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.

Perinatal Morbidity, Mortality, and Neurodevelopmental Outcomes of Neonates with Fetal Growth Restriction

Objective: This study aimed to assess perinatal morbidity, mortality rates, and neurodevelopmental outcomes in the management of fetal growth restriction (FGR) at a single tertiary institute. Methods: Among 2465 deliveries between 2013 and 2019, 109 cases of FGR were reviewed retrospectively for causes, indications for pregnancy termination, perinatal death, overall neonatal outcomes, and long-term prognosis. Results: Excluding FGR due to congenital anomalies (n = 17), the mortality rate was 3.3% (3/92). One neonate delivered at 23 weeks developed cerebral palsy (1.1%). Retinopathy of prematurity occurred in four neonates (4.3%). Neurodevelopmental disorders were present in six neonates (6.5%), all of whom were delivered at 32 - 38 weeks. Significantly lower gestational age at delivery, lower birth weight, and higher umbilical artery resistance indices were observed in neonates with neurodevelopmental disorders. Conclusions: Intact survival before 27 weeks of gestation at delivery with FGR is uncommon. Neurodevelopmental disorders may still develop after delivery at 32 - 38 weeks;consideration should be given to the timing of delivery usingfetal ductus venosus Doppler waveforms measurements to reduce neurodevelopmental disorders.

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.

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.

The Predictive Value of Plasma Fibronectin Concentration on Fetal Growth Retardation at Earlier Stage of the Third Trimester

In order to evaluate the predictive value of maternal plasma fibronectin (FN) concentration at 24-34 weeks on fetal intrauterine growth retardation (IUGR), a prospective double-blinded study was performed. The maternal plasma FN concentrations were measured by using a rate nephelometric procedure in the 130 initial normal nulliparous pregnant woman at 24-34 gestational weeks. The outcome of pregnancies and birth weight of their infants were followed up. IUGR was defined as that the birth weight was less than the 10th percentile for gestational age. The receiver operating characteristic curves and predictive values of FN predicting on outcome of pregnancy with IUGR were analyzed. The results showed that: (1) In a cohort of 130 initially normal nulliparous pregnant women, IUGR occurred in 14 cases during the follow-up; (2) The plasma FN levels in the women with IUGR (467.58±104.43 mg/L) were significantly higher than in the normal control group (299.44±105.55 mg/L, P<0.01). However, there was no significant difference in the mean maternal age, gravidity, sampling gestational ages, delivering gestational ages between the two groups (P>0.05); (3) The areas under ROC curve for predicting the outcome of pregnancy in IUGR was 0.893; (4) At the cut point of 475 mg/L FN level, the sensitivity, specificity, positive predictive value, negative predictive value and Kappa index for predicting the outcomes of pregnancy in IUGR were 57.14 %, 95.69 %, 61.54 %, 94.87 %, 0.5455 respectively. It was concluded that the maternal plasma FN might be used as an earlier predictor for screening of IUGR.

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.

Effect of Antenatal Depression on Fetal Growth Outcomes at the Jos University Teaching Hospital Jos, Plateau State, Nigeria

Background: Depression is the most prevalent psychiatric disorder in pregnancy and it is associated with psychosocial and obstetric factors. Studies have shown that pregnancy does not prevent women from becoming depressed;rather, it may be a time when depression occurs for the first time in some women. Antenatal depression has been identified as a risk factor for post natal depression, adverse obstetric outcomes, poorer neonatal outcomes and higher growth retardation in infants. Purpose: This study aimed to determine the fetal growth outcomes among depressed pregnant women in their third trimester attending antenatal clinic at the Jos University Teaching Hospital (JUTH), Jos, Plateau State, Nigeria. Method: A prospective cohort study design was used to assess 514 women who consented to the study (256 cases and 258 controls). A socio-demographic questionnaire was given to the women to fill out the study entry. Edinburgh Post Natal Depression Scale (EPDS) was used to screen for depression and MINI neuropsychiatric interviews were used to diagnose depression in those women found to be at risk of depression using the EPDS. Ultrasonography was used to determine the fetal weight in the third trimester of pregnancy. The birth weight of the babies born to the women was obtained from the birth register in the labor ward and the fetal growth rate was calculated from the estimated fetal weight on ultrasound scan in late pregnancy and the birth weight of babies. Result: The mean fetal weight in the third trimester for non-depressed women was slightly higher than in depressed women though the difference was not statistically significant (P = 0.431). The difference in the mean calculated fetal growth rate for fetuses of non-depressed women in the third trimester was statistically significantly higher than in depressed women (p = 0.000). Depressed women also had babies with lower birth weight than non-depressed women and the difference was statistically significant (p = 0.00).

