Development Of Fetal Growth Restriction Research Articles

The significance of Syndecan 1, a new marker for endothelial dysfunction, in cases of fetal growth retardation.

In the current study we aimed to investigate Syndecan 1 (SDC1) levels in pregnant women diagnosed with fetal growth restriction (FGR) and the relationship between SDC1 levels and clinical and doppler parameters in FGR cases associated with endothelial dysfunction, angiogenesis and uteroplacental insufficiency METHOD OF STUDY: A total of 90 pregnant women included in the study, (45 with FGR, 45 healthy control) matched by week of gestation and maternal age. Venous blood samples were collected and plasma concentrations of SDC1 were determined by a specific immunoassay. Doppler examination was performed to evaluate the relationship between the SDC1 levels and placental blood supply. Doppler parameters; meanUtA-PI(p <.001), CPR (p=.002) and CPUR (p <.001) were different between the groups, however MCA PI, umbilical artery PI and umbilical artery S/D were not (p>.05). While gestational age at delivery, birth weight, APGAR score at 1 and 5 min were significantly lower (all, p <.001) in the study group, non-reassure fetal heart rate tracing (p=.09) and NICU admission (p=.02) were significantly higher. SDC 1 level was 2,00±1,47ng/mL and 2,34±1,12ng/mL in the FGR and control groups, respectively (p=.008). In the study group SDC 1 level was 1,69±2,00 in those with gestational age below 32weeks and 2,13±1,18 in those with gestational age above 32weeks and there was a statistically significant difference between the groups (p=.015). Plasma SDC 1 concentration of 2,1850ng/mL or less had a sensitivity of 70%, a specificity of 72%, area under the ROC curve.65 (p<.005). Low maternal plasma SDC1 level may be associated with placental insufficiency and FGR. Low levels of SDC1 may be helpful as a predictor for the development of FGR during gestation.

OP15_6. Effect of pentaerythrityltetranitrate (PETN) on the development of fetal growth restriction in pregnancies with impaired uteroplacental perfusion at mid gestation – a double blinded randomised multicentre trial

OP15_6. Effect of pentaerythrityltetranitrate (PETN) on the development of fetal growth restriction in pregnancies with impaired uteroplacental perfusion at mid gestation – a double blinded randomised multicentre trial

Early pregnancy imaging predicts ischemic placental disease

IntroductionTo characterize early-gestation changes in placental structure, perfusion, and oxygenation in the context of ischemic placental disease (IPD) as a composite outcome and in individual sub-groups. MethodsIn a single-center prospective cohort study, 199 women were recruited from antenatal clinics between February 2017 and February 2019. Maternal magnetic resonance imaging (MRI) studies of the placenta were temporally conducted at two timepoints: 14–16 weeks gestational age (GA) and 19–24 weeks GA. The pregnancy was monitored via four additional study visits, including at delivery. Placental volume, perfusion, and oxygenation were assessed at both MRI timepoints. The primary outcome was defined as pregnancy complicated by IPD, with group assignment confirmed after delivery. ResultsIn early gestation, mothers with IPD who subsequently developed fetal growth restriction (FGR) and/or delivered small-for gestational age (SGA) infants showed significantly decreased MRI indices of placental volume, perfusion, and oxygenation compared to controls. The prediction of FGR or SGA by multiple logistic regression using placental volume, perfusion, and oxygenation revealed receiver operator characteristic curves with areas under the curve of 0.81 (Positive predictive value (PPV) = 0.84, negative predictive value (NPV) = 0.75) at 14–16 weeks GA and 0.66 (PPV = 0.78, NPV = 0.60) at 19–24 weeks GA. DiscussionMRI indices showing decreased placental volume, perfusion and oxygenation in early pregnancy were associated with subsequent onset of IPD, with the greatest deviation evident in subjects with FGR and/or SGA. These early-gestation MRI changes may be predictive of the subsequent development of FGR and/or SGA.

An miRNA-mRNA integrative analysis in human placentas and mice: role of the Smad2/miR-155-5p axis in the development of fetal growth restriction.

