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

Villitis of unknown aetiology (VUE) is a chronic inflammatory condition of the placenta that is associated with increased morbidity and mortality in perinatal medicine. The cause remains elusive and recent studies have explored immune-mediated, infectious and environmental triggers in the pathogenesis of VUE. The objective of this study was to identify the characteristics of VUE diagnoses at Mater Mothers' Hospital over a 5-year period, including any association with seasons, maternal age and histological patterns of the disorder. We retrospectively reviewed reports for placentas sent to Mater Pathology, Brisbane, over 5 years (December 2015 to November 2020). Case level data were retrieved including maternal age, the month of delivery, gestational age, parity, VUE status, recurrence, histopathological subtype and grade. Univariable and multivariable logistic regression was used to estimate the unadjusted and adjusted association between VUE and season, maternal age and trimester at delivery. While more placentas were examined during summer than winter (p=0.005), there was no evidence of seasonal variation in the incidence of VUE over the 5 years (p=0.17). Both univariable and multivariable logistic regression analyses showed that VUE increased with maternal age (p0.001) and gestational age (9.8% of examined placentas in the third trimester compared to 2.1% in first and second trimesters, p0.001). Seven of 714 women with VUE (0.98%) had one or more recurrences of the condition within the study period. Of these, VUE was of lower grade in two of the three women who were prescribed aspirin in the subsequent pregnancy. Furthermore, basal VUE without basal myometrial fibres (6.6%), was over-represented among clinically morbidly adherent placentas (MAP) reported in this cohort. Our study does not show evidence of a seasonal variation in VUE incidence. The immune-mediated pathogenesis of VUE is favoured, with our data showing increased rates of the condition as maternal age increases.

Pregnancy complications such as pre-eclampsia (PE) and intrauterine growth restriction (IUGR) are associated with structural and functional changes in the placenta. Different elastography techniques with an ability to assess the mechanical properties of tissue can identify and monitor the pathological state of the placenta. Currently available elastography techniques have been used with promising results to detect placenta abnormalities; however, limitations include inadequate measurement depth and safety concerns from high negative pressure pulses. Previously, we described a shear wave absolute vibro-elastography (SWAVE) method by applying external low-frequency mechanical vibrations to generate shear waves and studied 61 post-delivery clinically normal placentas to explore the feasibility of SWAVE for placental assessment and establish a measurement baseline. This next phase of the study, namely, SWAVE 2.0, improves the previous system and elasticity reconstruction by incorporating a multi-frequency acquisition system and using a 3-D local frequency estimation (LFE) method. Compared with its 2-D counterpart, the proposed system using 3-D LFE was found to reduce the bias and variance in elasticity measurements in tissue-mimicking phantoms. In the aim of investigating the potential of improved SWAVE 2.0 measurements to identify placental abnormalities, we studied 46 post-delivery placentas, including 26 diseased (16 IUGR and 10 PE) and 20 normal control placentas. By use of a 3.33-MHz motorized curved-array transducer, multi-frequency (80,100 and 120 Hz) elasticity measures were obtained with 3-D LFE, and both IUGR (15.30 ± 2.96 kPa, p = 3.35e

INTRODUCTION: Placental vascular disease, characterized by Maternal Vascular Malperfusion (MVM) lesions, is considered to be the underlying cause of pregnancy complications. Aim is to evaluate the relationship between the cumulative number of MVM lesion types, and adverse pregnancy- and neonatal outcomes.METHODS: This retrospective cohort study included 272 women with singleton gestations who gave birth at a Dutch tertiary hospital between 2017 and 2018 with available placental histopathology reports. Analyzed according to the Amsterdam Placental Workshop Group Consensus Statement, placentas were divided into groups based on the cumulative number of MVM lesions: no lesions (n = 124), 1-2 types (n = 124) and 3-5 types of lesions (n = 24).RESULTS: The proportion of placenta syndrome (PS) was highest (95.8%) in the 3-5 MVM lesions group (p < 0.001). The presence of MVM lesions was highly associated with PS during pregnancy (aOR 6.81, 95% CI 3.76-12.33). Furthermore, every additional type of MVM lesion corresponded with a threefold increased odds for the occurrence of PS (aOR 3.00, 95% CI 2.10-4.29). The group with 3-5 types of MVM lesions showed the highest incidence of adverse neonatal outcomes, lower mean birth weight, prolonged hospitalization, NICU admissions and neonatal deaths (aOR 6.47, 95% CI 0.33-127.68), corresponding with a fourfold increased odds for the occurrence of neonatal death for every additional MVM lesion (aOR 4.19, 95% CI 1.39-12.68).DISCUSSION: A higher number of MVM lesion types is strongly associated with an increased incidence of adverse pregnancy- and neonatal outcomes, indicating that guidelines should focus also on the amount of MVM lesion types for the monitoring/management of subsequent pregnancies.

Maternal folate deficiency was associated with preeclampsia (PE) and PE was associated with placental maternal vascular malperfusion (MVM). However, no study has examined the association of maternal folate status with placental MVM.We examined the association of maternal folate status and placental MVM in the Boston Birth Cohort. Primary exposure variables were maternal self-reported multivitamin supplement (2, 3-5,5 times/week) per trimester; and plasma folate levels (nmol/L) after birth. Primary outcome was presence/absence of placental MVM defined by the Amsterdam Placental Workshop Group standard classification. Covariates included demographics, chronic hypertension, clinically diagnosed PE, eclampsia and HELLP syndrome, gestational and pre-gestational diabetes, overweight/obesity, maternal cigarette smoking and alcohol use. Associations between folate and placental MVM were evaluated using multivariate logistic regressions.Of 3001 mothers in this study, 18.8% of mothers had PE, 37.5% had MVM. Mothers with the lowest self-reported frequency of folate intake had the highest risk of MVM (OR 1.45, 95% CI 1.03-2.05), after adjusting for the covariates. Consistently, among a subset of 939 mothers with plasma folate levels, folate insufficiency was associated with increased risk of MVM (OR 1.65, 95% CI 1.03-2.63), after adjusting for the covariables. As expected, mothers with low folate and placental MVM had highest rates of PE compared to those of high folate and no MVM (p 0.001).In this high-risk birth cohort, low maternal folate status was associated with increased risk of placental MVM. Further investigation should explore the association between folate status, placental findings and the great obstetrical syndrome.

