Mechanisms underlying the role of endoplasmic reticulum stress in the placental injury and fetal growth restriction in an ovine gestation model

Background Exposure to bisphenol A(BPA),an environmental pollutant known for its endocrine-disrupting properties,during gestation has been reported to increase the risk of fetal growth restriction(FGR)in an ovine model of pregnancy.We hypothesized that the FGR results from the BPA-induced insufficiency and barrier dysfunction of the placenta,oxidative stress,inflammatory responses,autophagy and endoplasmic reticulum stress(ERS).However,precise mechanisms underlying the BPA-induced placental dysfunction,and subsequently,FGR,as well as the potential involvement of placental ERS in these complications,remain to be investigated.Methods In vivo experiment,16 twin-pregnant(from d 40 to 130 of gestation)Hu ewes were randomly distributed into two groups(8 ewes each).One group served as a control and received corn oil once a day,whereas the other group received BPA(5 mg/kg/d as a subcutaneous injection).In vitro study,ovine trophoblast cells(OTCs)were exposed to 4 treatments,6 replicates each.The OTCs were treated with 400μmol/L BPA,400μmol/L BPA+0.5μg/m L tunicamycin(Tm;ERS activator),400μmol/L BPA+1μmol/L 4-phenyl butyric acid(4-PBA;ERS antagonist)and DMEM/F12 complete medium(control),for 24 h.Results In vivo experiments,pregnant Hu ewes receiving the BPA from 40 to 130 days of pregnancy experienced a decrease in placental efficiency,progesterone(P4)level and fetal weight,and an increase in placental estrogen(E2)level,together with barrier dysfunctions,OS,inflammatory responses,autophagy and ERS in type A cotyledons.In vitro experiment,the OTCs exposed to BPA for 24 h showed an increase in the E2 level and related protein and gene expressions of autophagy,ERS,pro-apoptosis and inflammatory response,and a decrease in the P4 level and the related protein and gene expressions of antioxidant,anti-apoptosis and barrier function.Moreover,treating the OTCs with Tm aggravated BPA-induced dysfunction of barrier and endocrine(the increased E2 level and decreased P4 level),OS,inflammatory responses,autophagy,and ERS.However,treating the OTCs with 4-PBA reversed the counteracted effects of Tm mentioned above.Conclusions In general,the results reveal that BPA exposure can cause ERS in the ovine placenta and OTCs,and ERS induction might aggravate BPA-induced dysfunction of the placental barrier and endocrine,OS,inflammatory responses,and autophagy.These data offer novel mechanistic insights into whether ERS is involved in BPA-mediated placental dysfunction and fetal development.

Associations of serum D-dimer and glycosylated hemoglobin levels with third-trimester fetal growth restriction in gestational diabetes mellitus

BACKGROUND Gestational diabetes mellitus(GDM)is a special type of diabetes that commonly occurs in women during pregnancy and involves impaired glucose tolerance and abnormal glucose metabolism;GDM is diagnosed for the first time during pregnancy and can affect fetal growth and development.AIM To investigate the associations of serum D-dimer(D-D)and glycosylated hemoglobin(HbA1c)levels with third-trimester fetal growth restriction(FGR)in GDM patients.METHODS The clinical data of 164 pregnant women who were diagnosed with GDM and delivered at the Obstetrics and Gynecology Hospital of Fudan University from January 2021 to January 2023 were analyzed retrospectively.Among these women,63 whose fetuses had FGR were included in the FGR group,and 101 women whose fetuses had normal body weights were included in the normal body weight group(normal group).Fasting venous blood samples were collected from the elbow at 28-30 wk gestation and 1-3 d before delivery to measure serum D-D and HbA1c levels for comparative analysis.The diagnostic value of serum D-D and HbA1c levels for FGR was evaluated by receiver operating characteristic analysis,and the influencing factors of third-trimester FGR in GDM patients were analyzed by logistic regression.RESULTS Serum fasting blood glucose,fasting insulin,D-D and HbA1c levels were significantly greater in the FGR group than in the normal group,while the homeostasis model assessment of insulin resistance values were lower(P<0.05).Regarding the diagnosis of FGR based on serum D-D and HbA1c levels,the areas under the curves(AUCs)were 0.826 and 0.848,the cutoff values were 3.04 mg/L and 5.80%,the sensitivities were 81.0%and 79.4%,and the specificities were 88.1%and 87.1%,respectively.The AUC of serum D-D plus HbA1c levels for diagnosing FGR was 0.928,and the sensitivity and specificity were 84.1%and 91.1%,respectively.High D-D and HbA1c levels were risk factors for third-trimester FGR in GDM patients(P<0.05).CONCLUSION D-D and HbA1c levels can indicate the occurrence of FGR in GDM patients in the third trimester of pregnancy to some extent,and their combination can be used as an important index for the early prediction of FGR.

