Fetal Growth Restriction Pregnancies Research Articles

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.

Externally validated nomogram for predicting short-term pregnancy outcome of singleton pregnancies with fetal growth restriction (FGR)

ObjectiveThis study aimed at developing an available predictive model of singleton pregnancies with fetal growth restriction (FGR) for accurate and individualised prognosis assessment.MethodsThe prediction nomogram was developed by using multivariable...

Fetal growth restriction exhibits various mTOR signaling in different regions of mouse placentas with altered lipid metabolism

Fetal growth restriction (FGR) is a common complication of pregnancy and can have significant impact on obstetric and neonatal outcomes. Increasing evidence has shown that the inhibited mechanistic target of rapamycin (mTOR) signaling in placenta is associated with FGR. However, interpretation of existing research is limited due to inconsistent methodologies and varying understanding of the mechanism by which mTOR activity contributes to FGR. Hereby, we have demonstrated that different anatomic regions of human and mouse placentas exhibited different levels of mTOR activity in normal compared to FGR pregnancies. When using the rapamycin-induced FGR mouse model, we found that placentas of FGR pregnancies exhibited abnormal morphological changes and reduced mTOR activity in the decidual-junctional layer. Using transcriptomics and lipidomics, we revealed that lipid and energy metabolism was significantly disrupted in the placentas of FGR mice. Finally, we demonstrated that maternal physical exercise during gestation in our FGR mouse model was associated with increased fetal and placental weight as well as increased placental mTOR activity and lipid metabolism. Collectively, our data indicate that the inhibited placental mTOR signaling contributes to FGR with altered lipid metabolism in mouse placentas, and maternal exercise could be an effective method to reduce the occurrence of FGR or alleviate the adverse outcomes associated with FGR.Graphical Human and mouse placentas have different mTOR signaling activities in different anatomic regions in normal and FGR pregnancies.Pregnant mice with FGR induced by rapamycin show smaller placentas, decreased mTOR activity in DJ layer of placenta and altered lipid metabolism.Maternal exercise partially alleviates the abnormal outcomes of FGR model.

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.

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.

Umbilical–portal–systemic venous shunt and intrauterine growth restriction: an inquiry from a prospective study

BackgroundThe investigation of the fetal umbilical-portal venous system is based on the premise that congenital anomalies of this system may be related to adverse perinatal outcomes. Several retrospective small studies have reported a well-established association between umbilical–portal–systemic venous shunts and fetal growth restriction. However, the prevalence of portosystemic shunts in the fetal growth restricted population is yet to be determined. ObjectivesThe aims of this study were:1. To determine the prevalence of fetal umbilical–portal–systemic venous shunts in pregnancies complicated by fetal growth restriction.2. To compare the perinatal and neonatal outcome of fetal growth restriction pregnancies with and without umbilical–portal–systemic venous shunts. Study DesignA prospective cross-sectional study of pregnancies diagnosed with fetal growth restriction, as defined by the Society for Maternal-Fetal Medicine fetal growth restriction guidelines. All participants underwent a detailed anomaly scan supplemented with a targeted scan of the fetal portal system. Venous shunts were diagnosed using color Doppler mode. The perinatal outcomes of fetal growth restriction pregnancies with and without umbilical–portal–systemic venous shunts were compared. ResultsOne hundred and fifty cases of fetal growth restriction were recruited. The prevalence of umbilical–portal–systemic venous shunts in our cohort was 9.3% (n=14). Compared to the control group (fetal growth restriction without umbilical–portal–systemic venous shunts, n=136), the study group had a significantly lower mean gestational age at time of fetal growth restriction diagnosis [29.7 (±5.6) vs. 32.47 (±4.6) weeks of gestation, p=0.036] as well as an earlier gestational week at delivery [33.50 (±6.0) vs. 36.13 (±2.8), p=0.005]. The study group had a higher rate of fetal death (21.4% vs. 0.7%, p<0.001) and accordingly a lower rate of live births (71.4% vs. 95.6%, p=0.001). Associated additional fetal vascular anomalies were significantly more prevalent in the study group compared to controls (35.7% vs. 4.4%, respectively, p=<0.001). The rate of other associated anomalies was similar. The study group had a significantly lower rate of abnormal uterine artery Doppler indices (0% vs. 40.4% p=0.011) and a higher rate of abnormal ductus venosus Doppler indices (64.3% vs. 23% p=0.001). There were no cases of hypertensive disorders of pregnancy in the study group compared to 12.5% in the control group (p=0.16). Other perinatal and neonatal outcomes were comparable. ConclusionsUmbilical–portal–systemic venous shunt is a relatively common finding in growth restricted fetuses. Compared to fetal growth restriction pregnancies with a normal portal system, these pregnancies complicated by FGR and umbilical–portal–systemic venous shunt are associated with different Doppler flow pattern, increased risk for fetal death, earlier presentation of fetal growth restriction, lower gestational age at delivery, additional congenital vascular anomalies and a lower rate of pregnancy induced hypertensive disorders. Meticulous sonographic evaluation of the portal system should be considered in the prenatal workup of fetal growth restriction, as umbilical–portal–systemic venous shunts may have implications on perinatal outcome.