Nocardioform placentitis (NP) has been associated with mid to late pregnancy loss in mares. To date, disease outbreaks have been described only in central Kentucky, although sporadic, isolated cases have been reported globally. This study describes a series of cases of NP that occurred in a sample population of 299 mares foaling in southeastern Pennsylvania and northeastern Maryland in 2020. These cases coincided with an outbreak of NP that occurred in Kentucky that same year. On farms that reported information on both normal and abnormal foalings, nocardioform organisms/DNA were isolated from 6.3% of placental samples based on aerobic culture and/or PCR. In cases with characteristic gross lesions of the chorion, 41% of cases were positive on aerobic culture and/or PCR. NP was confirmed in 16 mares that had not resided in Kentucky for breeding or any part of gestation. Characteristics of mares confirmed positive for NP, including age, gestation length, and problems during gestation are described. Standardbred mares bred by artificial insemination were less likely to be affected than Thoroughbred mares bred by natural cover. Affected mares had prolonged Stage III labor compared with normal mares. These findings suggest that regional increases in NP may occur outside of Kentucky, potentially in parallel with Kentucky outbreaks.

Does endometriosis have an effect on the placental histopathology pattern and perinatal outcome in singleton live births resulting from IVF treatment?Retrospective cohort study evaluating the data on all live births following IVF treatment between 2009 and 2017 at one university-affiliated tertiary hospital. All patients had placentas sent for full gross and histopathology assessment, irrespective of complication status or delivery mode. The primary outcomes of the study included anatomical, inflammation, vascular malperfusion and villous maturation placental disorders. The secondary outcomes included fetal, maternal, perinatal and delivery complications. A multivariate logistic model was used to adjust the results for confounding factors potentially associated with significant placental characteristics.A total of 1057 live births were included in the final analysis and were allocated to the group of women with endometriosis (n = 75) and those without (n = 982). After adjustment for confounding factors, endometriosis was found to be significantly associated with acute chorioamnionitis with moderate to severe maternal (odds ratio [OR] 2.2, 95% confidence interval [95% CI] 1.1-4.6) and fetal (OR 4.9, 95% CI 1.8-13.1) inflammatory response, placenta previa (OR 3.1, 95% CI 1.2-7.8), subchorionic fibrin deposition (OR 3.4, 95% CI 1.2-9.1), intervillous thrombosis (OR 3.4, 95% CI 1.5-8.1), and fetal vascular malperfusion (OR 5.1, 95% CI 1.4-18.1), as well as with preterm birth (OR 2.5, 95% CI 1.4-4.7).Endometriosis has a significant impact on the placental histopathology and is associated with a higher incidence of preterm birth.

Villitis of unknown etiology (VUE) is associated with fetal growth restriction (FGR) and adverse short-term neonatal outcomes. No investigation to date has found which VUE features are driving the association with FGR diagnosis.A retrospective cohort study of placenta pathology specimens (2013-2017) was conducted. Independent variables of interest were: VUE distribution (focal vs diffuse), location (basal vs non-basal), and grade (high vs low). The primary outcome was FGR, and secondary outcomes were neonatal intensive care unit (NICU) admission, NICU length of stay, Apgar scores7 at 1, 5, and 10-min, and recurrence rate of villitis in subsequent pregnancies. Association between VUE characteristics and our primary outcome were investigated using logistic regression. Secondary outcomes were explored with regression analyses and recurrence rate of VUE for members of the cohort with a recorded subsequent pregnancy was calculated.One hundred and twenty seven placentas were included. Adjusted models showed no difference in the odds of FGR between high-grade versus low-grade VUE [aOR 1.25 95% CI (0.50, 3.26), p = 0.6], focal/multi-focal vs diffuse cases [aOR 1.03 95% CI (0.28, 4.34), p =0.9], and basal vs non-basal VUE [aOR 0.06 95% CI (0.00, 1.10), p = 0.058]. After adjusting for prematurity37 weeks, there were lower odds of NICU admission in basal vs non-basal cases [aOR 0.25, 95% CI (0.06, 0.90), p = 0.048). There was no difference in the odds of neonates presenting with Apgar7 for the distinct VUE histopathology features. Three cases had recurrent VUE, resulting in a 6.8% [95% CI (3.02%, 10.61%)] recurrence rate. All recurrent cases were high-grade and identified with basal localization.There are no statistical associations between distinct VUE features and FGR diagnosis, however location of villitis may be associated with worse neonatal outcomes. Villitis of any type (severity, degree, location) could potentially drive insufficient placental function and poor fetal growth.

