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Background and Aims: Recent studies have indicated possible links between the microbiota and the fetal heart, while the relevant mechanism is still unknown. This study is aims to investigate whether analyzing the microbiota and metabolic profiles of amniotic fluid collected from pregnant women whose fetuses with or without non-syndromic congenital heart defects (CHDs), during the second and third trimester of pregnancy, could offer valuable insights into CHDs., Methods and Results: A case-control study was conducted with 17 cases diagnosed with non-syndromic CHDs (CHDs group) and 34 controls without congenital anomalies (control group) at a ratio of 1:2. The 16 S rDNA gene sequencing and metabolomics methods were employed to assess 51 amniotic fluid samples. The amniotic fluid microbiome from the CHDs group exhibited significantly higher Shannon and Simpson indices compared to the control group. At the genus level, 240 bacterial taxa were substantially enriched in the two groups, with 93 of those taxa being highly enriched in the case group. Compared to the control group, the case group exhibited 177 metabolites that were significantly increased and 480 metabolites that were down-regulated. The differential metabolites were primarily enriched in the steroid hormone biosynthesis, bile secretion and ovarian steroidogenesis, according to KEGG analysis. The observed variations in nine metabolites could attributed to fifty-eight distinct bacterial taxa. The nine differential metabolites were mainly associated with pathways involving steroid hormone biosynthesis, bile secretion, glycolysis, tricarboxylic acid (TCA) cycle, NADPH metabolism, and acyl transfer pathways., Conclusion: The CHDs group has disturbed amniotic fluid microbiota and metabolites, and more research was required to elucidate the mechanism., Competing Interests: Declarations. Ethics approval and consent to participate: The program was approved by the Ethics Committee of Sichuan University (No. 2010004) and West China Second University Hospital (No. 2015(011)). All subjects provided informed consent during the enrollment process. Consent for publication: The work has not been published elsewhere and does not contain any content that infringes upon the rights of others, including copyright or privacy rights. The author understand that once published, the work will be publicly accessible. Clinical trial number: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Intrauterine growth restriction (IUGR) is the second most common obstetric complication after preterm labor. Appropriate trophoblast differentiation and placental structure, growth and function are key for the maintenance of pregnancy and normal fetal growth, development and survival. Extravillous trophoblast cell proliferation, migration and invasion are regulated by molecules produced by the fetomaternal interface, including autocrine factors produced by the trophoblast, such as insulin‑like growth factor (IGF)‑1. The aim of the present study was to investigate expression patterns of IGF‑1Ea isoform in IUGR placenta compared with appropriate for gestational age (AGA) pregnancies. Placental frozen tissues were collected from 13 AGA and 15 IUGR third trimester pregnancies for detection of IGF‑1Ea mRNA expression using reverse transcription‑quantitative PCR. Formalin‑fixed paraffin‑embedded samples from 15 AGA and 47 IUGR pregnancies were analyzed immunohistochemically for the identification and localization of the IGF‑1Ea peptide and comparison of clinical and histopathological parameters. To the best of our knowledge, the present study is the first to show IGF‑1Ea expression in third trimester human placenta. The results indicated that similar IGF‑1Ea mRNA expression levels were present in placental specimens from both groups. Cytoplasmic IGF‑1Ea expression was localized in the perivillous syncytiotrophoblast, extravillous trophoblast and endothelium of the villous and decidual vessels in both groups. No significant difference in the scores and intensity of IGF‑1Ea expression in perivillous syncytiotrophoblasts were noted in the IUGR vs. AGA pregnancies. Most IUGR cases showed negative IGF‑1Ea expression in the extravillous trophoblast, whereas AGA pregnancies showed predominantly positive immunostaining. A sex‑specific expression pattern was noted in the extravillous trophoblast, with negative IGF‑1Ea expression in the placentas of female IUGR cases. Additionally, positive immunostaining for IGF‑1Ea peptide in fetal villous and maternal decidual vessels, was more frequently observed in the IUGR group compared with AGA. In conclusion, no difference in total IGF‑1Ea mRNA placental expression was observed between IUGR and AGA pregnancies, likely due to heterogeneity of histological structures expressing this isoform. Negative IGF‑1Ea immunohistological expression in the extravillous trophoblast from IUGR placentas, associated with histological changes of maternal malperfusion, may reflect the involvement of this isoform in defective placentation. The presence of IGF‑1Ea peptide in the endothelium of the villous vessels in IUGR placentas may indicate a reactive autocrine regulation to compensate for malperfused villi in IUGR pregnancy by regulating angiogenesis and vasodilation. The observed sex differences in IGF‑1Ea expression between IUGR and AGA placentas may indicate interactions between sex hormones and selective IGF‑1 binding proteins in regulating IGF‑1Ea synthesis; however, this requires further elucidation.

Objective: Prenatal stress physiology is often posited as a predictor of birth outcomes, including gestational age at birth and birthweight. However, research has predominantly relied on indicators in the maternal system, with few studies examining hormones of the fetal system. The current study focuses on fetal cortisol in the third trimester, as measured in neonatal hair, as a biological factor that might be associated with birth outcomes (gestational age at birth and birthweight). We report findings from two studies: a longitudinal cohort (Study 1), and a meta-analysis of the existing literature (Study 2)., Methodsstudy: Hair was collected for cortisol analysis from 168 neonates (55.95% female) shortly after birth. Gestational age at birth and birthweight were abstracted from medical records., Methodsstudy: An exhaustive search of four databases was conducted, yielding 155 total studies for screening. Papers reporting neonatal hair cortisol (collection <2 weeks postpartum) and birth outcomes among human neonates were retained for analysis, including Study 1 results ( k = 9)., Resultsstudy: Higher neonatal hair cortisol was related to longer gestation ( r = 0.28, p < .001) and higher birthweight, r = 0.16, p = .040. Sex did not moderate either association., Resultsstudy: Across the nine studies, higher neonatal hair cortisol predicted both longer gestation ( r = 0.35, p < .001, 95% confidence interval = 0.24-0.45) and higher birthweight ( r = 0.18, p = .001, 95% confidence interval = 0.07-0.28). Neonatal sex did not moderate these associations., Conclusions: Fetal cortisol exposure in the third trimester plays a role in normative maturation of the fetus, and findings reveal that higher cortisol is associated with positive birth outcomes., (Copyright © 2024 by the American Psychosomatic Society.)