Maternal serum fatty acid binding protein-4 level is upregulated in fetal growth restriction with abnormal Doppler flow patterns.

This study aimed to determine fatty acid binding protein-4 (FABP-4) concentrations in maternal serum of fetal growth restriction (FGR) pregnancies and controls of normal pregnancies. Furthermore, we hypothesized that the alterations in FABP-4 levels might correlate with FGR severity. We performed this prospective case-control study with 83 pregnant women. The study groups included 26 FGR pregnancies without abnormal fetal Doppler flow patterns and 25 pregnancies complicated with FGR accompanied by abnormal fetal Doppler flow patterns. The median serum FABP-4 concentrations were significantly higher in the FGR cases with abnormal Doppler flow pattern group (2.09 ng/mL) than in the FGR cases without abnormal Doppler flow pattern group (1.62 ng/mL) and the control group (1.20 ng/mL, p < 0.001). A significant negative correlation was observed between maternal serum FABP-4 levels and time to birth from blood sample collection (r = -0.356 and p = 0.001), gestational week at birth (r = -0.386 and p < 0.001), and birth weight (r = -0.394 and p < 0.001). A 1.35 ng/mL cut-off value of serum FABP-4 level could be used to discriminate FGR cases with a 78.4% sensitivity and 60.6% specificity. The optimal cut-off value of FABP-4 levels as an indicator for the diagnosis of FGR with abnormal Doppler flow pattern was estimated to be 1.76 ng/mL, which yielded a sensitivity of 84.0% and a specificity of 75.8%. FABP-4 is a crucial biomarker in the diagnosis and determining the severity of pregnancies with restricted fetal growth. We consider that FABP-4 is a powerful, reliable, and unique biomarker to diagnose FGR pregnancies.

Liposome-Encapsulated Anti-inflammatory Proteins for Targeted Delivery to the Placenta to Treat Fetal Growth Restriction.

Fetal growth restriction (FGR), the failure of a fetus to reach its genetically determined growth potential, is a serious complication affecting up to 10% of pregnancies. FGR is a major risk factor for stillbirth and, in the survivors, neurodevelopmental disorders. We have recently identified that the anti-inflammatory and pro-resolving molecule, lipoxin A4 (LXA4) and its soluble receptor, formyl-peptide receptor-2 (FPR-2) are significantly decreased in human placentas from FGR pregnancy. The LXA4 synthetic analog Compound 43 (C43) is considered a safe, anti-inflammatory therapy and is being developed as a treatment for disease conditions with an inflammatory basis, for example, asthma in children. Identification of therapies to treat FGR in utero comes with the need to mitigate their potential side effects and the use of nanoparticle-mediated delivery systems could facilitate this. Our current studies are focused on targeting the resolution of inflammation observed in FGR placentas, by synthesizing liposome-encapsulated C43 as a novel therapeutic to improve placental function in FGR. In this chapter, we provide a detailed methodological procedure for the preparation of liposomes and conjugation of the peptide sequences, which selectively bind to the outer placental syncytiotrophoblast layer or the vascular endothelium of the uterine spiral arterioles.

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.