Long-term implications of fetal growth restriction

Fetal growth restriction(FGR),or intrauterine growth restriction(IUGR),is a complication of pregnancy where the fetus does not achieve its genetic growth potential.FGR is characterized by a pathological retardation of intrauterine growth velocity in the curve of intrauterine growth.However,the FGR definition is still debated,and there is a lack of a uniform definition in the literature.True IUGR,compared to constitutional smallness,is a pathological condition in which the placenta fails to deliver an adequate supply of oxygen and nutrients to the developing fetus.Infants with IUGR,compared to appropriately grown gestational age infants,have a significantly higher risk of mortality and neonatal complications with long-term consequences.Several studies have demonstrated how suboptimal fetal growth leads to long-lasting physiological alterations for the developing fetus as well as for the newborn and adult in the future.The long-term effects of fetal growth retardation may be adaptations to poor oxygen and nutrient supply that are effective in the fetal period but deleterious in the long term through structural or functional alterations.Epidemiologic studies showed that FGR could be a contributing factor for adult chronic diseases including cardiovascular disease,metabolic syndrome,diabetes,respiratory diseases and impaired lung function,and chronic kidney disease.In this review we discussed pathophysiologic mechanisms of FGR-related complications and potential preventive measures for FGR.

Antenatal taurine reduces cerebral cell apoptosis in fetal rats with intrauterine growth restriction

From pregnancy to parturition, Sprague-Dawley rats were daily administered a low protein diet to establish a model of intrauterine growth restriction. From the 12th day of pregnancy, 300 mg/kg taurine was daily added to food until spontaneous delivery occurred. Brain tissues from normal neonatal rats at 6 hours after delivery, neonatal rats with intrauterine growth restriction, and neo- natal rats with intrauterine growth restriction undergoing taurine supplement were obtained for fur- ther experiments. The terminal deoxyribonucleotidyl transferase （TdT）-mediated biotin-16-dUTP nick-end labeling assay revealed that the number of apoptotic cells in the brain tissue of neonatal rats with intrauterine growth restriction significantly increased. Taurine supplement in pregnant rats reduced cell apoptosis in brain tissue from neonatal rats with intrauterine growth restriction. Immu- nohistochemical staining revealed that taurine supplement increased glial cell line-derived neuro- trophic factor expression and decreased caspase-3 expression in the cerebral cortex of intrauterine growth-restricted fetal rats. These results indicate that taurine supplement reduces cell apoptosis through the glial cell line-derived neurotrophic factor-caspase-3 signaling pathway, resulting in a protective effect on the intrauterine growth-restricted fetal rat brain.

Intrauterine growth restriction alters growth performance, plasma hormones,and small intestinal microbial communities in growing-finishing pigs

