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The aim of this study was to evaluate the association between placental abnormalities, placental biomarkers, and fetoplacental Dopplers in a cohort of pregnancies complicated by fetal growth restriction (FGR). We also ascertained the risk of perinatal mortality, severe neurological morbidity, and severe non-neurological morbidity by type of placental abnormality. This was a prospective cohort study. Multivariable logistic regression was used to evaluate the effect of early vs. late FGR, placental biomarkers and fetoplacental Dopplers on Maternal Vascular Malperfusion (MVM) which was the commonest placental abnormality identified. There were 161 (53.5 %) early FGR and 140 (46.5 %) late FGR cases. MVM abnormalities were present in 154 (51.2 %), VUE in 45 (14.6 %), FVM in 16 (5.3 %), DVM in 14 (4.7 %) and CHI in 4 (1.3 %) cases. The odds of MVM were higher in early compared to late FGR cohort (OR 1.89, 95%CI 1.14, 3.14, p = 0.01). Low maternal PlGF levels <100 ng/L (OR 2.34, 95%CI 1.27,4.31, p = 0.01), high sFlt-1 level (OR 2.13, 95%CI 1.35, 3.36, p = 0.001) or elevated sFlt-1/PlGF ratio (OR 3.48, 95%CI 1.36, 8.91, p = 0.01) were all associated with MVM. Increased UA PI > 95th centile (OR 2.91, 95%CI 1.71, 4.95, p=<0.001) and mean UtA PI z-score (OR 1.74, 95%CI 1.15, 2.64, p = 0.01) were associated with higher odds of MVM. Rates of severe non-neurological morbidity were highest in the MVM, FVM, and CHI cohorts (44.8 %, 50 %, and 50 % respectively). MVM was the commonest placental abnormality in FGR, particularly in early-onset disease. Low maternal PlGF levels, high sFlt-1 levels, elevated sFlt-1/PlGF ratio, and abnormal fetoplacental Dopplers were also significantly associated with MVM. MVM, FVM, and CHI abnormalities were associated with lower median birthweight, higher rates of preterm birth, operative birth for non-reassuring fetal status, and severe neonatal non-neurological morbidity. • MVM is the commonest placental abnormality in pregnancies complicated by FGR. • Early-onset FGR is more likely to have MVM abnormalities than late-onset disease. • MVM changes are associated with abnormal placental biomarkers and fetoplacental Dopplers. • Higher rates of hypertension and pre-eclampsia were seen in MVM, FVM, and CHI. • MVM, FVM, and CHI are strongly associated with adverse perinatal and pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Preeclampsia and fetal growth restriction (PE/FGR) are pregnancy complications known to be associated with poor utero-placental function due to abnormal "physiological" remodeling of spiral arteries and unfavorable maternal cardiovascular health. However, the prevalence and degree of impaired spiral artery remodeling has not been clearly established. Prospective, multi-center observational cohort study to assess the prevalence of lesions associated with abnormal development of spiral arteries in placental bed biopsies systematically obtained from 121 women undergoing Caesarian section for PE/FGR compared with a reference group of 149 healthy controls. PE/FGR was associated with a high prevalence of impaired spiral artery remodeling compared with controls (63.6 vs 10.1 %, p < 0.001), and a higher prevalence of non-remodeled spiral arteries without the presence of intramural trophoblast (45.5 vs 6.7 %, p < 0.001), despite abundant interstitial trophoblast invasion in surrounding decidua and myometrium. Normal remodeling was associated with circumferential presence of intramural trophoblast and hardly any trophoblast in surrounding tissue. Acute atherosis (28.9 vs 3.4 %, p < 0.001) and thrombosis (16.5 vs 5.4 %, p = 0.003) lesions were significantly more prevalent in PE/FGR. Impaired remodeling, acute atherosis and thrombosis lesions were equally present in both decidual and myometrial segments of the spiral arteries in both groups. Impaired remodeling was most prominent in the groups with FGR (with or without PE) and thrombosis was most often seen in the group with PE and FGR. PE/FGR is associated with a high prevalence of impaired physiological remodeling and vascular lesions of the uterine spiral arteries in the placental bed. [Display omitted] • Preeclampsia and fetal growth restriction are associated with inefficient trophoblast invasion. • Acute atherosis and thrombosis are more prevalent in spiral arteries of women with preeclampsia and/or FGR. • Normal remodeling is associated with circumferential intramural trophoblast. • Abnormal remodeling is associated with abundant extravascular trophoblast invasion. • Spiral artery lesions are more severe in the FGR group than in the preeclampsia alone group. [ABSTRACT FROM AUTHOR]

Poor placental angiogenesis is associated with several pregnancy complications including fetal growth restriction (FGR), which causes low birth weight (LBW) babies to have a high risk of growth disorders and metabolic disorders in adulthood. Recent research using syncytin knock-out mice showed significant disruption in the growth of placental vascularization. Syncytin-1 which encoded by ERVW-1 gene, is proposed to have a role in placental angiogenesis, but its relationship with other proangiogenic factors such as vascular endothelial growth factor (VEGF) in the placenta of LBW babies has not yet been determined. By knowing the mechanisms of FGR, more proactive preventive and therapeutic measures can be taken in the future. This study aimed to determine the expression of ERVW-1 , proangiogenic gene VEGF and its receptor (FLT-1), and hypoxia inducible factor-1 (HIF-1) in LBW placentas, and investigate the relationship between these genes' expression in the placenta of LBW babies. Total RNA was extracted from placental tissue. Total RNA is used as a cDNA synthesis template, followed by qRT-PCR. Correlations of ERVW-1, VEGF, FLT-1 and HIF-1 genes' expression were analyzed by linear regression. The age and body mass index of mothers with LBW and normal birth weight (NBW) babies were not significantly different. ERVW-1 expression in LBW placentas was lower than in NBW placentas, but VEGF, FLT-1 and HIF-1 expressions were higher. ERVW-1 was negatively correlated with HIF-1 and VEGF. Low expression of ERVW-1 in the placenta of LBW babies may result in impaired placental angiogenesis and possibly lead to hypoxia. • Lower expression of ERVW-1 was found in the placenta of Low Birth Weight babies. • Low ERVW-1 expression leads to hypoxia, as indicated by high HIF-1 expression. • Hypoxic conditions are compensated by upregulation of VEGF and its receptor, FLT-1. [ABSTRACT FROM AUTHOR]

Fetal growth restriction and underlying placental insufficiency are associated with increased oxidative stress. Current diagnostics fail to identify all growth restricted fetuses and newborns, due to focus on small size. This scoping review aims to summarize the available evidence on usefulness of cord blood oxidative stress biomarkers for identification of growth restricted newborns in need of monitoring and support because of associated health risks. MEDLINE and EMBASE were searched from inception to May 2024. Studies were included if oxidative stress biomarkers were measured in cord blood collected immediately after delivery in newborns suspected to be growth restricted. Biomarkers were categorized based on the origin and/or biological function and their interrelationships. Oxidative stress was determined for each individual biomarker and category. Literature search identified 78 studies on 39 different biomarkers, with a total of 2707 newborns with suspected growth restriction, and 4568 controls. Total oxidant/antioxidant status, catalase, glutathione, ischemia-modified albumin, and nucleated red blood cells were most consistently associated with suspected growth restriction. Reactive oxygen species/reactive nitrogen species, factors in their production, antioxidant enzymes, non-enzymatic antioxidants, and products of oxidative stress were not consistently associated. This review collates the evidence of associations between cord blood oxidative stress biomarkers and growth restriction. Total oxidant/antioxidant status, catalase, glutathione, ischemia-modified albumin, and nucleated red blood cells could potentially be candidates for developing a cord blood diagnostic tool for future clinical use. • Oxidative stress cord blood biomarkers useful to identify growth restricted newborns. • (Anti)oxidant status, CAT, GSH, IMA, NRBC most associated with growth restriction. • Offering possibilities for development of cord blood diagnostic tool for clinical use. [ABSTRACT FROM AUTHOR]

A high frequency of single nucleotide somatic mutations in the placenta has been recently described, but its relationship to placental dysfunction is unknown. We performed a pilot case-control study using paired fetal, maternal, and placental samples collected from healthy live birth controls (n = 10), live births with fetal growth restriction (FGR) due to placental insufficiency (n = 7), and stillbirths with FGR and placental insufficiency (n = 11). We quantified single nucleotide and structural somatic variants using bulk whole genome sequencing (30-60X coverage) in four biopsies from each placenta. We also assessed their association with clinical and histological evidence of placental dysfunction. Seventeen pregnancies had sufficiently high-quality placental, fetal, and maternal DNA for analysis. Each placenta had a median of 473 variants (range 111–870), with 95 % arising in just one biopsy within each placenta. In controls, live births with FGR, and stillbirths, the median variant counts per placenta were 514 (IQR 381–779), 582 (450–735), and 338 (245–441), respectively. After adjusting for depth of sequencing coverage and gestational age at birth, the somatic mutation burden was similar between groups (FGR live births vs. controls, adjusted diff. 59, 95 % CI -218 to +336; stillbirths vs controls, adjusted diff. −34, −351 to +419), and with no association with placental dysfunction (p = 0.7). We confirmed the high prevalence of somatic mutation in the human placenta and conclude that the placenta is highly clonal. We were not able to identify any relationship between somatic mutation burden and clinical or histologic placental insufficiency. • Somatic mutation is highly prevalent in the human placenta. • 95 % of comatic variants were present in just one of four biopsies in each placenta. • Somatic mutation estimates were driven by sequencing depth and gestational age. • Two variant calling algorithms yield very different somatic variation estimates. • We found no association between somatic variant burden and clinical outcome. [ABSTRACT FROM AUTHOR]

