Fetal Growth Restriction Group Research Articles

Prediction of severe preeclampsia and intrauterine growth restriction based on serum placental exosome miR-520a-5p levels during the first-trimester.

To assess the predictive capabilities of serum exosomal levels of micro-RNA-520a-5p (miR-520a-5p) concerning the occurrence of severe preeclampsia (sPE) and fetal growth restriction (FGR) during the first trimester of pregnancy. During the period spanning from October 2020 to October 2021, serum samples were procured from the first trimester and subsequently preserved by freezing at -80 ℃. These samples were obtained from 105 pregnant women in a nested case-control study. This cohort consisted of individuals who later developed sPE (sPE group, n = 35) and FGR (FGR group, n = 35) during the third trimester. Additionally, 35 women with normal blood pressure were denoted as normal pregnancy group. Serum samples from the first trimester were retrieved from all groups for further analysis after thawing. Exosomes were extracted from the serum samples collected during the first trimester and examined using transmission electron microscopy, western blot, and nanoparticle tracking analysis. Additionally, the determination of their placental origin was also established during the course of the study. Exosome miR-520a-5p levels were measured using real-time quantitative polymerase chain reaction assays, primarily involving quantitative reverse transcription polymerase chain reactions. Fetal placental tissues from the 3 groups were collected shortly after birth, and miR-520a-5p expression was measured using real-time quantitative polymerase chain reaction. Serum placental exosomes and fetal placental tissues were compared for miR-520a-5p levels. Placental trophoblasts were identified as the source of serum exosomes in all 3 groups. It was found that serum placental exosomes exhibited lower levels of miR-520a-5p in both the sPE and FGR groups when compared to the normal pregnancy group. This finding was consistent with observations made in postpartum placental tissues. The predictive accuracy for sPE using miR-520a-5p levels in serum placental exosomes during the first trimester was notably higher (area under the receiver operating characteristic curve = 0.806, P <.05) compared to the prediction of FGR (area under the receiver operating characteristic curve = 0.628, P <.05). Placenta-derived exosomes can be extracted from maternal serum during the first trimester of pregnancy and miR-520a-5p detected from the exosomes. The downregulation of miR-520a-5p serves as a more predictive indicator for the subsequent development of sPE compared to predicting FGR.

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

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. 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. 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. 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). 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.

Maternal vascular indices at 36 weeks' gestation in small and growth restricted fetuses.

To compare maternal vascular indices and hemodynamic parameters at 35-37 weeks' gestation, in pregnancies complicated by small for gestational age (SGA) fetuses and those with fetal growth restriction (FGR). This was a prospective observational non-intervention study in women with singleton pregnancies attending for a routine hospital visit at 35+0 to 36+6 weeks' gestation. The visit included recording of maternal demographic characteristics and medical history, vascular indices and hemodynamic parameters obtained by a non-invasive operator independent device, including pulse wave velocity, augmention index, cardiac output, stroke volume, central systolic and diastolic blood pressure, total peripheral resistance and fetal heart rate. Hypertensive disorders of pregnancy were excluded and the values in the SGA and FGR groups were compared between them and with unaffected pregnancies. Diagnosis of SGA was based on the birth of a baby with birthweight below the 10th percentile for gestational age. In FGR, in addition to a birthweight below the 10th percentile, at the 35-37 weeks scan Doppler studies had shown that the uterine artery or umbilical artery pulsatility index (PI) was above the 95th percentile for gestational age or the fetal middle cerebral artery PI was below the 5th percentile. In the 6,413 women included in the study there were 605 (9.4%) cases of SGA, 133 (2.1%) of FGR and 5,675 (88.5%) unaffected by SGA or FGR. Women with SGA or FGR, compared to unaffected pregnancies, had increased peripheral vascular resistance and reduced cardiac output. Central systolic and diastolic blood pressure were also increased, whereas aortic stiffness assessed by pulse wave velocity and augmentation index did not differ between affected and unaffected pregnancies. In the FGR, compared to the SGA group, central systolic and diastolic blood pressure were higher, whereas, heart rate was lower. In SGA and FGR pregnancies there are deranged maternal hemodynamic responses when these are compared to normal pregnancies. Mothers with FGR babies have higher central blood pressure compared to SGA ones, but it remains unclear whether these differences are driven by the size of the fetus or pathological fetal growth. This article is protected by copyright. All rights reserved.