Introduction: Functional disorder of the placenta is the principal cause of fetal growth restriction (FGR), usually cured with suitable clinical treatment and good nursing. However, some FGR mothers still give birth to small for gestational age (SGA) babies after treatment. The ineffectiveness of treatment in such a group of patients confused physicians of obstetrics and gynecology. Methods: In this study, we performed a microRNA-messenger RNA integrative analysis of gene expression profiles obtained from Gene Expression Omnibus. Differentially expressed genes were screened and checked using quantitative polymerase chain reaction. Target genes of significantly changed microRNA were screened and enriched for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Function of the obtained microRNA-messenger RNA was evaluated using HTR-8/SVneo trophoblast cells, human umbilical vein endothelial cells, and heterozygote male mice. Result: MiR-155-5p was upregulated (p = 0.001, fold-change = 2.275) in fetal-side placentals. Among the hub genes identified as key targets for miR-155-5p in fetal reprogramming, Smad2 was downregulated (p = 0.002, fold change = 0.426) and negatively correlated with miR-155-5p expression levels (r = -0.471, p < 1.0 E - 04) in fetal-side placental tissues. The miR-155-5p mimic blocks Smad2 expression and suppresses villous trophoblast cell and endothelial cell function (proliferation, migration, and invasion), indicating a close relationship with placental development. Luciferase assays further confirmed the targeting of miR-155-5p to Smad2. Furthermore, Smad2+/- heterozygote male mice were born small with low body weight (p = 0.0281) and fat composition (p = 0.013) in the fourth week post-natal. Discussion: We provide the first evidence of the role of the Smad2/miR-155-5p axis in the placental pathologies of FGR. Our findings elucidate the pathogenesis of FGR and provide new therapeutic targets.

Timing of Fetal Growth Restriction Development in Patients With Preeclampsia [ID: 1363469

INTRODUCTION: Preeclampsia (PEC) and fetal growth restriction (FGR) share common pathophysiology of placental insufficiency. In pregnancies complicated by PEC, the incidence of FGR increases significantly. We sought to examine the timing of FGR development in patients with PEC. METHODS: This was a retrospective cohort study of patients with PEC and singleton pregnancy who delivered at 23 weeks or greater. Patients who had been diagnosed with FGR prior to PEC diagnosis, those who were diagnosed with FGR at the same time as PEC, and those who delivered immediately after PEC diagnosis were excluded. Demographics were compared between patients with FGR and those without FGR. We plotted Kaplan-Meier curves for the interval from the diagnosis of PEC to the development of FGR. A Cox proportional hazards model was used to estimate the adjusted hazard ratios (HRs) for FGR. Our IRB approved this analysis. RESULTS: Of 392 patients with PEC, 31 (7.9%) developed FGR. Compared to patients who did not develop FGR, patients who developed FGR were more likely to have early-onset PEC and lower maternal weight and were less likely to have gestational diabetes (P&lt;.05). The incidence rate of FGR increased by 11.6% each week from the PEC diagnosis. Compared to patients with late-onset PEC, those with early-onset PEC had a significantly higher cumulative incidence of FGR (P&lt;.01). The Cox proportional hazards model showed that early-onset PEC was associated with FGR (adjusted HR 4.12, 95% CI 1.19–14.33) compared to late-onset PEC. CONCLUSION: Patients with early-onset PEC had a significantly higher incidence of FGR compared to those with late-onset PEC. There was a high cumulative incidence rate of FGR in patients with early-onset PEC. Patients with PEC should be followed by serial fetal growth ultrasound.

Integrated Bioinformatics Analysis to Screen Hub Gene Signatures for Fetal Growth Restriction.

Fetal growth restriction (FGR) is the impairment of the biological growth potential of the fetus and often leads to adverse pregnancy outcomes. The molecular mechanisms for the development of FGR, however, are still unclear. The purpose of this study is to identify critical genes associated with FGR through an integrated bioinformatics approach and explore the potential pathogenesis of FGR. We downloaded FGR-related gene microarray data, used weighted gene co-expression network analysis (WGCNA), differentially expressed genes (DEGs), and protein-protein interaction (PPI) networks to screen hub genes. The GSE24129 gene set was used for validation of critical gene expression levels and diagnostic capabilities. A weighted gene co-expression network was constructed, and 5000 genes were divided into 12 modules. Of these modules, the blue module showed the closest relationship with FGR. Taking the intersection of the DEGs and genes in the blue module as pivotal genes, 277 genes were identified, and 20 crucial genes were screened from the PPI network. The GSE24129 gene set verified the expression of 20 genes, and CXCL9, CXCR3, and ITGAX genes were identified as actual pivotal genes. The expression levels of CXCL9, CXCR3, and ITGAX were increased in both the training and validation sets, and ROC curve validation revealed that these three pivotal genes had a significant diagnostic ability for FGR. Single-gene GSEA results showed that all three core genes activated "hematopoietic cell lineage" and "cell adhesion molecules" and inhibited the "cGMP-PKG signaling pathway" in the development of FGR. CXCL9, CXCR3, and ITGAX may therefore be closely associated with the development of FGR and may serve as potential biomarkers for the diagnosis and treatment of FGR.

