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Chronic histiocytic intervillositis of unknown origin (CHI) is a rare placental disorder associated with adverse pregnancy outcomes, frequent recurrence, and a lack of effective preventive strategies. Recent insights indicate a potential link between CHI-associated inflammatory lesions and the inflammasome pathway, suggesting innovative therapeutic avenues. Here we show a potential role of the inflammasome pathway in CHI through comprehensive transcriptomic analysis of grade 2 or 3 histopathologic CHI samples, paired with placental controls. Additionally, we present case studies of three individuals with recurrent CHI, who have undergone treatment with anakinra and colchicine throughout pregnancy, resulting in improved perinatal outcomes. Notably, all cases are characterized by the birth of healthy, full-term infants, with reduced or absent intervillositis recurrence. Placental assessment unveils heightened activation of the NLRP3-PYCARD inflammasome pathway and IL-1β processing in CHI samples, with downregulation observed in treated pregnancy samples, devoid of intervillositis. Collectively, these findings suggest a potential therapeutic role for targeting the inflammasome pathway in preventing recurrent CHI in pregnant individuals., (© 2024. The Author(s).)

Placental infection is an important cause of late-term pregnancy loss and neonatal diseases in horses. Detection of changes in blood parameters especially during early placentitis could improve the diagnostic accuracy, treatment decision, and potential outcomes. The objectives of this 2-part study were to identify differences in circulating immunological, inflammatory, and hormonal parameters between mares with natural ascending placentitis and control mares; evaluate each and combination of parameters as predictors of placentitis; and determine how these parameters indicate severity of placentitis. Reproductive examination and blood sampling were prospectively performed on pregnant mares in a natural setting. Study 1 enrolled mares diagnosed with early stage of ascending placentitis based on ultrasonographic findings (n = 12), and gestationally age-matched mares with healthy pregnancies as controls (n = 12). Blood samples were classified as pre-onset (before) and early onset (at the time of ultrasonographic changes) of placentitis. There were no detected statistically significant differences between groups and timepoints in immunological and inflammatory parameters, including peripheral lymphocyte subpopulations, cytokine, and serum amyloid A concentrations. The placentitis group showed a reduced (P = 0.01) DHP/20α-DHP ratio when compared to the control group at the early onset timepoint. Plasma estradiol-17β concentration <359 pg/mL predicted ascending placentitis with acceptable accuracy (area under the curve, AUC = 0.71). Combined albumin <3.7 g/dL, estradiol-17β < 499 ng/mL, and DHP <33 ng/mL predicted 100 % of cases of ascending placentitis. In study 2, samples were classified according to the presence and severity of the abnormal ultrasonographic findings as mild (n = 11) and moderate-severe (n = 23), and gestationally age-matched with samples from control mares (n = 34). Mares with moderate-severe ascending placentitis had increased (P = 0.03) plasma 20α-DHP concentration and reduced (P = 0.03) DHP/20α-DHP ratio when compared to control mares. Our results suggest that the early events of ascending placentitis detected by ultrasonographic findings include hormonal alterations of feto-placental metabolism measurable in the mare's circulation, yet without obvious systemic immunological and inflammatory changes. Additional studies are warranted to further assess how hormonal markers and cutoff values could guide decisions for timely therapeutic intervention., Competing Interests: Declaration of competing interest None of the authors have any conflict of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The placenta is a unique and complex organ that combines the circulatory systems of two or more individuals within a single dynamic organ with a set, short lifespan. A diverse spectrum of disorders, including infections as well as metabolic, genetic, circulatory, and maturation defects, may affect its function. Pathology investigation of the placenta is key for identifying several pathogenic processes in both the mother and the foetus. Aberrant placentation, maternal and foetal vascular compromise, infection, inflammatory immunologic conditions, and disorders of maturation are elements of newly proposed classification schemes. The clinical impact of placental examination consists of diagnosing maternal and foetal disease, identifying the potential for recurrence, correlating clinical pathological findings with distinct morphologic features, and identifying the aetiology responsible for growth restriction or foetal death. Gestational trophoblastic disease occurs more frequently in the first trimester; however, in very rare cases, it can affect the term or third-trimester placenta. The application of reproducible nomenclature is expected to facilitate progress in the diagnosis and treatment of obstetric and foetal disorders with placental manifestation. Therefore, this review aims to facilitate communication between obstetricians, neonatologists, and pathologists involved in this diagnostic process.

Placental diseases may affect the outcome of pregnancy and long-term health of the mother and fetus. Fetal fraction is a key indicator for the success of non-invasive prenatal testing, and has been associated with gestational age, body mass index and fetal chromosomal aneuploidies. Many studies have found that fetal fraction is also related to placenta-derived diseases and may become a new predictor for such diseases. This article has summarized the association between the two, with an aim to provide new ideas for the prediction of placental diseases.

Nocardioform placentitis is a poorly understood disease of equine late gestation. The presence of nocardioform, filamentous branching gram-positive bacteria, has been linked to the disease, with Crossiella equi, Amycolatopsis spp., and Streptomyces spp. being the most frequently identified bacteria. However, these bacteria are not found in all clinical cases in addition to being isolated from healthy, normal postpartum placentas. To better understand this form of placentitis, we analyzed the microbial composition in the equine placenta (chorioallantois) of both healthy postpartum (control; n = 11) and nocardioform-affected samples (n = 22) using 16S rDNA sequencing. We found a lower Shannon index in nocardioform samples, a higher Chao1 index in nocardioform samples, and a difference in beta diversity between control and nocardioform samples (p < 0.05), suggesting the presence of dysbiosis during the disease. In the majority of the NP samples (77 %), one of the following genera-Amycolatopsis, Crossiella, Lentzea, an unidentified member of the Pseudonocardiaceae family, Mycobacterium, or Enterococcus -represented over 70 % of the relative abundance. Overall, the data suggest that a broader spectrum of potential opportunistic pathogens could be involved in nocardioform placentitis, extending beyond the traditionally recognized bacteria, resulting in a similar histomorphological profile., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The aim of this extended review of multicenter case series is to describe the prenatal ultrasound features and pathogenetic mechanisms underlying placental and umbilical cord anomalies and their relationship with adverse perinatal outcome. From an educational point of view, the case series has been divided in three parts; Part 1 is dedicated to placental abnormalities., Methods: Multicenter case series of women undergoing routine and extended prenatal ultrasound and perinatal obstetric care., Results: Prenatal ultrasound findings, perinatal care, and pathology documentation in cases of placental pathology are presented., Conclusions: Our case series review and that of the medical literature confirms the ethiopathogenetic role and involvement of placenta abnormalities in a wide variety of obstetrics diseases that may jeopardize the fetal well-being. Some of these specific pathologies are strongly associated with a high risk of poor perinatal outcome., (© 2024 Wiley Periodicals LLC.)

