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OBJECTIVE:  The aim of Placental Assessment in Response to Environmental Pollution Study (PARENTs) was to determine whether imaging of the placenta by novel multiparametric magnetic resonance imaging (MRI) techniques in early pregnancy could help predict adverse pregnancy outcomes (APOs) due to ischemic placental disease (IPD). Additionally, we sought to determine maternal characteristics and environmental risk factors that contribute to IPD and secondary APOs. STUDY DESIGN:  Potential patients in their first trimester of pregnancy, who agreed to MRI of the placenta and measures of assessment of environmental pollution, were recruited into PARENTs, a prospective population-based cohort study. Participants were seen at three study visits during pregnancy and again at their delivery from 2015 to 2019. We collected data from interviews, chart abstractions, and imaging. Maternal biospecimens (serum, plasma, and urine) at antepartum study visits and delivery specimens (placenta, cord, and maternal blood) were collected, processed, and stored. The primary outcome was a composite of IPD, which included any of the following: placental abruption, hypertensive disease of pregnancy, fetal growth restriction, or a newborn of small for gestational age. RESULTS:  In this pilot cohort, of the 190 patients who completed pregnancy to viable delivery, 50 (26%) developed IPD. Among demographic characteristics, having a history of prior IPD in multiparous women was associated with the development of IPD. In the multiple novel perfusion measurements taken of the in vivo placenta using MRI, decreased high placental blood flow (mL/100 g/min) in early pregnancy (between 14 and 16 weeks) was found to be significantly associated with the later development of IPD. CONCLUSION:  Successful recruitment of the PARENTs prospective cohort demonstrated the feasibility and acceptability of the use of MRI in human pregnancy to study the placenta in vivo and at the same time collect environmental exposure data. Analysis is ongoing and we hope these methods will assist researchers in the design of prospective imaging studies of pregnancy. KEY POINTS: · MRI was acceptable and feasible for the study of the human placenta in vivo.. · Functional imaging of the placenta by MRI showed a significant decrease in high placental blood flow.. · Measures of environmental exposures are further being analyzed to predict IPD..

IntroductionTo characterize early-gestation changes in placental structure, perfusion, and oxygenation in the context of ischemic placental disease (IPD) as a composite outcome and in individual sub-groups.MethodsIn a single-center prospective cohort study, 199 women were recruited from antenatal clinics between February 2017 and February 2019. Maternal magnetic resonance imaging (MRI) studies of the placenta were temporally conducted at two timepoints: 14-16 weeks gestational age (GA) and 19-24 weeks GA. The pregnancy was monitored via four additional study visits, including at delivery. Placental volume, perfusion, and oxygenation were assessed at both MRI timepoints. The primary outcome was defined as pregnancy complicated by IPD, with group assignment confirmed after delivery.ResultsIn early gestation, mothers with IPD who subsequently developed fetal growth restriction (FGR) and/or delivered small-for gestational age (SGA) infants showed significantly decreased MRI indices of placental volume, perfusion, and oxygenation compared to controls. The prediction of FGR or SGA by multiple logistic regression using placental volume, perfusion, and oxygenation revealed receiver operator characteristic curves with areas under the curve of 0.81 (Positive predictive value (PPV) = 0.84, negative predictive value (NPV) = 0.75) at 14-16 weeks GA and 0.66 (PPV = 0.78, NPV = 0.60) at 19-24 weeks GA.DiscussionMRI indices showing decreased placental volume, perfusion and oxygenation in early pregnancy were associated with subsequent onset of IPD, with the greatest deviation evident in subjects with FGR and/or SGA. These early-gestation MRI changes may be predictive of the subsequent development of FGR and/or SGA.

Problem: Early‐onset preeclampsia (EOPE) is a severe gestational hypertensive disorder with significant feto‐maternal morbidity and mortality due to uteroplacental insufficiency. Circulating extracellular vesicles of placental origin (EV‐P) are known to be involved in the pathophysiology of EOPE and might serve as an ideal reservoir for its specific biomarkers. Therefore, we aimed to characterize and perform comparative proteomics of circulating EV‐P from healthy pregnant and EOPE women before delivery. Method of Study: The EV‐P from both groups were isolated using immunoaffinity and were characterized using transmission electron microscopy, dynamic light scattering, nanoparticle tracking analysis, and immunoblotting. Following IgG albumin depletion, the pooled proteins that were isolated from EV‐P of both groups were subjected to quantitative TMT proteomics. Results: Circulating term EV‐P isolated from both groups revealed ∼150 nm spherical vesicles containing CD9 and CD63 along with placental PLAP and HLA‐G proteins. Additionally, the concentration of EOPE‐derived EV‐P was significantly increased. A total of 208 proteins were identified, with 26 among them being differentially abundant in EV‐P of EOPE women. This study linked the pathophysiology of EOPE to 19 known and seven novel proteins associated with innate immune responses such as complement and TLR signaling along with hemostasis and oxygen homeostasis. Conclusion: The theory suggesting circulating EVs of placental origin could mimic molecular information from the parent organ—"the placenta"—is strengthened by this study. The findings pave the way for possible discovery of novel prognostic and predictive biomarkers as well as provide insight into the mechanisms driving the pathogenesis of EOPE. [ABSTRACT FROM AUTHOR]

We examined 164 pregnant women who were divided into three groups. Group I included 76 pregnant women (46.4 %) with euthyroid goiter of I–II degree. Group II consisted of 63 pregnant women (38.4 %) with subclinical hypothyroidism and diffuse thyroid goiter of I–II degree. Group III was the controls and consisted of 25 (15.2 %) pregnant women without thyroid pathology. The placenta was studied with the characteristics of ultrasound placentography, placental maturation disorders, the area and localization were determined, and pathological changes in the placental tissue were detected. Changes in the systolic-diastolic ratio in the uterine arteries and umbilical cord arteries were assessed, the resistance index in the uterine arteries, the pulsatile index in the fetal aorta and middle cerebral artery were determined using the method of color Doppler mapping of blood flow in the mother-placenta-fetus system. Study of the echographic picture of structural changes in the placenta revealed a significant impairment of its maturation, especially in the group with euthyroidism. Ultrasound screening revealed that in every second pregnant woman with thyroid disease, the condition of the placenta did not correspond to the gestational age, there were swelling, cysts and placental infarctions, a high frequency of diffuse changes in placental tissue, and hyperechogenic inclusions in the amniotic fluid. An increase in the resistance index in the uterine arteries of pregnant women, especially those with subclinical hypothyroidism, is noteworthy. With increasing gestational age, the peripheral resistance of the placental microvasculature increases due to involutional-dystrophic changes and circulatory disorders, which allows us to develop criteria for the prognosis and diagnosis of placental dysfunction, and to prevent perinatal disorders in pregnant women with thyroid disease. [ABSTRACT FROM AUTHOR]

Chronic venous disease (CVD) comprises a spectrum of morphofunctional disorders affecting the venous system, affecting approximately 1 in 3 women during gestation. Emerging evidence highlights diverse maternofetal implications stemming from CVD, particularly impacting the placenta. While systemic inflammation has been associated with pregnancy-related CVD, preliminary findings suggest a potential link between this condition and exacerbated inflammation in the placental tissue. Inflammasomes are major orchestrators of immune responses and inflammation in different organs and systems. Notwithstanding the relevance of inflammasomes, specifically the NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3)- which has been demonstrated in the placentas of women with different obstetric complications, the precise involvement of this component in the placentas of women with CVD remains to be explored. This study employs immunohistochemistry and real-time PCR (RT-qPCR) to examine the gene and protein expression of key components in both canonical and non-canonical pathways of the NLRP3 inflammasome (NLRP3, ASC—apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain—caspase 1, caspase 5, caspase 8, and interleukin 1β) within the placental tissue of women affected by CVD. Our findings reveal a substantial upregulation of these components in CVD-affected placentas, indicating a potential pathophysiological role of the NLRP3 inflammasome in the development of this condition. Subsequent investigations should focus on assessing translational interventions addressing this dysregulation in affected patient populations. [ABSTRACT FROM AUTHOR]