Objective: The stress experienced by a woman during pregnancy not only has a negative impact on her well-being and physical health but also adversely affects the fetus. Stress is strongly linked with time perspective, defined as the tendency to focus on the past, present, or future. The study aimed to investigate how couples' balanced time perspective was related to maternal prenatal hair cortisol concentration and perceived stress in the first and third trimesters of pregnancy., Method: The participants were pregnant women and their male partners (84 couples). Women completed online questionnaires: the Zimbardo Time Perspective Inventory (ZTPI), the Dark Future Scale (DFS), and the Perceived Stress Scale, while men completed online versions of the ZTPI and the DFS. These questionnaire measurements were conducted in the first and third trimesters. Maternal cortisol levels were measured in hair samples taken during gynecological visits, in the first and third trimesters., Results: The study revealed that the more unbalanced the partner's time perspective, the more unbalanced the pregnant woman's time perspective and, consequently, the higher the stress perceived by the pregnant woman. This effect was present in both the first (B = 1.06, SE =.36, p <.001, 95 % CI [.398, 1.826]) and the third trimesters (B =.98, SE =.36, p <.001, 95 % CI [.327, 1.774]). Moreover, the more unbalanced the partner's time perspective, the more unbalanced the woman's time perspective and, consequently, the lower the hair cortisol concentration in the first trimester (B = -.08, SE =.04, p <.05, 95 % CI [-.171, -.010]). Partner's unbalanced time perspective in the first trimester was also a predictor of stress perceived by the woman in the third trimester (t = 2.38, p <.05)., Conclusions: The results suggest the significance of the partner's time perspective for the pregnant woman's mental health. The partner's unbalanced, negative time perspective in the first trimester may increase the pregnant woman's stress in the third trimester. This effect can be even stronger than that of the woman's time perspective., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Prenatal glucocorticoids are one of the most widely proposed prenatal programming mechanisms, yet few studies exist that measure fetal cortisol via neonatal hair. Neonatal hair provides a window into the fetal experience and represents cortisol accumulation in the third trimester of pregnancy. In the current study, we test the links between two types of anxiety over the course of gestation (pregnancy-related anxiety and general anxiety) with neonatal hair cortisol., Method: Pregnant individuals (N = 107) and their neonates (59.8% female) participated in the current study. Prenatal pregnancy-related anxiety and general anxiety were measured using the Pregnancy Related Anxiety Scale (PRAS) and the State-Trait Anxiety Inventory (STAI), in each trimester of pregnancy. Hierarchical linear modeling was used to model the intercept and slope of each type of anxiety over gestation. Neonatal hair samples were collected shortly after birth (Median days = 1.17, IQR = 0.75-2.00)., Results: Both higher pregnancy-related anxiety and general anxiety at the beginning of pregnancy and a flatter decline of pregnancy-related anxiety over gestation were associated with lower neonatal hair cortisol. After inclusion of gestational age at birth and parity as covariates, pregnancy-related anxiety (intercept: β = -0.614, p =.012; slope: β = -0.681, p =.006), but not general anxiety (intercept: β = -0.389, p =.114; slope: β = -0.302, p =.217) remained a significant predictor. Further, when both general and pregnancy-related anxiety were entered into the same model, only pregnancy-related anxiety (intercept and slope) were significant predictors of neonatal hair cortisol, indicating an association with pregnancy-related anxiety above and beyond general anxiety., Conclusion: Cortisol plays a central role in maturation of fetal organ systems, and at the end of gestation, higher cortisol has beneficial effects such as promoting fetal lung maturation. Further, lower maternal cortisol is linked to less optimal cognitive development and altered brain development. As maternal higher anxiety in early pregnancy and a flatter decrease over time are both associated with lower neonatal hair cortisol, maternal pregnancy-related anxiety could be a target of future intervention efforts., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Gestational diabetes mellitus (GDM) is defined as impaired glucose tolerance in pregnancy and without a history of diabetes mellitus. While there are limited metabolomic studies involving advanced maternal age in China, we aim to investigate the metabolomic profiling of plasma and urine in pregnancies complicated with GDM aged at 35-40 years at early and late gestation., Methods: Twenty normal and 20 GDM pregnant participants (≥ 35 years old) were enlisted from the Complex Lipids in Mothers and Babies (CLIMB) study. Maternal plasma and urine collected at the first and third trimester were detected using gas chromatography-mass spectrometry (GC-MS)., Results: One hundred sixty-five metabolites and 192 metabolites were found in plasma and urine respectively. Urine metabolomic profiles were incapable to distinguish GDM from controls, in comparison, there were 14 and 39 significantly different plasma metabolites between the two groups in first and third trimester respectively. Especially, by integrating seven metabolites including cysteine, malonic acid, alanine, 11,14-eicosadienoic acid, stearic acid, arachidic acid, and 2-methyloctadecanoic acid using multivariant receiver operating characteristic models, we were capable of discriminating GDM from normal pregnancies with an area under curve of 0.928 at first trimester., Conclusion: This study explores metabolomic profiles between GDM and normal pregnancies at the age of 35-40 years longitudinally. Several compounds have the potential to be biomarkers to predict GDM with advanced maternal age. Moreover, the discordant metabolome profiles between the two groups could be useful to understand the etiology of GDM with advanced maternal age., (© 2022. The Author(s).)

Background/objective: Prevalence of pre-pregnancy obesity and excessive gestational weight gain (GWG) are higher among women of color with low SES. Dysregulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis and its end-product, cortisol, during pregnancy is hypothesized to be associated with excessive GWG. However, past studies have produced inconsistent findings and often did not include health disparities populations. This study examined the association between pre-pregnancy body mass index (BMI), third trimester diurnal cortisol, and GWG in low-income, predominantly Hispanic women., Subjects/methods: The MADRES study is an ongoing prospective cohort study of primarily Hispanic, low-income pregnant women and their children in Los Angeles, California. Data from 176 participants were included in this study. Total cortisol secretion (area under the curve, AUC) was quantified using four salivary cortisol samples (awakening, 30 min after awakening, afternoon, and bedtime) that were collected at home on one day during the third trimester of pregnancy. Moderation of the association between total cortisol and GWG by pre-pregnancy BMI was tested using multiple linear regression with a multiplicative interaction term., Results: There was no association between total cortisol secretion and GWG overall (p = 0.82), but the association between total cortisol and GWG was stronger for women with class 1 pre-pregnancy obesity compared to women with normal pre-pregnancy BMI (interaction term p = 0.04)., Conclusions: Results suggest that obesity status before pregnancy may be exacerbating the physiological impact of cortisol on GWG., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: To explore the migration process of the conus medullaris (CM) and propose a normal range of CM levels during the third trimester., Method: We retrospectively collected the ultrasonographic and clinical data of 588 fetuses during the third trimester. We located the CM and assigned scores. One-way analysis of variance and linear regression analyses were used to statistically analyze CM migration. Statistical significance was set at p < 0.05., Results: The CM levels were statistically different among the different gestational weeks of the third trimester. The CM level showed a linear regression correlation with the gestational weeks. On an average, the CM migrated from the top third of the L2 vertebra to the L1/2 intervertebral disc level., Conclusion: The CM continues to migrate, from the top third of the L2 vertebra to the L1/2 intervertebral disc level, during the third trimester. The term infant could have the CM at the normal adult level at birth. At the beginning of the third trimester, a CM located above the L2/3 intervertebral disc level could be normal; the CM location at the L3 vertebra level could be physiological and needs follow-up; and a CM presenting below the L3 vertebra level might indicate tethered cord syndrome. The fetus with a CM significantly above the L1/2 intervertebral disc level may have caudal regression syndrome., (© 2021 John Wiley & Sons Ltd.)

Neutrophils are activated and extensively infiltrate blood vessels in preeclamptic women. To identify genes that contribute to neutrophil activation and infiltration, we analyzed the transcriptomes of circulating neutrophils from normal pregnant and preeclamptic women. Neutrophils were collected at 30 weeks' gestation and RNA and DNA were isolated for RNA sequencing and 5-hydroxy-methylcytosine (5-hmC) sequencing as an index of dynamic changes in neutrophil DNA methylation. Women with normal pregnancy who went on to develop mild preeclampsia at term had the most uniquely expressed genes (697) with 325 gene ontology pathways upregulated, many related to neutrophil activation and function. Women with severe preeclampsia who delivered prematurely had few pathways up- or downregulated. Cluster analysis revealed that gene expression in women with severe preeclampsia was an inverse mirror image of gene expression in normal pregnancy, while gene expression in women who developed mild preeclampsia was remarkably different from both. DNA methylation marks, key regulators of gene expression, are removed by the action of ten-eleven translocation (TET) enzymes, which oxidize 5-methylcytosines (5mCs), resulting in locus-specific reversal of DNA methylation. DNA sequencing for 5-hmC revealed no differences among the three groups. Genome-wide DNA methylation revealed extremely low levels in circulating neutrophils suggesting they are de-methylated. Collectively, these data demonstrate that neutrophil gene expression profiles can distinguish different preeclampsia phenotypes, and in the case of mild preeclampsia, alterations in gene expression occur well before clinical symptoms emerge. These findings serve as a foundation for further evaluation of neutrophil transcriptomes as biomarkers of preeclampsia phenotypes. Changes in DNA methylation in circulating neutrophils do not appear to mediate differential patterns of gene expression in either mild or severe preeclampsia.

In this study, we aimed to analyse the clinical features of the third-trimester pregnant women, with echogenic amniotic fluid and to compare their obstetric and neonatal outcomes with pregnant women with normal amniotic fluid echogenicity. This case-control study was conducted in a tertiary antenatal care centre. A total of 560 term (37-42 weeks of gestation) singleton women; 280 with echogenic particles in amniotic fluid and 280 with clear amniotic fluid, who delivered within 24 h after the ultrasound scan were evaluated. The women in the two groups were similar in terms of age, parity, body mass index, foetal birth weight, and gestational age. More patients in the particulate amnion group had lower Apgar scores (<7) in 1st and 5th minutes than controls ( p  = .006, p  = .031 respectively) however the rate of admission to neonatal intensive care was similar. Vernix stained amniotic fluid was more common in the study group (48.8%, p  = .031), the rate of meconium-stained amniotic fluid was similar in the study and control groups (9.6-9.2%, p  = .881). The primary caesarean section rate was higher in women with particulate amnion (18.4%, p  = .037). Echogenic particles in the amniotic fluid in the third trimester could not be attributed to meconium, however, higher rates of primary caesarean section may require further attention.IMPACT STATEMENT What is already known on this subject? Previous studies showed that high-density intra-amniotic particles were possibly related to vernix caseosa, intra-amniotic bleeding, and meconium. The number of study groups in these studies was also limited. What do the results of this study add? Additional to other previous studies, we found an increased rate of intra-amniotic echogenic particles in male foetuses. What are the implications of these findings for clinical practice and/or further research? The presence of echogenic particles on ultrasound was not related to increased risk for the presence of meconium. Significantly more neonates born to mothers with intra-amniotic echogenic particles tended to have lower Apgar scores (<7), however, this significant difference did not affect the need for NICU admission. The presence of echogenic particles in the amniotic fluid of the third-trimester pregnant women could not be attributed to meconium and adverse perinatal outcomes, however, the higher rates of primary caesarean section may require further attention.