The placenta is a transient organ that forms during pregnancy and acts as a biological barrier, mediating exchange between maternal and fetal circulation. Placental disorders, such as preeclampsia, fetal growth restriction, placenta accreta spectrum, and gestational trophoblastic disease, originate in dysfunctional placental development during pregnancy and can lead to severe complications for both the mother and fetus. Unfortunately, treatment options for these disorders are severely lacking. Challenges in designing therapeutics for use during pregnancy involve selectively delivering payloads to the placenta while protecting the fetus from potential toxic side effects. Nanomedicine holds great promise in overcoming these barriers; the versatile and modular nature of nanocarriers, including prolonged circulation times, intracellular delivery, and organ-specific targeting, can control how therapeutics interact with the placenta. In this review, nanomedicine strategies are discussed to treat and diagnose placental disorders with an emphasis on understanding the unique pathophysiology behind each of these diseases. Finally, prior study of the pathophysiologic mechanisms underlying these placental disorders has revealed novel disease targets. These targets are highlighted here to motivate the rational design of precision nanocarriers to improve therapeutic options for placental disorders., (© 2023 Wiley‐VCH GmbH.)

Chorioangiomas are benign angiomas arising from chorionic tissue and they are the most common non-trophoblastic tumors of the placenta, as they are observed in 1% of all placentas examined. Most chorioangiomas are small and asymptomatic, often undetected during a prenatal ultrasound, and their clinical significance is still unknown. Large chorioangiomas, measuring more than 4-5 cm in diameter, can usually be detected prenatally by gray-scale or color Doppler sonography, and may be associated with maternal or fetal complications, such as preeclampsia, maternal mirror syndrome, preterm delivery, nonimmune fetal hydrops, fetal growth restriction and fetal demise. We herein describe the clinical-pathological features of a monocentric series of 30 placental chorioangiomas and discuss their clinical-pathological features and possible molecular mechanisms underlying their development., (Copyright © 2024 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Chronic Intervillositis of Unknown Etiology (CIUE) is a rare idiopathic inflammatory disorder of the placenta. The evidence suggests an increased risk for poor obstetrical outcomes and a risk of recurrence as high as 100 %. This meta-analysis examined CIUE prevalence, recurrence, association with autoimmune disorders, reproductive outcomes, pregnancy complications, and the benefits of medical treatments. A systematic review, following PRISMA guidelines, involved a thorough search across multiple databases including Medline, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Evidence Based Medical Reviews, and Scopus. Out of 590 initially identified studies, 19 studies were included for both qualitative synthesis and meta-analysis after full-text review. Risk of bias was assessed using appropriate tools: The Risk Of Bias In Non-randomized Studies of Interventions tool was applied to twelve studies, while the Joanna Briggs Institute case series critical appraisal tool was used for seven studies. Our findings confirm that CIUE is a rare condition (0.7 %). CIUE is associated with decreased live birth rates (53 %), increased recurrent pregnancy loss (23 %), fetal loss beyond 22 weeks gestation (25 %), a higher prevalence of autoimmune diseases (14 %), and a recurrence rate of 30 % in subsequent pregnancies. Moreover, individuals with CIUE had higher rates of pregnancy complications, including gestational hypertension (19 %), intrauterine growth restriction (45 %), and preterm births (43 %). No significant improvement in live birth rate was observed among treated CIUE patients; however, caution is warranted when interpreting these findings due to the limited sample size. Future research in CIUE is crucial given its rarity and complexity., Competing Interests: Declaration of Competing Interest Dr. Mohamed A. Bedaiwy: Research grants from Canadian Institutes of Health Research (CIHR) and Ferring Pharmaceutical. He is on the advisory board for AbbVie, Pfizer, and Baxter. Other authors do not have any declarations of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Chronic histiocytic intervillositis (CHI) is a rare inflammatory placental disease characterized by diffuse infiltration of monocytes into the intervillous space and is associated with adverse pregnancy outcomes. No treatment is currently validated and although in some small reports, steroids with hydroxychloroquine have been described. There are no data for other therapies in refractory cases., Patients and Methods: We here report four cases of patients with a history of CHI treated with immunoglobulins during a subsequent pregnancy. The four patients with recurrent CHI had failed to previous immunomodulatory therapies with steroids and hydroxychloroquine. All patients had at least four pregnancy losses with histopathological confirmation of CHI for at least one pregnancy loss. The usual pregnancy-loss etiology screening and immunological screening were negative for all the patients., Results: For three patients, intravenous immunoglobulins were initiated at the βHCG positivity at 1 g/kg every 15 days until delivery. In one case with combined therapy since the beginning of the pregnancy, intravenous immunoglobulins were introduced at 20 WG because of severe growth restriction. Two patients had live births at 36 WG and one patient at 39 WG. One patient, who presented early first-trimester hypertension and severe placental lesions, failed to intravenous immunoglobulins and had a pregnancy loss at 15 WG., Conclusion: This is the first report demonstrating the potential benefit of intravenous immunoglobulins in recurrent chronic intervillositis. Larger studies are needed to confirm this potential benefit for patients presenting severe cases of recurrent CHI., (© 2024 The Author(s). American Journal of Reproductive Immunology published by John Wiley & Sons Ltd.)