Aim: Placenta accreta spectrum disorders (PAS) are a global threat to maternal well-being. The aim of this study was to assess differences in clinical characteristics and maternal outcomes between Turkish natives and Syrian refugees giving birth with a diagnosis of PAS at a tertiary centre, and to experience the management of this condition in the unique context of Türkiye, home to one of the world's largest refugee populations. Material and Method: A retrospective study was conducted using the medical records of 228 singleton pregnancies at high risk of PAS, between January 2019 and October 2022. PAS risk assessment was initially performed by ultrasound at mid-trimester, with diagnosis confirmed histologically or clinically, indicating the presence of placental retention following attempted manual removal. The study population was divided into two groups: native and refugee. We investigated disparities in demographic and medical characteristics and primary maternal and neonatal outcomes. Results: The study found an increased prevalence of previous cesarean delivery (p=0.005), anterior placenta (p<0.000), placenta previa (p=0.047), and deeper placental invasion (increta/percreta) (p<0.000) in the native group (n=161). The native group had a significantly higher rate of estimated blood loss (2093.5±1516.4 mL vs. 714.1±731.6 mL, p<0.000) and peripartum hysterectomy (p=0.005) compared to the refugee group (n=67). The refugee group had a notably higher incidence of delayed diagnosis (p<0.000) and a shorter surgery duration (p=0.027) compared to the native group. Conclusion: The current study highlights significant differences in patient characteristics and outcomes between native and refugee pregnant women with PAS. Despite facing challenges, these women did not encounter adverse perinatal outcomes, indicating the efficacy of healthcare interventions. [ABSTRACT FROM AUTHOR]

Pregnancy-related complications (PRC) impact maternal and fetal morbidity and mortality and place a huge burden on healthcare systems. Thus, effective diagnostic screening strategies are crucial. Currently, national and international guidelines define patients at low risk of PRC exclusively based on their history, thus excluding the possibility of identifying patients with de novo risk (patients without a history of disease), which represents most women. In this setting, previous studies have underlined the potential contribution of non-coding RNAs (ncRNAs) to detect patients at risk of PRC. However, placenta biopsies or cord blood samples are required, which are not simple procedures. Our review explores the potential of ncRNAs in biofluids (fluids that are excreted, secreted, or developed because of a physiological or pathological process) as biomarkers for identifying patients with low-risk pregnancies. Beyond the regulatory roles of ncRNAs in placental development and vascular remodeling, we investigated their specific expressions in biofluids to determine favorable pregnancy outcomes as well as the most frequent pathologies of pregnant women. We report distinct ncRNA panels associated with PRC based on omics technologies and subsequently define patients at low risk. We present a comprehensive analysis of ncRNA expression in biofluids, including those using next-generation sequencing, shedding light on their predictive value in clinical practice. In conclusion, this paper underscores the emerging significance of ncRNAs in biofluids as promising biomarkers for risk stratification in PRC. The investigation of ncRNA expression patterns and their potential clinical applications is of diagnostic, prognostic, and theragnostic value and paves the way for innovative approaches to improve prenatal care and maternal and fetal outcomes. [ABSTRACT FROM AUTHOR]

Pre-eclampsia (PE) is a placenta-mediated disease and remains a major cause of maternal and neonatal mortality and morbidity. As PE develops, normal pregnancy's hypercoagulable balance is disrupted, leading to platelet hyperactivation, excessive pathological hypercoagulability, and perturbed fibrinolysis. This narrative review aims to summarize the current knowledge regarding hemostasis in PE compared with healthy gestation and the potential effects of maternal PE on neonatal hemostasis. Finally, it aims to discuss hemostasis assessments for normal pregnancies and PE, emphasizing the role of viscoelastic tests, namely, thromboelastography (TEG) and thromboelastometry (ROTEM), for monitoring PE-associated hemostatic alterations. The use of TEG/ROTEM for assessing the hemostatic profile of PE women has been little considered, even though conventional coagulation tests (CCTs) have not helped to monitor hemostasis in this population. Compared with normal pregnancy, TEG/ROTEM in PE reveals an excessive hypercoagulability analogous with the severity of the disease, characterized by higher-stability fibrin clots. The TEG/ROTEM parameters can reflect PE severity and may be used for monitoring and as predictive markers for the disease. [ABSTRACT FROM AUTHOR]

Background The spectrum of placental adhesive disorders (PAD) forms an important cause for emergency cesarean hysterectomy, requiring an accurate prenatal diagnosis for optimal obstetric management. Purpose The aim of this study was to assess the utility of magnetic resonance imaging (MRI) and to identify the individual MRI features that are most useful in the evaluation of PAD. Materials and Methods This was a retrospective review of the MRI of 24 women with abnormal placentation, confirmed using histopathology/intraoperative findings as the reference standard. Patients were categorized as negative or positive for PAD (placenta accreta, increta, and percreta) on MRI and compared with the reference standard. We assessed the diagnostic performance of MRI and the features that best correlated with the presence of PAD. Results Among the 24 women (mean age: 29.8 years) with risk factors, 16 had PAD (6 accreta, 7 increta, and 3 percreta). There was a history of previous lower segment cesarean section and placenta previa in 14 (87.5%). MRI could identify the presence of PAD in all (100% sensitivity) and its absence in three out of eight patients (37.5% specificity). The features with highest sensitivity were intraplacental dark bands (100%), myometrial thinning/loss of interface with myometrium (100%), placental heterogeneity (75%), and uterine contour abnormality (75%). Conclusion MRI is an important modality for the investigation of PAD in suspected cases, with excellent sensitivity and good accuracy. Identifying the presence of risk factors, low-signal-intensity bands, and thinning/loss of placental–myometrial interface will aid in its diagnosis. [ABSTRACT FROM AUTHOR]

In the therapy of placenta-originated diseases during pregnancy, the main challenges are fetal exposure to drugs, which can pass through the placenta and cause safety concerns for fetal development. The design of placenta-resident drug delivery system is an advantageous method to minimize fetal exposure as well as reduce adverse maternal off-target effects. By utilizing the placenta as a biological barrier, the placenta-resident nanodrugs could be trapped in the local placenta to concentrate on the treatment of this abnormal originated tissue. Therefore, the success of such systems largely depends on the placental retention capacity. This paper expounds on the transport mechanism of nanodrugs in the placenta, analyzes the factors that affect the placental retention of nanodrugs, and summarizes the advantages and concerns of current nanoplatforms in the treatment of placenta-originated diseases. In general, this review aims to provide a theoretical basis for the construction of placenta-resident drug delivery systems, which will potentially enable safe and efficient clinical treatment for placenta-originated diseases in the future. [ABSTRACT FROM AUTHOR]

To compare the clinical and morphological characteristics of the "mother-placenta-fetus" system in high risk pregnant women of three groups: no SARS-CoV-2 infection, mild SARS-CoV-2 infection, and severe SARS-CoV-2 infection. A case-control study was performed for all deliveries, at 28 weeks' gestation or greater, who had standard indications for placental pathologic examination. Three groups were formed: (1) control group (no SARS-CoV-2 infection), (2) mild SARS-CoV-2 infection, (3) severe SARS-CoV-2 infection. High-risk pregnancies were registered in all cases in the study groups. The examination of the placenta and the selection of fragments of placental tissue were carried out in accordance with the consensus recommendations of the Amsterdam Placental Workshop Group. The sections were subjected to standard processing and stained with hematoxylin and eosin according to the standard protocol. All cases were reviewed by two pathologists, which did not know any information on pregnancy outcome and clinical data. Statistical analysis was performed using SPSS, p<0.05 was considered statistically significant. Women with severe SARS-CoV-2 infection had an increased rate of multimorbidity including diabetes, chronic hypertension and obesity (p<0.01) compared with the other groups. Placentas at severe COVID-19 course were damaged by both chronic and acute injuries, in comparison to the mild and control groups (p<0.001). Also an important finding in severe COVID-19 was diffuse necrosis of the villous trophoblast – homogenization, diffuse circular eosinophilic masses surrounding the chorionic villi. Women with multimorbidity are an "at-risk" subgroup for severe SARS-CoV-2 infection and greater likelihood of both placental damage and perinatal hypoxic-ischemic events. These results suggest that patient education, SARS-CoV-2 disease monitoring and preventive measures would be of benefit to this group. [ABSTRACT FROM AUTHOR]

The placenta is a heterogeneous organ whose development involves complex interactions of trophoblasts with decidual, vascular, and immune cells at the fetal-maternal interface. It maintains a critical balance between maternal and fetal homeostasis. Placental dysfunction can lead to adverse pregnancy outcomes including intra-uterine growth restriction, pre-eclampsia, or pre-term birth. Exposure to environmental pollutants contributes to the development of placental abnormalities, with poorly understood molecular underpinning. Here we used a mouse (C57BL/6) model of environmental pollutant exposure by administration of a particulate matter (SRM1649b at 300 μg/day/mouse) suspension intra-nasally beginning 2 months before conception and during gestation, in comparison to saline-exposed controls. Placental transcriptomes, at day 19 of gestation, were determined using bulk RNA-seq from whole placentas of exposed (n = 4) and control (n = 4) animals and scRNAseq of three distinct placental layers, followed by flow cytometry analysis of the placental immune cell landscape. Our results indicate a reduction in vascular placental cells, especially cells responsible for structural integrity, and increase in trophoblast proliferation in animals exposed to particulate matter. Pollution-induced inflammation was also evident, especially in the decidual layer. These data indicate that environmental exposure to air pollutants triggers changes in the placental cellular composition, mediating adverse pregnancy outcomes.