The pathological decrease of fetal growth during gestation can lead to subsequent poor health outcomes for the fetus. This process is commonly controlled by the placenta, the interface between mother and baby during gestation. Sex-specific gene expression has been implicated in placental function, therefore, there is a need to determine if it is important during reduced fetal growth. We therefore aimed to characterise placental gene expression at term to evaluate sex-specific genetic changes that occur in small for gestational age (SGA) infants.RNA-sequencing of twelve human placental tissue samples collected from pregnancies yielding either term appropriate for gestational age (AGA) or SGA infants identified at delivery. Candidate genes associated with fetal size and fetal sex were identified using differential gene expression and weighted gene co-expression network analyses. Single-cell sequencing data was used for candidate validation and to estimate candidate transcript expression in specific placental cell populations.Differential gene expression and weighted gene co-expression network analyses identified 403 candidate transcripts associated with SGA infants. One hundred and three of these transcripts showed sex-specific expression. . Published placental sequencing datasets were used to validate the key expression results from the twelve placental samples initially studied; the sex-independent transcript expression for genes involved in cell cycle processes in males (7 transcripts) and endoplasmic reticulum stress in females (17 transcripts).This study identified the activation of multiple molecular mechanisms involved in the placental response to an adverse environmental stressor. Mechanisms such as disrupted protein synthesis were shared between infant biological sex when comparing AGA to SGA, whilst other pathways such as cell cycle and endoplasmic reticulum stress appear as independent/specific to either males or females when investigating reduced fetal growth. This data suggests that sexual dimorphism is an important consideration when examining placental dysfunction and poor fetal growth.

OBJECTIVE: To examine the association of fetal/placental DNA copy number variants (CNVs) with pathologic placental lesions (PPLs) in pregnancies complicated by stillbirth. DESIGN: A secondary analysis of stillbirth cases in the Stillbirth Collaborative Research Network case-control study. SETTING: Multicenter, 59 hospitals in 5 geographic regions in the USA. POPULATION: 387 stillbirth cases (2006–2008). METHODS: Using standard definitions, PPLs were categorized by type including maternal vascular, fetal vascular, inflammatory and immune/idiopathic lesions. Single-nucleotide polymorphism array detected CNVs of at least 500kb. CNVs were classified into two groups: normal, defined as no CNVs>500kb or benign CNVs, and abnormal, defined as pathogenic or variants of unknown clinical significance. MAIN OUTCOME MEASURES: The proportions of abnormal CNVs and normal CNVs compared between stillbirth cases with and without PPLs using the Wald Chi-squared test. RESULTS: Of 387 stillborn fetuses, 327 (84.5%) had maternal vascular PPLs and 60 (15.6%) had abnormal CNVs. Maternal vascular PPLs were more common in stillborn fetuses with abnormal CNVs compared with those with normal CNVs (81.7% vs. 64.2%; p=0.008). The proportions of fetal vascular, maternal/fetal inflammatory, and immune/idiopathic PPLs were similar among stillborn fetuses with abnormal CNVs compared to those with normal CNVs. Pathogenic CNVs in stillborn fetuses with maternal vascular PPLs spanned several known genes. CONCLUSIONS: Abnormal placental/fetal CNVs were associated with maternal vascular PPLs in stillbirth cases. Findings may provide insight on the mechanisms of specific genetic abnormalities associated with placental dysfunction and stillbirth.

Background Morbidly adherent placenta (MAP) represents a risk factor for a maternal adverse outcome and its incidence continues to rise following the increasing rate of caesarean deliveries. The detection of a pathology of placental adherence in the first trimester is challenging. Transvaginal ultrasound represents (TVUS) a reliable tool for accurate and timely diagnosis. Case We report on a case of MAP in a pregnant woman at 10 weeks of gestation with two prior caesarean deliveries. She presented with abdominal pain and hematometra. The first trimester diagnosis was made with TVUS and confirmed with magnetic resonance imaging. The patient required an urgent hysterectomy. Conclusion Antenatal care in the first trimester in women with a previous cesarean delivery should include a detailed examination of the placenta with TVUS.

Purpose: To investigate the role of hypoxia-inducible transcription factor-1 alpha (HIF-1α) and angiogenetic factor endothelin-1 (ET-1) expression in regulating hypoxia and placental development by routine histopathological methods. Methods: Twenty preeclamptic and normal placentas were used. Placenta tissue pieces were examined histopathologically after routine paraffin follow-ups. HIF-1α and ET-1 proteins were examined immunohistochemically, and placental tissues were examined ultrastructurally. Results: Increase in syncytial proliferation, endothelial damage in vessels, and increase in collagen were observed in preeclamptic placentas. As a result of preeclampsia, an increase was observed in HIF-1α and ET-1 protein levels in the placenta. Dilatation of endoplasmic reticulum and loss of cristae in mitochondria were observed in trophoblast cells in preeclamptic placental sections. Conclusions: High regulation of oxygen resulting from preeclampsia has been shown to be a critical determinant of placentagenesis and plays an important role in placental differentiation, changes in maternal and fetal blood circulation, trophoblastic invasion, and syncytial node increase. It has been thought that preeclampsia affects secretion by disrupting the endoplasmic reticulum structure and induces mitochondrial damage, and that ET-1 may potentially help in the induction of stress pathways as a result of hypoxia in preeclampsia.