Background: The interaction of the gut microbiota with key metabolic and physiological processes may be associated with poor growth outcomes in animals born with intrauterine growth restriction(IUGR).Results: Growth performance, plasma hormone concentrations, and intestinal microbiota composition were analyzed in IUGR pigs and in normal birth weight(NBW) pigs when the NBW pigs reached 25, 50, and 100 kg of body weight(BW). Compared to NBW pigs, IUGR pigs had lower initial, weaned, and final BW, and lower average daily gain and average daily feed intake in all the considered time points. In the 25 kg BW group, IUGR pigs had higher concentrations of plasma ghrelin and pancreatic polypeptide(PP), but lower insulin concentration than NBW pigs, while the situation was reversed in the 50 kg BW group. As compared to NBW pigs, IUGR pigs had higher microbial alpha diversity in the jejunum and ileum;in the 50 and 100 kg BW groups, IUGR pigs had higher Firmicutes abundance but lower Proteobacteria abundance in the jejunum, and lower Lactobacillus abundance in the jejunum and ileum;in the 25 kg BW group, IUGR pigs showed higher unclassified Ruminococcaceae abundance in the ileum;and in 25 and 50 kg BW groups, IUGR pigs showed lower Ochrobactrum abundance in the jejunum.Spearman's correlation revealed that Lactobacillus was negatively correlated with growth performance, while unclassified Ruminococcaceae was positively correlated. Predictive metagenomic analysis detected significantly different expression of genes in the intestinal microbiota between IUGR and NBW pigs, suggesting different metabolic capabilities between the two groups.Conclusions: Growing-finishing IUGR pigs showed lower growth performance, higher microbial alpha diversity, and differences in plasma hormone concentrations compared to NBW pigs. Alterations in the abundance of Firmicutes,Proteobacteria, Ruminococcaceae, Lactobacillus, and Ochrobactrum in the small intestine may be associated with IUGR, and may therefore serve as a future target for gut microbiota intervention in growing-finishing IUGR pigs.

Effect of Bushen Yiqi Huoxue Recipe on Placental Vasculature in Pregnant Rats with Fetal Growth Restriction Induced by Passive Smoking

Interactions of vascular endothelial growth factor （VEGF） with receptors VEGFR1/Fltl and VEGFR2/Flk1, and those of angiopoietins （Ang-1, Ang-2） with receptor Tie2 play important roles in placental angiogenesis. This study investigated vascular morphology and expression of these angiogenic factors in rat placenta on the day 15, 18, 21 of gestation （D 15, D 18 and D21）. The rats were randomly assigned into 3 groups： normal group, model group [fetal growth restriction （FGR） model], and Bushen Tqi Huoxue （BYHR） recipe treatment group （BYHR group, the pregnant rats with FGR were treated with BYHR recipe）. Morphological analysis indicated that during initial villous formation, fetal nucle- ated erythrocytes （FNEs） appeared in maternal blood sinus （MBS）. Subsequently, FNEs were sur- rounded by endothelial cells to form fetal capillary （FC） and then by trophoblast cells to form villi. As pregnancy proceeded, FC density increased progressively with increasing endothelial identification staining （EIS） in normal and BYHR groups. Whereas, villous formation was suppressed, normal in- crease in FC density was impaired and EIS was weakened in model group. Quantitative PCR analysis showed that VEGF and Flkl mRNA increased over gestation in all groups, indicating that VEGF might play a pivotal role in FC growth during late gestation. VEGF mRNA was increased on D15, while de- creased on D21 in model group as compared with normal group and BYHR group. Immunohistochemi- cally, Ang-2 protein was highly expressed in FNEs, gradually disappeared as villi matured, and decreased over gestation in all groups, indicating that Ang-2 might play a pivotal role in villous formation, which was further supported by decreased Ang-2 mRNA and protein expression in model group on D 15. Ang-1 mRNA, Tie2 mRNA and Ang-1/Ang-2 ratio increased from D15 to D18 in all groups as placenta matured. Ang-1 mRNA, Tie2 mRNA and Ang-1/Ang-2 ratio were decreased on D18 in model group as compared with normal and BYHR groups, indicating delayed maturity of FGR placenta. Alterations in angiogenic factors may result in altered placental vasculature and cause placental insufficiency. BYHR recipe could balance the angiogenic factors to promote the formation and maturation of FGR placental vasculature.