The congenital condition gastroschisis is associated with delayed villous development and placental malperfusion, suggesting placental involvement. This study uses RNA sequencing to compare the placental transcriptome in pregnancies with and without gastroschisis. 180 coding genes were differentially expressed, mapping to multiple gene ontology pathways. Altered placental gene expression may represent fetal signalling to the placenta, and these changes could contribute to the pathogenesis of gastroschisis and associated morbidities, including fetal growth restriction. • Gastroschisis is a congenital condition where the infant's intestines extend outside the abdomen. • Developmental and vascular defects are associated with Gastroschisis. • Gastroschisis associated changes in the placental transcriptome were observed. • These changes may reflect altered fetal to placental signalling. [ABSTRACT FROM AUTHOR]

To evaluate the maternal and fetal hemodynamic effects of treatment with a nitric oxide donor and oral fluid in pregnancies complicated by fetal growth restriction. 30 normotensive participants with early fetal growth restriction were enrolled. 15 participants were treated until delivery with transdermal glyceryl trinitrate and oral fluid intake (Treated group), and 15 comprised the untreated group. All women underwent non-invasive assessment of fetal and maternal hemodynamics and repeat evaluation 2 weeks later. In the treated group, maternal hemodynamics improved significantly after two weeks of therapy compared to untreated participants. Fetal hemodynamics in the treated group showed an increase in umbilical vein diameter by 18.87 % (p < 0.01), in umbilical vein blood flow by 48.16 % (p < 0.01) and in umbilical vein blood flow corrected for estimated fetal weight by 30.03 % (p < 0.01). In the untreated group, the characteristics of the umbilical vein were unchanged compared to baseline. At the same time, the cerebro-placental ratio increased in the treated group, while it was reduced in the untreated group, compared to baseline values. The treated group showed a higher birthweight centile (p = 0.03) and a lower preeclampsia rate (p = 0.04) compared to the untreated group. The combined therapeutic approach with nitric oxide donor and oral fluid intake in fetal growth restriction improves maternal hemodynamics, which becomes more hyperdynamic (volume-dominant). At the same time, in the fetal circuit, umbilical vein flow increased and fetal brain sparing improved. Although a modest sample size, there was less preeclampsia and a higher birthweight suggesting beneficial maternal and fetal characteristics of treatment. • Early fetal growth restriction is characterized by altered maternal hemodynamics. • NO donor improves maternal hemodynamics reducing vascular resistance. • NO donor increases fetal umbilical vein blood flow and fetal oxygenation. • NO donor might reduce the incidence of preeclampsia and improve the birthweight. [ABSTRACT FROM AUTHOR]

Placental insufficiency may lead to preeclampsia and fetal growth restriction. There is no cure for placental insufficiency, emphasizing the need for monitoring fetal and placenta health. Current monitoring methods are limited, underscoring the necessity for imaging techniques to evaluate fetal-placental perfusion and oxygenation. This study aims to use MRI to evaluate placental oxygenation and perfusion in the reduced uterine perfusion pressure (RUPP) model of placental insufficiency. Pregnant rats were randomized to RUPP (n = 11) or sham surgery (n = 8) on gestational day 14. On gestational day 19, rats imaged using a 7T MRI scanner to assess oxygenation and perfusion using T2* mapping and 3D-DCE MRI sequences, respectively. The effect of the RUPP on the feto-placental units were analyzed from the MRI images. RUPP surgery led to reduced oxygenation in the labyrinth (24.7 ± 1.8 ms vs. 28.0 ± 2.1 ms, P = 0.002) and junctional zone (7.0 ± 0.9 ms vs. 8.1 ± 1.1 ms, P = 0.04) of the placenta, as indicated by decreased T2* values. However, here were no significant differences in fetal organ oxygenation or placental perfusion between RUPP and sham animals. The reduced placental oxygenation without a corresponding decrease in perfusion suggests an adaptive response to placental ischemia. While acute reduction in placental perfusion may cause placental hypoxia, persistence of this condition could indicate chronic placental insufficiency after ischemic reperfusion injury. Thus, placental oxygenation may be a more reliable biomarker for assessing fetal condition than perfusion in hypertensive disorders of pregnancies including preeclampsia and FGR. • The RUPP model shows a decrease in placental oxygenation five days after surgery. • Stable fetal organ oxygenation was observed following RUPP surgery. • The RUPP model insights guide imaging and therapeutic strategies development. • Placental oxygenation metrics may serve as biomarkers for assessing fetal health. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR) may affect placental transfer of key nutrients to the fetus, such as the fatty acid docosahexaenoic acid (DHA). Major facilitator superfamily domain containing 2A (MFSD2A) has been described as a specific DHA carrier in placenta, but its expression has not been studied in FGR. The aim of this study was to evaluate for the first time the placental MFSD2A levels in late-FGR pregnancies and the maternal and cord plasma DHA. 87 pregnant women from a tertial reference center were classified into late-FGR (N = 18) or control (N = 69). Fatty acid profile was determined in maternal and cord venous plasma, as well as placental levels of MFSD2A and of insulin mediators like phospho-protein kinase B (phospho-AKT) and phospho-extracellular regulated kinase (phospho-ERK). Maternal fatty acid profile did not differ between groups. Nevertheless, late-FGR cord vein presented higher content of saturated fatty acids than control, producing a concomitant decrease in the percentage of some unsaturated fatty acids. In the late-FGR group, a lower DHA fetal/maternal ratio was observed when using percentages, but not with concentrations. No alterations were found in the expression of MFSD2A in late-FGR placentas, nor in phospho-AKT or phospho-ERK. MFSD2A protein expression was not altered in late-FGR placentas, in line with no differences in cord DHA concentration between groups. The increase in the saturated fatty acid content of late-FGR cord might be a compensatory mechanism to ensure fetal energy supply, decreasing other fatty acids percentage. Future studies are warranted to elucidate if altered saturated fatty acid profile in late-FGR fetuses might predispose them to postnatal catch-up and to long-term health consequences. • First study about placental MFSD2A levels in fetal growth restriction. • Fetuses with late-FGR presented higher content of saturated fatty acids. • No alterations in placental MFSD2A or fetal DHA concentration in late-FGR. [ABSTRACT FROM AUTHOR]

To longitudinally and cross-sectionally study the differences in the uterine artery pulsatility index (UTPI), umbilical artery pulsatility index (UAPI) and placental vascularization indices (PVIs, derived from 3-dimensional power Doppler) between normal and placental insufficiency pregnancies throughout gestation. UTPI, UAPI and PVI were measured 6 times at 4- to 5- week intervals from 11 to 13+6 weeks–36 weeks. Preeclampsia (PE) and fetal growth restriction (FGR) were defined as placental insufficiency. Comparisons of UTPI, UAPI and PVI between normal and insufficiency groups were performed by one-way repeated measures analysis of variance. A total of 125 women were included: monitored regularly from the first trimester to 36 weeks of gestation: 109 with normal pregnancies and 16 with placental insufficiency. Longitudinal study of the normal pregnancy group showed that UTPI and UAPI decreased significantly every 4 weeks, while PVIs increased significantly every 8 weeks until term. In the placental insufficiency group however, this decrease occurred slower at 8 weeks intervals and UTPI stabilized after 24 weeks. No significant difference was noted in PVIs throughout pregnancy. Cross-sectional study from different stages of gestation showed that UTPI was higher in the insufficiency group from 15 weeks onward and PVIs were lower after 32 weeks. Compared to high-risk pregnancies with normal outcome, UTPI and UAPI needed a longer time to reach a significant change in those with clinical confirmation of placental insufficiency pregnancies and no significant change was found in PVI throughout gestation. UTPI was the earliest factor in detecting adverse outcome pregnancies. • Longitudinal investigation of utero-placental circulation in different outcomes. • Cross-sectional comparison of hemodynamic changes in different outcomes. • Changes in VI and VFI were smaller than in UTPI and UAPI. • Hemodynamic changes were smaller in placental insufficient pregnancies. • UTPI was the earliest factor in detecting adverse outcome pregnancies. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR) can lead to fetal mental development abnormalities, malformations, and even intrauterine death. Defects in the trophoblasts at the maternal-fetal interface may contribute to FGR. However, the impact of trophoblasts on FGR is still not well understood. Therefore, the objective of this study is to characterize the heterogeneity of placental cells at the single-cell level and investigate the role of trophoblast subtypes in the pathogenesis of FGR at the cellular and molecular levels. Single-cell RNA sequencing was performed on the maternal side of placentas from two normal pregnant women and two pregnant women with FGR. Lentivirus transfection was used to establish a FN1 knockout model in trophoblast HTR-8-Svneo cells. The effect of FN1 knockout on cell migration and invasion of HTR-8-Svneo cells was assessed through wound healing and transwell assays. Nine cell types were annotated in 39,161 cells derived from single-cell RNA sequencing. The FGR group exhibited a decrease in the percentage of trophoblasts, especially in subtype of extravillous trophoblasts (EVTs). The expression of FN1 was reduced in trophoblasts and EVTs. Furthermore, the protein expression levels of FN1 in the placentas of FGR patients were significantly lower than those of normal pregnant women. The cell migration and invasion ability of HTR-8-Svneo cells were inhibited after the knockdown of FN1. The dysregulation of the trophoblast subtype-EVTs is involved in placental dysplasia related to FGR. The association between aberrant placental trophoblasts and reduced FN1 expression may contribute to insufficient remodeling of spiral arteries and the formation of FGR. • The cell composition and gene expression profile in trophoblasts were remodeled in FGR. • FN1 expression in the placentas of FGR patients is lower than that in normal. • The reduced FN1 induces FGR through attenuating cell invasion of trophoblasts. [ABSTRACT FROM AUTHOR]