Cilj: Istražiti i odrediti broj i vrstu T limfocitnog infiltrata kao i broj T reg limfocita u žarištima VUE posteljica trudnoća kompliciranih PE i usporediti ih s brojem u posteljicama s VUE bez PE. Istražiti i odrediti broj T reg limfocita i NK stanica u decidui bazalis posteljica s VUE s i bez PE i kontrolne skupine urednih trudnoća te ih međusobno usporediti. Istražiti stupanj i žarišta VUE u posteljicama trudnoća kompliciranih PE i usporediti ih sa stupnjem i žarištima VUE u posteljicama trudnoća bez PE. Materijali i metode: Ispitivane skupine čine 27 posteljica s VUE iz trudnoća kompliciranih PE i 27 posteljica s nalazom VUE iz trudnoća bez PE, te 20 posteljica iz urednih trudnoća. Klinička dijagnoza PE postavljena je prema strogim kriterijima arterijske hipertenzije i proteinurije, a dijagnoza VUE prema prisutnosti limfohistiocitnog infiltrata koji je zahvaćao različitu proporciju posteljičnih resica. Broj i vrsta T limfocitnog infiltrata u žarištima VUE kao i broj T reg i NK stanica u decidui bazalis određeni su imunohistokemijskom uporabom specifičnih antitijela: CD3, CD4, CD25, FOXP3, CD8, CD45LCA, CD68 i CD56. Određivani su i broj žarišta i stupanj VUE. Rezultati: Nije bilo statistički značajne razlike u smislu broja žarišta i stupnja VUE između skupine s VUE i PE i VUE bez PE. Nije nađena statistički značajna razlika u smislu pariteta, majčinih godina, porođajne mase djece, dužine djece i gestacijske dobi između navedenih skupina, ali je pronađena statistički značajna razlika u porođajnoj masi i gestacijskoj dobi između skupina VUE s i bez PE i kontrolne skupine. Analiza broja T limfocita između skupina s VUE s i bez PE ukazala je na statistički značajnu razliku u ukupnom broju CD4+ limfocita, broju resica infiltriranih s CD4+ limfocitima te omjeru CD4+/CD8+ u skupini s VUE i PE u odnosu na skupinu s VUE bez PE. Nije uočena statistički značajna razlika ukupnog broja i vrste upalnih stanica, niti broja zahvaćenih resica ispitivanih posteljica infiltriranih s CD3, CD8, CD25, FOXP3, CD45LCA i CD68. Analiza T reg limfocita i NK stanica u decidui u posteljicama s VUE s i bez PE te urednih trudnoća ukazala je na statistički značajne razlike u broju CD4+ limfocita između skupina s VUE s i bez PE, te s VUE i PE i kontrole. Nije bilo statistički značajne razlike između skupine s VUE bez PE i kontrole. CD25+ i FOXP3+ bili su negativni. Nismo dokazali statistički značajnu razliku u broju NK stanica između ispitivanih skupina. Zaključak: T reg limfociti koji iskazuju markere CD4+CD25+FOXP3+, a koji su analizirani u smislu prisutnosti i upliva u žarištima VUE istraživanih posteljica, kao i decidui, pronađeni su pojedinačno i oskudno i bez statistički značajne razlike između ispitivanih skupina. Prirodnoubojičke stanice koje su CD56+, a koje smo analizirali u decidui ispitivanih posteljica nisu se pokazale značajnim ni u jednoj skupini. Žarišta vilitisa posteljica s VUE iz trudnoća kompliciranih PE imaju statistički značajnije veći broj CD4 + limfocita, kao i CD4+/CD8+ omjer nego posteljice s VUE bez PE. Slijedeće istraživanje trebalo bi napraviti na većem uzorku posteljica s VUE i PE, uz analizu cjelokupne subpopulacije CD4+ limfocita, te paralelnu analizu subpopulacije CD4+ limfocita iz periferne krvi istih trudnica, a koji vjerovatno pridonose upalnom odgovoru i simptomima PE. Fiziologija imune interakcije između fetusa i majke za vrijeme trudnoće je još uvijek neistraženo područje koje sve više zaokuplja interes istraživača. Upravo razumijevanje imunološke interakcije za vrijeme normalne trudnoće moglo bi pripomoći istraživanju poremećaja povezanih sa trudnoćom kao što je PE., Objective: To compare immunohistochemical expression of different T type lymphocytes as well as T reg lymphocytes in foci of VUE in placentae from pregnancies complicated with PE and in foci of VUE in placentae without PE. To compare immunohistochemical expression of T reg lymphocytes and NK cells in the basal decidua, in placentae with VUE from pregnancies with and without PE and from normal pregnancies. To compare grade and number of foci between VUE in placentae from pregnancies complicated with PE and in placentae from pregnancies without PE. Material and methods: Fiftyfour placentae were collected from pregnancies who had villitis of unknown etiology with [N=27] and without [N=27] preeclampsia and twenty [N=20] from normal pregnancies. Clinical diagnosis of PE was made according to the strict criteria of hypertension and proteinuria, and diagnosis of VUE according to the presence of lymphohistiocytic infiltrate affecting varying proportions of the villous tree of the placenta. Immunohistochemistry for the number and type of T cell inflammatory infiltrate in VUE foci as well as T reg and NK cells in basal decidua was performed on formalin fixed and paraffin-embedded sections by use of the CD3, CD4, FOXP3, CD25, CD8, CD45, CD56 and CD68 antibodies. Cytomorphological characteristics of examined placentas were determined by the number of foci and grade of VUE. Results: There was no statistical difference in terms of foci and grade of VUE between VUE with and without PE. Also, there was no statistical difference in terms of parity, maternal age, birth weight, birth length and gestational age, but there was a statistical difference in terms of birth weight and gestational age between VUE with and without PE and control group. There was statistically significant difference in total CD4+ lymphocytes count, number of villi infiltrate with CD4+ lymphocytes and CD4+/CD8+ ratio between VUE with and without PE. No statistically significant difference of the total number and type of inflammatory cells and number of villi infiltrated with CD3, CD8, CD25, FOXP3, CD45 and CD68 between the study groups was detected. Analysis of T reg and NK cells infiltrate in the basal decidua among all three investigated groups revealed statistically significant difference in total CD4+ lymphocytes count between group with VUE with and without PE and with VUE with PE and control group. There was no statistically significant difference between group with VUE without PE and control group. CD25+ i FOXP3+ were negative. No statistically significant difference of the total number of decidual CD56 cells in basal decidua between the study groups was noticed. Conclusion: T reg lymphocytes expressing the CD4+, CD25+ and FOXP3+ markers were analysed for their presence and influx in VUE foci in the placentae, and were detected individually and rarely, without statistically significant between-group difference, also in decidua. Natural killer cells which were analysed in decidua were detected also individually and rarely without statistically significant between group difference. This study results revealed statistically significantly larger CD4+ T lymphocyte population and CD4+/CD8+ ratio in placentae with VUE with PE compared to VUE without PE. Future studies should include a greater sample of VUE and PE and focus on analysis of the overall CD4+ lymphocyte subpopulation and concurrent analysis of CD4+ lymphocyte subpopulation from peripheral blood collected from the same pregnant women, as these cells probably contribute to the inflammatory response and symptoms of PE, while also being relevant for proper understanding of these intriguing inflammatory lesions of human placenta. The physiology of the immune interaction between the fetus and the mother during pregnancy is an unexplored field that has received increasing attention during the past years. The understanding of immune interactions during normal pregnancy could help guide the research of pregnancy-associated disorders such as PE what would finally allow the development of effective therapeutic tools.