The genetics and clinical outcomes in 151 cases of fetal growth restriction: A Chinese single-center study

ObjectiveTo determine the detection rate of chromosomal abnormalities and pregnancy outcomes in fetuses with intrauterine growth restriction.Study designA total of 151 fetal samples with intrauterine growth restriction were were divided into the isolated fetal growth restriction (FGR) group, FGR group with structural malformation, and FGR group with non-structural malformation, according to ultrasound abnormalities. The enrolled patients were divided into an early onset FGR group (<32 weeks) and a late-onset FGR group (≥32 weeks). Chromosomal karyotype and microarray analyses were performed and pregnancy outcomes were monitored.ResultsThe karyotypes of 122 patients were analyzed. Four patients exhibited abnormal chromosome numbers or structures. Variations in copy number were detected in 151 cases; 19 cases were found to have chromosomal abnormalities, with a positivity rate of 12.6 %. There was one trisomy in 18 cases, one trisomy in 21 cases, eight pathogenic copy number variations (CNVs), and nine CNVs of unknown clinical significance. The detection rate of FGR combined with structural malformation was significantly higher than that of isolated FGR group. The detection rate of FGR with structural malformations was significantly higher than that with non-structural malformations. The positive detection rate in the FGR group was similar to that in the FGR group with non-structural malformations, with no statistical significance. Chromosomal abnormalities were detected in 17 patients with early onset FGR, with a positivity rate of 13.8 %. Two cases of chromosomal abnormalities were detected in the late-onset FGR group, with a positive rate of 7.1 %, with no statistical significance. A total of 151 fetuses with FGR were followed up for pregnancy outcomes, resulting in 36 cases of pregnancy termination and 13 cases of loss to follow-up. Among the 102 delivered fetuses, six exhibited delayed growth and development, one presented with hypospadias, and another failed the hearing screening. The remaining 94 fetuses demonstrated normal growth and development.ConclusionsThis study confirms the value of CNV detection in fetuses and dynamic ultrasound monitoring for fetuses with intrauterine growth restriction.

Long-term neurological outcomes of offspring misdiagnosed with fetal growth restriction.

Fetal growth restriction (FGR) is a major determinant of adverse short- and long-term perinatal outcomes. The current definition of FGR (estimated fetal weight measurement < 10th percentile) may lead, at times, to a false diagnosis of fetuses that are eventually born appropriate for gestational age (AGA). Our objective was to investigate the potential association between a misdiagnosis of antepartum fetal growth restriction and long-term neurological outcomes in offspring. A population-based cohort analysis was performed including deliveries between the years 1991-2020 in a tertiary medical center. We compared neurological hospitalization during childhood among AGA infants falsely diagnosed as FGR versus AGA infants without a false FGR diagnosis. A Kaplan-Meier survival curve was used to assess cumulative morbidity and a Cox proportional hazards model was employed to control for confounders. During the study period, 324,620 AGA infants met the inclusion criteria; 3249 of them were falsely classified as FGR. These offspring had higher rates of hospitalizations due to various neurological conditions, as compared to those without an FGR diagnosis (OR 1.431, 95% CI 1.278-1.608; P < 0.001). In addition, cumulative hospitalization incidence was elevated in the FGR group (log-rank P-value < 0.001). When controlling for confounders, a false FGR diagnosis remained independently associated with long-term neurological morbidities (adjusted HR 1.086, 95% CI 1.003-1.177, P = 0.043). Misdiagnosis of FGR in the antepartum period is associated with an increased risk for offspring long-term neurological morbidities.

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.

Maternal serum vasohibin-1 and vasohibin-2 concentrations in pregnant women diagnosed with late fetal growth restriction or small for gestational age fetus

Aims: Vasohibin 1, a member of the vasohibin family, is an inhibitor of angiogenesis, while vasohibin 2 stimulates angiogenesis. Placental expressions of vasohibins and their relationship with preeclampsia have been investigated, but their effects on intrauterine fetal growth are unknown. In this context, we aimed to investigate the concentrations of vasohibin 1 and 2 in the serum of pregnant women diagnosed with late fetal growth restriction (FGR) or small for gestational age (SGA) in the third trimester. Methods: This prospective non-interventional cohort study was conducted on 81 pregnant women, 26 of whom were diagnosed with late FGR, 28 were SGA, and 27 were healthy controls. Three groups were compared in terms of serum vasohibin 1 and 2 concentrations in the third trimester. Results: Three groups were similar in terms of demographic characteristics and gestational age at blood sampling for vasohibin 1 and 2 (p &lt; 0.05). The median vasohibin 1 concentration was determined as 1227.41 ng/mL in the late FGR group, 1311.15 ng/mL in the SGA group, and 1391.38 ng/mL in the control group (p = 0.139). The median vasohibin 2 concentration was determined as 11.24 ng/mL in the late FGR group, 11.86 ng/mL in the SGA group, and 14.34 ng/mL in the control group (p = 0.198). Conclusion: Serum vasohibin 1 and 2 concentrations were found to be similar in pregnant women diagnosed with late FGR and SGA and pregnant women with AGA fetuses. Vasohibin 1 and 2 are involved in the regulation of placental angiogenesis, but their roles in intrauterine fetal growth remain unclear.