Background: Many pathological insults are associated with elevation of blood pressure levels during pregnancy resulting in a difficult pregnancy and a poor outcome on both mother and baby. Objective: In this study, we examine the histological and immunohistochemical markers of the placentae in cases of hypertension in pregnancy and preeclampsia and compared them to a placenta of normal pregnancy among a random sample of Iraqi pregnant women. Materials and Methods: Ninety women divided into three groups, 30 in each, selected with straightforward pregnancies (Group A), mothers with pregnancy-induced hypertension (Group B), and preeclamptic mothers (Group C) were chosen from the indoor patients of the gynecology and obstetrics department of Al-Khansaa teaching hospital in Mosul for placental tissues examination. Histological examination was done by using hematoxylin and eosin stain (H & E), and immunohistochemistry was achieved by using immunohistochemical markers named: insulin-like growth factor-1 (IGF-1) and basic fibroblast growth factor (b-FGF) markers, which are expressed in placental tissues. Results: Different changes were observed in the placentae affected when compared with normal one, such as syncytial knots formation, thickening of trophoblastic basement membrane, cytotrophoblastic cellular proliferation, fibrinoid necrosis, endothelial proliferation, calcified and hyalinised villous spots, villous edema, and atherosis of the uteroplacental arteries. Significant immunohistochemical changes were obtained when compared with normal placentae where elevation of both b-FGF and IGF-1 in preeclamptic placentae was observed when compared to hypertensive and control cases. Conclusion: Significant changes appeared in the placentae of hypertensive and preeclamptic mothers, both in histological and immunohistochemical examinations. [ABSTRACT FROM AUTHOR]

Background: Pregnant women have an increased risk of getting infected with SARS-CoV-2 and are more prone to severe illness. Data on foetal demise in affected pregnancies and its underlying aetiology is scarce and pathomechanisms remain largely unclear. Case: Herein we present the case of a pregnant woman with COVID-19 and intrauterine foetal demise. She had no previous obstetric or gynaecological history, and presented with mild symptoms at 34 + 3 weeks and no signs of foetal distress. At 35 + 6 weeks intrauterine foetal death was diagnosed. In the placental histopathology evaluation, we found inter- and perivillous fibrin depositions including viral particles in areas of degraded placental anatomy without presence of viral entry receptors and SARS-CoV-2 infection of the placenta. Conclusion: This case demonstrates that maternal SARS-CoV-2 infection in the third trimester may lead to an unfavourable outcome for the foetus due to placental fibrin deposition in maternal COVID-19 disease possibly via a thrombogenic microenvironment, even when the foetus itself is not infected. Novelty: Symptomatic COVID-19 of the mother may cause microthrombotic events in the placenta. These microthrombotic events may lead to placental insufficiency and reduced growth velocity. Further systematic clinical studies investigating the thrombogenic effect of a SARS-CoV-2 infection in pregnancy are warranted. Although a single case report, the findings support previous concerns about placental insufficiency after SARS-CoV-2 infection. This report adds to existing literature and could help support recommendations for additional antenatal testing in similar settings. [ABSTRACT FROM AUTHOR]

Background: Placental dysfunction, a root cause of common syndromes affecting human pregnancy, such as preeclampsia (PE), fetal growth restriction (FGR), and spontaneous preterm delivery (sPTD), remains poorly defined. These common, yet clinically disparate obstetrical syndromes share similar placental histopathologic patterns, while individuals within each syndrome present distinct molecular changes, challenging our understanding and hindering our ability to prevent and treat these syndromes. Methods: Using our extensive biobank, we identified women with severe PE (n = 75), FGR (n = 40), FGR with a hypertensive disorder (FGR + HDP; n = 33), sPTD (n = 72), and two uncomplicated control groups, term (n = 113), and preterm without PE, FGR, or sPTD (n = 16). We used placental biopsies for transcriptomics, proteomics, metabolomics data, and histological evaluation. After conventional pairwise comparison, we deployed an unbiased, AI-based similarity network fusion (SNF) to integrate the datatypes and identify omics-defined placental clusters. We used Bayesian model selection to compare the association between the histopathological features and disease conditions vs SNF clusters. Results: Pairwise, disease-based comparisons exhibited relatively few differences, likely reflecting the heterogeneity of the clinical syndromes. Therefore, we deployed the unbiased, omics-based SNF method. Our analysis resulted in four distinct clusters, which were mostly dominated by a specific syndrome. Notably, the cluster dominated by early-onset PE exhibited strong placental dysfunction patterns, with weaker injury patterns in the cluster dominated by sPTD. The SNF-defined clusters exhibited better correlation with the histopathology than the predefined disease groups. Conclusions: Our results demonstrate that integrated omics-based SNF distinctively reclassifies placental dysfunction patterns underlying the common obstetrical syndromes, improves our understanding of the pathological processes, and could promote a search for more personalized interventions. [ABSTRACT FROM AUTHOR]

The original SARS-CoV-2 lineages have been replaced by successive variants of concern (VOCs) over time. The aim of this study was to perform an assessment of the placental infection by SARS-CoV-2 according to the predominant variant at the moment of COVID-19 diagnosis. This was a prospective study of SARS-CoV-2-positive pregnant women between March 2020 and March 2022. The population was divided into pregnancies affected by COVID-19 disease during 2020 (Pre-VOC group) and pregnancies affected after December 2020 by SARS-CoV-2 variants of concern (VOC group). The presence of virus was assessed by RT-PCR, and the viral variant was determined by whole genome sequencing. A total of 104 placentas were examined, among which 54 cases belonged to the Pre-VOC group and 50 cases belonged to the VOC group. Sixteen positive placental RT-PCR tests for SARS-CoV-2 were reported. The NGS analysis confirmed the SARS-CoV-2 lineage in placenta tissue. All samples corresponded to the Pre-VOC group, whereas no placental presence of SARS-CoV-2 was detected in the VOC group (16, 29.6% vs. 0, 0.0% p = 0.000). Preterm birth (9, 16.7% vs. 2, 4%; p = 0.036) and hypertensive disorders of pregnancy (14, 25.9% vs. 3, 6%; p = 0.003) were more frequent in the Pre-VOC group than in the VOC group. Finally, the VOC group was composed of 23 unvaccinated and 27 vaccinated pregnant women; no differences were observed in the sub-analysis focused on vaccination status. In summary, SARS-CoV-2-positive placentas were observed only in pregnancies infected by SARS-CoV-2 wildtype. Thus, placental SARS-CoV-2 presence could be influenced by SARS-CoV-2 variants, infection timing, or vaccination status. According to our data, the current risk of SARS-CoV-2 placental infection after maternal COVID disease during pregnancy should be updated. [ABSTRACT FROM AUTHOR]

Aim: The ongoing global COVID-19 pandemic, caused by the SARS-CoV-2 virus, has generated significant apprehensions in maternalfetal medicine. Initially considered to affect the respiratory system primarily, recent findings have indicated that the pandemic has far-reaching implications for various physiological functions, particularly in pregnant individuals. This study focused on examining the influence of COVID-19 on placental histopathology in pregnant women infected with SARS-CoV-2. Material and Methods: We conducted a comparative study involving two groups of pregnant women with similar demographic characteristics: a group testing positive for COVID-19 (n=31) and a control group of COVID-19-negative pregnant women (n=31). After delivery, placental tissues were collected and subjected to comprehensive histopathological examination to determine any potential alterations in the placenta induced by SARS-CoV-2 infection. Results: Our study revealed substantial histopathological alterations in pregnant women with COVID-19 placentas. Notably, the COVID-19 group displayed a higher incidence of cesarean deliveries, possibly due to concerns related to maternal-fetal transmission and respiratory complications. Furthermore, neonates born to mothers in the COVID-19 group had significantly lower birth weights. Several placental histopathological changes, including villous fibrin deposits, thrombosis, intervillous hemorrhage, agglutination, avascular fibrotic villi, and syncytial knots, were markedly increased in the COVID-19 group, indicating compromised fetal blood circulation. Although not statistically significant, trends toward elevated villous infarction, fetal vascular malperfusion, and chorioamnionitis were observed. Conclusion: Our study underscores the potential risks associated with COVID-19 on placental health, maternal well-being, and neonatal outcomes. We must understand the underlying physiological mechanisms behind these pathological changes to provide optimal maternal-fetal care during this ongoing crisis. Comprehensive and multicentric studies are urgently required to confirm and expand our findings. [ABSTRACT FROM AUTHOR]

The human placenta and its specialized cytotrophoblasts rapidly develop, have a compressed lifespan, govern pregnancy outcomes, and program the offspring's health. Understanding the molecular underpinnings of these behaviors informs development and disease. Profiling the extraembryonic epigenome and transcriptome during the 2nd and 3rd trimesters revealed H3K9 trimethylation overlapping deeply DNA hypomethylated domains with reduced gene expression and compartment-specific patterns that illuminated their functions. Cytotrophoblast DNA methylation increased, and several key histone modifications decreased across the genome as pregnancy advanced. Cytotrophoblasts from severe preeclampsia had substantially increased H3K27 acetylation globally and at genes that are normally downregulated at term but upregulated in this syndrome. In addition, some cases had an immature pattern of H3K27ac peaks, and others showed evidence of accelerated aging, suggesting subtype-specific alterations in severe preeclampsia. Thus, the cytotrophoblast epigenome dramatically reprograms during pregnancy, placental disease is associated with failures in this process, and H3K27 hyperacetylation is a feature of severe preeclampsia.