EP18.17: Prediction of pre‐eclampsia and fetal growth restriction in pregnancies with systemic lupus erythematosus

EP18.17: Prediction of pre‐eclampsia and fetal growth restriction in pregnancies with systemic lupus erythematosus

Dysfunction of ZNF554 promotes ROS-induced apoptosis and autophagy in Fetal Growth Restriction via the p62-Keap1-Nrf2 pathway

Fetal growth restriction (FGR) is one of the most common complications of an abnormal pregnancy. Placental dysplasia has been established as a significant contributing factor to FGR. Zinc finger protein 554 (ZNF554) is a member of the Krüppel-associated box domain zinc finger protein subfamily, primarily expressed in the placenta and essential for maintaining normal pregnancy outcomes. However, its precise role in FGR remains uncertain. In this study, we confirmed that ZNF554 was low expressed in the placenta of the FGR pregnancy. To further elucidate the impact of ZNF554 on trophoblasts, we conducted experiments using siRNA and overexpression plasmids on HTR8/SVneo and JEG3 cells. Our findings revealed that silencing ZNF554 increased apoptosis and inhibited migration and invasion, while overexpression reduced apoptosis and promoted migration and invasion. Notably, ZNF554 knockdown decreased cellular antioxidant capacity and elevated the production of reactive oxygen species (ROS). Conversely, ZNF554 activated the nuclear factor E2-related factor 2 (NRF2) signaling pathway, exerting its antioxidant effects. Additionally, ZNF554 knockdown promoted cellular autophagy by suppressing P62 and enhancing LC3-II/LC3-I expression. Importantly, the antioxidant N-acetylcysteine (NAC) partially mitigated the impact of ZNF554 knockdown on mitochondrial ROS in trophoblast cells and subsequent effects on cellular autophagy and apoptosis. In conclusion, our results suggest that ZNF554 plays a pivotal role in modulating trophoblast cell invasion and may serve as a prognostic marker and potential therapeutic target for FGR.

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

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

Abstract P204: Acute Kidney Injury Prior To Pregnancy Induces Renal And Endothelial Dysfunction Which Predisposes Pregnant Rats To Adverse Pregnancy Outcomes

Clinical data report an increase in adverse pregnancy outcomes in women with a history of AKI despite clinical recovery prior to pregnancy. We developed a rat model of pregnancy post-AKI in which female Sprague-Dawley (SD) rats recover normal creatinine clearance 30 days post-AKI, however, exhibit endothelial dysfunction, elevated plasma creatinine and fetal growth restriction (FGR) during pregnancy compared to sham. We hypothesized that AKI-induced endothelial dysfunction predisposes pregnant rats to adverse pregnancy events including renal dysfunction and FGR, and further, that sildenafil will ablate endothelial dysfunction and prevent AKI-induced FGR. Female SD rats were randomized to 45-minute warm bilateral renal ischemia reperfusion or sham (N=6-8/grp) and 15 days post-surgery were put on vehicle or sildenafil chow (50 mg/kg/day) and mated 30 days post sham/AKI surgery. Gestational day 1 (GD1) was determined via vaginal smear. Plasma and 24-hour urine collection, vascular and renal injury were analyzed in pre-pregnancy (30 days post-AKI/Sham) or late pregnancy (GD20). Although previous cohorts show creatinine clearance normalizes 30 days post-AKI, urine kidney injury marker-1 (KIM-1) was greater in AKI rats compared to sham after 30 days (580±169 pg/24hrs vs 257±17, P=0.09) which remained elevated at GD20 of pregnancy (283±28 vs 216±12, P=0.06). Mason Trichrome revealed increases in glomerular (0.93±0.08 vs 0.04±0.04 score, *P&lt;0.05) and tubular fibrosis (1.7±0.19 vs 0.0±0.0, *P&lt;0.05) in post-AKI pregnant rats at GD20 compared to sham. Endothelial-dependent relaxation to acetylcholine (ACh) in 3 rd order mesenteric arteries, measured by wire myography, was impaired in both 30-day post-AKI rats (concentration-response, 1nM-10μM, 2-w ANOVA, RM, *P&lt;0.05) and in post-AKI GD20 groups (*P&lt;0.05) compared to respective shams. Sildenafil treatment restored endothelial function at GD20 (P&gt;0.05) and restored pup weights in post-AKI pregnant GD20 rats (1.18g±0.23 g vs 2.11±0.19, *P&lt;0.05). Collectively, these data indicate that AKI induces endothelial dysfunction in female rats predisposing them to adverse renal adaptations and FGR in pregnancy, which is potentially prevented by improvement of endothelial function with sildenafil.