The associations between maternal and fetal exposure to endocrine-disrupting chemicals and asymmetric fetal growth restriction: a prospective cohort study.

Recent evidence has revealed associations between endocrine-disrupting chemicals (EDCs) and placental insufficiency due to altered placental growth, syncytialization, and trophoblast invasion. However, no epidemiologic study has reported associations between exposure to EDCs and asymmetric fetal growth restriction (FGR) caused by placenta insufficiency. The aim of this study was to evaluate the association between EDC exposure and asymmetric FGR. This was a prospective cohort study including women admitted for delivery to the Maternal Fetal Center at Seoul St. Mary's Hospital between October 2021 and October 2022. Maternal urine and cord blood samples were collected, and the levels of bisphenol-A (BPA), monoethyl phthalates, and perfluorooctanoic acid in each specimen were analyzed. We investigated linear and non-linear associations between the levels of EDCs and fetal growth parameters, including the head circumference (HC)/abdominal circumference (AC) ratio as an asymmetric parameter. The levels of EDCs were compared between fetuses with and without asymmetric FGR. Of the EDCs, only the fetal levels of BPA showed a linear association with the HC/AC ratio after adjusting for confounding variables (β = 0.003, p < 0.05). When comparing the normal growth and asymmetric FGR groups, the asymmetric FGR group showed significantly higher maternal and fetal BPA levels compared to the normal growth group (maternal urine BPA, 3.99 μg/g creatinine vs. 1.71 μg/g creatinine [p < 0.05]; cord blood BPA, 1.96 μg/L vs. -0.86 μg/L [p < 0.05]). In conclusion, fetal exposure levels of BPA show linear associations with asymmetric fetal growth patterns. High maternal and fetal exposure to BPA might be associated with asymmetric FGR.

Potential Association of Gut Microbial Metabolism and Circulating mRNA Based on Multiomics Sequencing Analysis in Fetal Growth Restriction.

Fetal growth restriction (FGR) is a significant contributor to negative pregnancy and postnatal developmental outcomes. Currently, the exact pathological mechanism of FGR remains unknown. This study aims to utilize multiomics sequencing technology to investigate potential relationships among mRNA, gut microbiota, and metabolism in order to establish a theoretical foundation for diagnosing and understanding the molecular mechanisms underlying FGR. In this study, 11 healthy pregnant women and nine pregnant women with FGR were divided into Control group and FGR group based on the health status. Umbilical cord blood, maternal serum, feces, and placental tissue samples were collected during delivery. RNA sequencing, 16S rRNA sequencing, and metabolomics methods were applied to analyze changes in umbilical cord blood circulating mRNA, fecal microbiota, and metabolites. RT-qPCR, ELISA, or western blot were used to detect the expression of top 5 differential circulating mRNA in neonatal cord blood, maternal serum, or placental tissue samples. Correlation between differential circulating mRNA, microbiota, and metabolites was analyzed by the Spearman coefficient. The top 5 mRNA genes in FGR were altered with the downregulation of TRIM34, DEFA3, DEFA1B, DEFA1, and QPC, and the upregulation of CHPT1, SMOX, FAM83A, GDF15, and NAPG in newborn umbilical cord blood, maternal serum, and placental tissue. The abundance of Bacteroides, Akkermansia, Eubacterium_coprostanoligenes_group, Phascolarctobacterium, Parasutterella, Odoribacter, Lachnospiraceae_UCG_010, and Dielma were significantly enriched in the FGR group. Metabolites such as aspartic acid, methionine, alanine, L-tryptophan, 3-methyl-2-oxovalerate, and ketoleucine showed notable functional alterations. Spearman correlation analysis indicated that metabolites like methionine and alanine, microbiota (Tyzzerella), and circulating mRNA (TRIM34, SMOX, FAM83A, NAPG) might play a role as mediators in the communication between the gut and circulatory system interaction in FGR. Metabolites (METHIONINE, alanine) as well as microbiota (Tyzzerella) and circulating mRNA (TRIM34, SMOX, FAM83A, NAPG) were possible mediators that communicated the interaction between the gut and circulatory systems in FGR.