Giant chorioangiomas are a potentially life-threatening condition that may require intrauterine therapy. We describe a case of a large chorioangioma (4cm) diagnosed at 30 weeks of gestation causing severe fetal anemia and hydrops. An intrauterine blood transfusion was performed at 31 weeks with reversal of the anemia and hydrops. The neonate was born at 37 weeks showing respiratory distress syndrome that required neonatal intensive care unit admission but was discharged at 30 days of life. Further evaluation at two months of age showed no signs of abnormal neurodevelopment. When timely indicated, intrauterine transfusion of a hydropic fetus with anemia due to a giant chorioangioma is a potentially life-saving therapy that shows good neurodevelopment of the surviving fetus.

Context.— There are 3 types of decidual vasculopathy, namely, acute atherosis, fibrinoid medial necrosis, and mural arterial hypertrophy. Persistence of vascular trophoblasts is also known to be related to maternal vascular malperfusion, but detailed study is lacking. Objective.— To define atherosis of trophoblast type and distinguish it from atherosis of macrophage type with clinical significance. Design.— A total of 1322 placentas from 2021 were collected with clinical, neonatal, and placental information, and routine placental pathology examination was performed. Decidual vasculopathy was classified on the basis of the new classification scheme including atherosis of macrophage type, atherosis of trophoblast type, fibrinoid medial necrosis, mural arterial hypertrophy, and mixed-type vasculopathy. The significance of these morphologic changes was examined on the basis of clinical, neonatal, and placental pathology features. Results.— Decidual vasculopathy is classified as classic type, mural hypertrophy, and mixed type. Classic-type vasculopathy is further separated as atherosis and fibrinoid medial necrosis. Atherosis is defined as atherosis of macrophage type and atherosis of trophoblast type. Each category of decidual vasculopathy was evaluated in association with maternal, neonatal, and placental pathologic findings. Atherosis of macrophage type and mixed-type vasculopathy showed statistically significant association with preeclampsia/pregnancy-induced hypertension, low birth weight, and low placental weight. Atherosis of trophoblast type was associated with lower placental weight but not with other specific clinical features. Neonates of female sex were associated with mural arterial hypertrophy. Conclusions.— Atherosis of trophoblast type is a distinct pathologic feature in late pregnancy, and it is associated with lower placental weight. New classification of decidual vasculopathy helps with better stratification and categorization of placental maternal vascular abnormalities of late pregnancy.

PURPOSE OF REVIEW: Preeclampsia complicates 5–10% of all pregnancies and is a leading cause of maternal and perinatal mortality and morbidity. The placenta plays a pivotal role in determining pregnancy outcome by supplying the fetus with oxygen and nutrients and by synthesizing hormones. Placental function is highly dependent on energy supplied by mitochondria. It is well-known that preeclampsia is originated from placental dysfunction, although the etiology of it remains elusive. RECENT FINDINGS: During the last three decades, substantial evidence suggests that mitochondrial abnormality is a major contributor to placental dysfunction. In addition, mitochondrial damage caused by circulating bioactive factors released from the placenta may cause endothelial dysfunction and subsequent elevation in maternal blood pressure. SUMMARY: In this review, we summarize the current knowledge of mitochondrial abnormality in the pathogenesis of preeclampsia and discuss therapeutic approaches targeting mitochondria for treatment of preeclampsia.

To determine the effect of 3 distinct comparison groups on associations between placental abnormalities and neonatal hypoxic-ischemic encephalopathy (HIE).This single-center, prospective case-control study of singletons of gestational age ≥36 weeks with predefined criteria for HIE (n = 30) and 3 control groups was conducted from June 2015 to January 2018. The control groups were infants born by repeat cesarean delivery (n = 60), infants born small for gestational age (SGA; n = 80), and infants receiving positive-pressure ventilation (PPV) at birth (n = 70). One pathologist blinded to infant category reviewed placental sections using the Amsterdam Placental Workshop criteria. Logistic regression with group contrasts relative to HIE was used to analyze primary placental pathologies, and ORs with 95% CIs provided effect sizes.The odds of maternal vascular malperfusion were increased among HIE group placentas compared with placentas of the repeat cesarean delivery (OR, 4.50; 95% CI, 1.45-14.00) and PPV (3.88; 1.35-11.16) groups, but not those of the SGA group. The odds of fetal vascular malperfusion were increased in the HIE group compared with the SGA group (OR, 9.75; 95% CI, 1.85-51.51). The odds of acute chorioamnionitis were higher in the HIE group compared only with the repeat cesarean delivery group, reflecting a similar incidence of chorioamnionitis in SGA group and PPV group placentas. The absence of placental findings was lowest in the HIE group (6.7%), followed by the SGA (18.8%), PPV (31.4%), and repeat cesarean delivery (75%) groups.Associations with placental abnormalities among infants with HIE varied based on the specific placental abnormality and the control group. Potentially important associations between placental pathology and HIE may be obscured if control groups are not well designed.