The effect of maternal position on placental blood flow and fetoplacental oxygenation in late gestation fetal growth restriction: a magnetic resonance imaging study.

Fetal growth restriction (FGR) and maternal supine going-to-sleep position are both risk factors for late stillbirth. This study aimed to use magnetic resonance imaging (MRI) to quantify the effect of maternal supine position on maternal-placental and fetoplacental blood flow, placental oxygen transfer and fetal oxygenation in FGR and healthy pregnancies. Twelve women with FGR and 27 women with healthy pregnancies at 34-38weeks' gestation underwent MRI in both left lateral and supine positions. Phase-contrast MRI and a functional MRI technique (DECIDE) were used to measure blood flow in the maternal internal iliac arteries (IIAs) and umbilical vein (UV), placental oxygen transfer (placental flux), fetal oxygen saturation (FO2 ), and fetal oxygen delivery (delivery flux). The presence of FGR, compared to healthy pregnancies, was associated with a 7.8% lower FO2 (P=0.02), reduced placental flux, and reduced delivery flux. Maternal supine positioning caused a 3.8% reduction in FO2 (P=0.001), and significant reductions in total IIA flow, placental flux, UV flow and delivery flux compared to maternal left lateral position. The effect of maternal supine position on fetal oxygen delivery was independent of FGR pregnancy, meaning that supine positioning has an additive effect of reducing fetal oxygenation further in women with FGR, compared to women with appropriately grown for age pregnancies. Meanwhile, the effect of maternal supine positioning on placental oxygen transfer was not independent of the effect of FGR. Therefore, growth-restricted fetuses, which are chronically hypoxaemic, experience a relatively greater decline in oxygen transfer when mothers lie supine in late gestation compared to appropriately growing fetuses. KEY POINTS: Fetal growth restriction (FGR) is the most common risk factor associated with stillbirth, and early recognition and timely delivery is vital to reduce this risk. Maternal supine going-to-sleep position is found to increase the risk of late stillbirth but when combined with having a FGR pregnancy, maternal supine position leads to 15 times greater odds of stillbirth compared to supine sleeping with appropriately grown for age (AGA) pregnancies. Using MRI, this study quantifies the chronic hypoxaemia experienced by growth-restricted fetuses due to 13.5% lower placental oxygen transfer and 26% lower fetal oxygen delivery compared to AGA fetuses. With maternal supine positioning, there is a 23% reduction in maternal-placental blood flow and a further 14% reduction in fetal oxygen delivery for both FGR and AGA pregnancies, but this effect is proportionally greater for growth-restricted fetuses. This knowledge emphasises the importance of avoiding supine positioning in late pregnancy, particularly for vulnerable FGR pregnancies.

Reduced adipose tissue in growth-restricted fetuses using quantitative analysis of magnetic resonance images.