Objective: To investigate the predictive value of pre-induction digital examination, sonographic measurements and parity for the prediction of non-reassuring fetal status and cord arterial pH < 7.2 prior to the induction of labor (IOL)., Method: This was a prospective observational study, including 384 term pregnancies undergoing IOL. Before the IOL, the Bishop score (BS) by digital examination, sonographic Doppler parameters and the estimated fetal weight (EFW) was assessed. The fetal cord arterial was sampled to measure the pH at delivery. Multivariate logistic regression analysis was performed to identify independent predictors of non-reassuring fetal status and low cord arterial pH., Results: Forty four cases (11.5%) had non-reassuring fetal status, and 76 cases (19.8%) had fetal cord arterial pH < 7.2. In the non-reassuring fetal status group, the incidence of cord arterial pH < 7.2 was significantly higher than that in the normal fetal heart rate group (χ 2  = 6.401, p = 0.011). Multivariate analysis indicated that significant independent predictors of non-reassuring fetal status were nulliparity (adjusted odds ratio [AOR]: 3.746, p = 0.003), EFW < 10 th percentile (AOR: 3.764, p = 0.003) and cerebroplacental ratio (CPR) < 10 th centile (AOR:4.755, p < 0.001). In the prediction of non-reassuring fetal status, the performance of the combination of nulliparity and EFW < 10th percentile was improved by the addition of CPR < 10th percentile (AUC: 0.681, (95%CI: 0.636 to 0.742) vs 0.756, (95%CI:0.713 to 0.795)), but the difference was not significant (DeLong test: z = 1.039, p = 0.053).. None of the above variables were predictors of cord arterial pH < 7.2., Conclusion: The risk of fetal acidosis has increased in cases of non-reassuring fetal status. Nulliparity, small for gestational age and CPR < 10th centile are independent predictors for non-reassuring fetal status in term fetuses, though the addition of CPR < 10th centile could not significantly improve the screening accuracy.

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., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2021. Published by Elsevier B.V.)

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.

Introduction: Lysophosphatidylcholine Acyltransferase 1 (LPCAT1) is necessary for surfactant production in fetal lungs. Mechanisms responsible for its regulation during gestation remain to be elucidated. Our goal is to evaluate molecular mechanisms regulating LPCAT1 expression during gestation and after glucocorticoid administration., Methods: Placentas throughout gestation were assayed for LPCAT1 protein levels. A placental cell line, HTR-8/SVneo (HTR), was used as a model to test the effects of placental oxygen tension found during pregnancy as well as the effects of dexamethasone used therapeutically in the clinic., Results: LPCAT1 protein levels are maximal in late third trimester placental samples and are expressed strongly on the basal plate. LPCAT1 was maximally upregulated at 4% O 2 (P < 0.01), corresponding to oxygen tension found in placenta at term. Mitochondrial nuclear retrograde regulator 1 (MNRR1), a bi-organellar (mitochondria and nucleus) regulator, transcriptionally activates LPCAT1. Antenatal corticosteroids (ACS) upregulate LPCAT1, at least in part, by an MNRR1-dependent pathway. HTR cells treated with 25 nM dexamethasone for 24 h exhibited a 2-fold increase in LPCAT1 levels compared to controls. In MNRR1 knockout cells, the response to ACS is significantly blunted., Discussion: LPCAT1 appears to be induced by MNRR1. Hypoxia and corticosteroids increase LPCAT1 expression through an MNRR1 dependent pathway. LPCAT1 protein levels can be measured in maternal plasma and rise throughout gestation and in response to ACS., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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 (PM 2.5 ), nitrogen dioxide (NO 2 ) 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 NO 2 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 .

Premature rupture of membranes (PROM) is usually associated with pregnant and neonatal complications. Most of the PROM cases are caused by ascending asymptomatic genital infection. In China, PROM (15.3%) is more common than spontaneous preterm labor (7.3%) and leads to more adverse pregnancy outcomes. Here, we designed a prospective cohort study to measure the metabolomics changes in vaginal swab samples and explored their potential contribution to PROM. A total of 260 differentially expressed metabolites were identified and further analyzed. In the PROM group, N-acetyl-D-galactosamine and sucrose were downregulated (P = 0.0025, P = 0.0195, respectively), both of which are the upstream metabolites of the glycolysis pathway. Furthermore, estriol 3-sulfate 16-glucuronide (P = 0.0154) and 2-methoxy-17beta-estradiol 3-glucosiduronic acid (P = 0.004), two final metabolites in steroid hormone biosynthesis, were both downregulated in the PROM group. Finally, we found two catechin metabolites (epigallocatechin-7-glucuronide, P = 0.0009; 4'-methyl-epigallocatechin-7-glucuronide, P = 0.01) as well as DL-citrulline (P = 0.0393) were also significantly downregulated in the PROM group compared with the healthy control (HC) group, which are related to important antioxidant and anti-inflammatory activities in the human body. Altogether, metabolite changes in glycolysis, steroid hormone biosynthesis, and antioxidant/anti-inflammatory pathways may contribute to (or be a consequence of) vaginal dysbiosis and PROM. Metabolite pathway analysis is a new and promising approach to further investigate the mechanism of PROM and help prevent its unfavorable pregnant outcomes at a functional level. Trial registration number: ChiCTR2000034721.

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., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Introduction: Inverted discordant p57 expression in chorionic villi, characterized by a loss of nuclear staining in cytotrophoblast with retained staining in villous stromal cells, is rarely described. Following an incidental finding of such peculiar staining pattern in rare clusters of dysmorphic chorionic villi (DCV) in a perinatal autopsy case, we reviewed our archived cases of third trimester placentas with DCV to systematically analyze these curious foci., Methods: Histopathological features and p57 expression of 26 placentas with DCV were carefully studied by light microscopy and p57 immunohistochemistry. p57 pattern of expression was correlated with a comprehensive list of maternal, fetal, and placental features to reveal potential associations., Results: Inverted discordant p57 expression was observed in 17/26 (65.4%) cases, encompassing all cases with aberrant p57 immunostaining in this series. Among the many features investigated, only the focality (occurring as a single focus) of DCV (Fisher's exact test, p = 0.008) and small cluster size of ≤30 villi (Fisher's exact test, p = 0.034) correlated significantly with inverted discordant p57 staining. Other common features of DCV with inverted discordant p57 expression include larger villous size compared with surrounding tertiary villi (13/17, 76.4%), prominent but not hyperplastic and focally to moderately hyperplastic syncytiotrophoblast (17/21, 80.9%), abnormal shapes/irregular contours (17/22, 77.3%), and markedly hypovascular villous stroma (11/17, 64.7%). No distinctive maternal or fetal features were observed., Discussion: Inverted discordant p57 expression in DCV of third trimester placentas is likely underreported, and might not be an unusual occurrence outside of suspected molar specimens., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The developmental origin of health and diseases theory supports the critical role of the fetal exposure to children's health. We developed a physiologically based pharmacokinetic model for human pregnancy (pPBPK) to simulate the maternal and fetal dosimetry throughout pregnancy. Four models of the placental exchanges of chemicals were assessed on ten chemicals for which maternal and fetal data were available. These models were calibrated using non-animal methods: in vitro (InV) or ex vivo (ExV) data, a semi-empirical relationship (SE), or the limitation by the placental perfusion (PL). They did not impact the maternal pharmacokinetics but provided different profiles in the fetus. The PL and InV models performed well even if the PL model overpredicted the fetal exposure for some substances. The SE and ExV models showed the lowest global performance and the SE model a tendency to underprediction. The comparison of the profiles showed that the PL model predicted an increase in the fetal exposure with the pregnancy age, whereas the ExV model predicted a decrease. For the SE and InV models, a small decrease was predicted during the second trimester. All models but the ExV one, presented the highest fetal exposure at the end of the third trimester. Global sensitivity analyses highlighted the predominant influence of the placental transfers on the fetal exposure, as well as the metabolic clearance and the fraction unbound. Finally, the four transfer models could be considered depending on the framework of the use of the pPBPK model and the availability of data or resources to inform their parametrization., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Proton magnetic resonance spectroscopy ( 1 H-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 1 H-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 ​ms and analyzed in LCModel., Results: We successfully acquired and analyzed fetal 1 H-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., Competing Interests: Declaration of competing interest All authors declare no competing financial interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aim: Poor glucose control is associated with adverse outcomes in pregnancies with pre-existing diabetes. However, strict glucose control increases the risk of severe hypoglycaemia, particularly in the first trimester. Therefore, we aimed to investigate whether less tight glucose control in the first trimester determines adverse outcomes or can be compensated for by good control in late pregnancy., Methods: Retrospective data were collected from 517 singleton pregnancies complicated by pre-existing diabetes delivering between 2010 and 2017. Three hundred and thirty-six pregnancies fulfilled the inclusion criteria of having available HbA 1c values either pre-conception or in the first trimester (65% type 1 diabetes, 35% type 2 diabetes)., Results: Higher HbA 1c values in the first trimester were associated with increasing rates of large for gestational age (LGA) neonates, preterm delivery or neonatal intensive care unit admissions. Multiple regression analysis demonstrated third trimester HbA 1c , type 1 diabetes, multiparity and excess weight gain, but not first trimester HbA 1c , to be independently predictive for LGA. Pre-eclampsia and third trimester HbA 1c increased the risk for preterm delivery. If HbA 1c was ≤ 42 mmol/mol (6.0%) in the third trimester, rates of adverse outcomes were not significantly higher even if HbA 1c targets of ≤ 48 mmol/mol (6.5%) had not been met in the first trimester. Good first trimester glucose control did not modify the rates of adverse outcomes if HbA 1c was > 42 mmol/mol (6.0%) in the third trimester., Conclusions: Less tight glycaemic control, for example due to high frequency of severe hypoglycaemia in the first trimester, does not lead to increased adverse neonatal events if followed by tight control in the third trimester. Besides glycaemic control, excess weight gain is a modifiable predictor of adverse outcome., (© 2020 Diabetes UK.)