Preeclampsia is a devastating medical complication of pregnancy that can lead to significant maternal and fetal morbidity and mortality. It is currently believed that there is abnormal placentation in as early as the first trimester in women destined to develop preeclampsia. Although the etiology of the abnormal placentation is being debated, numerous epidemiologic and experimental studies suggest that imbalances in circulating angiogenic factors released from the placenta are responsible for the maternal signs and symptoms of preeclampsia. In particular, circulating levels of soluble fms-like tyrosine kinase 1, an antiangiogenic factor, are markedly increased in women with preeclampsia, whereas free levels of its ligand, placental, growth factor are markedly diminished. Alterations in these angiogenic factors precede the onset of clinical signs of preeclampsia and correlate with disease severity. Recently, the availability of automated assays for the measurement of angiogenic biomarkers in the plasma, serum, and urine has helped investigators worldwide to demonstrate a key role for these factors in the clinical diagnosis and prediction of preeclampsia. Numerous studies have reported that circulating angiogenic biomarkers have a very high negative predictive value to rule out clinical disease among women with suspected preeclampsia. These blood-based biomarkers have provided a valuable tool to clinicians to accelerate the time to clinical diagnosis and minimize maternal adverse outcomes in women with preeclampsia. Angiogenic biomarkers have also been useful to elucidate the pathogenesis of related disorders of abnormal placentation such as intrauterine growth restriction, intrauterine fetal death, twin-to-twin transfusion syndrome, and fetal hydrops. In summary, the discovery and characterization of angiogenic proteins of placental origin have provided clinicians a noninvasive blood-based tool to monitor placental function and health and for early detection of disorders of placentation. Uncovering the mechanisms of altered angiogenic factors in preeclampsia and related disorders of placentation may provide insights into novel preventive and therapeutic options.

Maternal floor infarction (MFI) and massive perivillous fibrin deposition (MPFD) are overlapping placental disorders of unknown etiology, associated with adverse obstetric outcome, and a significant risk of recurrence. We describe a 31-year-old mother with asymptomatic thrombocytopenia throughout pregnancy and a positive lupus anticoagulant. She delivered a normal female neonate at term, whose weight was small for gestational age, with a placenta weighing less than the 10th percentile. Placental examination showed MPFD together with excessive subchorionic fibrinoid deposition. The placenta showed diffuse C4d deposition and an immune-mediated reaction was postulated for the pathogenesis of the placental changes. We suggest that excessive subchorionic fibrinoid deposition may be part of the morphologic spectrum of MFI/MPFD.

Superb microvascular imaging (SMI) is a new Doppler method that enables the visualization of low-velocity blood flow. The aim of the study described here was to clarify whether SMI can detect prenatal pathological findings in pathologic placentas. In this prospective diagnostic observational study, pregnant women who were admitted to our center for perinatal management were enrolled. Ultrasound examinations to identify placental pathologies using SMI were performed before delivery. After delivery, the placental tissue was clipped for microscopic examination at locations determined under ultrasound guidance. The accuracy of prenatal ultrasound detection of placental pathologies was compared between women who were admitted because of fetal growth restriction (FGR), pre-eclampsia and other indications. The highest accuracy was observed with placental infarction in FGR (positive predictive value = 100%, sensitivity = 89%, area under the curve = 0.945). As a result, it became clear that SMI can accurately detect placental pathologic findings, such as placental infarction and avascular villi. This modality may improve perinatal management in cases of placental dysfunction.

To examine the performance of a model combining maternal risk factors, uterine artery pulsatility index (UtA-PI) and estimated fetal weight (EFW) at 19-24 weeks' gestation, for predicting all antepartum stillbirths and those due to impaired placentation, in a training dataset used for development of the model and in a validation dataset.The data for this study were derived from prospective screening for adverse obstetric outcome in women with singleton pregnancy attending for routine pregnancy care at 19 + 0 to 24 + 6 weeks' gestation. The study population was divided into a training dataset used to develop prediction models for placental dysfunction-related antepartum stillbirth and a validation dataset to which the models were then applied. Multivariable logistic regression analysis was used to develop a model based on a combination of maternal risk factors, EFW Z-score and UtA-PI multiples of the normal median. We examined the predictive performance of the model by, first, the ability of the model to discriminate between the stillbirth and live-birth groups, using the area under the receiver-operating-characteristics curve (AUC) and the detection rate (DR) at a fixed false-positive rate (FPR) of 10%, and, second, calibration by measurements of calibration slope and intercept.The study population of 131 514 pregnancies included 131 037 live births and 477 (0.36%) stillbirths. There are four main findings of this study. First, 92.5% (441/477) of stillbirths were antepartum and 7.5% (36/477) were intrapartum, and 59.2% (261/441) of antepartum stillbirths were observed in association with placental dysfunction and 40.8% (180/441) were unexplained or due to other causes. Second, placental dysfunction accounted for 80.1% (161/201) of antepartum stillbirths at 32 weeks' gestation, 54.2% (52/96) at 32 + 0 to 36 + 6 weeks and 33.3% (48/144) at ≥ 37 weeks. Third, the risk of placental dysfunction-related antepartum stillbirth increased with increasing maternal weight and decreasing maternal height, was 3-fold higher in black than in white women, was 5.5-fold higher in parous women with previous stillbirth than in those with previous live birth, and was increased in smokers, in women with chronic hypertension and in parous women with a previous pregnancy complicated by pre-eclampsia and/or birth of a small-for-gestational-age baby. Fourth, in screening for placental dysfunction-related antepartum stillbirth by a combination of maternal risk factors, EFW and UtA-PI in the validation dataset, the DR at a 10% FPR was 62.3% (95% CI, 57.2-67.4%) and the AUC was 0.838 (95% CI, 0.799-0.878); these results were consistent with those in the dataset used for developing the algorithm and demonstrate high discrimination between affected and unaffected pregnancies. Similarly, the calibration slope was 1.029 and the intercept was -0.009, demonstrating good agreement between the predicted risk and observed incidence of placental dysfunction-related antepartum stillbirth. The performance of screening was better for placental dysfunction-related antepartum stillbirth at 37 weeks' gestation compared to at term (DR at a 10% FPR, 69.8% vs 29.2%).Screening at mid-gestation by a combination of maternal risk factors, EFW and UtA-PI can predict a high proportion of placental dysfunction-related stillbirths and, in particular, those that occur preterm. Such screening provides poor prediction of unexplained stillbirth or stillbirth due to other causes. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Introduction: Heterogeneous patterns of placental lesions in stillbirth signal important variations in placental histopathology that may be diagnostic in stillbirth. We explore placental heterogeneity and its associations with maternal characteristics (including HIV) using latent class analysis. Methods: Placental and maternal data and slides were assessed retrospectively for 122 confirmed stillbirths (gestational age ≥ 28 weeks) delivered at a major South African academic hospital between January 2016–July 2018. The slides were reviewed by 2 pathologists and classified using the Amsterdam Consensus Classification System. Latent class analyses were conducted on raw data. Results: We identify 5 latent placental classes in stillbirth based on similarity in patterns of observed diagnostic criteria and their associations with maternal characteristics. Three classes bear similarity to generalized patterns of placental injury identified previously. Our study shows that intrauterine infection was the commonest histopathological condition associated with stillbirth in our setting. Novel findings include 2 classes, distinguished by high placental RPH and maternal HIV, respectively, and the non-emergence of a class distinguished by VUE. Conclusion: The size and content of the latent classes and their similarity/dissimilarity to the more generalized patterns identified previously suggest potential new avenues for investigation and theory development concerning the role of the placenta in stillbirth and the impact of HIV.