We aimed to examine the effect of uterine arterial (UtA) blood flow changes after tadalafil treatment for fetal growth restriction (FGR) using two-dimensional (2D) phase-contrast magnetic resonance imaging (PC-MRI). We recruited 14 pregnant women with FGR aged 20–44 years, at ≥20 weeks' gestation, between May 2019 and July 2020. They underwent 2D PC-MRI for UtA blood flow measurement 3 days (interquartile range: 2–4) after diagnosis. This group (FGR group) was compared with 14 gestational age (GA)-matched healthy pregnant women (control group). Six patients in the FGR group received treatment with tadalafil administered at 20 mg twice daily after the first MRI until delivery. They underwent a second MRI a week later. The median total UtA blood/body surface area was 420 mL/min/m2 (290–494) in the FGR group and 547 mL/min/m2 (433–681) in the control group (p = 0.01). Percent increase in blood flow were significantly different between the FGR cases treated with tadalafil and control at 15.8 % (14.3–21.3) and 4.2 % (3.6–8.7), respectively (p = 0.03). UtA blood flow in pregnant women with FGR was significantly lower than that in healthy pregnant women. Tadalafil is expected to improve UtA blood flow, thereby improving placental function in pregnant patients with FGR. • Two-dimensional PC-MRI can accurately measure uterine arterial blood flow. • Tadalafil may improve UtA blood flow and placental function in patients with FGR. • Pregnant women with FGR had much less UtA blood flow than healthy pregnant women. • Estimated fetal body weight was greater in the tadalafil-treated FGR group. [ABSTRACT FROM AUTHOR]

Hypertensive disorders of pregnancy (HDP) and fetal growth restriction (FGR) are common obstetrical complications, often with pathological features of maternal vascular malperfusion (MVM) in the placenta. Currently, clinical placental pathology methods involve a manual visual examination of histology sections, a practice that can be resource-intensive and demonstrates moderate-to-poor inter-pathologist agreement on diagnostic outcomes, dependant on the degree of pathologist sub-specialty training. This study aims to apply machine learning (ML) feature extraction methods to classify digital images of placental histopathology specimens, collected from cases of HDP [pregnancy induced hypertension (PIH), preeclampsia (PE), PE + FGR], normotensive FGR, and healthy pregnancies, according to the presence or absence of MVM lesions. 159 digital images were captured from histological placental specimens, manually scored for MVM lesions (MVM- or MVM+) and used to develop a support vector machine (SVM) classifier model, using features extracted from pre-trained ResNet18. The model was trained with data augmentation and shuffling, with the performance assessed for patch-level and image-level classification through measurements of accuracy, precision, and recall using confusion matrices. The SVM model demonstrated accuracies of 70 % and 79 % for patch-level and image-level MVM classification, respectively, with poorest performance observed on images with borderline MVM presence, as determined through post hoc observation. The results are promising for the integration of ML methods into the placental histopathological examination process. Using this study as a proof-of-concept will lead our group and others to carry ML models further in placental histopathology. [Display omitted] • MVM lesions are common in cases of HDP and FGR. • SVM classifier was tested for its ability to classify MVM lesions in placenta images. • The best performing model demonstrated a classification accuracy of 79 %. • Poorest model performance was observed at the MVM diagnostic threshold. [ABSTRACT FROM AUTHOR]

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. • ZNF554 was downregulated in FGR placental tissues. • ZNF554 regulates proliferation, migration, invasion and apoptosis of trophoblast cells. • Knockdown of ZNF554 induces ROS production and autophagy in trophoblast cells through the p62-Keap1-Nrf2 signaling pathway. • NAC partially alleviated oxidative damage and apoptosis of mitochondria caused by ZNF554 dysfunction in trophoblast cells. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR) is a common complication of pregnancy. Lipid metabolism and distribution may contribute to the progression of FGR. However, the metabolism-related mechanisms of FGR remain unclear. The aim of this study was to identify metabolic profiles associated with FGR, as well as probable genes and signaling pathways. Metabolomic profiles at the maternal-fetal interface (including the placenta, maternal and fetal serum) from pregnant women with (n = 35) and without (n = 35) FGR were analyzed by gas chromatography-mass spectrometry (GC-MS). Combined with differentially expressed genes (DEGs) from the GSE35574 dataset, analysis was performed for differential metabolites, and identified by the Metabo Analyst dataset. Finally, the pathology and screened DEGs were further identified. The results showed that fatty acids (FAs) accumulated in the placenta and decreased in fetal blood in FGR cases compared to controls. The linoleic acid metabolism was the focus of placental differential metabolites and genes enrichment analysis. In this pathway, phosphatidylcholine can interact with PLA2G2A and PLA2G4C, and 12(13)-EpOME can interact with CYP2J2. PLA2G2A and CYP2J2 were elevated, and PLA2G4C was decreased in the FGR placenta. In conclusion, accumulation of FAs in the placental ischemic environments, may involve linoleic acid metabolism, which may be regulated by PLA2G2A, CYP2J2, and PLA2G4C. This study may contribute to understanding the underlying metabolic and molecular mechanisms of FGR. [Display omitted] • Fatty acids are closely related to fetal growth restriction. • Linoleic acid metabolism was the focus of placental differential metabolism analysis. • Metabolites in linoleic acid metabolism may be biological markers for diagnosis of placental-derived FGR. • Linoleic acid metabolism may be regulated by PLA2G2A, CYP2J2, and PLA2G4C. [ABSTRACT FROM AUTHOR]

Late fetal growth restriction (FGR) is associated with mild growth restriction and normal or mild abnormal doppler flows. The cerebroplacental ratio (CPR) has been demonstrated as more sensitive to hypoxia than its individual components in these fetuses. We hypothesized that abnormal CPR in late FGR is reflected in specific placental vascular malperfusion lesions. Retrospective cohort study of late FGR newborns between 2012 and 2022 in a tertiary hospital. Overall, 361 cases were included: 104 with pathological CPR (study group), and 257 with normal doppler flows (control group). The primary outcome was a composite of maternal vascular malperfusion lesions (MVM) and fetal vascular malperfusion lesions (FVM). Secondary outcomes were macroscopic placental characteristics and various obstetrical and neonatal outcomes. The study group had lower birthweight compared with the normal CPR group (2063.5 ± 470.5 vs. 2351.6 ± 387.4 g. P < 0.0001), higher rates of composite adverse neonatal outcomes (34.2% vs. 22.5%, p < 0.0001), lower mean placental weight (318 ± 71.6 vs. 356.6 ± 76.5 g, p < 0.0001), as well as a higher prevalence of Vascular lesions of MVM (15.3% vs. 5.0%, p = 0.002), villous lesions of FVM (37.5% vs. 24.9%, p = 0.02), and composite FVM lesions (36.5% vs. 25.6%, p = 0.04). On multivariate regression analysis for MVM lesions and composite FVM lesions, abnormal CPR was found as an independent risk factor (aOR 2.17, 95% CI 1.63–4.19, and aOR 1.31, 95% CI 1.09–3.97, respectively). Abnormal CPR in late FGR is reflected in placental histopathologic vascular malperfusion lesions, and the incidence of these lesions is higher than in FGR placentas with normal CPR. • Abnormal CPR is associated with adverse neonatal outcomes. • Placental malperfusion lesions are more prevalent in FGR with abnormal CPR. • Vascular lesions of MVM and villous lesions of FVM are associated with abnormal CPR. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR) is associated with placental abnormalities, and its precise diagnosis is challenging. This study aimed to explore the role of radiomics based on placental MRI in predicting FGR. A retrospective study using T2-weighted placental MRI data were conducted. A total of 960 radiomic features were automatically extracted. Features were selected using three-step machine learning methods. A combined model was constructed by combining MRI-based radiomic features and ultrasound-based fetal measurements. The receiver operating characteristic curves (ROC) were conducted to assess model performance. Additionally, decision curves and calibration curves were performed to evaluate prediction consistency of different models. Among the study participants, pregnant women who delivered from January 2015 to June 2021 were randomly divided into training (n = 119) and test (n = 40) sets. Forty-three other pregnant women who delivered from July 2021 to December 2021 were used as the time-independent validation set. After training and testing, three radiomic features that were strongly correlated with FGR were selected. The area under the ROC curves (AUCs) of the MRI-based radiomics model reached 0.87 (95% confidence interval [CI]: 0.74–0.96) and 0.87 (95% CI: 0.76–0.97) in the test and validation sets, respectively. Moreover, the AUCs for the model comprising MRI-based radiomic features and ultrasound-based measurements were 0.91 (95% CI: 0.83–0.97) and 0.94 (95% CI: 0.86–0.99) in the test and validation sets, respectively. MRI-based placental radiomics could accurately predict FGR. Moreover, combining placental MRI-based radiomic features with ultrasound indicators of the fetus could improve the diagnostic accuracy of FGR. • Placental radiomic features based on MRI are reliable predictors for FGR. • Placental MRI radiomics is complementary to ultrasound in diagnosing FGR. • Combining MRI with ultrasound tests by machine-learning can predict FGR efficiently. [ABSTRACT FROM AUTHOR]