BackgroundPlacental malaria (PM) has been associated with a higher risk of malaria during infancy. However, it is unclear whether this association is causal, and is modified by infant sex, and whether intermittent preventive treatment in pregnancy (IPTp) can reduce infant malaria by preventing PM.MethodsData from a birth cohort of 656 infants born to HIV-uninfected mothers randomised to IPTp with dihydroartemisinin-piperaquine (DP) or Sulfadoxine-pyrimethamine (SP) was analysed. PM was categorized as no PM, active PM (presence of parasites), mild-moderate past PM (> 0-20% high powered fields [HPFs] with pigment), or severe past PM (> 20% HPFs with pigment). The association between PM and incidence of malaria in infants stratified by infant sex was examined. Causal mediation analysis was used to test whether IPTp can impact infant malaria incidence via preventing PM.ResultsThere were 1088 malaria episodes diagnosed among infants during 596.6 person years of follow-up. Compared to infants born to mothers with no PM, the incidence of malaria was higher among infants born to mothers with active PM (adjusted incidence rate ratio [aIRR] 1.30, 95% CI 1.00-1.71, p = 0.05) and those born to mothers with severe past PM (aIRR 1.28, 95% CI 0.89-1.83, p = 0.18), but the differences were not statistically significant. However, when stratifying by infant sex, compared to no PM, severe past PM was associated a higher malaria incidence in male (aIRR 2.17, 95% CI 1.45-3.25, p

We aimed to examine the impact of maternal hypothyroidism on placental pathology and perinatal outcomes in singleton live births resulting from IVF, using medical records of IVF births between 2009 and 2017 at a tertiary hospital. The primary outcomes included anatomical, inflammation, vascular malperfusion, and villous maturation placental features. Secondary outcomes included foetal, maternal, perinatal, and delivery complications. There were 1,057 live births, of which 103 (9.7%) and 954 (90.3%) were in the study and control groups, respectively. Patients in the study group were more likely to have diabetes mellitus, polycystic ovarian syndrome, gestational diabetes mellitus, and non-reassuring foetal heart rate (NRFHR) tracing during delivery. After adjustment for potential confounding factors, hypothyroidism was significantly associated with the bilobed placenta (aOR 4.1; 95% CI 1.2–14.3), retroplacental haematoma (aOR 2.4; 95% CI 1.2–4.9), decidual arteriopathy (aOR 2.0; 95% CI 1.2–4.1) and subchorionic thrombi (aOR 2.4; 95% CI 1.3–5.0). Additionally, there was a statistically significant relationship with NRFHR tracing. The incidence of acute chorioamnionitis and severe foetal inflammatory response was higher in the study group. In conclusion, the placental histopathology patterns of singleton IVF live births show that maternal hypothyroidism has a significant impact on adverse perinatal outcomes. [ABSTRACT FROM AUTHOR]

Modeling preeclampsia remains difficult due to the nature of the disease and the unique characteristics of the human placenta. Members of the Hominidae superfamily have a villous hemochorial placenta that is different in structure from those of other therian mammals, including the mouse hemochorial placenta, making this common animal model less ideal for studying this disease. Human placental tissues delivered from pregnancies complicated by preeclampsia are excellent for assessing the damage the disease causes but cannot answer how or when the disease begins. Symptoms of preeclampsia manifest halfway through pregnancy or later, making it currently impossible to identify preeclampsia in human tissues obtained from an early stage of pregnancy. Many animal and cell culture models recapitulate various aspects of preeclampsia, though none can on its own completely capture the complexity of human preeclampsia. It is particularly difficult to uncover the cause of the disease using models in which the disease is induced in the lab. However, the many ways by which preeclampsia-like features can be induced in a variety of laboratory animals are consistent with the idea that preeclampsia is a two-stage disease, in which a variety of initial insults may lead to placental ischemia, and ultimately systemic symptoms. The recent development of stem cell-based models, organoids, and various coculture systems have brought in vitro systems with human cells ever closer to recapitulating in vivo events that lead to placental ischemia. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the associations between placental histopathology (signs of maternal and fetal vascular malperfusion, delayed villous maturation, villitis of unknown etiology) and subtypes of preeclampsia by onset, clinical aspects of the disease and neonatal outcome. Methods: Placental slides from preeclamptic pregnancies were retrospectively reviewed according to a uniform scheme. Information regarding obstetrical anamnesis, clinical data and perinatal outcome was collected from charts, and statistical analysis was performed in order to demonstrate associations between microscopic placental alterations and different aspects of preeclampsia. Results: A total of 49 cases were studied. Diffuse signs of maternal vascular malperfusion and avascular villi were more common in early‐onset‐preeclampsia associated with worse prognosis. Preeclampsia with fetal growth restriction had more often diffuse signs of maternal and fetal vascular malperfusion and villitis of unknown etiology. Recurring preeclampsia was associated with more common perivasculitis. Umbilical and uterine artery Doppler indices were associated with medial hypertrophy and/or acute atherosis of maternal decidual vessels. Large foci of avascular villi correlated with extent of maternal 24‐h‐proteinuria which itself correlated with outcome of preeclampsia. Rate of capillarisation of villi was significantly lower in case of hypertension requiring a three‐drug combination of antihypertensive medications versus hypertension treated with one or two drugs, preeclampsia with growth restriction, and stillbirth versus live birth. Conclusions: Early‐ versus late‐onset‐preeclampsia showed a markedly different profile of histopathological features and perinatal outcome, reflecting their distinguished pathogenesis and prognosis; preeclampsia complicated with fetal growth restriction also had distinctive features. Qualitative and quantitative changes define placental pathology of preeclampsia. [ABSTRACT FROM AUTHOR]

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Purpose: To evaluate the relationship between maternal left ventricular systolic function, utero-placental circulation, and risk of adverse neonatal outcomes in women with cardiac disease. Methods: 119 women managed in the pregnancy heart clinic (2019–2021) were identified. Women were classified by their primary cardiac condition. Adverse neonatal outcomes were: low birth weight (< 2500 g), small-for-gestational-age (< 10th birth-weight centile), pre-term delivery (< 37 weeks' gestation), and fetal demise (> 20 weeks' gestation). Parameters of left ventricular systolic function (global longitudinal strain, radial strain, ejection fraction, average S', and cardiac output) were calculated and pulsatility index was recorded from last growth scan. Results: Adverse neonatal outcomes occurred in 28 neonates (24%); most frequently in valvular heart disease (n = 8) and cardiomyopathy (n = 7). Small-for-gestational-age neonates were most common in women with cardiomyopathy (p = 0.016). Early pregnancy average S' (p = 0.03), late pregnancy average S' (p = 0.02), and late pregnancy cardiac output (p = 0.008) were significantly lower in women with adverse neonatal outcomes than in those with healthy neonates. There was a significant association between neonatal birth-weight centile and global longitudinal strain (p = 0.04) and cardiac output (p = 0.0002) in late pregnancy. Pulsatility index was highest in women with cardiomyopathy (p = 0.007), and correlated with average S' (p < 0.0001) and global longitudinal strain (p = 0.03) in late pregnancy. Conclusion: Women with cardiac disease may not tolerate cardiovascular adaptations required during pregnancy to support fetal growth. Adverse neonatal outcomes were associated with reduced left ventricular systolic function and higher pulsatility index. The association between impaired systolic function and reduced fetal growth is supported by insufficient utero-placental circulation. [ABSTRACT FROM AUTHOR]