Fetal Growth Restriction Is Associated with Pregnancy Associated Plasma Protein A and Uterine Artery Doppler in First Trimester

Fetal growth restriction (FGR) is a major cause of stillbirth and poor neurodevelopmental outcomes. The early prediction may be important to establish treatment options and improve neonatal outcomes. The aim of this study was to assess the association of parameters used in first-trimester screening, uterine artery Doppler pulsatility index and the development of FGR. In this retrospective cohort study, 1930 singleton pregnancies prenatally diagnosed with an estimated fetal weight under the third percentile were included. All women underwent first-trimester screening assessing maternal serum pregnancy-associated plasma protein A (PAPP-A), free beta-human chorionic gonadotrophin levels, fetal nuchal translucency and uterine artery Doppler pulsatility index (PI). We constructed a Receiver Operating Characteristics curve to calculate the sensitivity and specificity of early diagnosis of FGR. In pregnancies with FGR, PAPP-A was significantly lower, and uterine artery Doppler pulsatility index was significantly higher compared with the normal birth weight group (0.79 ± 0.38 vs. 1.15 ± 0.59, p < 0.001 and 1.82 ± 0.7 vs. 1.55 ± 0.47, p = 0.01). Multivariate logistic regression analyses demonstrated that PAPP-A levels and uterine artery Doppler pulsatility index were significantly associated with FGR (p = 0.009 and p = 0.01, respectively). To conclude, these two parameters can predict FGR < 3rd percentile.

Is the expression of placental epithelial and lymphoid markers associated with the perinatal outcomes in preeclampsia?

This study aimed to investigate the association of the epithelial and lymphoid immune markers with the adverse perinatal conditions such as early-onset preeclampsia (EOPE), fetal growth restriction (FGR) and intrauterine fetal death (IUFD) in preeclampsia in the placentae of preeclamptic patients. A total of 60 pregnant patients were included in this study. The immunohistochemistry method was used to determine the expression levels of CD4, CD8, CD4 / CD8, CD68, P53, MDM2, CK18, CK19, E-cadherin, and β-catenin. In our study, the increase in E-cadherin expression in the preeclamptic fetal-maternal placental region was associated with EOPE and FGR development preeclampsia and the decrease in the expression of CD4 and CD8, which are involved in the local immunomodulation, was associated with IUFD. Our data reveal that the increase in the expression of CK18, CK19, E-cadherin, and β-catenin and the decrease in CD4 and CD8 play a role in the pathogenesis of preeclampsia.

Toxic effects of maternal cadmium exposure on the metabolism and transport system of amino acids in the maternal livers

Fetal growth restriction (FGR) is one of the most common obstetric diseases, and affects approximately 10 % of all pregnancies worldwide. Maternal cadmium (Cd) exposure is one of the factors that may increase the risk of the development of FGR. However, its underlying mechanisms remain largely unknown. In this study, using Cd-treated mice as an experimental model, we analyzed the levels of some nutrients in the circulation and the fetal livers by biochemical assays; the expression patterns of several key genes involved in the nutrient uptake and transport, and the metabolic changes in the maternal livers were also examined by quantitative real-time PCR and gas chromatography-time of flight-mass spectrometry method. Our results showed that, the Cd treatment specifically reduced the levels of total amino acids in the peripheral circulation and the fetal livers. Concomitantly, Cd upregulated the expressions of three amino acid transport genes (SNAT4, SNAT7 and ASCT1) in the maternal livers. The metabolic profiling of maternal livers also revealed that, several amino acids and their derivatives were also increased in response to the Cd treatment. Further bioinformatics analysis indicated that the experimental treatment activated the metabolic pathways, including the alanine, aspartate and glutamate metabolism, valine, leucine and isoleucine biosynthesis, arginine and proline metabolism. These findings suggest that maternal Cd exposure activate the amino acid metabolism and increase the amino acid uptake in the maternal liver, which reduces the supply of amino acids to the fetus via the circulation. We suspect that this underlies the Cd-evoked FGR.