The reproductive features of equine leptospirosis are often neglected. Equine genital leptospirosis is characterized as a silent chronic syndrome, and besides abortions, leads to placental abnormalities, stillbirths, and birth of weak foals. This study aimed to study the occurrence of placental abnormalities associated with Leptospira interrogans infection in naturally infected mares under field conditions. The studied herd had a high occurrence of placentitis and abortions. Ten pregnant mares, eight with placental abnormalities on ultrasonography and were selected. Serum and cervicovaginal mucus (CVM) samples were collected for serology and PCR, respectively. Positive samples in lipL32-PCR were submitted to the sequencing of the secY gene. In lipL32-PCR of CVM, five out of 10 (50%) mares were positive and all were characterized as Leptospira interrogans. Our results highlight the presence of placental abnormalities in the reproductive subclinical leptospirosis syndrome. We encourage field veterinarians to include leptospirosis testing in their reproductive management., Competing Interests: Declaration of competing interest None of the authors has any financial or personal relationships that could inappropriately influence or bias the content of the paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Fetal vascular malperfusion (FVM) is an important pattern of placental injury. Although the significance of distal villous FVM (clusters of sclerotic and/or mineralized chorionic villi) is well documented, the clinical significance of proximal (large vessel) lesions of FVM is less clear, which is the aim of this retrospective analysis. To evaluate the clinical significance and placental associations of single and coexisting categories of lesions of large vessel FVM, 24 clinical and 44 placental phenotypes of 804 consecutive placentas with at least 1 lesion of proximal vessel FVM from the second half of pregnancy, divided according to the type or category of the individual FVM lesion (fetal vascular ectasia, fetal vascular thrombi, intramural fibrin deposition, and stem vessel obliteration): 689, 341, 286, and 267 placentas, respectively (first analysis) and single or coexisting large fetal vessel lesions (1, 2, 3, and 4 coexisting categories of lesions: 276, 321, 162, and 45 placentas, respectively) were statistically compared (analysis of variance, χ 2 , univariate analysis). Because of multiple comparisons, Bonferroni-corrected P < .001 was used as a threshold of statistical significance. In this population of high-risk pregnancies dominated by fetal congenital anomalies, single individual or 1 to 2 coexisting categories of lesions of the large vessel FVM, including fetal vascular thrombi, did not consistently correlate with clinical or placental variables and were not prognostically useful, but the coexistence of 3 or 4 lesions was associated with the most advanced gestational age, fetal congenital anomalies, distal villous FVM, particularly high-grade, chorangioma or chorangiomatosis, hypercoiled umbilical cord, perivascular stem edema, and marginate or vallate placenta. Therefore, the finding of multiple lesions of the large vessel FVM not only merits a diligent search for the distal villous lesions including the CD34 immunostaining, but also justifies putting the large vessel (global) FVM on the final placental diagnosis line, which in the case of up to only 2 lesions may not be justified., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Placental mesenchymal dysplasia (PMD) is an exceptionally rare placental anomaly characterised by placentomegaly and grape-like vesicles resembling partial mole on ultrasonography, yet it can coexist with a viable fetus. We present the case of a primigravida who presented at 22 weeks gestation with a suspected partial mole but with a normally growing fetus. The differential diagnoses considered included placental mesenchymal disease, partial mole and twin pregnancy with molar pregnancy. With normal beta HCG levels and prenatal invasive testing reports, a probable diagnosis of PMD was made, and after thorough counselling, the decision was made to continue the pregnancy. The pregnancy progressed until 37 weeks, culminating in the uneventful delivery of a 2.4 kg healthy male infant. Histopathology confirmed PMD. Early recognition and management of PMD pose significant challenges, given its rarity. Prenatal identification of PMD during both early and late gestation could avert unnecessary termination of pregnancy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Placenta membranacea is an uncommon placental anomaly. Here, we present the case of a 30-year-old primiparous woman admitted for thickened placenta and reduced amniotic fluid. A follow-up ultrasound, performed after 48 h, revealed that the placental parenchyma was thin and not adequately visualized, enclosing a substantial volume of flowing blood (150 mm), with an amniotic fluid index of 18 mm. An emergency cesarean section was promptly performed. Following fetal delivery, a substantial accumulation of dark red blood within the fetal membranes created a "blood bag", estimated at approximately 3000 ml. This observation aligned with the ultrasound findings, and both placental morphology and pathological results substantiated the diagnosis of placenta membranacea., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To evaluate maternal risk factors associated with chronic villitis of unknown etiology (VUE) and to describe cooccurring placental pathologies., Study Design: A retrospective case-control study was conducted using placental pathology records from deliveries ≥ 20 weeks between 2010 and 2018. Cases were placentas with documented chronic villitis without infectious cause, hereafter called VUE. Controls were placentas without this diagnosis, matched to the cases 2:1. Maternal and neonatal demographic and clinical data were collected. Descriptive statistics are reported with Fisher's exact test or a chi-squared test, as appropriate, and multivariable conditional logistic regression was conducted., Results: Our study included 352 cases with VUE and 657 controls. A diagnosis of gestational diabetes ( p  = 0.03) and gestational hypertension ( p  = 0.06) was 1.5 times more likely to occur in those with a VUE diagnosis. A trend was also seen for chronic hypertension (odds ratio [OR] = 1.7, p  = 0.07) and preeclampsia (OR = 1.5, p  = 0.09) compared with controls. Placentas with VUE, specifically high-grade VUE, were more likely to be small for gestational age ( p  = 0.01), and to be diagnosed with other placental findings including lymphoplasmacytic or chronic deciduitis ( p  < 0.01), maternal ( p  < 0.01) and fetal vascular malperfusion ( p  = 0.02), and chorionitis (acute or chronic; p  < 0.01)., Conclusion: Gestational diabetes and hypertension were associated with a diagnosis of VUE, and overall, VUE placentas have more abnormal placental findings compared with control. Understanding VUE risk factors may facilitate prenatal care strategies and counseling to achieve the best outcomes for pregnant patients and their neonates., Key Points: · VUE is a common inflammatory lesion of the placenta.. · Gestational diabetes and hypertension are associated with a VUE diagnosis.. · Findings of other placental pathologies increase in VUE.., Competing Interests: None declared., (Thieme. All rights reserved.)

Introduction: Placental chorangioma is a benign non-trophoblastic vascular proliferation of the placental chorion favored to represent hamartoma-like or hyperplastic capillary lesions. As the exact pathophysiology has not been established, we investigated the molecular characteristics of placental chorangiomas using exploratory whole exome sequencing., Methods: Three cases were retrospectively selected and whole exome sequencing was performed on macrodissected lesions. DNA extraction, DNA quantification, library preparation and sequencing were performed with IDT xGen™ Exome Hybridization Panel v2 for library capture. Sequencing data was analyzed with an in-house bioinformatics pipeline for single-nucleotide variants and insertions/deletions., Results: All neonates were delivered at term and had birth weights ranging from 11th-35th percentile for gestational age. All mothers presented with hypertensive disorder during pregnancy. Chorangiomas ranged from 0.7 cm to 5.1 cm and were well-circumscribed near the fetal surface. Case 1 showed a background of chorangiosis and acute subchorionitis, while case 2 had foci of chronic lymphocytic villitis. Whole exome sequencing did not reveal any significant pathologic variants., Discussions: The absence of molecular alteration in placental chorangioma is likely indicative of the reactive/non-neoplastic nature of this lesion. The presence of compromised blood flow in the form of hypertensive disorders in our cases may be one of its underlying pathophysiologic mechanisms., Competing Interests: Declaration of competing interest The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Placenta accreta spectrum disorders are associated with severe maternal morbidity and mortality. Placenta accreta spectrum disorders involve excessive adherence of the placenta preventing separation at birth. Traditionally, this condition has been attributed to excessive trophoblast invasion; however, an alternative view is a fundamental defect in decidual biology., Objective: This study aimed to gain insights into the understanding of placenta accreta spectrum disorder by using single-cell and spatially resolved transcriptomics to characterize cellular heterogeneity at the maternal-fetal interface in placenta accreta spectrum disorders., Study Design: To assess cellular heterogeneity and the function of cell types, single-cell RNA sequencing and spatially resolved transcriptomics were used. A total of 12 placentas were included, 6 placentas with placenta accreta spectrum disorder and 6 controls. For each placenta with placenta accreta spectrum disorder, multiple biopsies were taken at the following sites: placenta accreta spectrum adherent and nonadherent sites in the same placenta. Of note, 2 platforms were used to generate libraries: the 10× Chromium and NanoString GeoMX Digital Spatial Profiler for single-cell and spatially resolved transcriptomes, respectively. Differential gene expression analysis was performed using a suite of bioinformatic tools (Seurat and GeoMxTools R packages). Correction for multiple testing was performed using Clipper. In situ hybridization was performed with RNAscope, and immunohistochemistry was used to assess protein expression., Results: In creating a placenta accreta cell atlas, there were dramatic difference in the transcriptional profile by site of biopsy between placenta accreta spectrum and controls. Most of the differences were noted at the site of adherence; however, differences existed within the placenta between the adherent and nonadherent site of the same placenta in placenta accreta. Among all cell types, the endothelial-stromal populations exhibited the greatest difference in gene expression, driven by changes in collagen genes, namely collagen type III alpha 1 chain (COL3A1), growth factors, epidermal growth factor-like protein 6 (EGFL6), and hepatocyte growth factor (HGF), and angiogenesis-related genes, namely delta-like noncanonical Notch ligand 1 (DLK1) and platelet endothelial cell adhesion molecule-1 (PECAM1). Intraplacental tropism (adherent versus non-adherent sites in the same placenta) was driven by differences in endothelial-stromal cells with notable differences in bone morphogenic protein 5 (BMP5) and osteopontin (SPP1) in the adherent vs nonadherent site of placenta accreta spectrum., Conclusion: Placenta accreta spectrum disorders were characterized at single-cell resolution to gain insight into the pathophysiology of the disease. An atlas of the placenta at single cell resolution in accreta allows for understanding in the biology of the intimate maternal and fetal interaction. The contributions of stromal and endothelial cells were demonstrated through alterations in the extracellular matrix, growth factors, and angiogenesis. Transcriptional and protein changes in the stroma of placenta accreta spectrum shift the etiologic explanation away from "invasive trophoblast" to "loss of boundary limits" in the decidua. Gene targets identified in this study may be used to refine diagnostic assays in early pregnancy, track disease progression over time, and inform therapeutic discoveries., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Tumor necrosis factor-α (TNF-α) antagonists are highly effective in controlling autoimmune diseases. This has led to speculation that they might also be useful in treating inflammatory placental conditions, such as chronic villitis of unknown etiology (VUE). VUE affects 10-15% of term placentas and is associated with recurrent fetal growth restriction (FGR) and pregnancy loss. We aimed to evaluate outcomes in patients with autoimmune diseases with and without anti-TNF-α biologic exposure during gestation. This retrospective cohort study compared pregnant women with autoimmune disease taking anti-TNF-α biologics (n = 89) to pregnant women with autoimmune disease but not taking a biologic (n = 53). We extracted data on all patients meeting our inclusion criteria over a 20-year period. Our primary outcome was the diagnosis of VUE by histology. Our secondary outcomes were maternal and neonatal complications such as preeclampsia, FGR, and neonatal intensive care admission. Kruskal-Wallis and chi-squared tests were performed as appropriate for statistical analysis. Maternal characteristics were comparable between groups, and there was no increase in adverse pregnancy outcomes based on anti-TNF-α treatment. Exposure to anti-TNF-α therapy had no significant effect on the incidence of VUE or other obstetric complications. Within the cohort exposed to anti-TNF-α biologics during pregnancy, the rate of VUE was 9.3%, which is comparable to the reported general population risk. Our data support the safety profile of biologic use in pregnancy., (© 2023. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Context.—: Chronic histiocytic intervillositis (CHI) is a rare condition characterized by maternal immune cell infiltration into the human placenta. CHI is strongly associated with fetal growth restriction, miscarriage, and stillbirth, and knowledge of its etiology, and consequently effective treatment, is limited. Currently, diagnosis is largely subjective and varies between centers, making comparison between studies challenging., Objective.—: To objectively quantify and interrelate inflammatory cells and fibrin in placentas with CHI compared with controls and determine how pathology may be altered in subsequent pregnancies following diagnosis. Macrophage phenotype was also investigated in untreated cases of CHI., Design.—: Computerized analysis was applied to immunohistochemically stained untreated (index) cases of CHI, subsequent pregnancies, and controls. Index placentas were additionally stained by immunofluorescence for M1 (CD80 and CD86) and M2 macrophage markers (CD163 and CD206)., Results.—: Quantification revealed a median 32-fold increase in macrophage infiltration in index cases versus controls, with CHI recurring in 2 of 11 (18.2%) subsequent pregnancies. A total of 4 of 14 placentas (28.6%) with a diagnosis of CHI did not exhibit infiltration above controls. Macrophages in index pregnancies strongly expressed CD163. There was no significant difference in fibrin deposition between index cases and controls, although subsequent pregnancies displayed a 2-fold decrease compared with index pregnancies. CD3+ T cells were significantly elevated in index pregnancies; however, they returned to normal levels in subsequent pregnancies., Conclusions.—: In CHI, intervillous macrophages expressed CD163, possibly representing an attempt to resolve inflammation. Computerized analysis of inflammation in CHI may be useful in determining how treatment affects recurrence, and alongside pathologist expertise in grading lesion severity., (© 2024 College of American Pathologists.)