Background We examined the relationship between placental histopathology and transplacental antibody transfer in pregnant patients after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Methods Differences in plasma concentrations of anti-receptor biding domain (RBD) immunoglobulin (Ig)G antibodies in maternal and cord blood were analyzed according to presence of placental injury. Results Median anti-RBD IgG concentrations in cord blood with placental injury (n = 7) did not differ significantly from those without injury (n = 16) (median 2.7 [interquartile range {IQR}, 1.8–3.6] vs 2.7 [IQR, 2.4–2.9], P = 0.59). However, they were associated with lower transfer ratios (median 0.77 [IQR, 0.61–0.97] vs 0.97 [IQR, 0.80–1.01], P = 0.05). Conclusions SARS-CoV-2 placental injury may mediate reduced maternal-fetal antibody transfer. [ABSTRACT FROM AUTHOR]

Background: The prevalence of obesity among women of child-bearing age has contributed to an increased risk of pregnancy complications with a disproportional impact on women of lower socioeconomic status and among certain racial groups. In particular, socio-demographic and historical factors have resulted in higher rates of premature births and small-for-gestational age infants among Black women, which may be associated with placental function during pregnancy. The current study investigated the influence of maternal prepregnancy adiposity and race on the associations between inflammatory proteins, placental growth hormone (PGH), and infant birthweight. This information was collected for a subsample of 109 participants (Black, n = 39 vs. White, n = 70) from the Brain and Early Experiences (BEE) study. Methods: Serum samples were acquired late in the second trimester to assess PGH levels, C-reactive protein (CRP), interleukin 6 (IL-6), interleukin 8 (IL-8), and interleukin-1 receptor antagonist (IL-1Ra). Participant questionnaire responses provided information on pre-pregnancy BMI, health, race, educational attainment, and infant birthweight. Bivariate correlations and multiple linear regression models were utilized to evaluate associations by race between preconception adiposity, inflammatory markers and PGH. Results: After controlling for covariates including maternal age and education, gestational age, and fetal sex, regression models indicated that pre-pregnancy BMI was negatively associated with PGH (β=-0.42, p<0.05) and IL-8 was positively associated with PGH (β=0.35, β<0.05) among the Black mothers only; neither were significantly associated with PGH in the White mothers. When extending models to birth outcomes, BMI was positively associated with birthweight corrected for gestational age (BWz) (β=0.24, β<0.05) and educational attainment was negatively associated with BWz (β=0.28, p<0.05) for infants of White women. In contrast, neither variable was predictive of BWz for infants of Black mothers. Conclusion: Future work is needed to investigate racial differences in the association between adiposity and placental functioning, which are likely to contribute to differential effects on pregnancy outcomes and fetal growth. [ABSTRACT FROM AUTHOR]

Placenta accreta spectrum (PAS) is one of the major causes of maternal morbidity and mortality worldwide with increasing incidence. PAS refers to a group of pathological conditions ranging from the abnormal attachment of the placenta to the uterus wall to its perforation and, in extreme cases, invasion into surrounding organs. Among them, placenta accreta is characterized by a direct adhesion of the villi to the myometrium without invasion and remains the most common diagnosis of PAS. Here, we identify the potential regulatory miRNA and target networks contributing to placenta accreta development. Using small RNASeq followed by RT-PCR confirmation, altered miRNA expression, including that of members of placenta-specific miRNA clusters (e.g., C19MC and C14MC), was identified in placenta accreta samples compared to normal placental tissues. In situ hybridization (ISH) revealed expression of altered miRNAs mostly in trophoblast but also in endothelial cells and this profile was similar among all evaluated degrees of PAS. Kyoto encyclopedia of genes and genomes (KEGG) analyses showed enriched pathways dysregulated in PAS associated with cell cycle regulation, inflammation, and invasion. mRNAs of genes associated with cell cycle and inflammation were downregulated in PAS. At the protein level, NFκB was upregulated while PTEN was downregulated in placenta accreta tissue. The identified miRNAs and their targets are associated with signaling pathways relevant to controlling trophoblast function. Therefore, this study provides miRNA:mRNA associations that could be useful for understanding PAS onset and progression. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidence indicates that maternal hypothalamic-pituitary-adrenal (HPA) axis activity over pregnancy differs according to maternal history of childhood maltreatment. DNA methylation of the placental 11-beta-hydroxysteroid dehydrogenase (BHSD) type 2 enzyme regulates fetal exposure to maternal cortisol, yet the association between maternal history of childhood maltreatment and methylation of placental 11BHSD type 2 has not been previously studied. Methods: We examined if maternal cortisol production at 11 and 32 weeks' gestation (n = 89) and placental methylation of the 11BHSD type 2 gene (n = 19) differed among pregnant women with and without histories of childhood maltreatment. Twenty-nine percent of participants reported a history of childhood maltreatment (physical/sexual abuse). Results: Women with histories of childhood maltreatment displayed lower cortisol in early gestation, hypo-methylation of placental 11BHSD type 2, and lower levels of cord blood cortisol. Conclusion: Preliminary results suggest alterations in cortisol regulation over pregnancy according to maternal history of childhood maltreatment. [ABSTRACT FROM AUTHOR]

During pregnancy, certain viral infections are known to significantly affect fetal development. Data regarding the impact of COVID-19 viral infection in pregnancy, specifically in asymptomatic or mild cases, remains limited. This presents a challenge in providing prenatal counseling and antepartum surveillance in pregnancies complicated by COVID-19 infection. Placenta studies have demonstrated that vascular malperfusion patterns attributed to COVID-19 appear to depend on the timing of infection. Given these placental changes, we aim to evaluate the impact of COVID-19 on fetal growth in pregnant patients with asymptomatic or mild disease, stratified by trimester of infection. We hypothesize that COVID-19 infection, especially early in pregnancy, increases the risk of fetal growth restriction (FGR). Study design. This is a single institution, retrospective cohort study of patients ages 16–55 years old with a singleton delivery between December 10, 2020, and April 19, 2021 who had not received a COVID-19 vaccination prior to delivery. COVID-19 infection during pregnancy was defined as a positive SARS-CoV-2 RT-PCR test. FGR was defined as an estimated fetal weight less than the 10th percentile for gestational age or abdominal circumference less than the 10th percentile for gestational age. Maternal and fetal characteristics, including FGR, were compared between women with versus without COVID-19 infection during pregnancy. Among 1971 women with a singleton delivery, 208 (10.6 %) had a prior asymptomatic or mild COVID-19 infection during pregnancy. With the exception in the median prenatal BMI being significantly higher in the COVID-19 group (median, 27.5 vs 26.3, p = 0.04), there were no significant differences in demographics, baseline maternal comorbidities or gestational age between those with versus without COVID-19 infection during pregnancy, or in the proportion of their offspring with FGR (3.4 % (7/208) vs 4.8 % (84/1763), p = 0.36). When the 208 women were stratified by the timing of their COVID-19 infection, the proportion with an offspring with FGR was 8.7 % (2/23), 1.2 % (1/84), and 4.0 % (4/101), for those first diagnosed with COVID-19 during the 1st, 2nd, and 3rd trimesters, respectively (p = 0.72 Cochran-Armitage test for trend). Asymptomatic or mild COVID-19 infection in pregnancy, regardless of timing of infection, does not appear to be associated with FGR. Routine serial fetal growth assessment may not be warranted solely for history of COVID-19 infection. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite the relevance of biometrical and blood flow assessments for studying fetoplacental physiology during pregnancy, there is no detailed description of any animal model, which is needed to extrapolate results to human pregnancy. Here, we examined biometry and intrauterine blood flow in pregnant guinea pigs from the second trimester until term. We show that fetal and placental biometry, as well as changes in the main vascular beds across pregnancy, compared qualitatively to data from humans. These findings emphasize that the guinea pig is a reliable model to study fetal development and placental function with translational significance for human pregnancy. Background: Biometrical and blood flow examinations are fundamental for assessing fetoplacental development during pregnancy. Guinea pigs have been proposed as a good model to study fetal development and related gestational complications; however, longitudinal growth and blood flow changes in utero have not been properly described. This study aimed to describe fetal and placental growth and blood flow of the main intrauterine vascular beds across normal guinea pig pregnancy and to discuss the relevance of this data for human pregnancy. Methods: Pregnant guinea pigs were studied from day 25 of pregnancy until term (day ~70) by ultrasound and Doppler assessment. The results were compared to human data from the literature. Results: Measurements of biparietal diameter (BPD), cranial circumference (CC), abdominal circumference, and placental biometry, as well as pulsatility index determination of umbilical artery, middle cerebral artery (MCA), and cerebroplacental ratio (CPR), were feasible to determine across pregnancy, and they could be adjusted to linear or nonlinear functions. In addition, several of these parameters showed a high correlation coefficient and could be used to assess gestational age in guinea pigs. We further compared these data to ultrasound variables from human pregnancy with high similarities. Conclusions: BPD and CC are the most reliable measurements to assess fetal growth in guinea pigs. Furthermore, this is the first report in which the MCA pulsatility index and CPR are described across guinea pig gestation. The guinea pig is a valuable model to assess fetal growth and blood flow distribution, variables that are comparable with human pregnancy. [ABSTRACT FROM AUTHOR]