NCOA2-induced secretion of leptin leads to fetal growth restriction via the NF-κB signaling pathway.

Fetal growth restriction (FGR) is one of the most common fetal complications during pregnancy in the obstetrics department, with poor therapeutic efficacy. The local inflammatory response of the placenta has gradually become known as the main mechanism for the occurrence and development of FGR. The aim of this study was to improve the knowledge of placental inflammatory response mechanisms in regulating gene expression. The differentially expressed genes (DEGs) in FGR patients were analyzed through bioinformatics analysis. The expression of gene level was detected by immunohistochemistry (IHC) staining, quantitative polymerase chain reaction (qPCR), or enzyme-linked immunosorbent assay (ELISA). The proliferation, migration, and apoptosis of HTR-8/SVneo trophoblast cells stimulated with lipopolysaccharide (LPS) was performed by Cell Counting Kit-8 (CCK-8) assay, clone formation assay, Transwell assay, and flow cytometry. The mechanisms of gene expression in regulating placental inflammatory response were elucidated by western blotting. Nuclear receptor coactivator 2 (NCOA2) was identified as a very critical gene in the progression of FGR by bioinformatics analysis and the expression of NCOA2 was shown to be down-regulated in FGR patients. Overexpression of NCOA2 promoted the proliferation, migration, and inhibited apoptosis and pro-inflammatory cytokines secretion in HTR-8/SVneo trophoblast cells stimulated with LPS via the nuclear factor (NF)-κB pathway. In addition, leptin was increased in both tissue and peripheral blood samples of FGR patients, and overexpression of NCOA2 inhibited the secretion of leptin in HTR-8/SVneo trophoblast cells stimulated with LPS. All these findings suggest that NCOA2-induced secretion of leptin leads to FGR progression via the NF-κB pathway and provides a clinical therapeutic target in FGR and a potent marker for the identification of FGR.

IL-27 deficiency inhibits proliferation and invasion of trophoblasts via the SFRP2/Wnt/β-catenin pathway in fetal growth restriction.

Background: Fetal growth restriction (FGR) is characterized by restricted fetal growth and dysregulated placental development. The etiology and pathogenesis still remain elusive. IL-27 shows multiple roles in regulating various biological processes, however, how IL-27 involves in placentation in FGR pregnancy hasn't been demonstrated. Methods: The levels of IL-27 and IL-27RA in FGR and normal placentae were determined by immunohistochemistry, western blot and RT-PCR. HTR-8/SVneo cells and Il27ra-/- murine models have been adopted to evaluate the effects of IL-27 on the bio-functions of trophoblast cells. GO enrichment and GSEA analysis were performed to explore the underlying mechanism. Findings: IL-27 and IL-27RA was lowly expressed in FGR placentae and administration of IL-27 on HTR-8/SVneo could promote its proliferation, migration and invasion. Comparing with wildtypes, Il27ra-/- embryos were smaller and lighter, and the placentae from which were poorly developed. In mechanism, the molecules of canonical Wnt/β-catenin pathway (CCND1, CMYC, SOX9) were downregulated in Il27ra-/- placentae. In contrast, the expression of SFRP2 (negative regulator of Wnt) was increased. Overexpression of SFRP2 in vitro could impair trophoblast migration and invasion capacity. Interpretation: IL-27/IL-27RA negatively regulates SFRP2 to activate Wnt/β-catenin, and thus promotes migration and invasion of trophoblasts during pregnancy. However, IL-27 deficiency may contribute to the development of FGR by restricting the Wnt activity.