Concentrations of Polybrominated Diphenyl Ethers in Maternal Blood,Placental Size,and Risk for Fetal Growth Restriction:A Nested Case-control Study

Objective To explore the effects of prenatal exposure to polybrominated diphenyl ethers(PBDEs)on placental size and birth outcomes.Methods Based on the perspective Wenzhou Birth Cohort,this nested case-control study included 101 fetal growth restriction(FGR)and 101 healthy newborns.Maternal serum samples were collected during the third trimester and measured for PBDEs by gas chromatography tandem mass spectrometry.The basic information of mother-newborn pairs was collected from questionnaires,whereas the placental size and birth outcomes of newborns were obtained from hospital records.Results A total of 19 brominated diphenyle ether(BDE)congeners were detected in maternal serum samples.Higher concentrations of BDE-207,-208,-209,and∑19PBDEs were detected in FGR cases than in controls.Increased BDE-207,-208,-209,and∑19PBDEs levels in maternal serum were related to decreased placental length,breadth,surface area,birth weight,birth length,gestational age,and Quetelet index of newborns.After adjusting for confounders,BDE-207 and∑19PBDE concentrations in maternal serum were significantly associated with an increased risk of FGR.Conclusion A negative association was found between PBDE levels in maternal serum and placental size and birth outcomes.Prenatal PBDE exposure may be associated with elevated risk of the incidence of FGR birth.

Impairments of spatial learning and memory in rat offspring with fetal growth restriction

Objective： Throughout the world, fetal growth restriction（FGR） is one of the most severe complications occurring during pregnancy. It is subsequently associated with neurologic abnormalities in chldren. Our aim was to investigate the spatial learning and memory ability of rat offspring born With FGR. Methods：A rat model of FGR was constructed using the method of passive smoking. Spatial learning and memory were studied in rat offspring born with FGR by assessing the animals＇ performance using the Morris water maze task. Results： At 1- and 2- months of age, both female and male offspring rats showed impairment of performance, while at 4 months of age, only female rats showed impaired performance. The FGR offspring spent a longer time swimming and used inefficient strategies（P〈 0.05, respectively）. However, there were no significant maze performance FGR effects in the 4 month old male rats. In all groups of FGR offspring, irrespective of age or sex, the time spent in the platform quadrant by the rat was significantly less than that in the control group（P〈 0.05）. Conclusion： The Morris water maze performance decreased in rat offspring born with FGR. It is suggested that FGR can cause impairments of spatial learning and memory in young animals.

Effects of maternal methyl donor intake during pregnancy on ileum methylation and function in an intrauterine growth restriction pig model

Background Intrauterine growth retardation(IUGR)affects intestinal growth,morphology,and function,which leads to poor growth performance and high mortality.The present study explored whether maternal dietary methyl donor(MET)supplementation alleviates IUGR and enhances offspring’s growth performance by improving intestinal growth,function,and DNA methylation of the ileum in a porcine IUGR model.Methods Forty multiparous sows were allocated to the control or MET diet groups from mating until delivery.After farrowing,8 pairs of IUGR and normal birth weight piglets from 8 litters were selected for sampling before suckling colostrum.Results The results showed that maternal MET supplementation tended to decrease the IUGR incidence and increased the average weaning weight of piglets.Moreover,maternal MET supplementation significantly reduced the plasma concentrations of isoleucine,cysteine,urea,and total amino acids in sows and newborn pig-lets.It also increased lactase and sucrase activity in the jejunum of newborn piglets.MET addition resulted in lower ileal methionine synthase activity and increased betaine homocysteine S-methyltransferase activity in the ileum of newborn piglets.DNA methylation analysis of the ileum showed that MET supplementation increased the methyla-tion level of DNA CpG sites in the ileum of newborn piglets.Down-regulated differentially methylated genes were enriched in folic acid binding,insulin receptor signaling pathway,and endothelial cell proliferation.In contrast,up-regulated methylated genes were enriched in growth hormone receptor signaling pathway and nitric oxide biosyn-thetic process.Conclusions Maternal MET supplementation can reduce the incidence of IUGR and increase the weaning litter weight of piglets,which may be associated with better intestinal function and methylation status.