COVID-19 is an ongoing pandemic and has been extensively studied. However, the effects of COVID-19 during pregnancy, particularly on placental function, have not been verified. In this study, we used blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) to evaluate whether COVID-19 incidence during pregnancy has any lasting effects with respect to placental oxygenation. This is a case-control study, in which eight cases of singleton pregnancies before 30 weeks gestation with COVID-19 mothers were included. Placental oxygenation was evaluated using BOLD-MRI after 32 weeks of gestation. BOLD-MRI was consecutively performed under normoxia (21% O2), hyperoxia (100% O2), and normoxia for 4 min each. Individual placental time–activity curves were evaluated to calculate the peak score (peakΔR2*) and the time from the start of maternal oxygen administration to the time of peakΔR2* (time to peakΔR2*). Eighteen COVID-19-free normal pregnancies from a previous study were used as the control group. No significant differences were found between the two groups regarding maternal background, number of days of delivery, birth weight, and placental weight. The parameter peakΔR2* was significantly decreased in the COVID-19 group (8 ± 3 vs. 5 ± 1, p <.001); however, there was no significant difference in time to peakΔR2* (458 ± 74 s vs. 471 ± 33 s, p =.644). In this study, BOLD-MRI was used to evaluate placental oxygenation during pregnancy in COVID-19-affected patients. COVID-19 during pregnancy decreased placental oxygenation even post-illness, but had no effect on fetal growth; further investigation of the possible effects of COVID-19 on the fetus and mother is warranted. [ABSTRACT FROM AUTHOR]

Fetal death is a complication of pregnancy caused by multiple etiologies rather than being the end-result of a single disease process. Many soluble analytes in the maternal circulation, such as hormones and cytokines, have been implicated in its pathophysiology. However, changes in the protein content of extracellular vesicles (EVs), which could provide additional insight into the disease pathways of this obstetrical syndrome, have not been examined. This study aimed to characterize the proteomic profile of EVs in the plasma of pregnant women who experienced fetal death and to evaluate whether such a profile reflected the pathophysiological mechanisms of this obstetrical complication. Moreover, the proteomic results were compared to and integrated with those obtained from the soluble fraction of maternal plasma. This retrospective case-control study included 47 women who experienced fetal death and 94 matched, healthy, pregnant controls. Proteomic analysis of 82 proteins in the EVs and the soluble fractions of maternal plasma samples was conducted by using a bead-based, multiplexed immunoassay platform. Quantile regression analysis and random forest models were implemented to assess differences in the concentration of proteins in the EV and soluble fractions and to evaluate their combined discriminatory power between clinical groups. Hierarchical cluster analysis was applied to identify subgroups of fetal death cases with similar proteomic profiles. A p-value of <.05 was used to infer significance, unless multiple testing was involved, with the false discovery rate controlled at the 10% level (q < 0.1). All statistical analyses were performed by using the R statistical language and environment-and specialized packages. Nineteen proteins (placental growth factor, macrophage migration inhibitory factor, endoglin, regulated upon activation normal T cell expressed and presumably secreted (RANTES), interleukin (IL)-6, macrophage inflammatory protein 1-alpha, urokinase plasminogen activator surface receptor, tissue factor pathway inhibitor, IL-8, E-Selectin, vascular endothelial growth factor receptor 2, pentraxin 3, IL-16, galectin-1, monocyte chemotactic protein 1, disintegrin and metalloproteinase domain-containing protein 12, insulin-like growth factor-binding protein 1, matrix metalloproteinase-1(MMP1), and CD163) were found to have different plasma concentrations (of an EV or a soluble fraction) in women with fetal death compared to controls. There was a similar pattern of change for the dysregulated proteins in the EV and soluble fractions and a positive correlation between the log2-fold changes of proteins significant in either the EV or the soluble fraction (ρ = 0.89, p <.001). The combination of EV and soluble fraction proteins resulted in a good discriminatory model (area under the ROC curve, 82%; sensitivity, 57.5% at a 10% false-positive rate). Unsupervised clustering based on the proteins differentially expressed in either the EV or the soluble fraction of patients with fetal death relative to controls revealed three major clusters of patients. Pregnant women with fetal death have different concentrations of 19 proteins in the EV and soluble fractions compared to controls, and the direction of changes in concentration was similar between fractions. The combination of EV and soluble protein concentrations revealed three different clusters of fetal death cases with distinct clinical and placental histopathological characteristics. [ABSTRACT FROM AUTHOR]

The identification of fetal growth disorders is an important clinical priority given that they increase the risk of perinatal morbidity and mortality as well as long-term diseases. A subset of small-for-gestational-age (SGA) infants are growth-restricted, and this condition is often attributed to placental insufficiency. Syndecan-1, a product of the degradation of the endothelial glycocalyx, has been proposed as a biomarker of endothelial damage in different pathologies. During pregnancy, a "specialized" form of the glycocalyx—the "syncytiotrophoblast glycocalyx"—covers the placental villi. The purpose of this study was to determine whether the concentration of maternal plasma syndecan-1 can be proposed as a biomarker for fetal growth restriction. A cross-sectional study was designed to include women with normal pregnancy (n = 130) and pregnant women who delivered an SGA neonate (n = 50). Doppler velocimetry of the uterine and umbilical arteries was performed in women with an SGA fetus at the time of diagnosis. Venipuncture was performed within 48 h of Doppler velocimetry and plasma concentrations of syndecan-1 were determined by a specific and sensitive immunoassay. (1) Plasma syndecan-1 concentration followed a nonlinear increase with gestational age in uncomplicated pregnancies (R2 = 0.27, p <.001); (2) women with a pregnancy complicated with an SGA fetus had a significantly lower mean plasma concentration of syndecan-1 than those with an appropriate-for-gestational-age fetus (p =.0001); (3) this difference can be attributed to fetal growth restriction, as the mean plasma syndecan-1 concentration was significantly lower only in the group of women with an SGA fetus who had abnormal umbilical and uterine artery Doppler velocimetry compared to controls (p =.00071; adjusted p =.0028). A trend toward lower syndecan-1 concentrations was also noted for SGA with abnormal uterine but normal umbilical artery Doppler velocimetry (p =.0505; adjusted p =.067); 4) among women with an SGA fetus, those with abnormal umbilical and uterine artery Doppler findings had a lower mean plasma syndecan-1 concentration than women with normal Doppler velocimetry (p =.02; adjusted p =.04); 5) an inverse relationship was found between the maternal plasma syndecan-1 concentration and the umbilical artery pulsatility index (r = −0.5; p =.003); and 6) a plasma syndecan-1 concentration ≤ 850 ng/mL had a positive likelihood ratio of 4.4 and a negative likelihood ratio of 0.24 for the identification of a mother with an SGA fetus who had abnormal umbilical artery Doppler velocimetry (area under the ROC curve 0.83; p <.001). Low maternal plasma syndecan-1 may reflect placental diseases and this protein could be a biomarker for fetal growth restriction. However, as a sole biomarker for this condition, its accuracy is low. [ABSTRACT FROM AUTHOR]

Pathological placentation (placenta previa and placenta accreta) is one of the main problems in modern obstetrics, which negatively affects maternal and perinatal mortality rates. The use of modern technologies for the timely diagnosis of this pregnancy complication and the correct route of the patient allow to reduce blood loss significantly, to save not only the life of the mother and the child, but also to save the uterus in some cases. The objective: to evaluate the diagnostic possibilities of ultrasound examination of pathological placentation. Materials and methods. An ultrasound examination was performed in 86 pregnant women with pathological placentation. Ultrasound signs of pathological placentation are divided into two groups depending on the gray or color image. Results. In 92 % of examined pregnant women with pathological placentation, the clear zone was lost. In patients with placenta previa a loss of the hypoechoic retroplacental zone was found in 70 % of cases, a significant number of placental lacunae of various shapes and sizes – 87 %, segmental thinning of the myometrium <1 mm – 50 %. Protrusion of the uterus into the surrounding tissues is often observed due to placenta accreta, in cases of placenta percreta – the exophytic mass indicates the invasion of the placental tissue through the myometrium into the extrauterine organs. 80 % of pregnant women with placenta previa and 75 % of patients with placenta accreta have hypervascularization within or under the placental bed. Conclusions. Ultrasound examination is an affordable and effective method of visualization of pathological placentation. The following criteria for placenta accreta were established and confirmed: myometrial thinning <1 mm, placental lacunae, bladder wall rupture, loss of the lunate zone, placental protrusion, subplacental vascularization, uterovesicular hypervascularization, and vessels that vascularize the lacunae. [ABSTRACT FROM AUTHOR]