Objective: To elucidate particular placental pathology findings that are associated with hypoxic ischemic encephalopathy (HIE) and determine which patterns are associated with adverse fetal/neonatal outcomes., Study Design: Multi-institutional retrospective case-control study of newborns with HIE (2002-2022) and controls. Four perinatal pathologists performed gross and histologic evaluation of placentas of cases and controls., Results: A total of 265 placentas of neonates with HIE and 122 controls were examined. Infants with HIE were more likely to have anatomic umbilical cord abnormalities (19.7% vs 7.4%, P  = .003), fetal inflammatory response in the setting of amniotic fluid infection (27.7% vs 13.9%, P  = .004), and fetal vascular malperfusion (30.6% vs 9.0%, P  = <.001) versus controls. Fetal vascular malperfusion with maternal vascular malperfusion was more common in those who died of disease ( P  = .01)., Conclusion: Placental pathology examination of neonates with HIE may improve our understanding of this disorder and its adverse outcomes., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: To evaluate the occurrence of retained products of conception (RPOC) after termination of pregnancy in the first trimester and to assess the vascular signals with transvaginal ultrasonography (TVUS) examination in the detection of retained products., Methods: A retrospective cohort study was performed using TVUS examination in patients following termination of pregnancy. In cases of RPOC, 3 scales of vascular signal were identified: type 1, no or small amount, spot flow signals; type 2, medium amount, strip-like flow signals; type 3, rich amount, circumferential-like flow signals. The correlation between vascular signals and placenta accreta spectrum (PAS) staging was proposed by sonography and histopathology findings., Results: The 3 vascular patterns were differently distributed within non-RPOC as well as RPOC patients with and without PAS: type 1 vascular signal detection rates of non-RPOC and RPOC were 97.8% (262/268) and 28.1% (18/64), respectively. Of 64 cases of RPOC, 48.4% (31/64) of the patients had type 2 vascular signals. Vascular signals were enhanced in RPOC with PAS patients whose diagnosis was confirmed by histopathology., Conclusions: The vascularity (amount of flow), vascular pattern (spot, strip- or circumferential-like flow), and the flow penetrating myometrium were significant findings for distinguishing concomitant RPOC with and without PAS. Additionally, RPOC may contribute to PAS progression, or PAS and RPOC in coordination strengthen the observed vascular signals., (Copyright © 2023 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. All rights reserved.)

Background: The term placenta accreta spectrum (PAS) is commonly used to describe abnormal trophoblastic invasion of the myometrium, serosa, or organs adjacent to the uterus. It is of great obstetric importance because of its high morbidity, risk of hemorrhage, admission to the intensive care unit, risk of hysterectomy, and high risk of iatrogenic pelvic lesions and even death. These risks are minimized when prenatal diagnosis is performed. Prenatal diagnosis of PAS is based on imaging findings suggestive of abnormal and pathologically adherent placentation, including placental lacunae (intraplacental sonolucent spaces), disruption of the bladder-uterine serosa interface, turbulent flow on color Doppler, and bridging vessels., Objective: In this article, we review the major prenatal imaging features of PAS using diagnostic modalities (first trimester, two-dimensional ultrasound, three-dimensional ultrasound, and magnetic resonance imaging) for the diagnosis of PAS., (© 2023 Wiley Periodicals LLC.)