The Proteome Landscape of Human Placentas for Monochorionic Twins with Selective Intrauterine Growth Restriction

In perinatal medicine,intrauterine growth restriction(IUGR)is one of the greatest challenges.The etiology of IUGR is multifactorial,but most cases are thought to arise from placental insufficiency.However,identifying the placental cause of IUGR can be difficult due to numerous confounding factors.Selective IUGR(sIUGR)would be a good model to investigate how impaired placentation affects fetal development,as the growth discordance between monochorionic twins cannot be explained by confounding genetic or maternal factors.Herein,we constructed and analyzed the placental proteomic profiles of IUGR twins and normal cotwins.Specifically,we identified a total of 5481 proteins,of which 233 were differentially expressed(57 up-regulated and 176 down-regulated)in IUGR twins.Bioinformatics analysis indicates that these differentially expressed proteins(DEPs)are mainly associated with cardiovascular system development and function,organismal survival,and organismal development.Notably,34 DEPs are significantly enriched in angiogenesis,and diminished placental angiogenesis in IUGR twins has been further elaborately confirmed.Moreover,we found decreased expression of metadherin(MTDH)in the placentas of IUGR twins and demonstrated that MTDH contributes to placental angiogenesis and fetal growth in vitro.Collectively,our findings reveal the comprehensive proteomic signatures of placentas for sIUGR twins,and the DEPs identified may provide in-depth insights into the pathogenesis of placental dysfunction and subsequent impaired fetal growth.

Fetal Growth Restriction: Mechanisms, Epidemiology, and Management

Fetal growth restriction(FGR)is the condition in which a fetus does not reach its intrinsic growth potential and in which the shortterm and long-term risks of severe complications are increased.FGR is a frequent complication of pregnancy with a complex etiology and limited management options,other than timely delivery.The most common pathophysiological mechanism is placental insufficiency,due to many underlying causes such as maternal vascular malperfusion,fetal vascular malperfusion and villitis.Identifying truly growth restricted fetuses remains challenging.To date,FGR is often defined by a cut-off of the estimated fetal weight below a certain percentile on a population-based standard.However,small fetal size as a single marker does not discriminate adequately between fetuses or newborns that are constitutionally small but healthy and fetuses or newborns that are growth restricted and thus at risk for adverse outcomes.In 2016,the consensus definition of FGR was internationally accepted to better pinpoint the FGR population.In this review we will discuss the contemporary diagnosis and management issues.Different diagnostic markers are considered,like Doppler measurements,estimated fetal growth,interval growth,fetal movements,biomarkers,and placental markers.

Isolation of microalgae with growth restriction and nutrient removal from alkaline wastewater

In order to isolate a well-tolerated microalgae strain and study its capability of wastewater treatment,a newly microalgae strain was isolated and identified from fresh water.The phylogenetic analysis indicates that this strain has a close relationship with Desmodesmus sp.,named as EJ 9-2.The effects of temperature,pH value and NaCl concentration on growth of Desmondesmus sp.were investigated;the capability of nutrient removal from alkaline wastewater was also observed.Desmodesmus sp.EJ 9-2 had a wide pH adaptation range(3-12)and could remove nitrogen,phosphorus and COD which might substantially decrease the cost of biofuel production.The research can provide evidence for outdoor large-scale cultivation of microalgae.

A Summary of Chinese Expert Consensus on Fetal Growth Restriction (An Update on the 2019 Version)

Fetal growth restriction(FGR)is a common complication of pregnancy associated with higher rates of perinatal mortality and morbidity,as well as a variety of long-term adverse outcomes.To standardize the clinical practice for the management of FGR in China,Fetal Medicine Subgroup,Chinese Society of Perinatal Medicine,Chinese Medical Association and Maternal-Fetal Medicine Committee,Chinese Society of Obstetrics and Gynecology,Chinese Medical Association organized an expert committee to provide official consensus-based recommendations on FGR.We evaluated the evidence provided by relevant high-quality literature,performed a three-round Delphi study and organized face-to-face meetings with experts from multidisciplinary backgrounds.The consensus includes the definition,prenatal screening,prevention,diagnosis,monitoring and management of FGR.