The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for amoxicillin for non-pregnant, pregnant and postpartum populations by compiling a database incorporating reported changes in the anatomy and physiology throughout the postpartum period. A systematic literature search was conducted to collect data on anatomical and physiological changes in postpartum women. Empirical functions were generated describing the observed changes providing the basis for a generic PBPK framework. The fraction unbound ([Formula: see text]) of predominantly albumin-bound drugs was predicted in postpartum women and compared with experimentally observed values. Finally, a specific amoxicillin PBPK model was newly developed, verified for non-pregnant populations and translated into the third trimester of pregnancy (29.4-36.9 gestational weeks) and early postpartum period (drug administration 1.5-3.8 h after delivery). Pharmacokinetic predictions were evaluated using published clinical data. The literature search yielded 105 studies with 1092 anatomical and physiological data values on 3742 postpartum women which were used to generate various functions describing the observed trends. The [Formula: see text] could be adequately scaled to postpartum women. The pregnancy PBPK model predicted amoxicillin disposition adequately as did the postpartum PBPK model, although clearance was somewhat underestimated. While more research is needed to establish fully verified postpartum PBPK models, this study provides a repository of anatomical and physiological changes in postpartum women that can be applied to future modeling efforts. Ultimately, structural refinement of the developed postpartum PBPK model could be used to investigate drug transfer to the neonate via breast-feeding in silico.

We examined the relationships between sleep and inflammatory biomarkers during late pregnancy. Seventy-four women underwent an overnight sleep assessment by polysomnography. Blood samples were collected before bedtime and again within 1 h upon awakening to measure C-reactive protein (CRP), interleukin (IL)-6, and IL-6 soluble receptor. Sleep parameters included variables characterizing sleep architecture and sleep continuity. The participants were 32.2 (SD = 4.1) years old, and the average gestational age was 32.8 (3.5) weeks. Controlling for covariates, evening CRP was negatively associated with N3 sleep (β = -0.30, P = 0.010). N3 sleep was also negatively associated with morning CRP (β = -0.26, P = 0.036), with a higher percentage of N3 sleep associated with a lower level of morning CRP. Contrarily, there was a tendency for a positive association between stage N2 sleep and morning CRP (β = 0.23, P = 0.065). Stage N1 sleep was associated with morning IL-6 (β = 0.28, P = 0.021), with a higher percentage of N1 sleep associated with a higher morning IL-6. No significant associations were found between morning inflammatory biomarkers and sleep continuity parameters. In conclusion, increased light sleep was associated with increased inflammatory biomarkers, whereas more deep sleep was associated with decreased inflammatory biomarkers. These findings further support the interactions between sleep and the immune system during late pregnancy., (© 2020 New York Academy of Sciences.)

Introduction: Preeclampsia (PE) is one of the leading causes of maternal mortality and morbidity worldwide. Recently, the role of epigenetic modifications in preeclampsia has been a focus of research. This study was to identified genes or pathways that may be associated with PE, and discuss whether the changes in the methylation level of these genes is related to the pathogenesis of PE., Methods: The methylation levels of placental tissues between PE (n = 4), preterm birth (PB, n = 4) and term birth (TB, n = 4) were detected by Illumina Infinium HumanMethylation850 K BeadChip. Pyrosequencing and qRT-PCR were used to validated the methylation and expression levels of the genes with the most significant differences., Results: The global methylation levels of placenta tissues in PE and PB were both higher compared to TB. After eliminated the effect of gestational age, there were 808 gene probes differentially methylated in PE compared to PB. We found 137 genes with 130 genes hypermethylated and 7 genes hypomethylated. CMIP, BLCAP and MICA genes were with the most significant differential methylation. The expression level of CMIP and BLCAP were both negatively correlated to the methylation levels, while the expression level of MICA was not related to its methylation levels., Conclusion: The methylation levels in placenta tissues were associated with gestational ages. We indicated the expression levels of the significantly methylated genes were negatively correlated with the methylation levels, further functional researches were still needed to find out whether they are associated with the onset of preeclampsia., Competing Interests: Declaration of competing interest We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2020. Published by Elsevier Ltd.)

Hyperglycemia in pregnancy (HIP) is related to adverse pregnancy outcomes. However, women with hyperglycemia in the second and third trimester of pregnancy (HISTTP) were not been observed. We aim to reveal associations between HISTTP and prematurity. To confirm which risk factor is better in predicting preterm delivery.This retrospective study included 660 patients, of which 132 have HISTTP and 528 have euglycemia. Univariate analysis was used to extract risk factors and multivariates logistic regression analysis to obtain odds ratio (OR) for prematurity. Mean decrease gini (MDG) in random forest algorithm was used to rank the risk factors.HISTTP women have higher prepregnancy BMI and a higher percentage of family history of hypertension, maternal adiposity, maternal anemia, gestational diabetes mellitus (GDM), prematurity, neonatal asphyxia in 1-minute (P < .05). Univariate analysis of prematurity showed that preterm women had higher rate of HISTTP (P < .01), second births, elderly pregnancy, hypertention, family history of hypertention and multiple perinatal infant (P < .05). Multivariate logistic regression analysis indicates that HISTTP (OR = 2.984, P = .0017), maternal hypertension (OR = 5.208, P = .001) and multiple perinatal infants (OR = 59.815, P < .0001) are independent risk factors for prematurity. After ranked the MDG, the top 3 risk factors were multiple perinatal infants, maternal hypertension, HISTTP. MDG of HISTTP is higher than that of GDM.Women with HISTTP deserve to be concerned, whose prematurity rate are increased. HISTTP is an independent risk factor and a better predictor of prematurity.

Purpose: With the wide implementation of the universal two-child policy in China, the number of pregnant women in advanced maternal age (AMA) will increase gradually. We aimed to assess the association between age at menarche (AAM) and insulin resistance (IR) before delivery in AMA. Methods: A total of 80 pregnant women in AMA were consecutively enrolled before delivery in Zhongda hospital. Pregnant women were stratified into early menarche group and late menarche group according to the age of regular menstruation (about 13 years). At delivery, serum glucose and lipid levels were measured. IR was calculated by the method of homeostasis model assessment 2(HOMA2). Results: The fasting blood insulin (17.68(9.72-36.71) and 10.35(7.76-15.10), respectively; p  = .006) and HOMA-IR (2.08(1.18-4.37) and 1.24(0.89-1.78), respectively; p  = .005) were higher in early menarche group than in late menarche group. AAM was inversely associated with HOMA-IR in AMA ( r = -0.27, p  = .014). In the multivariable analysis, AAM in late menarche group was negatively related to the level of HOMA-IR compared to those in early menarche group ( β = -2.275, p ≤.0001). Conclusions: Taken together, our findings suggest that AAM was inversely associated with HOMA-IR in AMA. Furthermore, pregnant women in AMA with early menarche might have higher HOMA-IR levels than those with late menarche. Clinical trial registration: Chinese Clinical Trial Registry (No. ChiCTR-RRC-16008714), retrospectively registered.