Background: Placenta accreta spectrum disorders are associated with substantial maternal morbidity and mortality. Despite a preoperative diagnosis, the rate of complications remains high, and the condition is generally associated with the need for a hysterectomy., Objective: This study aimed to evaluate the outcomes of a new uterine-preserving technique (called the combined approach, including surgical hemostasis, bilateral ligation of the descending branches of the uterine arteries, and hemostatic external supraplacental stitch with the use of the Zhukovsky double-balloon tamponade in patients with placenta accreta spectrum disorders) during cesarean delivery in women with placenta accreta spectrum disorders vs the surgical technique used until 2014., Study Design: This retrospective cohort study included 147 patients with placenta accreta spectrum disorders who were divided into 2 groups: the study group (n=95) is to undergo cesarean delivery using the combined approach, and the control group (n=52) is to undergo the surgical technique used until 2014, which included bilateral uterine artery ligation, which is the transfusion of plasma, red blood cells, platelets, and protease inhibitors., Results: The volume of blood loss was 1.5-fold lower (P=.0010), the number of blood transfusions was 5.1-fold lower (P=.026), and the rate of bladder injuries was 19-fold lower (P=.012) in the study group than that in the control group. The duration of hospital stay after delivery was 4 days lesser (P=.001) and the number of hysterectomies was 4.5-fold lower in the study group than in the control group (P=.023). The study groups did not differ in terms of placenta accreta spectrum type., Conclusion: The combined approach during cesarean delivery proved to be more effective than the surgical technique used until 2014 in reducing the number of hysterectomies, blood loss volume, number of blood transfusions, and duration of hospital stay in patients with placenta accreta spectrum disorders., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The present study aims to compare prophylactic common iliac artery (CIA) temporary clamping and preoperative balloon occlusion for managing placenta accreta spectrum (PAS) disorders., Study Design: Between January 2019 and June 2020, 46 patients with PAS disorders were included. Of them, 26 patients were offered CIA balloon occlusion (Group A), while temporary CIA clamping was done for the other 20 patients (Group B). Primary outcomes were procedure-related complications, and secondary outcomes included intraoperative and postoperative complications, reoperation rates, total procedure time, blood loss, and amount of blood transfusion., Results: Blood loss was statistically non-significant higher in group B than in group A (p-value = 0.143). Only one patient in group A and three in group B needed reoperation. The bleeding continued for a mean of 1.6 days in group A and 1.7 days in group B, with non-significant statistical differences between both groups p value = 0.71. Nine patients in group A (34.6%) and four in group B (20%) required ICU admission. The mean Apgar score was 7 and 6.6 in babies of group A and group B patients, respectively. The median number of allogeneic blood transfusions performed was two in patients in group A and 1 in group B (p-value = 0.001)., Conclusion: Both techniques offer good choices for patients with PAS to decrease mortality and morbidity rates. The selection of a better technique depends on institutional references and physicians' experience., (© 2023 Japan Society of Obstetrics and Gynecology.)

COVID-19 pregnancies are associated with increased rates of premature delivery and stillbirths. It is still a matter of debate whether there is a COVID-19-associated pattern of placenta pathology. We updated our previously published results on a systematic literature review and meta-analysis of COVID-19 pregnancies. In total, 38 reports on 3677 placentas were evaluated regarding histopathological changes. Maternal vascular malperfusion (32%), fetal vascular malperfusion (19%), acute and chronic inflammation (20% and 22%) were frequent pathologies. In non-COVID-19 pregnancies, placentas show similar histologic patterns and mainly similar frequencies of manifestation. It has to be taken into account that there might be an observation bias, because some findings are diagnosed as a "pathology" that might have been classified as minor or unspecific findings in non-COVID-19 placentas. COVID-19 placentitis occurs in 1-2% of cases at the most. In conclusion, this updated meta-analysis indicates that COVID-19 infection during pregnancy does not result in an increased rate of a specific placenta pathology and COVID-19 placentitis is rare., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Placental foetal vascular malperfusion (FVM) may be responsible for complicated foetal or neonatal condition. By highlighting endothelial fragmentation, the double E-cadherin/CD34 immunostain highlights distal villous endothelial fragmentation of recent FVM not seen on haematoxylin-eosin stained sections. We routinely perform the stain on a grossly unremarkable placental sections of placentas predominantly from pregnancies with mass-forming foetal anomalies and umbilical cord complications. The stain can upgrade the FVM and/or reveal its temporal heterogeneity, both useful in establishing the cause of foetal death or poor neonatal condition. It also highlights the basement membranes of syncytiotrophoblastic cells which, in conjunction with endothelial staining, is helpful in the diagnosis of widening thereof in distal villous hypomaturity. It can distinguish mineralised stem occluding thrombi from mineralised trophoblastic pseudo inclusions - the former outlined by CD34, the latter by E-cadherin - thus helping to differentiate FVM from placental aneuploidies. The E-cadherin component helps in the diagnosis of trophoblastic lesions of shallow placental implantation featuring an increased number of extravillous trophoblasts in placental membranes and chorionic disc. Therefore, the double immunostain is helpful in histological diagnosis of placental lesions and patterns of injury.

MPVFD (Massive perivillous fibrin deposition) is placental lesion characterized by extensive massive deposits of fibrin in the intervillous space, extending over at least 25 % of the placental volume. Currently, this pathology can only be detected through histopathological examination of the placenta after a pregnancy has ended. The underlying mechanisms are poorly studied, there is no biomarker available for the diagnosis of MPVFD and treatment protocols are experimental and still lacking. The objective of this study is to systematically review the literature on the associated clinicopathologic features, treatment, and prognosis of MPVFD. We ended up with 17 studies, of these 12 studies were considered relevant for this article and included in the final analysis. All studies reporting MPVFD are retrospective. MPVFD is associated with recurrent miscarriage, intra uterine fetal death (IUFD), intra uterine growth restriction (IUGR) and preterm delivery. The prevalence in pregnancies with a delivery after 22 weeks of gestation was at 1.1 % and even higher to 2.7 % in recurrent early miscarriages. The reported risk of fetal death in MPVFD ranges mainly from 15 to 80 %. Preterm delivery is spontaneous in 50 to 70 % of cases and induced by of a severe intrauterine growth restriction (IUGR) in 30 to 50 % of cases depending on the study. Its causes and treatment are still poorly understood, although several avenues have been explored. This review summarizes current understanding of the prevalence, diagnostic features, clinical consequences, immune pathology, and potential prophylaxis against recurrence in this chronic inflammatory placental syndrome., 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 © 2023 Elsevier B.V. All rights reserved.)

Placental histopathologic lesions are dichotomized into "present" or "absent" and have limited inter-rater reliability. Continuous metrics are needed to characterize placental health and function. Tissue sections (N = 64) of human placenta were stained with CD34 antibody and hematoxylin. Proportion of the villous space occupied by fetal vascular endothelium (%FVE; pixels positive for CD34/total pixels) was evaluated for effect sizes associated with pregnancy outcomes, smoking status, and subtypes of lesions (n = 30). Time to fixation>60 min significantly increased the quantification. Large effect sizes were found between %FVE and both preterm birth and intrauterine growth restriction. These results demonstrate proof-of-concept for this vascular estimation., Competing Interests: Declaration of competing interest The authors have no interests to declare relating to this work., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