The role of the ratio of first trimester CRL (crown rump length) measurement to NT (nuchal translucency) measurements in predicting early-onset fetal growth restriction (FGR)

Objective: Our aim is to evaluate the role of the ratio of first-trimester CRL (crown rump length) measurement to NT (nuchal translucency) measurements in predicting early-onset fetal growth restriction (FGR) and to contribute to the existing literature.&#x0D; Methods: In the present case-control study, fetuses with early-onset FGR were compared to a frequency matched low risk control group. This study was conducted in the perinatology clinic of Ankara Bilkent City Hospital between 2020 and 2023. Maternal age, gravidity, parity, crown-rump length (CRL), and nuchal translucency (NT) measurements were compared between pregnant women with early onset FGR (n=39) and pregnant women without FGR (n=50).&#x0D; Results: The mean age of pregnant women with FGR who participated in the study was 27.1±0.8, and the mean age of pregnant women without FGR was 26.3±0.6, and no statistically significant difference was found between the two groups (p=0.4)). Mean CRL was 54.98±1.08 mm in the group with FGR and 56.99±1.11 mm in the group without FGR; there was no significant difference between the two groups (p=0.2). The NT value was 1.11 ± 0.04 mm in the FGR group and 1.13 ± 0.02 mm in the without FGR group, there was no significant difference between the two groups (p=0.73). The mean CRL/NT ratio was 52.00±2.33 in the group with early onset FGR and 51.46±1.48 in the group without FGR and there was no statistically significant difference between the two groups (p=0.83).&#x0D; When the early developing FGR group is evaluated within itself, the mean age at diagnosis was 31.7±0.3 weeks. EFW mean percentile at diagnosis was 4.5±0.6 and ac percentile was 2.9±0.4. The mean umbilical artery systole/diastole ratio (UA-SD) was 2.9±0.16 and the mean umbilical artery pulsatility index (UA-PI) was 1.02±0.05.&#x0D; Conclusion: Crown-rump length to nuchal translucency ratio is not clinically useful to predict early-onset FGR.

Evaluation of Fetal Breathing-Related Nasal Fluid Flow Doppler in the Third Trimester in Pregnant Women with Fetal Growth Restriction: Preliminary Observations.

To investigate the fetal breathing-related nasal fluid flow Doppler waveforms as an indicator of fetal respiratory function in fetuses diagnosed with fetal growth restriction (FGR) in the third trimester. This prospective, non-interventional case-control study was conducted on 96 pregnant women, including 23 pregnant women diagnosed with FGR in the third trimester as the FGR group and 73 healthy pregnant women with fetuses appropriate for gestational age (AGA) as the control group. Fetal breathing-related nasal fluid flow Doppler was examined in the fetuses of the participants. Inspiration and expiration duration, inspiration and expiration peak velocity, total breathing duration, and number of fetal breaths per minute were calculated. Both groups were similar in terms of the duration of inspiration, duration of expiration, and total breathing duration (p=0.463, p=0.711, p=0.520, respectively). Peak inspiratory velocity and peak expiratory velocity were significantly lower in the FGR group than in the control group, and the number of fetal breaths per minute was similar in both groups (p=0.027, p=0.012, p=0.768, respectively). When participants were regrouped into those whose newborn was admitted to the neonatal intensive care unit (NICU) after birth and those who were not, all fetal nasal fluid flow Doppler parameters were similar in both groups. Although the number of participants was too small to draw a definitive conclusion, FGR appears to be associated with a decrease in peak inspiratory and expiratory velocity. The clinical significance of changes in fetal breathing-related nasal fluid flow Doppler parameters in FGR is as yet unclear, and their use in clinical follow-up and predicting unfavorable perinatal outcomes are the subjects of future research.

FGR-associated placental insufficiency and capillary angiogenesis involves disruptions in human placental miRNAs and mRNAs

Fetal growth restriction (FGR) is one of the most common pregnancy complications culminating in adverse fetal outcome, including preterm birth, neonatal mortality and stillbirth. Compromised placental development and function, especially disruption in angiogenesis and inadequate nutrient supply are contributing factors. Fetal sex also influences placental function. Knowledge of gene expression changes and epigenetic factors contributing to placental dysfunction in FGR pregnancies will help identify biomarkers and help target interventions. This study tested the hypothesis that FGR pregnancies are associated with disruptions in miRNA - an epigenetic factor and mRNAs involving key mediators of angiogenesis and microvessel development. Changes in expression of key genes/proteins involved in placental dysfunction by RT-PCR and immunohistochemistry and miRNA changes by RNA sequencing were undertaken with term placenta from 12 control and 20 FGR pregnancies. Findings showed changes in expression of genes involved in steroidogenesis, steroid action, IGF family members, inflammatory cytokines and angiogenic factors in FGR pregnancies. In addition, upregulation of MIR451A and downregulation of MIR543 in placentas from FGR group with female newborns and upregulation of MIR520G in placentas from FGR group with male newborns were also noted. MIR451A and MIR543 have been implicated in angiogenesis. Consistent with gene changes, CD34, the microvessel angiogenesis marker, also showed reduced staining only in female FGR group. These findings provide evidence that epigentically regulated gene expression changes in angiogenesis and capillary development influence placental impairment in FGR pregnancies. Our preliminary observations also support for these changes to be driven in a sex-specific manner.