The Association of IL-17 and PlGF/sENG Ratio in Pre-Eclampsia and Adverse Pregnancy Outcomes

The aim of the study was to assess the role of concentrations of interleukin-17 (IL-17), placental growth factor (PlGF) and soluble endoglin (sENG), as well as the PlGF/sENG ratio in pregnancy complicated by pre-eclampsia (PE) and normal pregnancy. The concentrations of IL-17, PlGF and sENG were measured with the use of immunoenzymatic methods. The concentrations of IL-17 were significantly higher in PE patients when compared to control patients. In the group of patients with PE, the levels of IL-17 positively correlated with systolic blood pressure. On the other hand, IL-17 negatively correlated with neonatal birth weight. The concentrations of PLGF were significantly lower and sENG significantly higher in studied patients when compared to controls. The PlGF/sENG ratio in the PE group was significantly lower when compared to healthy third trimester pregnant patients. In the study group, negative correlations were observed between the sENG concentrations and thrombocyte levels. The higher concentrations of IL-17 in PE could suggest its role as an inflammatory agent in the pathogenesis of the syndrome. Moreover, the negative correlation between IL-17 and a neonatal birth weight could suggest the role of the cytokine in the development of fetal growth restriction (FGR) associated with PE. It seems possible that IL-17 can be a useful marker of the risk of FGR in pregnancy complicated by PE. Furthermore, the results suggested the potential role of sENG and the PlGF/sENG ratio in the prediction of adverse outcomes such as HELLP syndrome and DIC.

Mitochondrial dysfunction-induced high hCG associated with development of fetal growth restriction and pre-eclampsia with fetal growth restriction.

Mitochondrial dysfunction-induced high hCG associated with development of fetal growth restriction and pre-eclampsia with fetal growth restriction.

Maternal Serum Fractalkine Concentrations in Pregnancies Complicated by Fetal Growth Restriction

OBJECTIVE: Fractalkine is a newly discovered chemokine that is expressed in placental tissue during pregnancy and is subsequently shed into the maternal serum. Although there are a few studies examining the relationship between fractalkine and preeclampsia, its role in isolated fetal growth restriction has not been investigated yet. In this study, we aimed to investigate the relationship between isolated fetal growth restriction and maternal serum fractalkine concentrations. STUDY DESIGN: This cross-sectional study was conducted on 86 pregnant women, 25 of whom were diagnosed with fetal growth restriction in the third trimester, 23 were small for gestational age, and 38 were healthy controls. These three groups were compared in terms of maternal serum fractalkine concentrations. RESULTS: While the highest mean maternal serum fractalkine concentration was found in the small for gestational age group at 23.31 ng/mL, it was determined as 18.06 ng/mL in the fetal growth restriction group and 16.03 ng/mL in the control group. We did not find a statistical difference between the groups in terms of fractalkine concentrations (p=0.258). When the patients with fetal growth restriction and small for gestational age were evaluated as a single group and compared with the control group, the mean fractalkine concentration in the fetal growth restriction+small for gestational age group was higher than the control group, but this difference was not statistically significant (p=0.214). CONCLUSION: Maternal serum fractalkine concentration was higher in both fetal growth restriction and small for gestational age groups compared to healthy controls, but this difference was not statistically significant. The role of the fractalkine molecule in the development of fetal growth restriction remains to be clarified in future studies with larger series.

The Exploration of Fetal Growth Restriction Based on Metabolomics: A Systematic Review.

Fetal growth restriction (FGR) is a common complication of pregnancy and a significant cause of neonatal morbidity and mortality. The adverse effects of FGR can last throughout the entire lifespan and increase the risks of various diseases in adulthood. However, the etiology and pathogenesis of FGR remain unclear. This study comprehensively reviewed metabolomics studies related with FGR in pregnancy to identify potential metabolic biomarkers and pathways. Relevant articles were searched through two online databases (PubMed and Web of Science) from January 2000 to July 2022. The reported metabolites were systematically compared. Pathway analysis was conducted through the online MetaboAnalyst 5.0 software. For humans, a total of 10 neonatal and 14 maternal studies were included in this review. Several amino acids, such as alanine, valine, and isoleucine, were high frequency metabolites in both neonatal and maternal studies. Meanwhile, several pathways were suggested to be involved in the development of FGR, such as arginine biosynthesis, arginine, and proline metabolism, glyoxylate and dicarboxylate metabolism, and alanine, aspartate, and glutamate metabolism. In addition, we also included 8 animal model studies, in which three frequently reported metabolites (glutamine, phenylalanine, and proline) were also present in human studies. In general, this study summarized several metabolites and metabolic pathways which may help us to better understand the underlying metabolic mechanisms of FGR.