Fat-water MRI can be used to quantify tissues' lipid content. We aimed to quantify fetal third trimester normal whole-body subcutaneous lipid deposition and explore differences between appropriate for gestational age (AGA), fetal growth restriction (FGR), and small for gestational age fetuses (SGAs). We prospectively recruited women with FGR and SGA-complicated pregnancies and retrospectively recruited the AGA cohort (sonographic estimated fetal weight [EFW] ≥ 10th centile). FGR was defined using the accepted Delphi criteria, and fetuses with an EFW < 10th centile that did not meet the Delphi criteria were defined as SGA. Fat-water and anatomical images were acquired in 3T MRI scanners. The entire fetal subcutaneous fat was semi-automatically segmented. Three adiposity parameters were calculated: fat signal fraction (FSF) and two novel parameters, i.e., fat-to-body volume ratio (FBVR) and estimated total lipid content (ETLC = FSF*FBVR). Normal lipid deposition with gestation and differences between groups were assessed. Thirty-seven AGA, 18 FGR, and 9 SGA pregnancies were included. All three adiposity parameters increased between 30 and 39weeks (p < 0.001). All three adiposity parameters were significantly lower in FGR compared with AGA (p ≤ 0.001). Only ETLC and FSF were significantly lower in SGA compared with AGA using regression analysis (p = 0.018-0.036, respectively). Compared with SGA, FGR had a significantly lower FBVR (p = 0.011) with no significant differences in FSF and ETLC (p ≥ 0.053). Whole-body subcutaneous lipid accretion increased throughout the third trimester. Reduced lipid deposition is predominant in FGR and may be used to differentiate FGR from SGA, assess FGR severity, and study other malnourishment pathologies. Fetuses with growth restriction have reduced lipid deposition than appropriately developing fetuses measured using MRI. Reduced fat accretion is linked with worse outcomes and may be used for growth restriction risk stratification. • Fat-water MRI can be used to assess the fetal nutritional status quantitatively. • Lipid deposition increased throughout the third trimester in AGA fetuses. • FGR and SGA have reduced lipid deposition compared with AGA fetuses, more predominant in FGR.

Management of late-onset fetal growth restriction: pragmatic approach.

There is limited prospective evidence to guide the management of late-onset fetal growth restriction (FGR) and its differentiation from small-for-gestational age. The aim of this study was to assess prospectively a novel protocol in which ultrasound criteria were used to classify women with suspected late FGR into two groups: those at low risk, who were managed expectantly until the anticipated date of delivery, and those at high risk, who were delivered soon after 37 weeks of gestation. We also compared the outcome of this prospective cohort with that of a historical cohort of women presenting similarly with suspected late FGR, in order to evaluate the impact of the new protocol. This was a prospective study of women with a non-anomalous singleton pregnancy at ≥ 32 weeks' gestation attending a tertiary hospital in London, UK, between February 2018 and September 2019, with estimated fetal weight (EFW) ≤ 10th centile, or EFW > 10th centile in addition to a decrease in fetal abdominal circumference of ≥ 50 centiles compared with a previous scan, umbilical artery Doppler pulsatility index > 95th centile or cerebroplacental ratio < 5th centile. Women were classified as low or high risk based on ultrasound and Doppler criteria. Women in the low-risk group were delivered by 41 weeks of gestation, unless they subsequently met high-risk criteria, whereas women in the high-risk group (EFW < 3rd centile, umbilical artery Doppler pulsatility index > 95th centile or EFW between 3rd and 10th centiles (inclusive) with abdominal circumference drop or abnormal Dopplers) were delivered at or soon after 37 weeks. The primary outcome was adverse neonatal outcome and included hypothermia, hypoglycemia, neonatal unit admission, jaundice requiring treatment, suspected infection, feeding difficulties, 1-min Apgar score < 7, hospital readmission and any severe adverse neonatal outcome (perinatal death, resuscitation using inotropes or mechanical ventilation, 5-min Apgar score < 7, metabolic acidosis, sepsis, and cerebral, cardiac or respiratory morbidity). Secondary outcomes were adverse maternal outcome (operative delivery for abnormal fetal heart rate) and severe adverse neonatal outcome. Women managed according to the new protocol were compared with a historical cohort of 323 women delivered prior to the implementation of the new protocol, for whom management was guided by individual clinician expertise. Over 18 months, 321 women were recruited to the prospective cohort, of whom 156 were classified as low risk and 165 were high risk. Adverse neonatal outcome was significantly less common in the low-risk compared with the high-risk group (45% vs 58%; adjusted odds ratio (aOR), 0.6 (95% CI, 0.4-0.9); P = 0.022). There was no significant difference in the rate of adverse maternal outcome (18% vs 24%; aOR, 0.7 (95% CI, 0.4-1.2); P = 0.142) or severe adverse neonatal outcome (3.8% vs 8.5%; aOR, 0.5 (95% CI, 0.2-1.3); P = 0.153) between the low- and high-risk groups. Compared with women in the historical cohort classified retrospectively as low risk, low-risk women managed under the new protocol had a lower rate of adverse neonatal outcome (45% vs 58%; aOR, 0.6 (95% CI, 0.4-0.9); P = 0.026). Appropriate risk stratification to guide management of late FGR was associated with a reduced rate of adverse neonatal outcome in low-risk pregnancies. In clinical practice, a policy of expectantly managing women with a low-risk late-onset FGR pregnancy at term could improve neonatal and long-term development. Randomized controlled trials are needed to assess the effect of an evidence-based conservative management protocol for late FGR on perinatal morbidity and mortality and long-term neurodevelopment. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Placental Pathology and Its Associations With Clinical Signs in Different Subtypes of Fetal Growth Restriction.

