Amniotic fluid is clinically accessible via amniocentesis and its protein composition may correspond to birth timing. Early changes in the amniotic fluid proteome could therefore be associated with the subsequent development of spontaneous preterm delivery. OBJECTIVE: The main objective of this study was to perform unbiased proteomics analysis of the association between mid-trimester amniotic fluid proteome and spontaneous preterm delivery and gestational duration, respectively. A secondary objective was to validate and replicate the findings by enzyme-linked immunosorbent assay using a second independent cohort. METHODS: Women undergoing a mid-trimester genetic amniocentesis at Sahlgrenska University Hospital/Östra between September 2008 and September 2011 were enrolled in this study, designed in three analytical stages; 1) an unbiased proteomic discovery phase using LC-MS analysis of 22 women with subsequent spontaneous preterm delivery (cases) and 37 women who delivered at term (controls), 2) a validation phase of proteins of interest identified in stage 1, and 3) a replication phase of the proteins that passed validation using a second independent cohort consisting of 20 cases and 40 matched controls. RESULTS: Nine proteins were nominally significantly associated with both spontaneous preterm delivery and gestational duration, after adjustment for gestational age at sampling, but none of the proteins were significant after correction for multiple testing. Several of these proteins have previously been described as being associated with spontaneous PTD etiology and six of them were thus validated using enzyme linked immunosorbent assay. Two of the proteins passed validation; Neutrophil gelatinase-associated lipocalin and plasminogen activator inhibitor 1, but the results could not be replicated in a second cohort. CONCLUSIONS: Neutrophil gelatinase-associated lipocalin and Plasminogen activator inhibitor 1 are potential biomarkers of spontaneous preterm delivery and gestational duration but the findings could not be replicated. The negative findings are supported by the fact that none of the nine proteins from the exploratory phase were significant after correction for multiple testing.