Context: Across pregnancy, maternal serum cortisol levels increase up to 3-fold. It is not known whether maternal peripheral cortisol metabolism and clearance change across pregnancy or influence fetal cortisol exposure and development., Objectives: The primary study objective was to compare maternal urinary glucocorticoid metabolites, as markers of cortisol metabolism and clearance, between the second and third trimester of pregnancy. Secondary objectives were to test associations of total maternal urinary glucocorticoid excretion, with maternal serum cortisol levels and offspring birth weight z score., Design, Participants, and Setting: A total of 151 women with singleton pregnancies, recruited from prenatal clinic at the Pittsburgh site of the Measurement of Maternal Stress (MOMS) study, had 24-hour urine collections during both the second and third trimesters., Results: Between the second and third trimester, total urinary glucocorticoid excretion increased (ratio of geometric means [RGM] 1.37, 95% CI 1.22-1.52, P < .001), and there was an increase in calculated 5β-reductase compared to 5α-reductase activity (RGM 3.41, 95% CI 3.04-3.83, P < .001). During the third trimester total urinary glucocorticoid excretion and serum cortisol were negatively correlated (r = -0.179, P = .029). Mean total urinary glucocorticoid excretion across both trimesters and offspring birth weight z score were positively associated (β = 0.314, P = .001)., Conclusions: The estimated activity of maternal enzymes responsible for cortisol metabolism change between the second and third trimester of pregnancy. Additionally, maternal peripheral metabolism and clearance of cortisol may serve as a novel mechanism affecting fetal cortisol exposure and growth., (Published by Oxford University Press on behalf of the Endocrine Society 2020.)

Gestational diabetes mellitus (GDM) is a world-wide health challenge, which prevalence is expected to increase in parallel to the epidemic of obesity. Children born from GDM mothers have lower levels of docosahexaenoic acid (DHA) in cord blood, which might influence their neurodevelopment. Recently, the membrane transporter Major Family Super Domain 2a (MFSD2a) was associated with the selective transportation of DHA as lysophospholipids. The expression of the DHA membrane transporter MFSD2a is lower in GDM placentas, which could affect materno-fetal DHA transport. Humans with homozygous inactivating mutations in the MFSD2a gene present severe microcephaly and intellectual impairments. Herein, we intended to identify early blood biomarkers that may be of use during pregnancy to monitor the offspring development and the adequate nutritional interventions, such as nutritional supplementation, that may be selected to improve it. We evaluated MFSD2a expression in maternal blood at the third trimester of pregnancy, and its potential relationship with the expression of placental MFSD2a at delivery and child outcomes. Three groups of pregnant women were recruited: 25 controls, 23 GDM with dietary treatment, and 20 GDM with insulin treatment. Maternal and neonatal anthropometric and biochemical parameters were evaluated. MFSD2a was analyzed in placenta, blood and serum. MFSD2a protein expression in maternal blood was significantly lower in GDM groups and correlated with placental MFSD2a and Z-score neonatal head circumference during the first 6 months of life. The cord/maternal serum ratio of DHA, a solid indicator of materno-fetal DHA transport, was reduced in GDM groups and correlated with MFSD2a in maternal blood at the third trimester and in placenta at delivery. This indicates that altered MFSD2a levels in maternal blood during pregnancy might influence placental nutrient transport and fetal neurodevelopment. Furthermore, MFSD2a levels in maternal blood on the third trimester were inversely correlated to DHA in maternal serum lyso-PL. Thus, the level of MFSD2a in maternal blood could be used as a potential biomarker for the early detection of disturbances of MFSD2a expression during pregnancy and the subsequent consequences for the neurodevelopment of the child, as well as it may help to choose the optimal treatment approach for the affected subjects., (Copyright © 2020 Sánchez-Campillo, Ruiz-Palacios, Ruiz-Alcaraz, Prieto-Sánchez, Blanco-Carnero, Zornoza, Ruiz-Pastor, Demmelmair, Sánchez-Solís, Koletzko and Larqué.)

Introduction: Macrophages participate in the regulation immune and morphogenetic events in the placenta. However, these roles remain unclear for placental macrophages (Hofbauer cells). The aims of this study were to characterize the consecutive steps of cytokine production (intracellular synthesis and secretion) in placental macrophages in early and late gestation and to compare the secretory profiles of placental macrophages and villous tissue., Methods: Macrophages and villous tissue were isolated from placentas obtained from normal pregnancies at either 9-12 or 38-40 weeks of gestation. Intracellular cytokines were determined by flow cytometry after staining with monoclonal antibodies. Secreted cytokines were quantified by cytometric bead array and ELISA., Results: Two patterns of cytokine production were revealed in placental macrophages. Cytokines in the first group (IL-1, IL-6, IL-8, IL-10, TNFα) demonstrated low basal production and were stimulated by bacterial endotoxin. Cytokines in the second group (IL-11, IL-17A, IL-17F, TGF-β, VEGF) were characterized by constitutive production and did not respond to stimulation. Gestational age-dependent changes were observed: basal secretion of TNFα and IL-8 increased whereas IL-11 and IL-17 secretion decreased in third-trimester macrophages compared with the first-trimester cells. Comparison of cytokine production at the cellular and tissue levels suggested the contribution of the placental macrophages both in intraplacental and extraplacental cytokine production., Discussion: It would be safe to assume that the two patterns of cytokine production, revealed in our study, correspond to two regulatory roles of placental macrophages: "immune" and "morphogenetic". The inflammatory phenotype of macrophages is attenuated in early gestation and increases with the progression of pregnancy. The cytokines of the first group supposedly contribute to both local and extraplacental levels, whereas the cytokine effects of the second group are more likely confined to the placental tissue., Competing Interests: Declaration of competing interest The authors do not have any conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Creatine is a metabolite important for cellular energy homeostasis as it provides spatio-temporal adenosine triphosphate (ATP) buffering for cells with fluctuating energy demands. Here, we examined whether placental creatine metabolism was altered in cases of early-onset pre-eclampsia (PE), a condition known to cause placental metabolic dysfunction. We studied third trimester human placentae collected between 27-40 weeks' gestation from women with early-onset PE ( n = 20) and gestation-matched normotensive control pregnancies ( n = 20). Placental total creatine and creatine precursor guanidinoacetate (GAA) content were measured. mRNA expression of the creatine synthesizing enzymes arginine:glycine aminotransferase ( GATM ) and guanidinoacetate methyltransferase ( GAMT ), the creatine transporter ( SLC6A8 ), and the creatine kinases (mitochondrial CKMT1A & cytosolic BBCK ) was assessed. Placental protein levels of arginine:glycine aminotransferase (AGAT), GAMT, CKMT1A and BBCK were also determined. Key findings; total creatine content of PE placentae was 38% higher than controls ( p < 0.01). mRNA expression of GATM (p < 0.001), GAMT (p < 0.001), SLC6A8 (p = 0.021) and BBCK (p < 0.001) was also elevated in PE placentae. No differences in GAA content, nor protein levels of AGAT, GAMT, BBCK or CKMT1A were observed between cohorts. Advancing gestation and birth weight were associated with a down-regulation in placental GATM mRNA expression, and a reduction in GAA content, in control placentae. These relationships were absent in PE cases. Our results suggest PE placentae may have an ongoing reliance on the creatine kinase circuit for maintenance of cellular energetics with increased total creatine content and transcriptional changes to creatine synthesizing enzymes and the creatine transporter. Understanding the functional consequences of these changes warrants further investigation., Competing Interests: The authors declare no conflict of interest.

Raltegravir (RAL) is a HIV-integrase inhibitor recommended for treatment of HIV type 1 infection during pregnancy. The elimination of RAL to RAL glucuronide (RAL GLU) is mediated primarily by UDP glucuronosyltransferase 1A1 (UGT1A1). The present study shows the development and validation of 4 different methods for the analysis of RAL and RAL GLU in plasma and in urine samples. The methods were applied to evaluate the maternal-fetal pharmacokinetics of RAL and RAL GLU in a HIV-infected pregnant woman receiving RAL 400 mg twice daily. The sample preparation for RAL and RAL GLU analysis in 25 μL plasma and 100 μL diluted urine (10-fold with water containing 0.1% formic acid) were carried out by protein precipitation procedure. RAL and RAL GLU generate similar product mass fragments and require separation in the chromatographic system, so a suitable resolution was achieved for unchanged RAL and RAL GLU employing Ascentis Express C18 (75 × 4.6 mm, 2.7 μm) for both plasma and urine samples. The methods showed linearities at the ranges of 0.1-13.5 μg/mL RAL and 0.15-19.5 μg/mL RAL GLU in urine and 10-2000 ng/mL RAL and 2.5-800 RAL GLU in plasma. Precise and accurate evaluation showed coefficients of variation and relative errors ≤ 15%. The methods have been successfully applied in a maternal-fetal pharmacokinetic study., (Copyright © 2019. Published by Elsevier B.V.)