Helicobacter pylori's virulence and infection persistence define pre-eclampsia complicated by fetal growth retardation

AIM: To better understand the pathogenic role of Helicobacter pylori (H. pylori) in pre-eclampsia (PE), and whether it is associated or not with fetal growth retardation (FGR). METHODS: Maternal blood samples were collected from 62 consecutive pregnant women with a diagnosis of PE and/or FGR, and from 49 women with uneventful pregnancies (controls). Serum samples were evaluated by immunoblot assay for presence of specific antibodies against H. pylori antigens [virulence: cytotoxin-associated antigen A (CagA); ureases; heat shock protein B; flagellin A; persistence: vacuolating cytotoxin A (VacA)]. Maternal complete blood count and liver enzymes levels were assessed at delivery by an automated analyzer. RESULTS: A significantly higher percentage of H. pyloriseropositive women were found among PE cases (85.7%) compared to controls (42.9%, P < 0.001). There were no differences between pregnancies complicated by FGR without maternal hypertension (46.2%) and controls. Importantly, persistent and virulent infections (VacA/ CagA seropositive patients, intermediate leukocyte blood count and aspartate aminotransferase levels) were exclusively associated with pre-eclampsia complicated by FGR, while virulent but acute infections (CagA positive/ VacA negative patients, highest leukocyte blood count and aspartate aminotransferase levels) specifically correlated with PE without FGR. CONCLUSION: Our data strongly indicate that persistent and virulent H. pylori infections cause or contribute to PE complicated by FGR, but not to PE without feto-placental compromise.

Expression of soluble vascular endothelial growth factor receptor-1 and placental growth factor in fetal growth restriction cases and intervention effect of tetramethylpyrazine

Objective:To investigate the expression of soluble vascular endothelial growth factor receptor-1(sFlt-1) and placental growth factor(PLGF) in the fetal growth restriction(FGR) cases and the intervention mechanism of tetramelhylpyrazine.Methods:A total of 60 fetal growth restriction cases that admitted lo our hospital were randomly divided into ligustrazine intervention group(group A) and nutritional support group(group B).A total of 50 healthy pregnant women were also enrolled as control group(group C).Expression level of maternal serum sFlt1,FLGF and fetal growth parameters including HC,AC,FL,BPD,EFW as well as placenta PLGF,sFlt-1 mRNA expression were recorded and compared among the three groups.A total of 15 SD rats were selected and were divided into lliree groups.TMP group,alcohol and tobacco group and blank control group.Three groups of rats were dissected on the twentieth day of gestation.Result:Expression level of sFlt-1 and PLGF in group A was not significantly different from that of group C(P>0.05):but significant difference in SFlt1 and PLGF expression level was observed between group C and group B(P<0.05).Before treatment.HC,AC,FL,BPD and EFW of group A and group B were significant lower than those of group C.hut after treatment,those parameters in group A were significantly improved(P<0.05).In the animal experiment there was no significant difference in sFlt-1 between treatment group and FGR group without treatment or control group(P>0.05).There was significant difference in PLGF between FGR group with treatment and FGR group without treatment or control group(P<0.01).Conclusions:PLGF level is decreased and sFlt-1 increased in patients suffered from fetal growth restriction,and FGR rats show increased sFlt-1 and decreased PLGF.thus they can be indicator of the fetal growth restriction.Ligustrazinc can effectively improve sFlt-1,PLGF expression level in fetal growth restriction cases,which can be used as treatment for FGR.

Effect of behavior training on learning and memory of young rats with fetal growth restriction

Objective: To investigate the effect of behavior training on the learning and memory of young rats with fetal growth restriction (FGR). Methods: The model of FGR was established by passive smoking method to pregnant rats. The new-born rats were divided into FGR group and normal group, and then randomly subdivided into trained and untrained group respectively. Morris water maze behavior training was performed on postnatal months 2 and 4, then learning and memory abilities of young rats were measured by dark-avoidance testing and step-down testing. Results: In the dark-avoidance and step-down testing, the young rats’ performance of FGR group was worse than that of control group, and the trained group was better than the untrained group significantly. Conclusion: FGR young rats have descended learning and memory abilities. Behavior training could improve the young rats’ learning and memory abilities, especially for the FGR young rats.

Role of intergenic interactions among folate cycle genes in the development of fetal growth retardation