We evaluated placental alterations in different subtypes of fetal growth restriction (FGR) to determine any clinical associations. FGR placentas classified according to the Amsterdam criteria were correlated with clinical findings. Percentage of intact terminal villi and villous capillarization ratio were calculated in each specimen. Correlations of placental histopathology and perinatal outcomes were studied. 61 FGR cases were studied. Early-onset-FGR was more often associated with preeclampsia and recurrence than late-onset-FGR; placentas from early-onset-FGR often had diffuse maternal (or fetal) vascular malperfusion and villitis of unknown etiology. Decreased percentage of intact terminal villi was associated with pathologic CTG. Decreased villous capillarization was associated with early-onset-FGR and birth weight below the second percentile. Avascular villi and infarction were more common when femoral length/abdominal circumference ratio was >0.26, and perinatal outcome was poor in this group. In early-onset-FGR and preeclamptic FGR, altered vascularization of villi may have a key role in pathogenesis, and recurrent FGR is associated with villitis of unknown etiology. There is an association between femoral length/abdominal circumference ratio >0.26 and histopathological alterations of placenta in FGR pregnancies. There are no significant differences in the percentage of intact terminal villi between different FGR subtypes by onset or recurrency.

The Impact of Maternal Obesity on Neonatal Outcomes of Pregnancies Complicated by Fetal Growth Restriction.

This study aimed to characterize the relationship between maternal obesity, fetal abdominal size, and neonatal morbidity in pregnancies complicated by fetal growth restriction (FGR). Pregnancies complicated by FGR, which resulted in delivery of a live, singleton, nonanomalous infant at a single center between 2002 and 2013 were identified in a large, National Institutes of Health-funded database of detailed pregnancy and delivery information extracted by trained research nurses. Pregnancies complicated by diabetes were excluded. Fetal biometry measurements from third trimester ultrasounds performed at the same institution were extracted from another institutional database. Pregnancies were divided into cohorts based on fetal abdominal circumference (AC) gestational age percentile (<10th centile, 10-29th centile, 30-49th centile, and ≥50th centile) at the ultrasound closes to the date of delivery. Obesity was defined by prepregnancy body mass index >30 kg/m2. The primary outcome was a composite of neonatal morbidity (CM) including 5-minute Apgar < 7, arterial cord pH <7.0, sepsis, respiratory support, chest compressions, phototherapy, exchange transfusion, hypoglycemia requiring treatment, or neonatal death. Outcomes were compared between women with versus without prepregnancy obesity overall and then stratified by AC cohort. A total of 379 pregnancies met criteria; CM occurred in 136 (36%). Overall, there was no difference in CM between infants born to women with versus without obesity (risk ratio (RR): 1.11, 95% confidence interval: 0.79-1.56). When stratified according to AC at ultrasound closest to delivery, there was higher prevalence of CM occurring among women with prepregnancy obesity than those without prepregnancy obesity when the fetal AC was >50th or 30 to 49th centile However, these differences did not reach statistical significance. Our study identified no significant difference in risk of CM among growth-restricted infants of obese versus nonobese mothers, including among infants with very small AC. More research is needed to further examine the potential relationships postulated here. · No significant differences in neonatal outcomes of FGR pregnancies in obese versus nonobese patients.. · No significant differences in AC percentile distribution in FGR pregnancies in obese versus nonobese.. · Pregnancies complicated by obesity had a higher need for cardiac support but not chest compressions..