Despite the indispensable role of the placenta in the successful course of pregnancy, regulation of its dynamic transcriptome is still underexplored. The purpose of this literature review was to give an overview and draw attention to the contribution of genetic variation in shaping the human placental gene expression. Studies of placental transcriptome shaped by chromosomal variants are limited and may be confounded by cellular mosaicism and somatic genomic rearrangements. Even in relatively simple cases, such as aneuploidies, the placental transcriptome appears to differ from the assumed systematically increased transcript levels of the involved chromosomes. Single nucleotide variants modulating placental gene expression referred to as expression quantitative trait loci (eQTLs) have been analyzed only in ten candidate gene and three genome-wide association studies (GWAS). The latter identified 417 confident placental eGenes, supported by at least two independent studies. Functional profiling of eGenes highlighted biological pathways important in pregnancy, such as immune response or transmembrane transport activity. A fraction of placental eQTLs (1–3%) co-localize with GWAS loci for adult disorders (metabolic, immunological, neurological), suggesting a co-contributory role of the placenta in the developmental programming of health. Some placental eQTLs have been identified as risk factors for adverse pregnancy outcomes, such as rs4769613 (C > T), located near the FLT1 gene and confidently associated with preeclampsia. More studies are needed to map genetic variants shaping gene expression in different placental cell types across three trimesters in normal and complicated gestations and to clarify to what extent these heritable factors contribute to maternal and offspring disease risks.

Bizarre (atypical/symplastic) cells have been described in various gynecologic normal tissues and benign neoplasms. This type of bizarre cytologic change is usually an incidental finding and is regarded as a benign process. We describe 17 cases of bizarre chorionic-type trophoblast in second-trimester and third-trimester placentas that created concern for an underlying/undersampled or incipient intraplacental trophoblastic neoplasm, predominantly found in intervillous trophoblastic islands (11/17), placental septae (6/17), chorionic plate (1/17), and/or the chorion layer of fetal membranes (2/17). The bizarre trophoblastic cells exhibited sheet-like or nested architecture, had a multifocal/patchy distribution, and/or were present as individual cells within hyaline stroma; they were characterized by large nuclei with smudgy chromatin and occasional intranuclear pseudoinclusions. The degree of atypia was classified as mild (0/17), moderate (3/17), or severe (14/17). Mitotic figures and necrosis were not identified. A dual immunohistochemical stain for trophoblast (hydroxyl-delta-5-steroid dehydrogenase) and a proliferation marker (Ki-67), performed in 15 cases, demonstrated 0% to very low proliferative activity within the bizarre trophoblast (0% to 2% [10/15], 3% to 8% [5/15]). Immunohistochemical stains for fumarate hydratase showed intact/retained expression in the bizarre cells in 7 of 7 cases. Clinical follow-up ranged from 1 to 45 months, and all patients were alive and well without subsequent evidence of a gestational trophoblastic or other neoplasms. We conclude that bizarre chorionic-type trophoblast in second-trimester or third-trimester placentas have the potential to mimic an intraplacental trophoblastic neoplasm but are likely a benign degenerative change. This study expands the spectrum of bizarre cells that occur in the gynecologic tract.