Objectives: We aimed to demonstrate cell-cell adhesion and apoptotic changes in preeclamptic placentas by examining the expression of CD44 and IL-10., Material and Methods: Placenta samples of 15 preeclamptic and 15 healthy 35-38th week-pregnant women were involved in the study. Tissue samples were taken only from the maternal side of the placenta and fixed in 10% formaldehyde, then blocked in paraffin wax and 5 μm-thick sections were cut and stained with Masson Trichrome. Antigen retrieval was performed for sections, incubated with CD44 antibody and anti-IL-10 antibody. After the application of streptavidin peroxidase followed by AEC chromogen solution, sections were counterstained with Mayer hematoxylin., Results: In the preeclampsia group, increased CD44 positive expression was observed in maternal decidua cells and fibroblast cells close to root villi. CD44 was positively expressed in muscle cells around the blood vessels, mucosal connective tissue areas, syncytial nodes, and syncytial bridges. In the preeclampsia group, significant increased IL-10 expression was seen in subendothelial layers of the medium-sized vessels in the maternal region. IL-10 was also positively expressed in decidua cells outside the vessels, and inflamed connective tissue areas, chorionic villus cells with intense inflammation in intervillous spaces., Conclusions: CD44 was found to be an essential molecule in the regulation of vascular permeability, inflammatory response, activation of the cells, cell-to-cell interaction, and the signaling pathways to which they are associated. Since IL-10 regulates appropriate pregnancy outcomes and contributes to the balance of anti-inflammatory signals via both paracrine and autocrine regulators of trophoblast activity, we proposed that it might be a key to elucidate the etiology of preeclampsia with CD44 receptor.

Background and Objective: Little is known about acetaminophen (paracetamol) pharmacokinetics during pregnancy. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict acetaminophen pharmacokinetics throughout pregnancy., Methods: PBPK models for acetaminophen and its metabolites were developed in non-pregnant and pregnant women. Physiological and enzymatic changes in pregnant women expected to impact acetaminophen pharmacokinetics were considered. Models were evaluated using goodness-of-fit plots and by comparing predicted pharmacokinetic profiles with in vivo pharmacokinetic data. Predictions were performed to illustrate the average concentration at steady state (C ss,avg ) values, used as an indicator for efficacy, of acetaminophen achieved following administration of 1000 mg every 6 h. Furthermore, as a measurement of potential hepatotoxicity, the molar dose fraction of acetaminophen converted to N-acetyl-p-benzoquinone imine (NAPQI) was estimated., Results: PBPK models successfully predicted the pharmacokinetics of acetaminophen and its metabolites in non-pregnant and pregnant women. Predictions resulted in the lowest C ss,avg in the third trimester (median [interquartile range]: 4.5 [3.8-5.1] mg/L), while C ss,avg was 6.7 [5.9-7.4], 5.6 [4.7-6.3], and 4.9 [4.1-5.5] mg/L in non-pregnant, first trimester, and second trimester populations, respectively. Assuming a constant raised cytochrome P450 2E1 activity throughout pregnancy, the molar dose fraction of acetaminophen converted to NAPQI was highest during the first trimester (median [interquartile range]: 11.0% [9.1-13.4%]), followed by the second (9.0% [7.5-11.0%]) and third trimester (8.2% [6.8-10.1%]), compared with non-pregnant women (7.7% [6.4-9.4%])., Conclusion: Acetaminophen exposure is lower in pregnant than in non-pregnant women, and is related to pregnancy duration. Despite these findings, higher dose adjustments cannot be advised yet as it is unknown whether pregnancy affects the toxicodynamics of NAPQI. Information on glutathione abundance during pregnancy and NAPQI in vivo data are required to further refine the presented model.

Background: Several factors can influence the production of mothers' own milk., Purpose: To assess the influence of maternal psychological stress, maternal cortisol levels, and neonatal hair cortisol levels on timing of secretory activation., Methods: A prospective study was conducted at 2 public health centers in Andalusia, Spain. Participants were 60 pregnant women and their 60 neonates. Hair cortisol levels and psychological stress (pregnancy-specific stress [Prenatal Distress Questionnaire, PDQ] and perceived stress [Perceived Stress Scale, PSS]) were evaluated during the third trimester and the postpartum period. This study was part of the GESTASTRESS cohort study on the effects of stress during pregnancy., Results: Higher PDQ and PSS scores (P < .05) in the third trimester were associated with later onset of secretory activation. Higher postpartum maternal hair cortisol levels were associated with a delayed secretory activation of mother's own milk (P < .05)., Implications for Research: Future studies should look at the influence of psychological stress and cortisol levels on hormones involved in mother's own milk production., Implications for Practice: Neonatal nurses and other healthcare providers should be familiar with levels of neonates' exposure to maternal prenatal stress prior to birth.

Introduction: Pregnancy-induced increases in nicotine metabolism may contribute to difficulties in quitting smoking during pregnancy. However, the time course of changes in nicotine metabolism during early and late pregnancy is unclear. This study investigated how pregnancy alters the nicotine metabolite ratio (NMR), a common biomarker of nicotine metabolism among nonpregnant smokers., Methods: Urinary NMR (trans-3'-hydroxycotinine [3HC]/cotinine [COT]) was assessed using total (free + glucuronide) and free compounds among women (N = 47) from a randomized controlled trial for smoking cessation who self-reported smoking and provided a urine sample during early pregnancy (M ± SD = 12.5 ± 4.5 weeks' gestation), late pregnancy (28.9 ± 2.0 weeks' gestation), and 6 months postpartum (24.7 ± 1.2 weeks since childbirth). Urine samples were analyzed using liquid chromatography-tandem mass spectrometry and NMR were calculated as Total 3HC/Free COT, Free 3HC/Free COT, and Total 3HC/Total COT., Results: NMR was significantly higher during early and late pregnancy compared to postpartum and significantly increased from early to late pregnancy as measured by Total 3HC/Free COT (0.76, 0.89, 0.60; all p's < .05) and Free 3HC/Free COT (0.68, 0.80, 0.51; all p's < .05). Total 3HC/Total COT did not vary over time (p = .81)., Conclusions: Total 3HC/Free COT and Free 3HC/Free COT increased in the first trimester and continued to increase throughout pregnancy, suggesting a considerable increase in nicotine metabolism over gestation. Future analyses are needed to interpret the changes in NMR in the context of nicotine pharmacokinetics, as well as its impact on changes in smoking behavior and cessation outcomes., Implications: We observed that the NMR was significantly higher as early as 12 weeks' gestation and increased further as a function of gestational age. Among nonpregnant smokers, elevated NMR is associated with smoking phenotypes such as smoking more cigarettes per day and poorer response to nicotine patch; therefore, pregnancy-induced increases in the NMR may contribute to smoking during the first trimester of pregnancy and reducing or quitting smoking may become more challenging as the rate of nicotine metabolism accelerates over the course of pregnancy., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The extent to which the human term fetus utilizes cholesterol released from the placenta has remained elusive. Our aims were to estimate the net mass of cholesterol taken up by the uteroplacental unit, released by the placenta and taken up by the fetus. Thereby we aimed to explore the maternal-fetal cholesterol transfer and hypothesized that maternal levels and uteroplacental uptake were correlated to the fetal uptake of cholesterol., Methods: A cross-sectional in vivo study of 179 fasting, healthy women with uncomplicated singleton pregnancies. Blood flow in the uterine artery (n = 70) and umbilical vein (n = 125) was measured by Doppler ultrasound. Blood samples from the maternal radial artery, antecubital vein and uterine vein, and the umbilical artery and vein were obtained during cesarean section. Cholesterol was determined enzymatically., Results: We found a significant uteroplacental uptake (median [Q1,Q3]) of total (3.50 [-36.8,61.1]) and HDL cholesterol (6.69 [-3.78,17.9]) μmol/min, and a fetal uptake of HDL (8.07 [4.48,12.59]), LDL (5.97 [2.77,8.92]) and total cholesterol (13.2 [8.06,21.58]) μmol/min. Maternal cholesterol levels were not correlated to fetal uptake of cholesterol. There was a correlation between uteroplacental uptake of total (rho 0.35, p 0.003) and LDL cholesterol (rho 0.25, p 0.03) and the fetal uptake of LDL cholesterol from the umbilical circulation. The fetal uptake of cholesterol from HDL was higher than from LDL (p < 0.001)., Conclusion: Fetal cholesterol uptake is independent of maternal cholesterol levels, but related to the uteroplacental uptake of cholesterol from LDL. This suggests that the placenta influences maternal-fetal cholesterol transfer at term., (Copyright © 2019. Published by Elsevier Ltd.)