N-acetylcysteine and Hydroxychloroquine Ameliorate ADMA-Induced Fetal Growth Restriction in Mice via Regulating Oxidative Stress and Autophagy.

Fetal growth restriction (FGR) seriously threatens perinatal health. The main cause of FGR is placental malperfusion, but the specific mechanism is still unclear, and there is no effective treatment for FGR. We constructed a FGR mouse model by adding exogenous asymmetric dimethylarginine (ADMA) through in vivo experiments and found that ADMA could cause placental dysplasia and induce the occurrence of FGR. Compared with the control group, reactive oxygen species (ROS) production in the placenta was increased in mice with FGR, and the expression of autophagy-related proteins p-AKT/AKT, p-mTOR/mTOR, and P62 was significantly decreased, while the expression of Beclin-1 and LC3-II was significantly increased in the FGR group. Furthermore, ADMA had a favorable effect in promoting the formation of autophagosomes. Hydroxychloroquine (HCQ) and N-acetylcysteine (NAC) improved ADMA-induced disorders of placental development and alleviated ADMA-induced FGR. This study found that ADMA could cause excessive autophagy of trophoblasts by increasing the level of oxidative stress, ultimately leading to the occurrence of FGR, and HCQ and NAC had therapeutic effects on ADMA-induced FGR.

Prediction of preterm birth in growth-restricted and appropriate-for-gestational-age infants using maternal PlGF and the sFlt-1/PlGF ratio-A prospective study.

To assess the utility of placental growth factor (PlGF) levels and the soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) ratio to predict preterm birth (PTB) for infants with fetal growth restriction (FGR) and those appropriate for gestational age (AGA). Prospective, observational cohort study. Tertiary maternity hospital in Australia. There were 320 singleton pregnancies: 141 (44.1%) AGA, 83 (25.9%) early FGR (<32+0 weeks) and 109 (30.0%) late FGR (≥32+0 weeks). Maternal serum PlGF and sFlt-1/PlGF ratio were measured at 4-weekly intervals from recruitment to delivery. Low maternal PlGF levels and elevated sFlt-1/PlGF ratio were defined as <100 ng/L and >5.78 if <28 weeks and >38 if ≥28 weeks respectively. Cox proportional hazards models were used. The analysis period was defined as the time from the first measurement of PlGF and sFlt-1/PlGF ratio to the time of birth or censoring. The primary study outcome was overall PTB. The relative risks (RR) of birth within 1, 2 and 3 weeks and for medically indicated and spontaneous PTB were also ascertained. The early FGR cohort had lower median PlGF levels (54 versus 229 ng/L, p < 0.001) and higher median sFlt-1 levels (2774 ng/L versus 2096 ng/L, p < 0.001) and sFlt-1/PlGF ratio higher (35 versus 10, p < 0.001). Both PlGF <100 ng/L and elevated sFlt-1/PlGF ratio were strongly predictive for PTB as well as PTB within 1, 2 and 3 weeks of diagnosis. For both FGR and AGA groups, PlGF <100 ng/L or raised sFlt-1/PlGF ratio were strongly associated with increased risk for medically indicated PTB. The highest RR was seen in the FGR cohort when PlGF was <100 ng/L (RR 35.20, 95% CI 11.48-175.46). Low maternal PlGF levels and elevated sFlt-1/PlGF ratio are potentially useful to predict PTB in both FGR and AGA pregnancies.