Reduced Endothelial Progenitor Cells: A Possible Biomarker for Idiopathic Fetal Growth Restriction in Human Pregnancies.

Circulating endothelial progenitor cells (EPCs) may be necessary throughout pregnancy by ensuring proper placentation and embryonic growth. The lack of standardized EPC quantification techniques has prevented conclusive proof of an increase in EPC during pregnancy. The purpose of this study was to determine whether EPC levels change for healthy and idiopathic fetal growth restriction (FGR) pregnancies. The study population consisted of 48 healthy pregnant females with no previous history of IUGR (10 in the first trimester, 15 in the second, and 23 in the third), 48 women with pregnancy complicated by idiopathic FGR, and 15 non-pregnant women. By using flow cytometry, EPCs in maternal blood were recognized as CD45dim/CD34/KDR cells. ELISA was used to measure plasmatic cytokines. We ascertained a progressive rise in EPCs in healthy pregnancies that was apparent in the first but more pronounced in the third trimester. At comparable gestational ages, FGR-complicated pregnancies had impaired EPC growth. Placental growth factor and stromal-derived factor-1 levels in the blood were significantly lower in FGR than in healthy pregnancies, which may have contributed to the degradation of the EPCs. The count in EPCs might hold considerable promise toward developing a peculiar authentication marker for observing pregnancies, and could be the focus of cutting-edge tactics for the prognosis and treatment of FGR pregnancies.

Impact of Chorionic Somatomammotropin In Vivo RNA Interference Phenotype on Uteroplacental Expression of the IGF Axis.

While fetal growth is dependent on many factors, optimal placental function is a prerequisite for a normal pregnancy outcome. The majority of fetal growth-restricted (FGR) pregnancies result from placental insufficiency (PI). The insulin-like growth factors (IGF1 and IGF2) stimulate fetal growth and placental development and function. Previously, we demonstrated that in vivo RNA interference (RNAi) of the placental hormone, chorionic somatomammotropin (CSH), resulted in two phenotypes. One phenotype exhibits significant placental and fetal growth restriction (PI-FGR), impaired placental nutrient transport, and significant reductions in umbilical insulin and IGF1. The other phenotype does not exhibit statistically significant changes in placental or fetal growth (non-FGR). It was our objective to further characterize these two phenotypes by determining the impact of CSH RNAi on the placental (maternal caruncle and fetal cotyledon) expression of the IGF axis. The trophectoderm of hatched blastocysts (9 days of gestation, dGA) were infected with a lentivirus expressing either a non-targeting sequence (NTS RNAi) control or CSH-specific shRNA (CSH RNAi) prior to embryo transfer into synchronized recipient ewes. At ≈125 dGA, pregnancies were fitted with vascular catheters to undergo steady-state metabolic studies. Nutrient uptakes were determined, and tissues were harvested at necropsy. In both CSH RNAi non-FGR and PI-FGR pregnancies, uterine blood flow was significantly reduced (p ≤ 0.05), while umbilical blood flow (p ≤ 0.01), both uterine and umbilical glucose and oxygen uptakes (p ≤ 0.05), and umbilical concentrations of insulin and IGF1 (p ≤ 0.05) were reduced in CSH RNAi PI-FGR pregnancies. Fetal cotyledon IGF1 mRNA concentration was reduced (p ≤ 0.05) in CSH RNAi PI-FGR pregnancies, whereas neither IGF1 nor IGF2 mRNA concentrations were impacted in the maternal caruncles, and either placental tissue in the non-FGR pregnancies. Fetal cotyledon IGF1R and IGF2R mRNA concentrations were not impacted for either phenotype, yet IGF2R was increased (p ≤ 0.01) in the maternal caruncles of CSH RNAi PI-FGR pregnancies. For the IGF binding proteins (IGFBP1, IGFBP2, IGFBP3), only IGFBP2 mRNA concentrations were impacted, with elevated IGFBP2 mRNA in both the fetal cotyledon (p ≤ 0.01) and maternal caruncle (p = 0.08) of CSH RNAi non-FGR pregnancies. These data support the importance of IGF1 in placental growth and function but may also implicate IGFBP2 in salvaging placental growth in non-FGR pregnancies.