This case involves a pregnant patient in her late 20s whose pregnancy was complicated by placentamegaly and early-onset, severe fetal growth restriction (FGR). Investigations ruled out genetic and infectious aetiologies. The pregnancy eventually was further complicated by abnormal umbilical artery blood flow. Shared decision-making with the patient and obstetrical team led to delivery by caesarean section at 28 weeks and 4 days. The baby was admitted to the neonatal intensive care unit but, overall, did well. Placental pathology revealed a massive subchorionic thrombohaematoma (MST). This case highlights the importance of early detection, evaluation and management of pregnancies complicated by severe FGR as well as the significance of shared decision-making with patients. We aim to increase the awareness of MST in the differential diagnosis of placentamegaly, as this finding in combination with early and severe FGR has been shown to be a poor prognostic factor for the fetus., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Cannabis use is increasing among reproductive-age individuals and the risks associated with cannabis exposure during pregnancy remain uncertain., Objective: To evaluate the association between maternal cannabis use and adverse pregnancy outcomes known to be related to placental function., Design, Setting, and Participants: Ancillary analysis of nulliparous individuals treated at 8 US medical centers with stored urine samples and abstracted pregnancy outcome data available. Participants in the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be cohort were recruited from 2010 through 2013; the drug assays and analyses for this ancillary project were completed from June 2020 through April 2023., Exposure: Cannabis exposure was ascertained by urine immunoassay for 11-nor-9-carboxy-Δ9-tetrahydrocannabinol using frozen stored urine samples from study visits during the pregnancy gestational age windows of 6 weeks and 0 days to 13 weeks and 6 days (visit 1); 16 weeks and 0 days to 21 weeks and 6 days (visit 2); and 22 weeks and 0 days to 29 weeks and 6 days (visit 3). Positive results were confirmed with liquid chromatography tandem mass spectrometry. The timing of cannabis exposure was defined as only during the first trimester or ongoing exposure beyond the first trimester., Main Outcome and Measure: The dichotomous primary composite outcome included small-for-gestational-age birth, medically indicated preterm birth, stillbirth, or hypertensive disorders of pregnancy ascertained by medical record abstraction by trained perinatal research staff with adjudication of outcomes by site investigators., Results: Of 10 038 participants, 9257 were eligible for this analysis. Of the 610 participants (6.6%) with cannabis use, 32.4% (n = 197) had cannabis exposure only during the first trimester and 67.6% (n = 413) had ongoing exposure beyond the first trimester. Cannabis exposure was associated with the primary composite outcome (25.9% in the cannabis exposure group vs 17.4% in the no exposure group; adjusted relative risk, 1.27 [95% CI, 1.07-1.49]) in the propensity score-weighted analyses after adjustment for sociodemographic characteristics, body mass index, medical comorbidities, and active nicotine use ascertained via urine cotinine assays. In a 3-category cannabis exposure model (no exposure, exposure only during the first trimester, or ongoing exposure), cannabis use during the first trimester only was not associated with the primary composite outcome; however, ongoing cannabis use was associated with the primary composite outcome (adjusted relative risk, 1.32 [95% CI, 1.09-1.60])., Conclusions and Relevance: In this multicenter cohort, maternal cannabis use ascertained by biological sampling was associated with adverse pregnancy outcomes related to placental dysfunction.

Objectives: Studies suggest an association between placenta and congenital heart disease (CHD). We evaluated placental pathologies associated with major CHD. Methods: A prospective study included fetuses with major CHD, identified by fetal echocardiography. Fetal Doppler of umbilical artery (UA), middle cerebral artery (MCA), and placental histopathology were assessed. Outcome was measured by mortality at one month of age. Results: 21 cases were analyzed. Hypoplastic left heart syndrome was the commonest lesion (23.8%). Significant differences were detected among categories regarding MCA systolic/diastolic (S/D) ratio & pulsatility index ( p  = 0.023; 0.036), respectively. Placental histopathologies were demonstrated in 18(85.7%), predominately involved fetal malperfusion lesions 16/21(76.2%), especially chorangiosis (33.3%). No significant association was detected between placental histopathological abnormalities and Doppler parameter, diagnostic category, or mortality. Conclusion: The high prevalence of abnormal placental histopathological findings in major fetal CHD provides additional evidence of placental-cardiac interlinkage. No association was detected between abnormal placental histopathology and fetal Doppler measurements or neonatal outcome of CHD.

Introduction: Intraplacental choriocarcinoma is a gestational trophoblastic neoplasia located within the placenta. Due to the usual silent presentation, more than half of the cases are diagnosed incidentally. It has been demonstrated that this pathology is linked to feto-maternal hemorrhage (FMH), stillbirth, and intrauterine growth restriction. The aim of our review was to establish if there are recurrent signs that might lead to an early diagnosis and better management in cases complicated by FMH., Materials and Methods: We performed a systematic review of the literature from 2000 up to March 2023. The adopted research strategy included the following terms: (gestational choriocarcinoma obstetrics outcome) AND (intraplacental choriocarcinoma) AND (gestational choriocarcinoma). The MEDLINE (PubMed), Google Scholar, and Scopus databases were searched., Results: The research strategy identified 19 cases of FMH coexisting with intraplacental choriocarcinoma (IC), as described in 17 studies. The perinatal mortality rate was 36.8%. In eight cases, histological diagnosis of IC was made post-delivery. Metastatic lesions were found in 75% (6/8) of described cases. One case of maternal death has been described. Chemotherapy was necessary in seven cases. Sporadical prenatal ultrasound signs were described., Discussion: The diagnosis of IC is usually delayed, mostly due to aspecific symptoms and signs. Histological analysis of the placenta, when not routinely performed, should be performed when warning symptoms are encountered. The maternal prognosis was good, with a mortality rate of 5.5%. A fertility-sparing approach is always possible even in the presence of metastasis. Chemotherapy seems to be useful in cases of maternal and neonatal metastasis.

Objectives: There is a paucity of literature providing evidence-based guidelines for the management of large placental chorioangioma (≥ 4 cm in diameter). The objectives of this study were to compare outcomes between patients managed expectantly and those undergoing in-utero intervention and to describe the different in-utero techniques used for cessation of blood flow to the tumor and the associated outcome., Methods: This was a retrospective cohort study of 34 patients referred for the management of large placental chorioangioma in a single center between January 2011 and December 2022, who were managed expectantly or underwent in-utero intervention. In-utero intervention was performed when the fetus developed any signs of impending compromise, including high combined cardiac output (CCO), worsening polyhydramnios or abnormal fetal Doppler velocimetry findings. Interventions included radiofrequency ablation (RFA), interstitial laser ablation (ILA) and single-port or two-port fetoscopic laser photocoagulation (FLP). Treatment selection was dependent on the proximity of the tumor to the umbilical cord insertion (UCI) and placental location. The two-port technique was performed in patients with a chorioangioma with large feeding vessels (≥ 3 mm) located in the posterior placenta, in which one port was used for occlusion using bipolar forceps and the other port was used for laser photocoagulation of the feeding vessels downstream. The single-port technique was used for chorioangioma with small feeding vessels (< 3 mm) located in the posterior placenta. ILA or RFA was performed in cases with an anterior placenta. Supportive treatments, including amnioreduction and intrauterine transfusion (IUT), were performed for worsening polyhydramnios and suspected fetal anemia based on middle cerebral artery Doppler flow studies, respectively. Comparative statistical analysis between cases undergoing expectant management vs in-utero intervention was performed. Descriptive details were provided for patients who underwent in-utero intervention., Results: Thirty-four cases of large chorioangioma were evaluated, of which 25 (73.5%) were managed expectantly and nine (26.5%) underwent intervention. The frequency of polyhydramnios was significantly higher in the intervention group compared with the expectant-management group (66.7% vs 8.0%, P < 0.001). The live-birth rate among expectantly managed cases with large chorioangioma was significantly higher compared with that in cases that underwent in-utero intervention (96.0% vs 62.5%, P = 0.01). In the intervention group, preoperative CCO was elevated in all cases with available information and preoperative hydrops was present in 33.3% (3/9) of cases. One patient experienced fetal demise following IUT prior to planned FLP. Among the remaining eight patients, four underwent two-port FLP, two underwent single-port FLP, one underwent ILA and one underwent both ILA and RFA. All three cases in which hydrops was present at the time of intervention resulted in fetal demise., Conclusions: In-utero interventions aimed at cessation of blood flow in the feeding vessels are a therapeutic option for the management of cases with large chorioangioma. The two-port percutaneous technique appears to improve the efficiency of FLP when a large chorioangioma with large feeding vessels is located in the posterior placenta. We propose that in-utero interventions for large chorioangioma should be initiated prior to the development of fetal hydrops. © 2023 International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 International Society of Ultrasound in Obstetrics and Gynecology.)