Clinical significance of three-dimensional power Doppler combined with two-dimensional Doppler ultrasonography for evaluating fetal growth restriction

Objectives To assess the predictive accuracy of three-dimensional (3D) power Doppler combined with two-dimensional (2D) Doppler ultrasonography in detecting fetal growth restriction (FGR). Methods The study was conducted on singleton pregnancies presenting for growth ultrasound examinations between 20 and 40 weeks of gestation. 63 patients with FGR were enrolled and matched 1:1.8 for gestational age with normal fetuses. Both groups were further divided into subgroups, with 32 weeks as the threshold—early-onset and late-onset FGR groups, and corresponding control groups. Conventional 2D Doppler parameters and standardized 3D power Doppler measurements of the placenta, including vascularization index (VI), flow index (FI), and vascularization-flow index (VFI) were obtained for each patient. Results (1) The average gestational weeks of delivery and birth weight of newborns in early-onset and late-onset FGR case groups were lower than those in control groups, while the incidence of placenta previa and adverse pregnancy outcomes were higher than those in control groups. (2) The biparietal diameter, head circumference, abdominal circumference, femur length, estimated fetal weight, middle cerebral artery systolic/diastolic velocity ratio (S/D), pulsatility index (PI), resistance index (RI), and placental blood perfusion indices of vascular index (VI), flow index (FI), vascular flow index (VFI), and cerebro-placental ratio (CPR) of the early-onset and late-onset FGR case groups were all lower than those of the control group. Moreover, the S/D, PI, and RI of the umbilical and uterine arteries were higher than those of the corresponding control group. (3) For early-onset FGR, the area under the curve (AUC) of the umbilical artery PI was the largest (0.861), exhibiting the highest predictive value. When combined with the placental blood perfusion index, the AUC was 0.789. For late-onset FGR, the AUC of the CPR was 0.861. After integrating the placental blood perfusion index, the AUC increased to 0.877. The positive likelihood ratio (PLR) of combined 2D Doppler indexes (21.938) and negative likelihood ratio (NLR) of VFI (0.565) were the highest in the early-onset FGR group. The PLR of combined 3D Doppler indexes (8.536) and NLR of VFI (0.557) were the highest in the late-onset FGR group. Conclusions The combination of 3D Doppler indices with 2D Doppler ultrasonography demonstrated superior predictive value in diagnosing late-onset FGR compared to other conventional indicators. The 3D Dower index, VFI, has a good true-negative predictive value for both early- and late-onset FGR.

Phenotype of early-onset fetal growth restriction in sheep.

Fetal growth restriction (FGR) is a common pregnancy complication, caused by placental insufficiency, with serious adverse consequences for development in utero and postnatal wellbeing. There are no antenatal treatments to improve growth or organ development in FGR, and animal models are essential to mimic the physiological adaptations in FGR and to assess potential interventions. This study aimed to identify the temporal nature of reduced developmental trajectory in fetuses with FGR, and to examine the effects of common factors that may mediate differential growth such as glucocorticoid treatment. We hypothesised that the trajectory of growth would be adversely impacted by FGR. FGR was induced via surgical placental insufficiency in fetal sheep (89 days gestation/0.6 gestation; n=135) and compared to age-matched controls over the last third of gestation and into neonatal life (n=153). Body weight of FGR fetuses/lambs was significantly reduced compared to controls (p<0.0001) from 127 days of gestation (term is 148 days), with increased brain:body weight ratio (p<0.0001) indicative of brain sparing. All biometric measures of body size were reduced in the FGR group with the exception of biparietal (head) diameter. The trajectory of body growth in the last trimester of sheep pregnancy was significantly reduced in the FGR group compared to controls, and stillbirth rate increased with longer gestation. This work provides a well characterised FGR animal model that mimics the known physiological adaptations in human pregnancy and can be used to determine the efficacy of potential interventions.

Small for gestational age at preterm birth identifies adverse neonatal outcomes more reliably than antenatal suspicion of fetal growth restriction

Background Fetal growth restriction (FGR) is an important reason for premature delivery and a leading cause of perinatal morbidity and mortality. We aimed to evaluate whether classification as small for gestational age (SGA; <10th centile) at birth or antenatal suspicion of FGR was more strongly associated with neonatal morbidity and mortality in preterm infants. Methods A retrospective audit of infants born between 24 + 0 and 32 + 6 weeks of gestation from 2012–2019 and admitted to the Neonatal Unit at Mercy Hospital for Women (MHW). Infants were categorized according to whether FGR was listed as an antenatal complication in the medical records and whether they were SGA (<10th centile on Fenton chart) or appropriate for gestational age (AGA) at birth, and comparisons for neonatal outcomes were made. Results 371/2126 preterm infants (17.5%) had antenatal suspicion of FGR, and 166 (7.8%) were SGA at birth. No differences in any neonatal outcomes were found between infants with or without suspected FGR, except decreased intraventricular hemorrhage (IVH) in the FGR group. SGA classification was associated with increased rates of all morbidities other than IVH, including bronchopulmonary dysplasia, retinopathy of prematurity, and necrotizing enterocolitis, compared with the AGA group. Death was significantly higher in the SGA group (7.2%) compared with the AGA group (3.5%). Conclusion SGA by Fenton chart more reliably identified neonates at risk of adverse neonatal outcomes than antenatal suspicion of FGR, suggesting it is a reasonable clinical proxy. This most likely reflects the much lower tenth centile weight cutoffs on the Fenton charts compared to in-utero charts used antenatally to diagnose FGR based on ultrasound estimated fetal weight. SGA classification by Fenton approximately equates to <3rd centile on in-utero charts at our institution, therefore identifying the most severe FGR cases.