Background: To investigate the association of clinical characteristics at the time of non-hysteroscopic myomectomy before pregnancy and adverse obstetric outcomes in the next pregnancy.Methods: In this retrospective cohort study, we identified 248 women who underwent abdominal or laparoscopic myomectomy for intramural (IM) and/or subserosal (SS) uterine myomas in Bundang CHA Medical Center before pregnancy and delivered at the same hospital between 2010 and 2020. The association between clinical characteristics at the time of myomectomy and subsequent obstetric outcomes was analyzed using the Chi-square test, the Student t-test or one-way ANOVA, and multivariable analysis.Results: There was one case of uterine rupture. The gestational age at delivery was 37.7 ± 2.4 weeks. There were 2 (0.8%) cases of fetal loss before 23 weeks, but there were no cases of perinatal death. The risk of transfusion during or after delivery was higher in the group in which multiple myomas were removed compared to the group in which only one was removed (aOR = 2.41, 95% CI [1.20-4.86], p = 0.014). The risk of neonatal composite morbidity was higher in the group in which myomas including the IM type were removed, than in the group in which only SS myomas were removed (aOR = 14.29, 95% CI [1.82-99.57], p = 0.012). Although not statistically significant, the group in which the sum of the diameters of the three largest myomas was greater than 15 cm showed a higher frequency of preterm birth (19.3% vs. 10.1%, p = 0.001) and lower birth weight (2901 ± 625 g vs. 3063 ± 576 g, p = 0.001) compared to the group with diameters less than 15 cm. Placenta accreta/increta (7.9% vs. 3.8%, p = 0.043) and lower placental weight (646 ± 170 g vs. 750 ± 232 g, p = 0.034) were more common in patients with an interval between myomectomy and pregnancy of less than 12 months compared to more than 12 months.Conclusions: To our knowledge, this is the first study to investigate the association between clinical features at the time of myomectomy before pregnancy and various adverse obstetric and perinatal outcomes. If the removed myomas are multiple, IM, large, or the interval between myomectomy and pregnancy is short, the risk of obstetric and neonatal complications may increase. [ABSTRACT FROM AUTHOR]

For several years, a growing number of studies have highlighted the pivotal role of placental extracellular vesicles (EVs) throughout pregnancy. These membrane nanovesicles, heterogeneous in nature, composition and origin, are secreted by several trophoblastic cell types and are found in both the maternal and fetal compartments. They can be uptaken by recipient cells and drive a wide variety of physiological and pathological processes. In this review, we provide an overview of the different described roles of placental EVs in various aspects of normal pregnancy, from placenta establishment to maternal immune tolerance towards the fetus and protection against viral infections. In the second part, we present selected examples of pathological pregnancies in which placental EVs are involved, such as gestational diabetes mellitus, pre-eclampsia, and congenital infections. Since the abundance and/or composition of placental EVs is deregulated in maternal serum during pathological pregnancies, this makes them interesting candidates as non-invasive biomarkers for gestational diseases and opens a wide field of translational perspectives. [ABSTRACT FROM AUTHOR]

We aimed to perform a meta-analysis of the literature concerning histopathologic findings in the placentas of women with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection during pregnancy. Searches for articles in English included PubMed, Web of Science, Google Scholar, and reference lists (up to April 2021). Studies presenting data on placental histopathology according to the Amsterdam Consensus Group criteria in SARS-CoV-2 positive and negative pregnancies were identified. Lesions were categorized into: maternal and fetal vascular malperfusion (MVM and FVM, respectively), acute placental inflammation with maternal and fetal inflammatory response (MIR and FIR, respectively), chronic inflammatory lesions (CILs), and increased perivillous fibrin deposition (PVFD). A total of 15 studies reporting on 19,025 placentas, n  = 699 of which were derived from women who were identified as being infected with SARS-CoV-2 and 18,326 as SARS-CoV-2-negative controls, were eligible for analysis. No significant difference in incidence of MVM (odds ratio [OR]: 1.18, 95% confidence interval [CI]: 0.73–1.90), FVM (OR: 1.23, 95% CI: 0.63–2.42), MIR (OR: 0.66, 95% CI: 0.29–1.52) or FIR (OR: 0.85, 95% CI: 0.44–1.63), and CILs (OR: 0.97, 95% CI: 0.55–1.72) was found between placentae from gravida identified as being SARS-CoV-2 infected. However, placenta from gravida identified as being infected with SARS-CoV-2 were associated with significantly increased occurrence of PVFD (OR: 2.77, 95% CI: 1.06–7.27). After subgroup analyses based on clinical severity of COVID-19 infection, no significant difference was observed in terms of reported placental pathology between symptomatic or asymptomatic SARS-CoV-2 gravidae placenta. Current evidence based on the available literature suggests that the only pathologic finding in the placentae of women who are pregnant identified as having been infected with SARS-CoV-2 was an increased prevalence of PVFD. Key Points No association between SARS-CoV-2 and maternal or fetal placental malperfusion. No association between SARS-CoV-2 and maternal or fetal inflammatory response. SARS-CoV-2 is associated with increased perivillous fibrin deposition in placenta. [ABSTRACT FROM AUTHOR]

Abnormal placental angiogenesis during gestation resulting from high levels of anti-angiogenic factors, soluble fms-like tyrosine kinase-1 (sFLT1) and soluble endoglin, has been implicated in the progression of preeclampsia (PE). This heterogeneous syndrome (defined by hypertension with or without proteinuria after 20 weeks of pregnancy) remains a major global health burden with long-term consequences for both mothers and child. Previously, we showed that in vivo systemic human (hsFLT1) overexpression led to reduced placental efficiency and PE-like syndrome in mice. Galectins (gal-1, −3 and −9) are critical determinants of vascular adaptation to pregnancy and dysregulation of the galectin-glycan circuits is associated with the development of this life-threatening disease. In this study, we assessed the galectin-glycan networks at the maternal-fetal interface associated with the hsFLT1-induced PE in mice. We observed an increase on the maternal gal-1 expression in the decidua and junctional zone layers of the placenta derived from hs FLT1high pregnancies. In contrast, placental gal-3 and gal-9 expression were not sensitive to the hsFLT1 overexpression. In addition, O- and N-linked glycan expression, poly-LacNAc sequences and terminal sialylation were down-regulated in hsFLT1 high placentas. Thus, the gal-1-glycan axis appear to play an important role counteracting the anti-angiogenic status caused by sFLT1, becoming critical for vascular adaptation at the maternal-fetal interface. • Anti-angiogenic milieu induced by human soluble fms-like tyrosine kinase-1 (hsFLT1) alters the galectin-glycan circuits during pregnancy. • Decidual gal-1 is upregulated in hsFLT1 induced Preeclampsia (PE)-like syndrome in mice. • hsFLT1 exerts a strong influence on the O- and N-linked glycan expression, poly-LacNAc sequences and terminal sialylation at the maternal-fetal interface. [ABSTRACT FROM AUTHOR]

Development of the early embryo takes place under low oxygen tension. Under such conditions, the embryo implants and the trophectoderm, the outer layer of blastocyst, proliferate, forming the cytotrophoblastic shell, the early placenta. The cytotrophoblasts (CTBs) are the so-called epithelial 'stem cells' of the placenta, which, depending on the signals they receive, can differentiate into either extravillous trophoblast (EVT) or syncytiotrophoblast (STB). EVTs anchor the placenta to the uterine wall and remodel maternal spiral arterioles in order to provide ample blood supply to the growing fetus. STBs arise through CTB fusion, secrete hormones necessary for pregnancy maintenance and form a barrier across which nutrient and gas exchange can take place. The bulk of EVT differentiation occurs during the first trimester, before the onset of maternal arterial blood flow into the intervillous space of the placenta, and thus under low oxygen tension. These conditions affect numerous signaling pathways, including those acting through hypoxia-inducible factor, the nutrient sensor mTOR and the endoplasmic reticulum stress-induced unfolded protein response pathway. These pathways are known to be involved in placental development and disease, and specific components have even been identified as directly involved in lineage-specific trophoblast differentiation. Nevertheless, much controversy surrounds the role of hypoxia in trophoblast differentiation, particularly with EVT. This review summarizes previous studies on this topic, with the intent of integrating these results and synthesizing conclusions that resolve some of the controversy, but then also pointing to remaining areas, which require further investigation.