Solidification of Mg-Zn-Zr Alloys:Grain Growth Restriction,Dendrite Coherency and Grain Size

The solidification characterization of Mg-xZn-0.5Zr(x=0,1,3,4,5 wt%)alloys has been extensively investigated through thermal analysis,microstructure characterization and thermodynamic calculations.The impact of Zn content on the grain growth restriction,dendrite coherency and thus the final grain size has been investigated and discussed.Increasing Zn content,the grain size of Mg-xZn-0.5Zr alloy was firstly refined and then coarsened with the finest grain size of^50μm for the Mg-3 Zn-0.5 Zr(ZK31)alloy.Significant effects of the grain size on the mechanical properties were observed in the investigated alloys.The combination of growth restriction factor theory and dendrite coherency point provides a reasonable explanation of the grain size results.It helps to further understand the mechanisms of grain refinement and grain coarsening related to solute content,providing reference for alloy design and grain size prediction.

Selective Fetal Growth Restriction in Monochorionic Diamniotic Twins: Diagnosis and Management

Selective fetal growth restriction (sFGR) is a severe condition that complicates 10% to 15% of all monochorionic diamniotic (MCDA) twin pregnancies. Pregnancies complicated with sFGR are at high risk of intrauterine demise or adverse perinatal outcome for the twins. Three clinical types have been described according to the umbilical artery (UA) Doppler pattern observed in the smaller twin: type I, when the UA Doppler is normal;type II, when there is persistent absent or reversed end-diastolic blood flow in the UA Doppler;and type III, when there is intermittent absent and/or reversed end-diastolic blood flow in the UA Doppler. Clinical evolution and management options mainly depend on the type of sFGR. Type I is usually associated with a good prognosis and is managed conservatively. There is no consensus on the management of types II and III, but in earlier and more severe presentations, fetal interventions such as selective laser photocoagulation of placental anastomoses or selective fetal cord occlusion of the smaller twin may be considered. This review aims to provide updated information about the diagnosis, evaluation, follow-up, and management of sFGR in MCDA twin pregnancies.

The Update of Fetal Growth Restriction Associated with Biomarkers

Fetal growth restriction(FGR)has a prevalence of about 10%worldwide and is associated with an increased risk of perinatal mortality and morbidity.FGR is commonly caused by placental insufficiency and can begin early(<32 weeks)or in late(≥32 weeks)gestational age.A false positive antenatal diagnosis may lead to unnecessary monitoring and interventions,as well as cause maternal anxiety.Whereas a false negative diagnosis exposes the fetus to an increased risk of stillbirth and renders the pregnancy ineligible from the appropriate care and potential treatments.The clinical management of FGR pregnancies faces a complex challenge of deciding on the optimal timing of delivery as currently the main solution is to deliver the baby early,but iatrogenic preterm delivery of infants is associated with adverse short-and long-term outcomes.Early and accurate diagnosis of FGR could aid in better stratification of clinical management,and the development and implementation of treatment options,ultimately benefiting clinical care and potentially improving both short-and long-term health outcomes.The aim of this review is to present the new insights on biomarkers of placenta insufficiency,including their current and potential value of biomarkers in the prediction and prevention for FGR,and highlight the association between biomarkers and adverse outcomes in utero to explore the specific mechanism of impaired fetal growth that establish the basis for disease later in life.

Incidence and Clinical Features of Fetal Growth Restriction in 4 451 Women with Hypertensive Disorders of Pregnancy