Study Question: Are higher testosterone levels during pregnancy in women with polycystic ovary syndrome (PCOS) associated with longer offspring anogenital distance (AGD)?, Summary Answer: AGD was similar in 3-month-old children born of mothers with PCOS compared to controls., What Is Known Already: AGD is considered a marker of prenatal androgenization., Study Design, Size, Duration: Maternal testosterone levels were measured by mass spectrometry at Gestational Week 28 in 1127 women. Maternal diagnosis of PCOS before pregnancy was defined according to Rotterdam criteria. Offspring measures included AGD from anus to posterior fourchette (AGDaf) and clitoris (AGDac) in girls and to scrotum (AGDas) and penis (AGDap) and penile width in boys and body composition (weight and BMI SD scores) at age 3 months., Participants/materials, Setting, Methods: The study was part of the prospective study, Odense Child Cohort (OCC), and included mothers with PCOS (n = 139) and controls (n = 1422). The control population included women with regular menstrual cycles (<35 days) before conception and no signs of androgen excess (hirsutism and/or acne)., Main Results and the Role of Chance: AGD measures were comparable in offspring of women with PCOS compared to controls (all P > 0.2) despite significantly higher maternal levels of total testosterone (mean: 2.4 versus 2.0 nmol/l) and free testosterone (mean: 0.005 versus 0.004 nmol/l) in women with PCOS versus controls (both P < 0.001). In women with PCOS, maternal testosterone was an independent positive predictor of offspring AGDas and AGDap in boys. Maternal testosterone levels did not predict AGD in girls born of mothers with PCOS or in boys or girls born of women in the control group., Limitations, Reasons for Caution: The diagnosis of PCOS was based on retrospective information and questionnaires during pregnancy. Women participating in OCC were more ethnically homogenous, leaner, more educated and less likely to smoke compared to the background population. Our study findings, therefore, need to be reproduced in prospective study cohorts with PCOS, in more obese study populations and in women of other ethnicities., Wider Implications of the Findings: Our finding of the same AGD in girls born of mothers with PCOS compared to controls expands previous results of studies reporting longer AGD in adult women with PCOS. Our results suggest that longer AGD in adult women with PCOS could be the result of increased testosterone levels in puberty, perhaps in combination with weight gain., Study Funding/competing Interest(s): Financial grants for the study were provided by the Danish Foundation for Scientific Innovation and Technology (09-067180), Ronald McDonald Children Foundation, Odense University Hospital, the Region of Southern Denmark, the Municipality of Odense, the Mental Health Service of the Region of Southern Denmark, The Danish Council for Strategic Research, Program Commission on Health, Food and Welfare (2101-08-0058), Odense Patient data Explorative Network, Novo Nordisk Foundation (grant no. NNF15OC00017734), the Danish Council for Independent Research and the Foundation for research collaboration between Rigshospitalet and Odense University Hospital and the Health Foundation (Helsefonden). There is no conflict of interest of any author that could be perceived as prejudicing the impartiality of the research reported., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Placental insufficiency contributes to altered maternal-fetal amino acid transfer, and thereby to poor fetal growth. An important placental function is the uptake of tryptophan and its metabolism to serotonin (5-HT) and kynurenine metabolites, which are essential for fetal development. We hypothesised that placental 5-HT content will be increased in pregnancies affected with fetal growth restriction (FGR)., Methods: The components of the 5-HT synthetic pathway were determined in chorionic villus samples (CVS) from small-for gestation (SGA) and matched control collected at 10-12 weeks of human pregnancy; and in placentae from third trimester FGR and gestation-matched control pregnancies using the Fluidigm Biomarker array for mRNA expression, the activity of the enzyme TPH and 5-HT concentrations using an ELISA., Results: Gene expression for the rate limiting enzymes, TPH1 and TPH2; 5-HT transporter, SLC6A4; and 5-HT receptors HTR5A, HTR5B, HTR1D and HTR1E were detected in all CVS and third trimester placentae. No significant difference in mRNA was observed in SGA compared with control. Although there was no significant change in TPH1 mRNA, the mRNA of TPH2 and SLC6A4 was significantly decreased in FGR placentae (p < 0.05), while 5-HT receptor mRNA was significantly increased in FGR compared with control (p < 0.01). Placental TPH enzyme activity was significantly increased with a concomitant increase in the total placental 5-HT concentrations in FGR compared with control., Conclusion: This study reports differential expression and activity of the key components of the 5-HT synthetic pathway associated with the pathogenesis of FGR. Further studies are required to elucidate the functional consequences of increased placental 5-HT in FGR pregnancies., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Creatine is a metabolite involved in cellular energy homeostasis. In this study, we examined placental creatine content, and expression of the enzymes required for creatine synthesis, transport and the creatine kinase reaction, in pregnancies complicated by low birthweight. We studied first trimester chorionic villus biopsies (CVBs) of small for gestational age (SGA) and appropriately grown infants (AGA), along with third trimester placental samples from fetal growth restricted (FGR) and healthy gestation-matched controls. Placental creatine and creatine precursor (guanidinoacetate-GAA) levels were measured. Maternal and cord serum from control and FGR pregnancies were also analyzed for creatine concentration. mRNA expression of the creatine transporter (SLC6A8); synthesizing enzymes arginine:glycine aminotransferase (GATM) and guanidinoacetate methyltransferase (GAMT); mitochondrial (mtCK) and cytosolic (BBCK) creatine kinases; and amino acid transporters (SLC7A1 & SLC7A2) was assessed in both CVBs and placental samples. Protein levels of AGAT (arginine:glycine aminotransferase), GAMT, mtCK and BBCK were also measured in placental samples. Key findings; total creatine content of the third trimester FGR placentae was 43% higher than controls. The increased creatine content of placental tissue was not reflected in maternal or fetal serum from FGR pregnancies. Tissue concentrations of GAA were lower in the third trimester FGR placentae compared to controls, with lower GATM and GAMT mRNA expression also observed. No differences in the mRNA expression of GATM, GAMT or SLC6A8 were observed between CVBs from SGA and AGA pregnancies. These results suggest placental creatine metabolism in FGR pregnancies is altered in late gestation. The relevance of these changes on placental bioenergetics should be the focus of future investigations., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In women with obesity, excess gestational weight gain (≥270 g/week) occurs in two out of three pregnancies and contributes to metabolic impairments in both mother and baby. To improve obstetrical care, objectively assessed information on energy balance is urgently needed. The objective of this study was to characterize determinants of gestational weight gain in women with obesity., Methods: This was a prospective, observational study of pregnant women with obesity. The primary outcome was energy intake calculated by the energy intake-balance method. Energy expenditure was measured by doubly-labeled water and whole-room indirect calorimetry and body composition as 3-compartment model by air displacement plethysmography and isotope dilution in early (13-16 weeks) and late pregnancy (35-37 weeks)., Results: In pregnant women with obesity (n=54), recommended weight gain (n=8, 15%) during the second and third trimesters was achieved when energy intake was 125±52 kcal/d less than energy expenditure. In contrast, women with excess weight gain (67%) consumed 186±29 kcal/d more than they expended (P<0.001). Energy balance affected maternal adiposity (recommended: -2.5±0.8 kg fat mass, excess: +2.2±0.5, inadequate: -4.5±0.5, P<0.001), but not fetal growth. Weight gain was not related to demographics, activity, metabolic biomarkers, or diet quality. We estimated that energy intake requirements for recommended weight gain during the second and third trimesters were not increased as compared to energy requirements early in pregnancy (34±53 kcal/d, P=0.83)., Conclusions: We here provide the first evidence-based recommendations for energy intake in pregnant women with obesity. Contrary to current recommendations, energy intake should not exceed energy expenditure., Funding: This study was funded by the National Institutes of Health (R01DK099175; Redman, U54GM104940 and P30DK072476; Core support)., Trial Registration: clinicaltrials.gov: NCT01954342.

Cannabis is the most commonly used illicit drug among pregnant women. Moreover, over half of pregnant women who are consuming cannabis are also consuming alcohol; however, the consequences of combined prenatal alcohol and cannabis exposure on fetal development are not well understood. The current study examined behavioral development following exposure to ethanol (EtOH) and/or CP-55,940 (CP), a cannabinoid receptor agonist. From postnatal days (PD) 4-9, a period of brain development equivalent to the third trimester, Sprague-Dawley rats received EtOH (5.25 g/kg/day) or sham intubation, as well as CP (0.4 mg/kg/day) or vehicle. All subjects were tested on open field activity (PD 18-21), elevated plus maze (PD 25), and spatial learning (PD 40-46) tasks. Both EtOH and CP increased locomotor activity in the open field, and the combination produced more severe overactivity than either exposure alone. Similarly, increases in thigmotaxis in the Morris water maze were caused by either EtOH or CP alone, and were more severe with combined exposure, although only EtOH impaired spatial learning. Finally, developmental CP significantly increased time spent in the open arms on the elevated plus maze. Overall, these data indicate that EtOH and CP produce some independent effects on behavior, and that the combination produces more severe overactivity in the open field. Importantly, these data suggest that prenatal cannabis disrupts development and combined prenatal exposure to alcohol and cannabis may be particularly damaging to the developing fetus, which has implications for the lives of affected individuals and families and also for establishing public health policy., (© 2019 Wiley Periodicals, Inc.)