Development of a therapeutic that targets the pathophysiological elements of preeclampsia would be a major advance for obstetrics, with potential to save the lives of countless mothers and babies. We recently identified anti-inflammatory drug sulfasalazine as a prospective candidate therapeutic for treatment of preeclampsia. In primary human cells and tissues in vitro , sulfasalazine potently decreased secretion of anti-angiogenic sFlt-1 and sENG, increased production of pro-angiogenic PlGF, mitigated endothelial dysfunction, and promoted whole vessel vasodilation. Using nitric oxide synthase antagonist Nω-Nitro- l -arginine methyl ester hydrochloride, a preeclampsia-like phenotype was induced in pregnant mice, including high blood pressure, fetal growth restriction, and elevated circulating sFlt-1. Mice were treated with sulfasalazine or vehicle from gestational day (D)13.5, with blood pressure measurements across gestation, fetal measurements at D17.5, and wire myograph assessment of vasoactivity. Sulfasalazine had a modest effect on blood pressure, decreasing diastolic and mean blood pressure on D13.5, but not later in gestation, or systolic blood pressure. Sulfasalazine was not able to rescue fetal growth, in male or female fetuses. There was a suggestion of improved vasoactivity with sulfasalazine, but further clarification is required. In this mouse model of preeclampsia, sulfasalazine did not sustain reductions in blood pressure nor affect fetal parameters of size and weight, both desirable attributes of a viable preeclampsia therapeutic. While these data suggest sulfasalazine might improve vasoactivity, murine toxicity considerations limited the dose range of sulfasalazine that could be tested in the current study. • Sulfasalazine modestly decreases blood pressure in a mouse model of preeclampsia. • Sulfasalazine was unable to rescue fetal growth restriction. • Sulfasalazine may improve vasoactivity. [ABSTRACT FROM AUTHOR]

Transverse relaxation time (T2*) is related to tissue oxygenation and morphology. We aimed to describe T2* weighted MRI in selected fetal organs in normal pregnancies, and to investigate the correlation between fetal organ T2* and placental T2*, birthweight (BW) deviation, and redistribution of fetal blood flow. T2*-weighted MRI was performed in 126 singleton pregnancies between 23+6- and 41+3-weeks' gestation. The T2* value was obtained from the placenta and fetal organs (brain, lungs, heart, liver, kidneys, and spleen). In normal BW pregnancies (BW > 10th centile), the correlation between the T2* value and gestational age (GA) at MRI was estimated by linear regression. The correlation between fetal organ Z-score and BW group was demonstrated by boxplots and investigated by analysis of variance (ANOVA) for each organ. In normal BW pregnancies fetal organ T2* was negatively correlated with GA. We found a significant correlation between BW group and fetal organ T2* z-score in the fetal heart, kidney, lung and spleen. A positive linear correlation was demonstrated between fetal organ T2* and outcomes related to placental function such as BW deviation and placenta T2* in all investigated fetal organs except for the fetal liver. In the fetal heart, kidneys, and spleen the T2* value showed a significant correlation with fetal redistribution of blood flow (Middle cerebral artery Pulsatility Index) before delivery. Fetal T2* is correlated with BW, placental function, and redistribution of fetal blood flow, suggesting that fetal organ T2* reflects fetal oxygenation and morphological changes related to placental dysfunction. • The transversal relaxation time (T2*) is related to tissue oxygenation. • It is feasible to obtain reliable fetal T2* values from selected fetal organs. • Fetal organ T2* is reduced in low BW pregnancies compared to normal BW pregnancies. • Fetal organ T2* is associated with redistribution of fetal blood flow at delivery. • Fetal organ T2* may depict fetal oxygenation changes related to placental dysfunction. [ABSTRACT FROM AUTHOR]

Chronic histiocytic intervillositis (CHI) is a rare histopathological lesion in the placenta that is associated with poor reproductive outcomes. The intervillous infiltrate consists mostly of maternal mononuclear cells and fibrin depositions, which are both indicators for the severity of the intervillous infiltrate. The severity of the intervillous infiltrate as well as the clinical outcomes of pregnancy differ between cases. Our objective is to determine the relation between the severity of the intervillous infiltrate and the clinical outcomes of CHI. Cases of CHI were semi-quantitatively graded based on histopathological severity scores. Hereto, CD68 positive mononuclear cells were quantified, fibrin depositions visualized by both a PTAH stain and an immuohistochemical staining, and placental dysfunction was assessed via thrombomodulin staining. This study included 36 women with CHI. A higher CD68 score was significantly associated with a lower birthweight. Loss of placental thrombomodulin was associated with lower gestational age, lower birthweight, and a lower placenta weight. The combined severity score based on CD68 and PTAH was significantly associated with fetal growth restriction, and the joint score of CD68 and fibrin was associated with birthweight and placental weight. More severe intervillous infiltrates in CHI placentas is associated with a lower birth weight and placental weight. Furthermore, this study proposes thrombomodulin as a possible new severity marker of placental damage. More research is needed to better understand the pathophysiology of CHI. • CHI is associated with poor reproductive outcomes. • A higher CD68 score is associated with a lower birthweight. • Loss of placental thrombomodulin is associated with a lower gestational age. • Loss of placental thrombomodulin is associated with a lower birthweight and placenta weight. [ABSTRACT FROM AUTHOR]

Introduction: Little is known about the association between hypospadias and small fetuses, as well as the pathological implications of fetal growth restriction (FGR). Thus, we aimed to investigate the association between hypospadias and small fetuses using a database of fetal ultrasound and obstetric events.Methods: A cohort of male singleton infants delivered after 22 weeks of gestation at Keio University Hospital between 2013 and 2019 was retrospectively reviewed. FGR was defined according to the Delphi criteria. Logistic regression analysis was performed to identify the significant predictors of hypospadias. Placental pathology was reviewed in cases with hypospadias.Results: Of the 2,040 male infants included in the present study, 23 had hypospadias. The prevalences of a single umbilical artery (SUA), small for gestational age, maternal hypertensive disorders of pregnancy, and a small placenta, were significantly higher in infants with hypospadias. Multiple logistic regression analysis revealed that FGR (odds ratio [OR] = 9.39; 95% confidence interval [CI], 2.50-35.3) and the presence of a SUA (OR = 33.4; 95% CI, 8.00-139.5) were independently and significantly associated with hypospadias. When FGR was stratified by the time of onset, its association with hypospadias was significant regardless of the time of onset. Moreover, placental histological findings suggested that fetal vascular malperfusion might play a role in hypospadias.Discussion: FGR and SUAs are independent prenatal predictors of the development of hypospadias, and fetal vascular malperfusion of the placenta may be involved in the etiology of hypospadias. [ABSTRACT FROM AUTHOR]

Pregnancy pathologies including gestational diabetes, intrauterine fetal growth restriction, and pre-eclampsia are common and significantly increase the risk of poor pregnancy outcomes. Research to better understand the pathophysiology and improve diagnosis and treatment is therefore crucial. The ex vivo placenta perfusion model offers a unique system to study pregnancy pathology without the risk of harm to mother or fetus. The presence of a maternal and fetal circulation and intact villus tree, facilitates investigations into maternal-fetal transfer, altered hemodynamics and vascular reactivity in the human placenta. It also provides a platform to test novel therapeutic agents. Here we review the key studies which have utilized the ex vivo placenta perfusion model to study different aspects of such pregnancy pathologies. [ABSTRACT FROM AUTHOR]

Introduction: Placental pathology and pregnancy complications are associated with unfavorable regulation of the maternal immune system. Although much research has been performed towards the role of immune cells like macrophages and T cells in this context, little is known about the presence and function of mast cells (MC). MC can be sub classified in tryptase-positive (MCT) and tryptase- and chymase-positive (MCTC). This study investigates the presence of MC in the decidua of pregnancies complicated by fetal growth restriction (FGR) and stillbirth (SB).Methods: Placental tissue from FGR (n = 250), SB (n = 64) and healthy pregnancies (n = 42) was included. Histopathological lesions were classified according to the Amsterdam Placental Workshop Group criteria. Tissue sections were stained for tryptase and chymase. Decidual MC were counted manually, and the results were expressed as number of cells/mm2 decidual tissue.Results: A significant lower median number of MCTC was found in the decidua of FGR (0.40 per mm2; p < 0.001) and SB (0.51 per mm2; p < 0.05) compared to healthy controls (1.04 per mm2). No difference in MCT number (1.19 per mm2, 1.88 per mm2 and 1.37 per mm2 respectively) was seen between the groups. There was no difference in number of MCT and MCTC between placental pathological lesions.Discussion: Our findings suggest a shift in decidual MC balance towards MCT in pregnancy complications. No difference in numbers of MC subtypes was found to be related to histopathologic lesions. [ABSTRACT FROM AUTHOR]