Objective:To assess the clinical features of fetal growth restriction(FGR)in women with hypertensive disorders of pregnancy in China.Methods:This is a retrospective cohort study.The clinical data of 4451 women with hypertensive disorders of pregnancy were retrospectively collected from 11 tertiary hospitals across ten provinces in China during January 2015 to December 2015.The mean maternal age was(31.0±5.4)years old.Participants were divided into FGR group(n=670)and non-FGR group(n=3781).The incidence and clinical features of FGR,and its correlation with gestational age,previous FGR history,24-hour urinary protein excretion,and hemolysis,elevated liver enzyme and low platelet count(HELLP)syndrome were analyzed.Student’s t-test and Chi-square test were used when comparing clinical features between FGR and non-FGR groups.Results:The overall incidence of FGR was 15.1%(670/4451).The FGR incidence was 22.4%(433/1937)in women with severe preeclampsia and 18.6%(68/365)in women with chronic hypertension with superimposed preeclampsia,respectively.FGR was more prevalent in women who had preterm births than those who had term births(22.8%(432/1898)vs.9.3%(238/2553),P<0.001).It was also more prevalent in women with early-onset preeclampsia than those with late-onset preeclampsia(18.4%(189/1025)vs.14.0%(481/3426),P=0.001).Women with a previous FGR history had a significantly higher FGR incidence than those without an FGR history(66.7%(4/6)vs.15.7%(250/1596),P=0.007).The presence of abnormal results of the umbilical artery Doppler(13%(87/670)vs.2.4%(89/3781),P<0.001)and the middle cerebral artery Doppler(3.3%(22/670)vs.0.4%(15/3781),P<0.001)was higher in the FGR group compared with the non-FGR group,while the presence of increased uterine artery resistance was not statistically different(1.5%(10/670)vs.0.8%(29/3781),P=0.072).The FGR group delivered earlier than the non-FGR group((35.3±3.0)weeks vs.(36.4±4.3)weeks,P<0.001)with lower birth weight(1731.0±574.5)g vs.(2753.9±902.1)g,P<0.001,higher fetal or neonatal death(9.4%(63/670)vs.4.2%(157/3781),P<0.001),and higher cesarean section rate(82.5%(553/670)vs.70.2%(2656/3781),P<0.001).In the FGR group,more neonates had 5-minute Apgar score≤7(7.9%(53/670)vs.3.9%(149/3780),P<0.001),with higher neonatal intensive care unit admission rate(48.1%(322/670)vs.23.3%(881/3781),P<0.001).More cases of HELLP syndrome occurred in the FGR group(6.9%(46/670)vs.3.2%(122/3781),P<0.001).Women with FGR had heavier 24-hour urinary protein excretion than those without FGR((3.9±3.7)g vs.(3.1±4.2)g,P=0.005).Conclusion:In pregnancies with hypertensive disorders,increased risks of FGR are associated with preterm birth,birth before 34 weeks,and a previous FGR history.FGR is related to higher occurrence of abnormal uterine artery Doppler and umbilical artery Doppler.When hypertensive disorders is complicated by FGR,there appears to be higher maternal morbidity including higher rate of HELLP syndrome,cesarean section,and heavier proteinuria,as well as worse neonatal outcomes.

Association of an Increased Risk of Pre-eclampsia and Fetal Growth Restriction in Singleton and Twin Pregnancies with Female Fetuses

Objective: To investigate whether the fetal gender affects the incidence of pre-eclampsia (PE) and fetal growth restriction (FGR) in singleton and twin pregnancies.Methods: This was a 10-year single-center, retrospective, cohort study from January 2009 to January 2019. A total of 57,129 singleton and 3699 twin pregnancies aged between 18-55 years old were recruited at the Third Affiliated Hospital of Guangzhou Medical University, China. We used multivariable logistic regression to analyze the effect of fetal gender on the incidence of PE and FGR.Results: In singleton pregnancies, the incidence rates of PE and FGR with a female fetus were higher than those with a male fetus (6.4% (1713/26,793)vs. 5.9% (1803/30,336),P < 0.05 and 3.5% (932/26,793)vs. 2.4% (745/30,336),P < 0.05, respectively). A female fetus was an independent risk factor for either PE or FGR (adjusted odds ratio: 1.169 or 1.563;95% confidence interval: 1.036-1.319 or 1.349-1.810, respectively). In twin pregnancies, the incidence of early-onset PE was greater in pregnancies with two females compared with two males or one male plus one female (4.6% (46/1003)vs. 4.1% (54/1305)vs. 2.4% (33/1391),P < 0.05). Female-female twins was an independent risk factor for PE (adjusted odds ratio: 1.367, 95% confidence interval: 1.011-1.849), especially early-onset PE.Conclusion: The female fetus was associated with PE in both singleton and twin pregnancies and was also a risk factor of FGR in singleton pregnancies.