Clinical value of serum SIRT1 combined with uterine hemodynamics in predicting disease severity and fetal growth restriction in preeclampsia

Objective &#x0D; To investigate the effect and correlation of serum SIRT1 combined with uterine hemodynamic parameters on disease severity and fetal uterine growth restriction in the progression of preeclampsia, and to evaluate its clinical value as potential markers.&#x0D; Methods&#x0D; A total of 100 patients with preeclampsia who were hospitalized in Qufu Normal University Hospital from June 2017 to June 2021 were selected as the research objects. According to the severity, they were divided into Mild group (62 cases) and Severe group (38 cases), and according to whether the fetal growth restriction was combined or not, they were divided into the Combined fetal growth restriction group (56 cases) and the Uncomplicated fetal growth restriction group (44 cases). Serum SIRT1 expression and uterine artery hemodynamic parameters were detected, and spearman analysis was used to evaluate the association of serum SIRT1 expression and uterine artery hemodynamic parameters (peak-to-trough ratio of arterial blood velocity, pulsatility index, resistance index) with disease severity (systolic blood pressure, diastolic blood pressure, and random urinary protein levels) and fetal growth restriction (femoral length, biparietal diameter, head circumference and neonatal weight); unsupervised PCA analysis, supervised PLS-DA analysis, Cluster heat map analysis, ROC curve and AUC analysis were used to evaluate the diagnostic value of serum SIRT1 expression combined with uterine artery hemodynamic parameters in the severity of disease and fetal growth restriction in patients with preeclampsia.&#x0D; Results&#x0D; Serum SIRT1 expression was decreased in patients with severe preeclampsia (p &lt; 0.0001), arterial blood flow velocity peak-to-trough ratio, pulsatility index and resistance index were increased (p &lt; 0.001; p &lt; 0.0001), and serum SIRT1 expression and uterine artery hemodynamic parameters were closely related to disease severity (p &lt; 0.001; p &lt; 0.0001). In addition, the expression of serum SIRT1 in patients with preeclampsia combined with fetal growth restriction was decreased (p &lt; 0.0001), the peak-to-trough ratio of arterial blood flow velocity, pulsatility index and resistance index were increased (p &lt; 0.0001), and serum SIRT1 expression and uterine artery hemodynamics were closely related to fetal growth restriction (p &lt; 0.0001). Unsupervised PCA analysis and supervised PLS-DA analysis showed that patients with different severity of disease and patients with or without fetal growth restriction were similar within groups, and there were significant differences between groups; cluster heat map analysis showed that mild and severe groups were stratified clustering, the combined fetal growth restriction group and the uncombined group were hierarchically clustered; ROC curve and AUC analysis showed that serum SIRT1 expression combined with uterine artery hemodynamic parameters had a significant effect on the severity of preeclampsia and whether combined with fetal growth restriction. high diagnostic value.&#x0D; Conclusion &#x0D; Serum SIRT1 combined with uterine hemodynamic parameters in preeclampsia is closely related to disease severity and fetal growth restriction, and is expected to become potential biomarkers for early clinical intervention in patients.

Evaluation of carotid artery Doppler measurements in late-onset fetal growth restriction: a cross-sectional study