Effect of pentaerythritol tetranitrate (PETN) on the development of fetal growth restriction in pregnancies with impaired uteroplacental perfusion at midgestation—a randomized trial

Fetal growth restriction is strongly associated with impaired placentation and abnormal uteroplacental blood flow. Nitric oxide donors such as pentaerythritol tetranitrate are strong vasodilators and protect the endothelium. Recently, we demonstrated in a randomized controlled pilot study a 38% relative risk reduction for the development of fetal growth restriction or perinatal death following administration of pentaerythritol tetranitrate to pregnant women at risk, identified by impaired uterine perfusion at midgestation. Results of this monocenter study prompted the hypothesis that pentaerythritol tetranitrate might have an effect in pregnancies with compromised placental function as a secondary prophylaxis. This study aimed to test the hypothesis that the nitric oxide donor pentaerythritol tetranitrate reduces fetal growth restriction and perinatal death in pregnant women with impaired placental perfusion at midgestation in a multicenter trial. In this multicenter, randomized, double-blind, placebo-controlled trial, 2 parallel groups of pregnant women presenting with a mean uterine artery pulsatility index >95th percentile at 19+0 to 22+6 weeks of gestation were randomized to 50-mg Pentalong or placebo twice daily. Participants were assigned to high- or low-risk groups according to their medical history before randomization was performed block-wise with a fixed block length stratified by center and risk group. The primary efficacy endpoint was the composite outcome of perinatal death or development of fetal growth restriction. Secondary endpoints were neonatal and maternal outcome parameters. Between August 2017 and March 2020, 317 participants were included in the study and 307 were analyzed. The cumulative incidence of the primary outcome was 41.1% in the pentaerythritol tetranitrate group and 45.5% in the placebo group (unadjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; adjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; P=.43). Secondary outcomes such as preterm birth (unadjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; adjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; P=.01) and pregnancy-induced hypertension (unadjusted relative risk, 0.65; 95% confidence interval, 0.46-0.93; adjusted relative risk, 0.65; 95% confidence interval, 0.46-0.92; P=0.01) were reduced. Our study failed to show an impact of pentaerythritol tetranitrate on the development of fetal growth restriction and perinatal death in pregnant women with impaired uterine perfusion at midgestation. Pentaerythritol tetranitrate significantly reduced secondary outcome parameters such as the incidence of preterm birth and pregnancy-induced hypertension in these pregnancies.

MiR-1227-3p participates in the development of fetal growth restriction via regulating trophoblast cell proliferation and apoptosis

Fetal growth restriction (FGR) is a common obstetric disease, which is harmful to the pregnant women and fetuses. It has many influencing factors, but the specific etiology is not clear. MiRNA plays an important role in the fetal growth and development. In this article, we use TaqMan Low-Density Array to screen and analyze the differently expressed miRNAs in FGR-affected placenta (n = 40) and the normal placenta (n = 40). A total of 139 abnormally expressed miRNAs in the FGR-affected placenta were identified, and miR-1227-3p was the most highly downregulated miRNA. Importantly, miR-1227-3p may promote the proliferation in HTR-8/SVneo cells, while inhibited the apoptosis of HTR-8/SVneo cells. DAVID was used to analyze the pathway enrichment of target genes of miR-1227-3p to predict its mechanism of action. Furthermore, the putative targets of miR-1227-3p were predicted using the TargetScan, PicTar, DIANA LAB, and miRWalk database. The potential expression of target genes of miR-1227-3p, including PRKAB2, AKT1, PIK3R3, and MKNK1 were significantly increased in FGR-affected placenta. Taken together, miR-1227-3p may participate in the development of FGR via regulating trophoblast cell proliferation and apoptosis by targeting genes involved in the insulin pathway. MiR-1227-3p may have a potential clinical value in the prevention and treatment of FGR, we need to study further to prove its value in the future.