Objective:Metabolic disturbances in the folate cycle in mothers can lead to fetal growth retardation(FGR).This study was to analyze the role of intergenic interactions among maternal folate cycle genes in the development of FGR.Methods:This case-control study recruited 365 women in the third trimester of pregnancy,including 122 FGR patients and 243 controls.The women were genotyped for 5 polymorphisms of the 4 folate cycle genes:MTR(rs1805087),MTRR(rs1801394),serine hydroxymethyl transferase(SHMT1;rs1979277),and TYMS(rs699517 and rs2790).The SNP×SNP interactions in the two-,three-,and four-locus models were analyzed using the multifactor dimensionality reduction method and a modification of it(the model-based multifactor dimensionality reduction method).Results:Four loci of maternal folate cycle genes(rs1805087 MTR,rs2790 TYMS,rs1801394 MTRR,and rs1979277 SHMT1)were associated with FGR in 3 significant models of single nucleotide polymorphism(SNP)×SNP interactions(two-,three-,and four-locus models)(P<0.05).The highest contribution to FGR was made by polymorphic loci rs1979277 SHMT1(1.70%of entropy),rs1805087 MTR(0.96%),and interactions between rs1979277 SHMT1×rs1805087 MTR(-1.11%)and rs1801394 MTRR×rs1979277 SHMT1(-0.64%).The four-locus maternal genotype combination AG rs1801394 MTRR×AA rs1805087 MTR×CT rs1979277 SHMT1×AG rs2790 TYMS was associated with an increased risk of FGR(β=2.69,P=0.012).FGR-associated SNPs were correlated with the expression of 16 genes(MTR,MTRR,SHMT1,ALKBH5,CTD-2303H24.2,ENOSF1,FAM106A,FOXO3B,LGALS9C,LLGL1,MIEF2,NOS2P2,RP11-806L2.6,SMCR8,TOP3A,and USP32P2)in various tissues and organs related to FGR pathophysiology.Conclusion:SNP×SNP interactions of maternal folate cycle genes(MTR,MTRR,SHMT1,and TYMS)are associated with the development of FGR.

Development of fetal growth charts in twins stratified by chorionicity and mode of conception:a retrospective cohort study in China

Background:Twin pregnancies continue to increase worldwide;however,the current clinical prenatal evaluation for the intrauterine growth of twins still relies on the growth standards of singletons.We attempted to establish a set of fetal biometric references for Chinese twin pregnancies,stratified by chorionicity and conception mode as spontaneously conceived monochorionic diamniotic(SC-MCDA),spontaneously conceived dichorionic diamniotic(SC-DCDA),and assisted reproductive technology dichorionic diamniotic(ART-DCDA)twins.Methods:From 2016 to 2019,the ultrasonographic fetal biometric measurements were longitudinally collected in pregnant women,including fetal weight,biparietal diameter,head circumference,abdominal circumference,femur length,and humerus length.The linear mixed models were used to test the difference of growth patterns between groups,and the growth curve of each biometric parameter was modeled by a generalized additive model for location scale and shape.Results:A total of 929 twin pregnant women and 2019 singleton pregnant women,met the inclusion criteria.Among twin pregnancies,148 were SC-MCDA,215 were SC-DCDA,and 566 were ART-DCDA twins.Overall,SC-DCDA twins grew faster than SC-MCDA twins,while slower than ART-DCDA twins(all P<0.05),and all of the three groups showed significant differences comparing with singletons,especially during the third trimester.Hence,the customized fetal growth charts of each fetal biometric parameter were,respectively,constructed for SC-MCDA,SC-DCDA,and ART-DCDA twins.Conclusions:The fetal biometric trajectories demonstrated characteristic patterns according to chorionicity and conception mode.To fill the gap,we modeled fetal biometric parameters for Chinese SC-MCDA,SC-DCDA,and ART-DCDA twin pregnancies,hoping to provide a reference for the further establishment of fetal growth reference values for Chinese twin fetuses.

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.

Effects of Jinye Baidu Granule (金叶败毒颗粒) on Fetal Growth and Development with Maternal Active Human Cytomegalovirus Infection

To evaluate the effects of Jinye Baidu Granule （金叶败毒颗粒, JYBDG）, a traditional Chinese medicine compound prescription, on fetal growth and development with maternal active human cytomegalovirus infection. Methods： A prospective, randomized and controlled trial was adopted during January 1996 to June 2002. From the pregnant women with an abnormal pregnant history, 240 cases were screened to be infected by human cytomegalovirus （HCMV） by enzyme-linked immunoabsorbent assay （ELISA） and reverse transcription polymerase chain reaction （RT-PCR）. They were assigned according to the random number table to two groups. The 122 cases in the treatment group were administrated with JYBDG, one package each time, three times a day for two continuous weeks, while the other 118 in the control group did not receive any treatment. The negative conversion rate of both HCMV-IgM and HCMV late mRNA, the positive rate of HCMV-DNA in placenta and the intrauterine transmission rate between the two groups were compared, and fetal growth and development in partial fetuses were also observed. Results： The negative conversion rate of both HCMV-IgM and HCMV late mRNA, the positive rate of HCMV-DNA in placenta and the intrauterine transmission rate in the treatment group were 77. 05% （94/122）, 48.98% （48/98） and 21.74% （10/46） respectively, while those in the control group were 38. 14% （45/118）, 67.50% （54/80） and 52.63% （20/38） respectively, all showing significant difference between the two groups （P〈0.01）. Totally 35 normal infants and 11 abnormal infants were born in the treatment group, and the number in the control group was 20 and 18 respectively, and comparison between the two groups showed significant difference （P〈0.01）. Six months of child birth, the scores of both mental development index （MDI） and psychomotor development index （PDI） of infants were higher in the treatment group （20 cases） than those in the control group （20 cases）, but there was no significant difference between the two groups （P〉0.05）. Conclusion： JYBDG could decrease the intrauterine transmission of HCMV and is beneficial to fetal growth and development.

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.

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.