Background/Aim: It has been reported that both the internal carotid artery (ICA) and the common carotid artery (CCA) are associated with hypoxia, also observed in late-onset fetal growth restriction (FGR). However, it has not yet been investigated whether these Doppler measurements differ in cases of late-onset FGR. This study evaluated the ICA and the CCA Doppler parameters in late-onset FGR fetuses and compared these measurements with those of healthy fetuses. Methods: This cross-sectional observational study comprised 75 singleton pregnancies diagnosed with late-onset FGR between the 32nd and 37th weeks of gestation, alongside 75 healthy fetuses paired 1:1 based on obstetric history and gestational age between June 2022 and May 2023. The Delphi consensus of 2016 was used for the definition of late-onset FGR. The exclusion criteria were congenital anomalies, presence of any additional disease, maternal body mass index over 35 kg/m2, abdominal scars hindering ultrasound visualization, use of medications such as antenatal steroids, sympathomimetics, and indomethacin that affect vascular function, drug use, smoking during pregnancy, concurrent preeclampsia, and multiple pregnancies. Upon the patients' admission to the hospital, their demographic characteristics were documented, and ultrasonographic examinations and Doppler measurements were subsequently performed. The Doppler velocimetry of the umbilical artery (UA) encompassed measurements of the systolic to diastolic ratio (S/D), pulsatility index (PI), and peak systolic velocity (PSV). The carotid artery Doppler velocimetry of the middle cerebral artery (MCA), ICA, and CCA encompassed measurements of the PI, resistance index (RI), and PSV. We assessed the diagnostic performance of Doppler measurements for late-onset FGR through receiver operating characteristic (ROC) analysis. Results: In the late-onset FGR group, the mean UA-SD was higher (2.7 [0.6] vs. 2.5 [0.5], P=0.006), and the mean UA-PI (0.8 [0.2] vs. 0.9 [0.2], P=0.011) and mean PSV (35.6 [8.2] vs. 41.1 [7.1], P&lt;0.001) were lower compared to the control group. In the late-onset FGR group, carotid Doppler measurements were more pronounced than UA Doppler measurements. Moreover, ICA Doppler measurements exhibited superior diagnostic performance in predicting late-onset FGR compared to other Doppler measurements (Area under the curve [AUC]=0.777, P&lt;0.001 for ICA-PI; AUC=0.751, P&lt;0.001 for ICA-RI; AUC=0.749, P&lt;0.001 for ICA-PSV). Conclusion: In fetuses with late-onset FGR, UA Doppler measurements showed minimal differences compared to healthy fetuses, but differences in carotid Doppler measurements, especially in the ICA, were more pronounced. Therefore, in the management of fetuses suspected of having late-onset FGR, a more detailed Doppler examination might be required.

Impact of fetal growth restriction on pregnancy outcome in women undergoing expectant management for preterm pre-eclampsia.

To assess whether coexisting fetal growth restriction (FGR) influences pregnancy latency among women with preterm pre-eclampsia undergoing expectant management. Secondary outcomes assessed were indication for delivery, mode of delivery and rate of serious adverse maternal and perinatal outcomes. We conducted a secondary analysis of the Pre-eclampsia Intervention (PIE) and the Pre-eclampsia Intervention 2 (PI2) trial data. These randomized controlled trials evaluated whether esomeprazole and metformin could prolong gestation of women diagnosed with pre-eclampsia between 26 and 32 weeks of gestation undergoing expectant management. Delivery indications were deteriorating maternal or fetal status, or reaching 34 weeks' gestation. FGR (defined by Delphi consensus) at the time of pre-eclampsia diagnosis was examined as a predictor of outcome. Only placebo data from PI2 were included, as the trial showed that metformin use was associated with prolonged gestation. All outcome data were collected prospectively from diagnosis of pre-eclampsia to 6 weeks after the expected due date. Of the 202 women included, 92 (45.5%) had FGR at the time of pre-eclampsia diagnosis. Median pregnancy latency was 6.8 days in the FGR group and 15.3 days in the control group (difference 8.5 days; adjusted 0.49-fold change (95% CI, 0.33-0.74); P < 0.001). FGR pregnancies were less likely to reach 34 weeks' gestation (12.0% vs 30.9%; adjusted relative risk (aRR), 0.44 (95% CI, 0.23-0.83)) and more likely to be delivered for suspected fetal compromise (64.1% vs 36.4%; aRR, 1.84 (95% CI, 1.36-2.47)). More women with FGR underwent a prelabor emergency Cesarean section (66.3% vs 43.6%; aRR, 1.56 (95% CI, 1.20-2.03)) and were less likely to have a successful induction of labor (4.3% vs 14.5%; aRR, 0.32 (95% CI, 0.10-1.00)), compared to those without FGR. The rate of maternal complications did not differ significantly between the two groups. FGR was associated with a higher rate of infant death (14.1% vs 4.5%; aRR, 3.26 (95% CI, 1.08-9.81)) and need for intubation and mechanical ventilation (15.2% vs 5.5%; aRR, 2.97 (95% CI, 1.11-7.90)). FGR is commonly present in women with early preterm pre-eclampsia and outcome is poorer. FGR is associated with shorter pregnancy latency, more emergency Cesarean deliveries, fewer successful inductions and increased rates of neonatal morbidity and mortality. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.