Introduction: Villitis of unknown etiology (VUE) is associated with fetal growth restriction (FGR) and adverse short-term neonatal outcomes. No investigation to date has found which VUE features are driving the association with FGR diagnosis.Methods: A retrospective cohort study of placenta pathology specimens (2013-2017) was conducted. Independent variables of interest were: VUE distribution (focal vs diffuse), location (basal vs non-basal), and grade (high vs low). The primary outcome was FGR, and secondary outcomes were neonatal intensive care unit (NICU) admission, NICU length of stay, Apgar scores <7 at 1, 5, and 10-min, and recurrence rate of villitis in subsequent pregnancies. Association between VUE characteristics and our primary outcome were investigated using logistic regression. Secondary outcomes were explored with regression analyses and recurrence rate of VUE for members of the cohort with a recorded subsequent pregnancy was calculated.Results: One hundred and twenty seven placentas were included. Adjusted models showed no difference in the odds of FGR between high-grade versus low-grade VUE [aOR 1.25 95% CI (0.50, 3.26), p = 0.6], focal/multi-focal vs diffuse cases [aOR 1.03 95% CI (0.28, 4.34), p = >0.9], and basal vs non-basal VUE [aOR 0.06 95% CI (0.00, 1.10), p = 0.058]. After adjusting for prematurity <37 weeks, there were lower odds of NICU admission in basal vs non-basal cases [aOR 0.25, 95% CI (0.06, 0.90), p = 0.048). There was no difference in the odds of neonates presenting with Apgar <7 for the distinct VUE histopathology features. Three cases had recurrent VUE, resulting in a 6.8% [95% CI (3.02%, 10.61%)] recurrence rate. All recurrent cases were high-grade and identified with basal localization.Discussion: There are no statistical associations between distinct VUE features and FGR diagnosis, however location of villitis may be associated with worse neonatal outcomes. Villitis of any type (severity, degree, location) could potentially drive insufficient placental function and poor fetal growth. [ABSTRACT FROM AUTHOR]

Introduction: We aimed to systemically investigate the diagnostic capacity of soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) ratio in fetal growth restriction (FGR).Methods: We systematically searched the PubMed, MEDLINE, Cochrane Library, and EMBASE databases for relevant studies from inception to 15 May 2022. All potentially relevant studies were assessed and then pooled.Results: Eight studies with 339 patients and 5111 controls were included. A sFlt-1/PlGF ratio >33 was demonstrated a predictive value for FGR with a pooled sensitivity of [0.63, 95% confidence interval (CI) = 0.54-0.71], specificity of (0.84, 95% CI = 0.83-0.85), and area under the curve (AUC) of 0.8354. The pooled sensitivity, specificity, and AUC for the sFlt-1/PlGF ratio ≥85 group were 0.79 (95% CI = 0.66-0.89), 0.69 (95% CI = 0.65-0.74), and 0.8197, respectively.Discussion: These findings revealed that the sFlt-1/PlGF ratio could be a potential indicator in predicting FGR and FGR + PE. More studies are needed to support the conclusion. [ABSTRACT FROM AUTHOR]

Introduction: Fetal growth restriction (FGR) is a kind of obstetric complication that seriously endangers fetal life. Recent studies reported significant reduction of hsa&#95;circ&#95;0081343 in human placenta developed in FGR and is involved in cell migration, invasion, and apoptosis of trophoblast by acting as microRNA sponges. Autophagy is required for invasion of trophoblast cells and for vascular remodeling during placentation. In this study, we aimed to explore the mechanistic link between hsa&#95;circ&#95;0081343 and autophagy., Methods: We investigated the interactions between hsa&#95;circ&#95;0081343 and RNA-binding proteins were studied by RNA pull-down assay, mass spectrometry and RNA immunoprecipitation assay. The mechanism of nuclear translocation of Rbm8a were assessed by reverse transcription-quantitative PCR, Western blot, immunofluorescence and Co-Immunoprecipitation. Western blot, immunofluorescence and transmission electron microscopy were performed to elucidate the mechanism underlying hsa&#95;circ&#95;0081343 and/or Rbm8a mediated regulation of autophagy., Results: hsa&#95;circ&#95;0081343 served as an RNA-binding protein (RBP) sponge. RNA binding motif protein 8A (Rbm8a) was directly bound to hsa&#95;circ&#95;0081343 in the cytoplasm, while knockdown of hsa&#95;circ&#95;0081343 facilitated Rbm8a localization in the nucleus. We also identified Rbm8a as a potential import cargo for Importin13 (Ipo13), which transported Rbm8a across the nuclear membrane into the nucleus. Ipo13 recognized Rbm8a via a functional nuclear localization signal (NLS). Furthermore, the mechanistic study revealed that hsa&#95;circ&#95;0081343-mediated nuclear translocation of Rbm8a activated trophoblast autophagy., Discussion: Our results suggest that hsa&#95;circ&#95;0081343 could bind to RBP and the interaction between hsa&#95;circ&#95;0081343 and Rbm8a participate in regulating autophagy. These findings offer novel molecular targets and insights for a potential therapeutic strategy against FGR., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Uterine spiral artery (SpA) remodeling is critical for a successful pregnancy. The deficiency of SpA remodeling seriously affects the blood perfusion of the placenta, impacting the nutritional supply to the fetus and therefore fetal growth and development, which is one of the pathological causes of pregnancy related diseases. This process involves the interaction between all cells and related factors at the maternal-fetal interface, especially extravillous trophoblast cells (EVT), vascular smooth muscle cells (VSMCs) and decidual immune cells. Osteopontin (OPN), as a glycosylated protein, is widely localized in the extracellular matrix and participates in a variety of cellular activities such as migration, adhesion, differentiation and survival. OPN plays an important role in placental development, uterine decidualization and pregnancy success. This study focuses on the role of OPN in uterine spiral artery remodeling and its related molecular mechanism. [ABSTRACT FROM AUTHOR]

Fetal growth restriction (FGR) in human pregnancy is associated with perinatal mortality, short- and long-term morbidities. No prenatal therapy is currently established despite decades of research. We aimed to review interventions in animal models for prenatal FGR treatment, and to seek the next steps for an effective clinical therapy. We registered our protocol and searched MEDLINE, Embase, and The Cochrane Library with no language restrictions, in accordance with the PRISMA guideline. We included all studies that reported the effects of any prenatal intervention in animal models of induced FGR. From 3257 screened studies, 202 describing 237 interventions were included for the final synthesis. Mice and rats were the most used animals (79%) followed by sheep (16%). Antioxidants (23%), followed by vasodilators (18%), nutrients (14%), and immunomodulators (12%) were the most tested therapy. Two-thirds of studies only reported delivery or immediate neonatal outcomes. Adverse effects were rarely reported (11%). Most studies (73%), independent of the intervention, showed a benefit in fetal survival or birthweight. The risk of bias was high, mostly due to the lack of randomization, allocation concealment, and blinding. Future research should aim to describe both short- and long-term outcomes across various organ systems in well-characterized models. Further efforts must be made to reduce selection, performance, and detection bias. [ABSTRACT FROM AUTHOR]

Early placental development lays the foundation of a healthy pregnancy, and numerous tightly regulated processes must occur for the placenta to meet the increasing nutrient and oxygen exchange requirements of the growing fetus later in gestation. Inadequacies in early placental development can result in disorders such as fetal growth restriction that do not present clinically until the second half of gestation. Indeed, growth restricted placentae exhibit impaired placental development and function, including reduced overall placental size, decreased branching of villi and the blood vessels within them, altered trophoblast function, and impaired uterine vascular remodelling, which together combine to reduce placental exchange capacity. This review explores the importance of early placental development across multiple anatomical aspects of placentation, from the stem cells and lineage hierarchies from which villous core cells and trophoblasts arise, through extravillous trophoblast invasion and spiral artery remodelling, and finally remodelling of the larger uterine vessels. [ABSTRACT FROM AUTHOR]