Mitochondrial dysfunction-induced high hCG associated with development of fetal growth restriction and pre-eclampsia with fetal growth restriction

Fetal growth restriction (FGR) and pre-eclampsia with fetal growth restriction (PE/FGR) are high-risk perinatal diseases that may involve high levels of human chorionic gonadotropin (hCG) and mitochondrial dysfunction. However, little is known about how these factors affect placental function. We investigated how mitochondrial dysfunction and high hCG expression affected placental function in unexplained FGR and PE/FGR. We observed elevated expression of hCGβ and growth differentiation factor 15 mRNA and protein levels in the placenta with both diseases. Likewise, antiangiogenic factors, such as Ang2, IP10, sFlt1, IL8, IL1B, and TNFα, were also upregulated at the mRNA level. In addition, the expression of COXI and COXII which encoded by mitochondrial DNA were significantly decreased in both diseases, suggesting that mitochondrial translation was impaired. Treatment with hCG increased Ang2, IP10, IL8, and TNFα mRNA levels in a dose-dependent manner via the p38 and JNK pathways. Mitochondrial translation inhibitors increased hCGβ expression through stabilization of HIF1α, and increased IL8 and TNFα mRNA expression. These results revealed that high expression of hCG due to mitochondrial translational dysfunction plays an important role in the pathogenesis of FGR and PE/FGR.

The Role of High Concentrations of Homocysteine for the Development of Fetal Growth Restriction.

To assess homocysteine (Hcy) levels in the three trimesters of pregnancy in women with fetal growth restriction (FGR) and to evaluate the role of Hcy as a possible predictor of FGR. A total of 315 singleton pregnant women were included in the present prospective cohort study and were monitored since the 1st trimester of pregnancy before delivery. Newborns were monitored for the first 7 days of life. Patients who had risk factors for FGR were excluded. Fetal growth restriction was defined according to uterine fundal height (< 10 percentile), ultrasound fetometry (< 5 percentile), and anthropometry of newborns (< 5 percentile). The concentrations of Hcy were detected at between 10 and 14, between 20 and 24, and between 30 and 34 weeks of pregnancy by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristics (ROC) curve test and diagnostic odds ratio (DOR) were performed to evaluate the results of ELISA. The concentration of Hcy in patients with FGR was 19.65 umol/L at between 10 and 14 weeks, compared with 9.28 umol/L in patients with normal fetal growth (p < 0.0001). The optimal cut-off level for Hcy in the 1st trimester of pregnancy was > 13.9 umol/L with AUC 0.788, sensitivity of 75%, specificity of 83.6%, and DOR of 15.2. Assessment of serum Hcy concentration may be used as a predictor of FGR, with the highest diagnostic utility in the 1st trimester of pregnancy.

Effect of PM2.5 exposure on gestational hypertension, fetal size in preeclampsia-like rats.

Studies have shown intriguing associations between gestational PM2.5 exposure and preeclampsia (PE), as well as fetal growth restriction (FGR). This study investigated the impact of PM2.5 exposure on gestational hypertension and fetal outcome in a preeclampsia-like rat model. Pregnant Sprague Dawley rats were exposed to either filtered (FA) or PM2.5-contaminated air during the whole pregnancy period. A PE-like rat model was established by intraperitoneal injection of L-NAME (300mg/kg) from gestational day (GD) 12 to until GD20. Systolic blood pressure (SBP), weight gain, pup weight and placental weight were measured. The percentages of rat Treg/Th17 cells and Th17-related cytokines were examined by flow cytometry. Gene expression profiles were analyzed by microarray, and the expression of differentially expressed genes was validated by qRT-PCR. The results showed that maternal PM2.5 exposure had no effect on SBP but was associated with low birth weight (LBW) and a higher labyrinth/basal zone ratio. The percentages of splenic Th17 cells from the PM2.5 group of PE-like rats were higher than those from the FA or PM2.5 groups of healthy controls. A significantly decreased Treg/Th17 cell ratio was found in the PM2.5 group of PE-like rats. The mRNA expression of Foxp3 was downregulated, while the mRNA expression of RORα and RORγτ was upregulated after PM2.5 exposure. Furthermore, we observed that both the mRNA and protein levels of TNF-a, CCL2, CCL3 and CCR1 increased in the PM2.5 groups. Our study suggested that systemic inflammation may contribute to the development of FGR associated with PM2.5 exposure throughout pregnancy.