There is accumulating evidence on the perinatal aspects of COVID-19, but available data are still insufficient. The reports on perinatal aspects of COVID-19 have been published on a small group of patients. Vertical transmission has been noted. The SARS-CoV-2 genome can be detected in umbilical cord blood and at-term placenta, and the infants demonstrate elevated SARS-CoV-2-specific IgG and IgM antibody levels. In this work, the analysis of clinical characteristics of RT-PCR SARS-CoV-2-positive pregnant women and their infants, along with the placental pathology correlation results, including villous trophoblast immunoexpression status for SARS-CoV-2 antibody, is presented. RT-PCR SARS-CoV-2 amniotic fluid testing was performed. Neonatal surveillance of infection status comprised RT-PCR testing of a nasopharyngeal swab and the measuring of levels of anti-SARS-CoV-2 in blood serum. In the initial study group were 161 pregnant women with positive test results. From that group, women who delivered during the hospital stay were selected for further analysis. Clinical data, laboratory results, placental histomorphology results, and neonatal outcomes were compared in women with immunohistochemistry (IHC)-con SARS-CoV-2-positive and IHC SARS-CoV-2-negative placentas (26 cases). A positive placental immunoprofile was noted in 8% of cases (n = 2), whereas 92% of cases were negative (n = 24). Women with placental infection proven by IHC had significantly different pathological findings from those without. One infected neonate was noted (n = 1; 4%). Infection was confirmed in perinatal autopsy, as there was the intrauterine fetal demise. The potential course of the infection with the risk of vertical transmission and implications for fetal–neonatal condition is critical for proper clinical management, which will involve comprehensive, multidisciplinary perinatal care for SARS-CoV-2-positive patients. [ABSTRACT FROM AUTHOR]

The article focuses on study conducted to evaluate umbilical cord immune cells in pregnancies with autoimmune disorders (AID) and/or methylenetetrahydrofolate reductase (MTHFR) polymorphisms. Topics discussed include role of homeostasis of the placental maternal-fetal interface (MFI) in pregnancy; methodologies used in study on umbilical cords obtained from women with and without AID; and result showing impact of AID on number, distribution, and morphology of umbilical cord immune cells.

(1) Background: Despite the high number of cases of COVID-19 during pregnancy, SARS-CoV-2 congenital infection is rare. The role of the placenta as a barrier preventing the transmission of SARS-CoV-2 from the mother to the fetus is still being studied. This study aimed to evaluate the impact of SARS-CoV-2 infection on placental tissue. (2) Methods: This was a transversal monocentric observational study. In the study, we included pregnant women with COVID-19 who delivered at "Sfântul Pantelimon" Clinical Emergency Hospital between 1 April 2020 and 30 March 2022. Histological analyses, both macroscopic and microscopic, were performed for placentas that came from these cases. (3) Results: To date, a characteristic placental lesion has not been clearly demonstrated, but most findings include features of maternal and fetal vascular malperfusion, which probably reflect the reduction in placental blood flow due to low oxygen level from the hypoxic respiratory disease and underlying hypercoagulable state induced by the COVID-19 infection. (4) Conclusions: The histopathological aspects found in placentas that came from COVID-19-positive pregnant women are common for many other diseases, but when they are found together, they are highly suggestive for viral infectious involvement of the placenta. [ABSTRACT FROM AUTHOR]

The objective: to evaluate the clinical and prognostic value and meaning of the ratio of the anti-angiogenic factor of soluble fms-like tyrosine kinase-1 (sFlt-1) to the angiogenic factor of the placental growth factor (PlGF) in the dynamics of pregnancy as markers of various variants of placental dysfunction. Materials and methods. A retrospective cohort study of 40 pregnant women, who were distributed by gestation term (up to 34 weeks and after 34 weeks) and the level of sFlt-1:PlGF ratio (<38 is low level, > 110 – high level) was performed. The statistical comparison of the sFlt-1:PlGF ratio with the development of hypertensive disorders during pregnancy and fetal growth retardation (FGR), as well as the duration of the period from research to childbirth was calculated. Results. Preeclampsia (PE) developed in 12 persons out of 40 pregnant women. The sFlt-1:PlGF ratio in the period till 27 weeks of pregnancy in groups of women with PE and without it does not differ with a statistically significant level (p=0.3). In other gestation terms the sFlt-1:PlGF ratio in women with and without placental dysfunction is statistically significant (p<0.05). The sFlt-1:PlGF ratio >38 increases the risk of PE more than 4 times (RR = 4.6) and is statistically significant in a period till 34 weeks [95 % CI: 1.4-14,9]. After 34 weeks of pregnancy the sFlt-1:PlGF ratio >110 has a higher sensitivity (Se=0.75). An analysis of the sFlt-1:PlGF ratio for the purpose of FGR predicting, both in combination with hypertensive disorders during pregnancy or without them, demonstrated its high importance during pregnancy up to 34 weeks (p=0.001). A strongreverse correlation (ƿ= -0.7) was found between the value of the sFlt-1:PlGF ratio and the number of days from the date of research till childbirth at the level of significance of 0.0001 in pregnant women up to 34 weeks. Conclusions. The predictive value of the conventional method of assessing the preeclampsia (PE) risk and the preventive efficiency of acetylsalicylic acid is low. In the absence of clinical manifestation of PE the determination of the sFlt-1:PlGF ratio for a predication till 27 weeks of pregnancy is not informative, so it is not recommended. If the sFlt-1:PlGF ratio is > 38 in the period till 34 weeks, the relative risk is 4.6 [95 % CI: 1.4–14.9]. If the level of the sFlt-1:PlGF ratio is high at first investigation there is no sense to repeat the research in dynamics. In the case of low the sFlt-1:PlGF ratio for a reasonable suspicion of PE development, repeated research can help make an adequate clinical decision. The determination of the sFlt-1:PlGF ratio for a predication or confirmation of fetal growth retardation till 34 weeks is clinically reasonable and informative. There is a strong reverse correlation between the sFlt-1:PlGF ratio and the number of days before the current birth. [ABSTRACT FROM AUTHOR]

Background: In the context of the SARS-CoV-2 pandemic, our interest was to evaluate the effect of COVID-19 during pregnancy on placenta and coagulation factors. Methods: a prospective cohort study between January and July 2021 of 55 pregnant women stratified into: Group O, 16 patients with ongoing SARS-CoV-2 infection at delivery; Group R, 21 patients with a history of SARS-CoV-2 infection during pregnancy but who recovered prior to delivery; Group C, 18 control patients with no infection at any time. All women had nasopharyngeal SARS-CoV-2 RT-PCR tests performed within 72 h of delivery. Obstetrical complications were recorded and two physiological inhibitors of coagulation, protein Z (PZ) and dependent protease inhibitor (ZPI), were analyzed in maternal and cord blood. All placentae were analyzed by a pathologist for vascular malperfusion. Results: No patient in any group had a severe COVID-19 infection. More obstetrical complications were observed in Group O (O: n = 6/16 (37%), R: n = 2/21 (10%), C: n = 1/18 (6%), p = 0.03). The incidence of placental vascular malperfusion was similar among the groups (O: n = 9/16 (56%), R: n = 8/21 (42%), C: n = 8/18 (44%), p = 0.68). No PZ or ZPI deficiency was associated with COVID-19. However, an increased ZPI/PZ ratio was observed in neonates of Group R (O: 82.6 (min 41.3–max 743.6), R: 120.7 (29.8–203.5), C: 66.8 (28.2–2043.5), p = 0.04). Conclusion: COVID-19 was associated with more obstetrical complications, but not an increased incidence of placental lesions or PZ and ZPI abnormalities. [ABSTRACT FROM AUTHOR]

In humans, the placenta provides the only fetomaternal connection and is essential for establishing a pregnancy as well as fetal well-being. Additionally, it allows maternal physiological adaptation and embryonic immunological acceptance, support, and nutrition. The placenta is derived from extra-embryonic tissues that develop rapidly and dynamically in the first weeks of pregnancy. It is primarily composed of trophoblasts that differentiate into villi, stromal cells, macrophages, and fetal endothelial cells (FEC). Placental differentiation may be closely related to perinatal diseases, including fetal growth retardation (FGR) and hypertensive disorders of pregnancy (HDP), and miscarriage. There are limited findings regarding human chorionic villous differentiation and placental development because conducting in vivo studies is extremely difficult. Placental tissue varies widely among species. Thus, experimental animal findings are difficult to apply to humans. Early villous differentiation is difficult to study due to the small tissue size; however, a detailed analysis can potentially elucidate perinatal disease causes or help develop novel therapies. Artificial induction of early villous differentiation using human embryonic stem (ES) cells/induced pluripotent stem (iPS) cells was attempted, producing normally differentiated villi that can be used for interventional/invasive research. Here, we summarized and correlated early villous differentiation findings and discussed clinical diseases. [ABSTRACT FROM AUTHOR]