Introduction: To assess value of placental vascularization indices (PVIs) for predicting preeclampsia (PE) and fetal growth restriction (FGR) in different stages of pregnancy in high-risk women.Method: PVIs derived from 3-dimensional power doppler(3DPD) imaging were measured at seven stages of pregnancy: 11-13+6w, 15-19+6w, 20-23+6w, 24-27+6w, 28-31+6w, 32-36+6w, and ≥37w. PE and FGR were used as outcomes in logistic regression models. Area under the receiver operating characteristic (ROC) curve (AUC) of each PVI was calculated, cut-off points were determined to calculate the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR), and negative likelihood ratio (NLR). Finally, AUCs combined with baseline characteristics, uterine artery pulsatility index (UTPI) and PVIs were used to determine whether PVIs could increase the predictive value.Results: Adverse outcomes occurred in 10.9% of pregnancies. Statistical differences appeared in 32-36+6w only. AUCs of vascularization index (VI) and vascularization flow index (VFI) for 32-36+6w were 0.79 (0.70-0.87, p: 0.000), and 0.78 (0.69-0.88, p: 0.000). Sensitivity, specificity, PPV, NPV, PLR, and NLR for VI were 0.91, 0.63, 20%, 98%, 2.39, and 0.15, and those for VFI were 0.62, 0.84, 29%, 95%, 3.75, and 0.45. AUC increased from 0.79 to 0.85 by adding PVIs to baseline characteristics and UTPI model. No statistical significance was found before 32w.Discussion: VI and VFI were valuable for predicting PE and FGR at the 32-36+6w stage, while their values before 32w were poor. [ABSTRACT FROM AUTHOR]

Introduction: Cell-cell fusion of cytotrophoblasts into the syncytiotrophoblast layer is a key process in placental development. Syncytin, an endogenous retroviral envelope protein, is expressed in placental trophoblasts and specifically mediates syncytiotrophoblast layer formation. Syncytin deficiency has been observed in fetal growth-restricted placentas. Abnormal fetal growth, especially fetal growth restriction, is associated with the decreased expression of glucose transporters. Here, we aimed to determine the role of syncytin in fetal growth restriction in placental glucose transport capacity.Methods: To better explore the function of syncytin in fetal growth-restricted placenta, we generated an inducible knockout mouse model of syncytin-a gene. The expression levels of glucose transporters in BeWo cells were measured before and after HERV-W knockdown.Results: Syncytin-A disruption was associated with significant abnormalities in placental and fetal development in mice. Syncytin-A destruction causes extensive abnormalities in the maternal-fetal exchange structures in the labyrinth, including an extremely reduced number and dramatically irregular distribution of fetal vessels. Moreover, glucose transporter 1, glucose transporters 3, and connexin 26 expression levels decreased after E14.5. Consistently, low glucose transporter 1, glucose transporter 3, and connexin 26 levels were observed in HERV-W-silenced BeWo cells.Discussion: Syncytin-A is crucial for both syncytiotrophoblast layer development and morphogenesis, suggesting that syncytin-A disruption leads to fetal growth restriction associated with abnormalities in the maternal-fetal exchange barrier and decreased glucose transport. [ABSTRACT FROM AUTHOR]

Introduction: Multiple pregnancies are at increased risk of placental-related complications. The aim of the study was to investigate the prevalence and cumulative incidence of placental-related complications in twin pregnancies undergoing a late selective termination, compared to matched singleton and twin controls.Methods: A retrospective case-control study of post-selective late termination (≥20 weeks of gestation) singletons performed between 2009 and 2020 at a single tertiary center. Each post-termination pregnancy was matched to 2 singleton and 2 dichorionic twin pregnancies for: mode of conception, maternal age group and parity. The prevalence of composite placental related outcome was determined and compared. Kaplan-Meier curves were constructed, and log rank test was performed to compare the cumulative incidence of placental complications among groups.Results: Included were 90 post-selective termination pregnancies and 360 matched singletons and twins. These were subdivided according to trimester at procedure: 1) late 2nd trimester (N = 43, 20-27.6 weeks); 2) 3rd trimester (N = 47, ≥28 weeks). Placental-related complications presented earlier in the 3rd trimester selective termination group compared to singletons (median 35.5 vs median 37.4 weeks of gestation, P = 0.01). The cumulative incidence of placental-related complications in twins and post-selective termination singletons rose significantly earlier compared to singletons (P < 0.0001). A late 2nd trimester selective termination resulted in a comparable gestational age and cumulative incidence of placental-related complications as singletons.Discussion: Compared to singletons, the cumulative incidence of placental complications rises significantly earlier in post-third trimester selective termination singleton pregnancies. While a late 2nd trimester selective termination results in a cumulative incidence comparable to singletons. [ABSTRACT FROM AUTHOR]

Introduction: Intravoxel Incoherent Motion (IVIM) imaging has been used to assess placental microcirculatory flows. We proposed a joint analysis of flow-compensated (FC) and non-compensated (NC) diffusion MRI to estimate the fraction and velocity of ballistic microcirculatory flow (fb and vb), and evaluated the diagnostic performance of the new markers in maternal and fetal disorders.Methods: Gestational diabetes mellitus (GDM, n = 15) pregnancies and fetal growth restriction (FGR, n = 12), along with gestational age matched normal controls (n = 19 for GDM and 15 for FGR) underwent FC and NC-encoded IVIM scans at 1.5 T. fb and vb obtained from a FC-NC joint model, along with the conventional IVIM indices, were compared between patient groups for whole-placenta and maternal/fetal sides of the placenta. A linear support vector machine (SVM) was used to classify the GDM, FGR and controls.Results: vb of whole-placenta were significantly lower in both GDM (p = 0.017) and FGR (p = 0.043), compared with their controls, and the differences were more evident in the fetal side (p = 0.010 for GDM and p = 0.042 for FGR). fb and fFC showed group differences in the fetal side and DFC showed differences in whole-placenta for GDM patients. In the classification task, vb showed the highest diagnostic accuracy of 70.6% for GDM and 63.0% for FGR, and the combination of fb and vb further improved the detection accuracy to 73.5% and 66.7% for GDM and FGR, respectively.Discussion: vb showed superior performance in the diagnosis of GDM and FGR, indicating the potential of the joint FC-NC IVIM method for placenta examinations. [ABSTRACT FROM AUTHOR]

Introduction: Intravoxel Incoherent Motion (IVIM) MRI is a non-invasive, in vivo techniques which can assess placental perfusion quantitatively, and be useful for evaluating placental microcirculation. Our primary aim was to investigate whether fetal growth restriction (FGR) pregnancies have different placental perfusion and diffusion compared with normal pregnancies using IVIM. A secondary aim was to investigate correlations between placental IVIM parameters and gestational age in normal pregnancy.Methods: This study population included 17 FGR pregnancies and 36 normal pregnancies between 28 + 3 to 38 + 0 weeks. All women underwent a MRI examination including an IVIM sequence with 9 b-values on a 3.0 T MRI system. The standard diffusion coefficeint (D), pseudodiffusion (D*) and perfusion fraction (f) were calculated.Results: Placental f was significantly lower in the FGR group than that in the normal group (33.96 ± 2.62(%) vs 38.48 ± 5.31(%), p = 0.002). Placental D and D* in two groups showed no statistical significance (P > 0.05). Placental f moderately increased with increasing gestational age in normal pregnancies (r = 0.411, p = 0.013), and there existed a negative correlation between D values and gestational age (r = -0.390, p = 0.019).Discussion: The f values are able to distinguish FGR from normal pregnancies. It can be uses as a feasible index to evaluate placenta perfusion. Gestational age-associated changes in placental IVIM parameters likely reveal trajectories of microvascular perfusion fraction and diffusion characteristics in the normal developing placenta. [ABSTRACT FROM AUTHOR]

The (pro)renin receptor ((P)RR) is a multi-functional protein that can be proteolytically cleaved and released in a soluble form (s(P)RR). Recently, the (P)RR and s(P)RR have become of interest in pregnancy and its associated pathologies. This is because the (P)RR not only activates tissue renin angiotensin systems, but it is also an integral component of vacuolar-ATPase, activates the wingless/integrated (Wnt)/β-catenin and extracellular signal regulated kinases 1 and 2/mitogen-activated protein kinase signalling pathways, and stabilises the β subunit of pyruvate dehydrogenase. Additionally, s(P)RR is detected in plasma and urine, and maternal plasma levels are elevated in pregnancy complications including fetal growth restriction, preeclampsia and gestational diabetes mellitus. Therefore, s(P)RR has potential as a biomarker for these pregnancy pathologies. Preliminary functional findings suggest that s(P)RR may be important for regulating fluid balance, inflammation and blood pressure, all of which contribute to a successful pregnancy. The (P)RR and s(P)RR regulate pathways that are known to be important in maintaining pregnancy, however their role in the physiological context of pregnancy is poorly characterised. This review summarises the known and potential functions of the (P)RR and s(P)RR in pregnancy, and how their dysregulation may contribute to pregnancy complications. It also highlights the need for further research into the source and function of s(P)RR in pregnancy. Soluble (P)RR levels could be indicative of placental, kidney or liver dysfunction and therefore be a novel clinical biomarker, or therapeutic target, to improve the detection and treatment of pregnancy pathologies. [ABSTRACT FROM AUTHOR]