Dietary dimethylglycine sodium salt supplementation alleviates redox status imbalance and intestinal dysfunction in weaned piglets with intrauterine growth restriction

There are few studies on the mechanism of redox status imbalance and intestinal dysfunction in intrauterine growth restricted(IUGR)newborn piglets.Here,we investigated the mechanism of jejunum dysfunction in weaned piglets with IUGR and the mechanism through which dimethylglycine sodium salt(DMG-Na)supplementation improving the imbalance of their redox status.In this work,a total of 10 normal birth weight(NBW)newborn piglets and 20 IUGR newborn piglets were obtained.After weaning at 21 d,they were assigned to 3 groups(n=10/group):NBW weaned piglets fed standard basal diets(NBWC);one IUGR weaned piglets fed standard basal diets(IUGRC);another IUGR weaned piglets from the same litter fed standard basal diets plus 0.1%DMG-Na(IUGRD).The piglets in these 3 groups were sacrificed at 49 d of age,and the blood and jejunum samples were collected immediately.The growth performance values in the IUGRC group were lower(P<0.05)than those in the NBWC group.Jejunum histomorphological parameters,inflammatory cytokines,and digestive enzyme activity as well as serum immunoglobulin were lower(P<0.05)in the IUGRC group than those in the NBWC group.Compared with these in the NBWC group,the redox status of serum,jejunum,and mitochondria and the expression levels of jejunum redox status-related,cell adhesion-related,and mitochondrial function-related genes and proteins were suppressed in the IUGRC group(P<0.05).However,compared with those in the IUGRC group,the growth performance values,jejunum histomorphological parameters,inflammatory cytokines,digestive enzyme activity,serum immunoglobulin,redox status of serum,jejunum,and mitochondria,and the expression levels of jejunum redox status-related,cell adhesion-related,and mitochondrial function-related genes and proteins were improved(P<0.05)in the IUGRD group.In conclusion,dietary DMG-Na supplementation alleviates redox status imbalance and intestinal dysfunction in IUGR weaned piglets mainly by activating the sirtuin 1(SIRT1)/peroxisome proliferatoractivated receptorgcoactivator-1a(PGC1a)pathway,thereby improving their unfavorable body state.

Dietary rumen-protected L-arginine or N-carbamylglutamate attenuated fetal hepatic inflammation in undernourished ewes suffering from intrauterine growth restriction

This study aimed to explore whether dietary rumen-protected L-arginine(RP-Arg)or N-carbamylglutamate(NCG)supplementation to feed-restricted pregnant ewes counteracts fetal hepatic inflammation and innate immune dysfunction associated with intrauterine growth retardation(IUGR)in ovine fetuses.On d 35 of pregnancy,twin-bearing Hu ewes(n=32)were randomly assigned to 4 treatment groups(8 ewes and 16 fetuses per group)and fed diets containing 100%of the NRC requirements(CON),50%of the NRC requirements(RES),RES+RP-Arg(20 g/d)(RESA),or RES+NCG(5 g/d)(RESN).At 08:00 on d 110 of gestation,fetal blood and liver tissue samples were collected.The levels of triglyceride,free fatty acid,cholesterol andβ-hydroxybutyrate in the fetal blood of RESA and RESN groups were lower(P<0.05)than those of the RES group,but were higher(P<0.05)than those of the CON group.The interleukin(IL)-6 and IL-1 levels in fetal blood and liver tissue as well as the myeloid differentiation primary response 88(MyD88),transforming growth factorβ(TGFβ),and nuclear factor kappa B(NF-κB)mRNA levels in the fetal liver were decreased(P<0.05)by the NCG or RP-Arg supplementation compared to the RES treatment.Similarly,the toll-like receptor(TLR)-4,MyD88,TGFβ,and p-c-Jun N-terminal kinase(JNK)protein levels in the fetal liver were reduced(P<0.05)in the NCG and RP-Arg-supplemented groups compared to the RES group.These results showed that dietary supplementation of RP-Arg or NCG to underfed pregnant ewes could protect against IUGR fetal hepatic inflammation via improving lipid metabolism,down-regulating the TLR-4 and the inflammatory JNK and NF-icB signaling pathways,and decreasing cytokine production in ovine fetal blood and liver tissue.