Purpose: Bile acids are a group of cholesterol metabolites functioning as key regulators of glucose, lipid, and energy metabolism. Their homeostatic control is essential to the physiology of the normal pregnancy. Abnormalities of bile acids regulation in pregnancy lead to intrahepatic cholestasis of pregnancy, a serious condition associated with a number of fetal and maternal morbidities. Dysregulation of glucose and lipids is also tied to perturbations in bile acid concentrations. Changes in bile acid metabolic profiles in the second and third trimesters of pregnancy have been incompletely explored. We seek to establish pregnancy-specific normative ranges for a number of bile acids in women in the second and third trimesters and explore changes in their concentrations in the period from 12 to 40 weeks gestation., Procedure: In this cross-sectional study, a total of 782 normal pregnant women were enrolled including n = 290 in the second trimester (12-28 weeks) and n = 492 in the third trimester (29-40 weeks). The concentrations of 14 bile acids were measured by liquid chromatography and mass spectrometry (LC-MS) and compared at various time points. Reference intervals of these bile acids were calculated using standard statistical techniques., Results: A reference interval profile of 14 bile acids from a cohort of 782 normal pregnant women was developed. Significant differences in concentration were found between the second trimester and the third trimester. Unconjugated bile acids dominate the bile acid profile in the second trimester, while conjugated bile acids, especially (taurine-conjugated) dominate in the third trimester. 28-31 weeks gestation was the notable change period of bile acid metabolism., Conclusion: This study establishes pregnancy-specific reference intervals for bile acids in the second and third trimesters. As bile acid composition changes with gestational age, this study establishes a foundation for trimester-specific clinical interpretation of bile acid metabolic profiles in pregnant women., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Forkhead box P3 (Foxp3) is necessary for induction of the immunosuppressive functions in regulatory T cells. Recent data indicate that some non-lymphoid cells, such as certain tumor cells, also express Foxp3, which participates in tumorigenesis and is related to the invasive and proliferative behavior of the tumor. However, the expression of Foxp3 in trophoblasts has not been studied previously., Methods: Localization of Foxp3 in the villi and decidua in the first trimester was determined using immunohistochemistry. Foxp3 expression was detected by flow cytometry, and the expression levels in the first trimester placenta were compared with those in the term placenta. Additionally, the Foxp3 expression in trophoblasts in recurrent pregnancy loss (RPL) was analyzed by real-time polymerase chain reaction (RT-PCR), immunohistochemistry and Western blot., Results: Foxp3 is expressed by trophoblasts in early pregnancy in the villi and decidua. Foxp3 is expressed in the nuclei of both trophoblast cell columns and cytotrophoblasts. However, low Foxp3 expression was observed in syncytiotrophoblasts. Foxp3 was also expressed by the extravillous trophoblasts in early pregnancy in decidua. The Foxp3 expression in trophoblasts in the term placenta was significantly decreased compared with that in the normal early pregnancy. Moreover, decreased levels of Foxp3 mRNA and protein were observed in women with RPL., Discussion: The selective expression of Foxp3 in human trophoblasts suggest that Foxp3 expression may be associated with the proliferation and invasion behavior of trophoblasts. The decreased Foxp3 expression in the trophoblasts in RPL may contribute to better understanding of the pathological characteristics of RPL., (Copyright © 2019. Published by Elsevier Ltd.)

Prolonged stress affects the central nervous system, rendering individuals vulnerable to a wide range of mental health disorders. 76 healthy postpartum mothers were studied by means of functional magnetic resonance imaging within 6 days of childbirth. The subjects were required to perform the emotional Stroop task involving happy and anxious word-face combinations. Hair samples were collected to determine cumulative hair cortisol concentration (HCC) in the third trimester. HCC was found to be negatively correlated with the recruitment of the dorsal anterior cingulate cortex (ACC) and the midcingulate cortex (MCC). In response to the emotional interference of only anxious target faces, a negative correlation was seen between HCC and the bilateral orbitofrontal cortex, extending to the rostral ACC and the MCC. Women with lower HCC recruited brain areas relevant to emotional cognitive control, indicating that lower HCC helps preserve conflict monitoring and resolution capacities and thus benefits mental health in pregnancy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The prediction or early diagnosis of maternal complications is challenging mostly because the main conditions, such as preeclampsia, preterm birth, fetal growth restriction, and gestational diabetes mellitus, are complex syndromes with multiple underlying mechanisms related to their occurrence. Limited advances in maternal and perinatal health in recent decades with respect to preventing these disorders have led to new approaches, and "omics" sciences have emerged as a potential field to be explored. Metabolomics is the study of a set of metabolites in a given sample and can represent the metabolic functioning of a cell, tissue or organism. Metabolomics has some advantages over genomics, transcriptomics, and proteomics, as metabolites are the final result of the interactions of genes, RNAs and proteins. Considering the recent "boom" in metabolomic studies and their importance in the research agenda, we here review the topic, explaining the rationale and theory of the metabolomic approach in different areas of maternal and perinatal health research for clinical practitioners. We also demonstrate the main exploratory studies of these maternal complications, commenting on their promising findings. The potential translational application of metabolomic studies, especially for the identification of predictive biomarkers, is supported by the current findings, although they require external validation in larger datasets and with alternative methodologies.

Advanced neuroimaging techniques have improved our understanding of microstructural changes in the preterm supratentorial brain as well as the cerebellum and its association with impaired neurodevelopmental outcomes. However, the metabolic interrogation of the developing cerebellum during the early postnatal period after preterm birth remains largely unknown. Our study investigates the relationship between cerebellar neurometabolites measured by proton magnetic spectroscopy ( 1 H-MRS) in preterm infants with advancing post-menstrual age (PMA) and brain injury during ex-utero third trimester prior to term equivalent age (TEA). We prospectively enrolled and acquired high quality 1 H-MRS at median 33.0 (IQR 31.6-35.2) weeks PMA from a voxel placed in the cerebellum of 53 premature infants born at a median gestational age of 27.0 (IQR 25.0-29.0) weeks. 1 H-MRS data were processed using LCModel software to calculate absolute metabolite concentrations of N-acetylaspartate (NAA), choline (Cho) and creatine (Cr). We noted positive correlations of cerebellar concentrations of NAA, Cho and Cr (Spearman correlations of 0.59, 0.64 and 0.52, respectively, p value < 0.0001) and negative correlation of Cho/Cr ratio (R -0.5, p value 0.0002) with advancing PMA. Moderate-to-severe cerebellar injury was noted on conventional magnetic resonance imaging (MRI) in 14 (26.4%) of the infants and were noted to have lower cerebellar NAA, Cho and Cr concentrations compared with those without injury (p value < 0.001). Several clinical complications of prematurity including necrotizing enterocolitis, systemic infections and bronchopulmonary dysplasia were associated with altered metabolite concentrations in the developing cerebellum. We report for the first time that ex-utero third trimester cerebellar metabolite concentrations are decreased in very preterm infants with moderate-to-severe structural cerebellar injury. We report increasing temporal trends of metabolite concentrations in the cerebellum with advancing PMA, which was impaired in infants with brain injury on MRI and may have early diagnostic and prognostic value in predicting neurodevelopmental outcomes in very preterm infants.

Objective: The aim of study was to conduct immunohistochemical quantification of CD3+ and CD8+ decidual lymphocytes in preeclampsia., Methods: A study group included 30 cases of preeclampsia and a control group included 20 healthy pregnant women, all delivered by Cesarean section. Samples of placental bed were analyzed after immunohistochemical staining of CD45+, CD3+ and CD8+ cells., Results: The group with preeclampsia included a significantly higher number of CD3+ (p < 0.01) and CD8+ (p < 0.05) T lymphocytes., Conclusion: It is certain that thebalance dysregulation of T cell of the immune milieu of deciduais of importance in etiopathogenesis and manifestations of preeclampsia.

Placental mediated fetal growth restriction (FGR) is a leading cause of perinatal morbidity and mortality. Heparan sulphate proteoglycans (HSPG) are highly expressed in placentae and regulate haemostasis. We hypothesise that altered expression of HSPGs, glypicans (GPC) may contribute to the development of FGR and small-for-gestational-age (SGA). GPC expression was determined in first-trimester chorionic villous samples collected from women with later SGA pregnancies and in placentae from third-trimester FGR and gestation-matched uncomplicated pregnancies. The expression of both GPC1 and GPC3 were significantly reduced in first-trimester SGA as well as in the third-trimester FGR placentae compared to controls. This is the first study to report a relationship between altered placental GPC expression and subsequent development of SGA/FGR., (Copyright © 2018. Published by Elsevier Ltd.)