Introduction: Villitis of unknown etiology (VUE) is a histopathological lesion associated with adverse neonatal outcomes. We seek to define the obscure relationship between the severity and distribution of VUE and adverse neonatal outcomes., Methods: A retrospective chart review was conducted of pathologic findings from singleton placentas diagnosed with VUE between 2013 and 2019. Control placentas were matched 1:1 for gestational age and presence/absence of fetal IUGR. Neonatal outcomes of interest included: newborn resuscitation, NICU admission, Apgar scores and cord blood acidosis. Odds ratio and 95 % confidence intervals were calculated with controls as the reference., Results: 452 placentas were included. 35 % of pregnancies were complicated by IUGR. When analyzed by severity (low-grade: OR = 4.75 [2.86-8.14]; high-grade: OR = 4.76 [2.71-8.79]) and distribution (focal: OR = 5.24 [2.87-10.17]; multifocal: OR = 4.90 [2.90-8.59]), VUE was significantly associated with need for newborn resuscitation. No other neonatal outcomes of interest were significantly associated with VUE diagnosis., Discussion: We determined a statistically significant association between VUE severity and distribution and the need for newborn resuscitation. VUE lesions were not associated with any additional neonatal outcomes of interest. Further studies with larger sample sizes are required to confirm these associations for obstetric and neonatal case management., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Aim: circumvallate placenta, placental abruption and acute chorioamnionitis separately are associated with unfavourable clinical outcomes. We aimed to determine the prevalence and define whether an association exists between the three abnormalities., Methods: 16,042 placenta pathology reports between 1997 and 2020 from a tertiary care centre in the Netherlands were retrospectively analysed. For the statistical analysis, the chi-square test and bootstrapping were used to evaluate an association., Results: In our cohort the prevalence of circumvallate placenta is 2.2 %, placental abruption cases 4.0 % and acute chorioamnionitis 20.6 %. We observed a statistically significant association between all three placental abnormalities: circumvallate placenta, placental abruption and acute chorioamnionitis. In addition, there was also an association between circumvallate placenta and acute chorioamnionitis., Conclusion: Our results show that combined presence of circumvallate placenta, placental abruption and acute chorioamnionitis are associated in preterm birth (p = 0.001). A remarkable finding is that the combination of all three abnormalities (circumvallate placenta, placental abruption and acute chorioamnionitis) was not observed in term pregnancies >37 weeks., 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 article., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

There are approximately 5 million pregnancies per year in the USA, with 1 million ending in miscarriage (a loss occurring prior to 20 weeks of gestation) and over 20,000 ending in stillbirth at or beyond 20 weeks of gestation. As many as 50% of these losses are unexplained. Our objective was to evaluate the effect of expanding the placental pathology diagnostic categories to include the explicit categories of (1) dysmorphic chorionic villi and (2) small placenta in examining previously unexplained losses. Using a clinical database of 1256 previously unexplained losses at 6-43 weeks of gestation, the most prevalent abnormality associated with each loss was determined through examination of its placental pathology slides. Of 1256 cases analyzed from 922 patients, there were 878 (69.9%) miscarriages and 378 (30.1%) antepartum stillbirths. We determined the pathologic diagnoses for 1150/1256 (91.6%) of the entire series, 777/878 (88.5%) of the miscarriages (< 20 weeks' gestation), and 373/378 (98.7%) of the stillbirths (≥ 20 weeks' gestation). The most common pathologic feature observed in unexplained miscarriages was dysmorphic chorionic villi (757 cases; 86.2%), a marker associated with genetic abnormalities. The most common pathologic feature observed in unexplained stillbirths was a small placenta (128 cases; 33.9%). Our classification system reinforced the utility of placental examination for elucidating potential mechanisms behind pregnancy loss. The improved rate of diagnosis appeared to be the result of filling a gap in previous pregnancy loss classification systems via inclusion of the categories of dysmorphic chorionic villi and small placenta., (© 2023. The Author(s).)

Stillbirth affects a large proportion of pregnancies world-wide annually and continues to be a major public health concern. Several causes of stillbirth have been identified and include obstetrical complications, placental abnormalities, fetal malformations, infections, and medical complications in pregnancy. Placental abnormalities such as placental abruption, chorioangioma, vasa previa, and umbilical cord abnormalities have been identified as causes of death for a significant proportion of stillbirths. In the absence of placental abnormalities, the gross and histologic changes in the placenta in stillbirth are found when secondary to other etiologies. Here we describe both gross and histologic changes of the placenta that are associated with stillbirth., Competing Interests: Declaration of Competing Interest The authors have no relevant disclosures., (Copyright © 2023 Elsevier Inc. All rights reserved.)

MicroRNAs (miRNAs) are small single-stranded non-coding RNA molecules that play a role in regulating gene expression in a tissue-specific manner. Placental miRNAs expression pattern dynamically changes during pregnancy influencing cell proliferation, differentiation and apoptosis. Changes of specific miRNA levels have been described in pregnancies complicated by hypertensive disorders or gestational diabetes and a growing interest in understanding miRNA role on placental development and placental disorders is currently going on. The present review evaluates the possible roles of miRNAs in trophoblastic invasion and placental development as well as their potential role as biomarkers for the prediction of placental disorders focusing the attention on intrauterine growth restriction.

Background: Diagnostic performance of placenta accreta spectrum (PAS) by prenatal MRI is unsatisfactory. Deep learning radiomics (DLR) has the potential to quantify the MRI features of PAS., Purpose: To explore whether DLR from MRI can be used to identify pregnancies with PAS., Study Type: Retrospective., Population: 324 pregnant women (mean age, 33.3 years) suspected PAS (170 training and 72 validation from institution 1, 82 external validation from institution 2) with clinicopathologically proved PAS (206 PAS, 118 non-PAS)., Field Strength/sequence: 3-T, turbo spin-echo T2-weighted images., Assessment: The DLR features were extracted using the MedicalNet. An MRI-based DLR model incorporating DLR signature, clinical model (different clinical characteristics between PAS and non-PAS groups), and MRI morphologic model (radiologists' binary assessment for the PAS diagnosis) was developed. These models were constructed in the training dataset and then validated in the validation datasets., Statistical Tests: The Student t-test or Mann-Whitney U, χ 2 or Fisher exact test, Kappa, dice similarity coefficient, intraclass correlation coefficients, least absolute shrinkage and selection operator logistic regression, multivariate logistic regression, receiver operating characteristic (ROC) curve, DeLong test, net reclassification improvement (NRI) and integrated discrimination improvement (IDI), calibration curve with Hosmer-Lemeshow test, decision curve analysis (DCA). P < 0.05 indicated a significant difference., Results: The MRI-based DLR model had a higher area under the curve than the clinical model in three datasets (0.880 vs. 0.741, 0.861 vs. 0.772, 0.852 vs. 0.675, respectively) or MRI morphologic model in training and independent validation datasets (0.880 vs. 0.760, 0.861, vs. 0.781, respectively). The NRI and IDI were 0.123 and 0.104, respectively. The Hosmer-Lemeshow test had nonsignificant statistics (P = 0.296 to 0.590). The DCA offered a net benefit at any threshold probability., Data Conclusion: An MRI-based DLR model may show better performance in diagnosing PAS than a clinical or MRI morphologic model., Level of Evidence: 3 TECHNICAL EFFICACY STAGE: 2., (© 2023 International Society for Magnetic Resonance in Medicine.)