The leading cause of perinatal mortality is fetal growth restriction (FGR), defined as in utero fetal growth below the 10th percentile. Insufficient exchange of oxygen and nutrients at the maternal-fetal interface is associated with FGR. This transport occurs through the vasculature of the placenta, particularly in the terminal villi, where the vascular membranes have a large surface area and are the thinnest. Altered structure of the placenta villi is thought to contribute to decreased oxygen exchange efficiency, however, understanding how the three-dimensional microstructure and properties decrease this efficiency remains a challenge. Here, a novel, multiscale workflow is presented to quantify patient-specific biophysical properties, 3D structural features, and blood flow of the villous tissue. Namely, nanoindentation, optical coherence tomography, and ultrasound imaging were employed to measure the time-dependent material properties of placenta tissue, the 3D structure of villous tissue, and blood flow through the villi to characterize the microvasculature of the placenta at increasing length scales. Quantifying the biophysical properties, the 3D architecture, and blood flow in the villous tissue can be used to infer changes in maternal-fetal oxygen transport at the villous membrane. Overall, this multiscale understanding will advance knowledge of how microvascular changes in the placenta ultimately lead to FGR, opening opportunities for diagnosis and intervention., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Fetal growth restriction (FGR) is a clinically important human pregnancy disorder that is thought to originate early in pregnancy and while its aetiology is not well understood, the disorder is associated with placental insufficiency. Currently treatment for FGR is limited by increased surveillance using ultrasound monitoring and premature delivery, or corticosteroid medication in the third trimester to prolong pregnancy. There is a pressing need for novel strategies to detect and treat FGR at its early stage. Homeobox genes are well established as master regulators of early embryonic development and increasing evidence suggests they are also important in regulating early placental development. Most important is that specific homeobox genes are abnormally expressed in human FGR. This review focusses on identifying the molecular pathways controlled by homeobox genes in the normal and FGR-affected placenta. This information will begin to address the knowledge gap in the molecular aetiology of FGR and lay the foundation for identifying potential diagnostic and therapeutic targets., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

We aimed at testing systemic vascular resistance (SVR) for the correct identification of early fetal growth restriction (FGR). 61 normotensive patients, gestational age 29 + 0-32 + 0, with suspected diagnosis of early FGR, were submitted to USCOM and to an ultrasound evaluation. 24 patients met the criteria of FGR, and 9 patients developed umbilical artery Doppler alterations. SVR>1006 dyn s·cm-5 correctly identified patients with a subsequent diagnosis of FGR, whereas SVR>1222 dyn s·cm-5 was related to FGR with subsequent umbilical artery Doppler alterations. These data might be important to introduce USCOM in the clinical practice to identify and treat FGR. [ABSTRACT FROM AUTHOR]

Placental metabolism determines the amount of nutrients available to the fetus and may be altered in pregnancies complicated by fetal growth restriction (FGR). To study which metabolites are associated with FGR, we performed 1H high-resolution magic angle spinning magnetic resonance spectroscopy of placental tissue from endothelial nitric oxide synthase knockout (eNOS KO) mice, a model of FGR, and C57BL/6J controls at embryonic day 17.5 (n = 24/genotype). The relative concentration of glucose was increased in the placentas of eNOS KO mice compared to controls (p = 0.006). This study highlights the potential for glucose as a biomarker of abnormal placental metabolism that leads to FGR. [ABSTRACT FROM AUTHOR]

Introduction: Neural tube defects (NTDs) are amongst the most common congenital anomalies and are associated with significant postnatal morbidity, but also with a higher incidence of low birthweight and fetal growth restriction. Despite the placenta being a critical determinant of fetal growth, placental development has not been extensively studied in fetuses with NTDs.Methods: We performed a matched case-cohort study using data from the Collaborative Perinatal Project to assess the risk of placental pathology in pregnancies with an isolated fetal NTD (cases; n = 74) compared to those without any congenital anomalies (controls; n = 148). We hypothesised that cases would be at an increased risk of placental pathology compared to controls. Data were analysed using adjusted generalized linear and nominal logistic regression models. Results are presented as adjusted β or adjusted odds ratio (aOR; 95% confidence interval).Results: Cases had lower placental weight (β = -22.2 g [-37.8 to -6.6]), surface area (β = -9.6 cm2 [-18.3 to -1.0]) and birth length z-scores (β = -0.4 [-0.7 to -0.001]) compared to controls. Cases were more likely to have a single umbilical artery (vs. two; 6 [8.1%] vs. 1 [0.7%]; aOR = 301 [52.6-1726]), placental hypermaturity (9 [12.2%] vs. 5 [3.4%]; aOR = 6.8 [3.1-14.7]), many (vs. few) Hofbauer cells (9 [12.2%] vs. 7 [4.7%]; aOR = 3.02 [1.2-7.3]), and stromal fibrosis (9 [12.2%] vs. 10 [6.8%]; aOR = 3.0 [1.4-6.3]) in placental terminal villi compared to controls.Conclusions: Fetuses with isolated NTDs may be at increased risk of placental pathology, which could be contributing to poor fetal growth in these pregnancies and subsequent postnatal morbidities. [ABSTRACT FROM AUTHOR]

Cancer during pregnancy has been associated with (pathologically) small for gestational age offspring, especially after exposure to chemotherapy in utero. These infants are most likely growth restricted, but sonographic results are often lacking. In view of the paucity of data on underlying pathophysiological mechanisms, the objective was to summarize all studies investigating placental pathology related to cancer(treatment). A systematic search in PubMed/Medline, Embase (OVID) and SCOPUS was conducted to retrieve all studies about placental pathology in cancer during pregnancy or after cancer treatment, published until August 2020. The literature search yielded 5784 unique publications, of which 111 were eligible for inclusion. Among them, three groups of placental pathology were distinguished. First, various histopathologic changes including maternal vascular malperfusion have been reported in pregnancies complicated by cancer and after cancer treatment exposure, which were not specific to type of cancer(treatment). Second, cancer(treatment) has been associated with placental cellular pathology including increased oxidative damage and apoptosis, impaired angiogenesis and genotoxicity. Finally, involvement of the placenta by cancer cells has been described, involving both the intervillous space and rarely villous invasion, with such fetuses are at risk of having metastases. In conclusion, growth restriction is often observed in pregnancies complicated by cancer and its cause can be multifactorial. Placental histopathologic changes, cellular pathology and genotoxicity caused by the cancer(treatment) may each play a role. [ABSTRACT FROM AUTHOR]

Introduction: Fetal growth restriction (FGR) is a common obstetric complication that can lead to a variety of adverse perinatal outcomes and is associated with chronic diseases in adulthood. Since ubiquitin-specific protease 22 (USP22) is closely related to cell growth, differentiation and proliferation, we aimed to investigate the role of USP22 in FGR development.Methods: USP22 expression was detected in the placentas of eight normal and eight pregnant women with FGR. To observe changes in the formation and function of placental vasculature, USP22 expression was downregulated in human umbilical vein endothelial cells (HUVECs) using CRISPR/Cas9 and siRNAs. In addition, HUVECs with low and normal USP22 expression were analysed using RNA-seq.Results: We found that USP22 expression was significantly lower in the placentas of pregnant women with FGR than in normal pregnant women and that HUVECs were unable to survive after USP22 had been knocked out. Moreover, USP22 down-regulation in HUVECs led to decreased proliferation, angiogenesis, vasodilation, apoptosis, and systolic function. RNA-seq identified 3730 differentially expressed genes that were enriched in multiple signalling pathways, including cell cycle regulation, apoptotic signalling, and PI3K/Akt.Discussion: Together, the findings of this study demonstrate for the first time that abnormal USP22 expression may affect HUVEC proliferation and apoptosis, as well as essential angiogenesis and vasomotor functions during the development of FGR. [ABSTRACT FROM AUTHOR]

Fetal growth restriction arising from placental insufficiency is a leading cause of stillbirth. We recently identified low maternal circulating SPINT1 concentrations as a novel biomarker of poor fetal growth. Here we measured SPINT1 in a prospective cohort in Singapore. Circulating SPINT1 concentrations were significantly lower among 141 pregnant women destined to deliver small-for-gestational age infants (birthweight <10th centile), compared to 772 controls (p < 0.01) at as early as 26 weeks' gestation. There were no correlations between infant body composition and circulating SPINT1 concentrations at 26 weeks. This provides validation that low maternal SPINT1 concentration is associated with poor fetal growth. [ABSTRACT FROM AUTHOR]

Introduction: Brief hypercapnic challenge causes acute placental hypoperfusion with fetal brain sparing on BOLD-MRI. We hypothesize that this non-invasive imaging strategy can distinguish between normal pregnancy and chronic placental hypoperfusion (using the maternal hypoxia model).Methods: Eighteen pregnant female ICR mice were randomized to three groups: normoxia, late-onset hypoxia (12%O2;E13.5-17.5) and early-onset hypoxia (12%O2;E10.5-17.5). On E17.5, animals were imaged in a 4.7-T Bruker-Biospec MRI scanner. Fast coronal True-FISP was performed to identify organs of interest (placenta and fetal heart, liver and brain). BOLD-MRI was performed at baseline and during a 4-min hypercapnic challenge (5%CO2). %-change in placental and fetal signal was analyzed from T2*-weighted gradient echo MR images. Following MRI, fetuses and placentas were harvested, weighed and immuno-stained.Results: In normoxic mice, hypercapnia caused reduction in BOLD-MRI signal in placenta (-44% ± 7%; p < 0.0001), fetal liver (-32% ± 7%; p < 0.0001) and fetal heart (-54% ± 12%; p < 0.002), with relative fetal brain sparing (-12% ± 5%; p < 0.0001). These changes were markedly attenuated in both hypoxia groups. Baseline fetal brain/placenta SI ratio was highest in normoxic mice (1.14 ± 0.017) and reduced with increasing duration of hypoxia (late-onset hypoxia: 1.00 ± 0.026; early-onset hypoxia: 0.91 ± 0.016; p = 0.02). Both hypoxic groups exhibited fetal growth restriction with prominent placental glycogen-containing cells, particularly in early-onset hypoxia. There was increased fetal neuro- and intestinal-apoptosis in early-onset hypoxia only.Conclusions: BOLD-MRI with brief hypercapnic challenge distinguished between normoxia and both hypoxia groups, while fetal neuroapoptosis was only observed after early-onset hypoxia. This suggests that BOLD-MRI with hypercapnic challenge can identify chronic fetal asphyxia before the onset of irreversible brain injury. [ABSTRACT FROM AUTHOR]

Placental-associated diseases account for most cases of adverse perinatal outcome in developing countries. Doppler evaluation has been incorporated as a predictive parameter at early pregnancy for high-risk placental disease, in the diagnosis and management of those fetuses with impaired intrauterine growth and for the evaluation of fetal wellbeing in those high-risk pregnancies. Uterine Doppler at second trimester predicts most instances of early-onset preeclampsia and intrauterine growth restriction. However, the growing evidence of an effective early propylactic strategy, has turned Uterine Doppler an essential parameter to be included in first trimester predictive algorithms. Umbilical artery Doppler helps in the identification of small-for-gestational-age fetuses at higher risk, and is one of the essential vessels in the assessment of fetal hypoxia impairment, especially in the early cases. It helps in the decision timing for ending the pregnancy improving thus perinatal outcomes. Moreover, in high-risk pregnancies, umbilical artery Doppler has demonstrated to reduce the risk of perinatal deaths and the risk of obstetric interventions. On the other hand, middle cerebral artery Doppler reflects fetal adaptation to hypoxia, and with the cerebroplacental ratio, they improve the detection of fetuses a high risk of adverse perinatal outcome, mostly of those late small fetuses, where most instances of adverse outcome occur in fetuses with normal umbilical artery. Ductus venosous Doppler waveform is a surrogate parameter of the fetal base-acid status. Its use has demonstrated to improve perinatal outcomes, mainly reducing the risk of fetal intrauterine death. Alone or in combination with computerized CTG, it helps tailoring the best moment to end the pregnancy among early cases. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the accuracy of universal third trimester umbilical artery (UA) Doppler to predict adverse pregnancy outcome at term. We searched Medline, EMBASE, the Cochrane library and ClinicalTrials.gov from inception to October 2020 and we also analyzed previously unpublished data from a prospective cohort study of nulliparous women, the Pregnancy Outcome Prediction (POP) study. We included studies that performed a third-trimester ultrasound scan in unselected, low or mixed risk populations, excluding studies which only included high risk pregnancies. Meta-analysis was performed using the hierarchal summary receiver operating characteristic curve (HSROC) analysis and bivariate logit-normal models. We identified 13 studies (including the POP study) involving 67,764 pregnancies which met our inclusion criteria. The overall quality was variable and only six studies (N = 5777 patients) blinded clinicians to the UA Doppler result. The summary sensitivity and positive likelihood ratio (LR) for small for gestational age (SGA; birthweight <10th centile) were 21.7% (95% CI 13.2-33.6%) and 2.65 (95% CI 1.89-3.72) respectively. The summary positive LR for NICU admission and metabolic acidosis were 1.35 (95% CI 0.93-1.97) and 1.34 (95% CI 0.86-2.08) respectively. The results were similar in the POP study: associations with SGA (positive LR 2.66 [95% CI 2.11-3.36]) and severe SGA (birthweight <3rd centile; positive LR 3.27 [95% CI 2.29-4.68]) but no statistically significant association with neonatal morbidity. We conclude that third trimester UA Doppler has moderate predictive accuracy for small for gestational age but not for indicators of neonatal morbidity in unselected and low risk pregnancies. [ABSTRACT FROM AUTHOR]

Introduction: The choice of fetal growth chart to be used in antenatal screening for fetal growth restriction (FGR) has an important impact on the proportion of fetuses diagnosed as small for gestational age (SGA), and on the detection rate for FGR. We aimed to compare diagnostic accuracy of SGA diagnosed using four different common fetal growth charts [Hadlock, Intergrowth-21st (IG21), World Health Organization (WHO), and National Institute of Child Health and Human Development (NICHD)], for abnormal placental pathology.Methods: A secondary analysis of data from a prospective cohort study in low-risk nulliparous women. The exposure was SGA (birthweight <10th centile for gestational age) using each of the four charts. The outcomes were one of three types of abnormal placental pathology associated with fetal growth restriction: maternal vascular malperfusion (MVM), chronic villitis, and fetal vascular malperfusion.Results: A total of 742 nulliparous women met the study criteria. The proportion of SGA was closest to the expected rate of 10% using the Hadlock chart (12.7%). The detection rates (DR) and false positive rates (FPR) for MVM pathology were similar for the Hadlock (DR = 53.1%, FPR = 10.8%), WHO (DR = 59.4%, FPR = 14.2%), and NICHD (DR = 53.1%, FPR = 12.3%) charts, and each was superior when compared to the IG21 chart (DR = 34.4%, FPR = 3.8%, p < 0.001). The diagnosis of SGA was associated with increased risks of preeclampsia and preterm birth for all four charts.Discussion: The selection of fetal growth chart to be used in screening programs for FGR has important implications with regard to the false positive and detection rate for FGR. [ABSTRACT FROM AUTHOR]

Introduction: We aimed to investigate the effect of placental histologic chorioamnionitis (HC) on neonatal outcomes in pregnancies complicated by fetal growth restriction (FGR).Methods: - The computerized medical files of all pregnancies diagnosed with FGR (birthweight <10th percentile) at 24-42 weeks of gestation between 2008 and 2019 were reviewed. Maternal and neonatal outcomes were compared between FGR with and without evidence of placental HC. Placental lesions were classified according to "Amsterdam" criteria. Composite adverse neonatal outcome-included any of the following complications: neurological morbidity, neonatal respiratory assistance, RDS, NEC, sepsis, blood transfusion, phototherapy, hypoglycemia, or neonatal death. Composite severe adverse neonatal outcome included any of the following complications - neurological morbidity, blood transfusion, NEC, sepsis, RDS, neonatal death.Results: - Compared to FGR without HC (n = 446), FGR with HC (n = 57) was characterized by more advanced gestational age at delivery 39.2 (38.3-39.9) vs. 38.2 (36.9-39.2), weeks respectively, p < 0.001), higher rate of nulliparity (73.7% vs. 45.1%, p < 0.001), less vascular lesions of MVM (1.8% vs.11.2%, p = 0.02), higher rate of Apgar scores at 5 min <7 (10.5% vs. 2%, p = 0.004), increased neonatal death (7.0% vs. 0.9%, p = 0.007), higher rates of both composite adverse neonatal outcome (31.1% vs. 17.3% p = 0.02), and composite severe adverse neonatal outcome (16.3% vs. 8.2% p = 0.04). By multivariate regression analysis HC was found to be independently associated with composite adverse neonatal outcome (aOR = 1.21, 95% CI 1.08-2.38) and with severe composite adverse neonatal outcome (aOR = 1.39, 95% CI 1.16-3.76).Conclusions: Pregnancies complicated by FGR with concomitant HC were associated with higher rates of adverse neonatal outcomes. [ABSTRACT FROM AUTHOR]

Early-onset preeclampsia (PE) is a severe condition with highest risk of perinatal complications. In current study, we compared PE severity, laboratory results and placental pathological lesions between early-onset PE with fetal growth restriction (PE + FGR) and appropriate gestational age (PE + AGA) neonates, with the aim to identify potential maternal risk factors associated with FGR. A retrospective case study was conducted in 304 PE women, and 31 cases with mild PE were excluded. 276 patients with severe PE were divided into PE + FGR (163, 59.1%) and PE + AGA (113, 40.9%) groups and underwent clinical analysis. 244 cases were further submitted for pathologic examinations to compare the differences of placental lesions between these two groups. As compared to PE + AGA, the maternal pre-pregnancy BMI (P = 0.003) and the rate of anemia (P = 0.004) were lower in PE + FGR; while the rate of severe low serum albumin (P = 0.020) was higher. Moreover, severe low serum albumin level (aOR = 2.43, P = 0.046) and abnormal uric acid (aOR = 2.19, P = 0.033) were positively correlated to the incidence of FGR, while pre-pregnancy BMI (aOR = 0.39, P = 0.001) and anemia (aOR = 0.33, P = 0.001) showed negative correlation. The placental examinations further showed positively correlation between chronic villitis (aOR = 4.32, P = 0.028) and FGR. Surprisingly, general measures of maternal illness severity failed to present any significant correlation to FGR, except for blood pressure, which showed negative correlation. For the first time, we studied a relatively large case series of Chinses early-onset PE women, and identified multiple factors associated with FGR incidence. Our study provided some opinions on clinal diagnosis and treatment for early-onset PE with FGR. [ABSTRACT FROM AUTHOR]