Human pluripotent stem cells (hPSCs) form an ideal system to study the formation of placental cells, from an undifferentiated human embryonic stem cell state. The conventional human in vitro model systems to study the human placenta cannot be employed for understanding placental dysfunctions or the development of specialized placental cell types. Hence, human PSCs make an ideal model system to study human placental development and disorders. Here, we describe an efficient and validated protocol to reproducibly study the formation of human cytotrophoblasts (CTBs) and syncytiotrophoblast (STBs) from undifferentiated hPSCs. CTBs are the trophoblast stem cells that can differentiate into specialized placental cell types such as STBs. The multinucleated STB plays vital role in the exchange of nutrients and gases across the placenta and secretes several hormones during pregnancy, such as human chorionic gonadotropin β (hCGβ). Here we describe two methods of seeding the hPSCs: chemical (clumps method) and enzymatic methods (single cells) to differentiate them to CTB and STB, activating BMP (B) signaling and inhibiting ACTIVIN/NODAL and FGF signaling pathways (2i), thus naming our protocol as "B2i" (Sudheer et al., Stem Cells Dev 21:2987-3000, 2012). This protocol forms the perfect model system for understanding in vitro placentation, modeling diseases arising from abnormal placentation that cause complications such as miscarriage, preeclampsia or intrauterine growth restriction (IUGR), and drug discovery for placental disorders., (© 2023. Springer Science+Business Media, LLC.)

Lymphoma is the fourth most common tumor to display placental metastasis. This study aimed to report a case of high-grade lymphoma involving the placenta and review the literature on lymphomas metastatic to the placenta. A systematic review was performed following the PRISMA guidelines, using the keywords "lymphoma" AND "placenta." All case reports and case series on lymphoma infiltrating the placenta were collected. Eight cases from 7 studies, including the present case, were synthesized. The mean patient age is 29.5 years. The clinical presentation is non-specific. Hematologic derangements included cytopenias or cytoses, and elevated prothrombin time. The mean gestational age (GA) when a diagnosis of lymphoma was rendered is 27 weeks. Five cases presented with either lymphadenopathy or visceral masses on imaging. Four of these cases eventually led to maternal demise. The mean GA when the fetus was delivered is 31 3/4 weeks. Grossly, most placentas had non-specific findings. Leukemic infiltrates were mostly seen within intervillous spaces. Intravillous infiltrates were associated with high-grade lymphomas, resulting in either maternal demise or stillborn fetuses. This study suggests that the placenta has mechanisms to guard against malignancies; however, these defense mechanisms are not foolproof and may be breached by tumor cells., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Placentae collected from elective terminations during the first trimester are commonly used as control samples in research. However, it is widely acknowledged that many complications of pregnancies can occur or originate during the early stage of gestation. This raises the question that the placentae collected from the first trimester may not accurately reflect normal placental conditions. In this study, 95 placentae were collected from elective terminations and histology was performed. Out of these, 53 placentae (56 %) exhibited the typical structure of placental villi, indicating normal development. However, 42 placentae (44 %) showed placental hydrops, with varying degrees of severity (mild, moderate, or severe). Placental hydrops has been linked to several complicated pregnancies in the later stages of gestation. Our findings suggest that the development of pregnancy pathologies could start in the first trimester, as observed by the presence of hydrops. Placental researchers should be aware of when using first-trimester placentae from termination as controls in studies. However, it remains unclear whether pathological morphologies resolve or ameliorate as the pregnancy progression or whether such placentae continue to have such pathology, but clinical symptoms/signs do not manifest., Competing Interests: Declaration of competing interest None of the authors have a conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Type-III vasa previa (VP) is a rare form of VP, not necessarily associated with other placental or vascular anomalies, in which aberrant vessels run from the placenta to the amniotic membranes, near the internal cervical os, before returning to the placenta. Early diagnosis of Type-III VP is important but technically challenging. The objective of this study was to gather the current available evidence on the perinatal diagnosis and outcome of Type-III VP., Methods: A systematic review of the literature on the perinatal diagnosis of atypical Type-III VP was carried out in PubMed, MEDLINE and EMBASE accordingto PRISMA guidelines from inception to March 2023. Data extraction and tabulation were performed by two operators and checked by a third senior author. The quality of the included studies was evaluated using the National Institutes of Health tool for the quality assessment of case-series studies. Our local ultrasound database was searched for previously unreported recent cases. Characteristics of prenatally and postnatally diagnosed Type-III VP, including clinical features and perinatal outcomes, were summarized using descriptive statistics., Results: Eighteen cases of Type-III VP were included, of which 16 were diagnosed prenatally (14 cases were retrieved from 10 publications and two were unpublished cases from our center) and two were diagnosed postnatally (retrieved from two publications). All prenatal cases were diagnosed on transvaginal ultrasound at a mean gestational age of 29 weeks (median, 31 weeks; range, 19-38 weeks). Conception was achieved with in-vitro fertilization in 4/16 (25.0%) cases. There were no prenatal symptoms in 15/18 (83.3%) cases, while in two (11.1%) cases there was vaginal bleeding and in one (5.6%) preterm labor occurred. In 15/18 (83.3%) cases, at least one placental abnormality was observed, including low-lying insertion (9/17), succenturiate or accessory lobe (1/17), velamentous cord insertion (3/18) and marginal insertion (9/18). All prenatally diagnosed cases were liveborn and were delivered by Cesarean section before rupture of membranes at a median gestational age of 35 weeks (range, 32-38 weeks) without neonatal complications. Emergency Cesarean section was performed in 2/16 (12.5%) cases with a prenatal diagnosis and 1/2 (50.0%) cases with a postnatal diagnosis (P = 0.179). Among those with data available, an Apgar score of ≤ 7 was observed in the prenatally vs postnatally diagnosed group in 5/13 vs 1/1 cases, respectively, at the 1-min evaluation and 3/13 vs 1/1 cases, respectively, at the 5-min evaluation., Conclusions: The prenatal diagnosis of Type-III VP is challenging, with few cases reported in the literature; however, it is crucial for minimizing the risk of adverse outcome by enabling early-term elective Cesarean delivery prior to rupture of membranes. Given that clinical manifestations and risk factors are non-specific, and that Type-III VP cannot be excluded when there is a normal cord insertion or a singular placental mass, systematic screening by transvaginal ultrasound in the general pregnant population is recommended, particularly in those with a low-lying or morphologically abnormal placenta and those who conceived using assisted reproductive technology. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology., (© 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.)