Placental inflammatory lesions are important findings that lead fetal and neonatal morbidity and mortality, and can be divided into two broad subcategories, acute inflammation caused by microorganisms and chronic inflammation caused by host immune responses. Recently, a diagnostic framework for these lesions has been established, and uniform diagnostic criteria have been recommended by the Amsterdam International Consensus Group. Chorioamnionitis is representative of the acute inflammatory lesion, and is the most frequent pathological diagnosis in placental pathology. The hallmark of chorioamnionitis is neutrophil infiltration in the membrane/chorioamnionic plate and fetal vessels. The inflammatory response can be both maternal (inflammation in the membrane or chorioamnionic plate) and fetal (inflammation in the fetal vessels-umbilical vessels or chorionic vessel). Recent studies have shown that the fetal inflammatory response is associated with neonatal mortality and morbidity. Furthermore, chronic inflammatory lesions, such as villitis of unknown etiology and chronic histiocytic intervillositis, are also important. Although their etiology remains unknown, the maternal immune response against paternal antigens has been considered a possible factor. These inflammatory lesions are associated with fetal demise and fetal growth restriction. Inflammatory lesions in the placenta are useful for understanding intrauterine conditions, guiding treatment, and predicting complications.

We examined the influence of confined placental mosaicism (CPM) as a cause of fetal growth restriction (FGR), and whether CPM can be screened using cell-free DNA (cfDNA) analysis of the maternal plasma. We analyzed cfDNA in the maternal plasma of 40 FGR cases with an estimated fetal weight of less than - 2.0 SD using massively parallel sequencing to detect chromosomal aberrations. Fetal and placental genotyping was performed to confirm CPM cases. cfDNA analyses of maternal plasma detected suspected CPM cases with chromosomal aneuploidy or copy number variations in 5 of 40 cases (12.5%). For 4 cases in which the entire placenta consisted of cells with chromosomal abnormalities, fetal growth was severely restricted. CPM can be screened by cfDNA analysis in maternal plasma, accounting for approximately 10% of the causes of moderate or severe FGR, and the higher the proportion of abnormal karyotype cells in the placenta, the more severe the placental dysfunction and FGR.

To examine the frequency of placental abnormalities in a multicenter cohort of newborn infants with hypoxic-ischemic encephalopathy (HIE) and to determine the association between acuity of placental abnormalities and clinical characteristics of HIE.Infants born at ≥36 weeks of gestation (n = 500) with moderate or severe HIE were enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy Trial. A placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute and chronic placental abnormalities using a standard classification system.Complete placental pathologic examination was available for 321 of 500 (64%) trial participants. Placental abnormalities were identified in 273 of 321 (85%) and were more common in infants ≥40 weeks of gestation (93% vs 81%, P = .01). A combination of acute and chronic placental abnormalities (43%) was more common than either acute (20%) or chronic (21%) abnormalities alone. Acute abnormalities included meconium staining of the placenta (41%) and histologic chorioamnionitis (39%). Chronic abnormalities included maternal vascular malperfusion (25%), villitis of unknown etiology (8%), and fetal vascular malperfusion (6%). Infants with chronic placental abnormalities exhibited a greater mean base deficit at birth (-15.9 vs -14.3, P = .049) than those without such abnormalities. Patients with HIE and acute placental lesions had older mean gestational ages (39.1 vs 38.0, P .001) and greater rates of clinically diagnosed chorioamnionitis (25% vs 2%, P .001) than those without acute abnormalities.Combined acute and chronic placental abnormalities were common in this cohort of infants with HIE, underscoring the complex causal pathways of HIE.ClinicalTrials.gov: NCT02811263.

Nuclear Receptor Subfamily 4 Group A Member 2 (NR4A2) transcripts are elevated in the circulation of individuals whose pregnancies are complicated by preterm fetal growth restriction (FGR). In this paper, we show that the cases with preeclampsia (PE) have increased circulating NR4A2 transcripts compared to those with normotensive FGR. We aimed to establish whether the dysfunctional placenta mirrors the increase in NR4A2 transcripts and further, to uncover the function of placental NR4A2. NR4A2 expression was detected in preterm and term placental tissue; expressed higher at term. NR4A2 mRNA expression and protein were not altered in placentas from preterm FGR or PE pregnancies. Hypoxia (1% O2 compared to 8% O2) significantly reduced cytotrophoblast NR4A2 mRNA expression, but not placental explant NR4A2 expression. Silencing cytotrophoblast NR4A2 expression under hypoxia (via short interfering (si)RNAs) did not alter angiogenic Placental Growth Factor, nor anti-angiogenic sFlt-1 mRNA expression or protein secretion, but increased expression of cellular antioxidant, oxidative stress, inflammatory, and growth genes. NR4A2 expression was also not altered in a model of tumour necrosis factor-α-induced endothelial dysfunction, or with pravastatin treatment. Further studies are required to identify the origin of the circulating transcripts in pathological pregnancies, and investigate the function of placental NR4A2.

Background During pregnancy, trophoblast cell invasion needs to be finely controlled. Aberrant trophoblast cell invasion is associated with placental diseases. Epidermal growth factor (EGF) and its receptor, EGFR, are expressed in trophoblast cells. Although the pro-invasive effect of EGF on trophoblast cells has been reported, the underlying mechanism remains largely unknown. Results In the present study, we conducted an RNA sequencing (RNA-seq) to HTR-8/SVneo human trophoblast cells in response to EGF and identified KISS1 as a target gene of EGF. The human KISS1 gene encodes kisspeptin, also known as metastin, which can suppress tumor metastasis. Our results showed that EGF treatment downregulated KISS1 expression and secretion by activating the EGFR-mediated PI3K/AKT signaling pathway. In addition, the expression of inhibitor of DNA-binding protein 3 (ID3) was downregulated by EGF and that was required for the EGF-suppressed KISS1 expression. Functionally, transwell invasion assays demonstrated that EGF stimulated human trophoblast cell invasion by downregulating KISS1 expression. Preeclampsia (PE) is a placental disease characterized by insufficient trophoblast cell invasion. Our clinical results revealed that serum levels of EGF were downregulated while serum and placental levels of KISS1 were upregulated in PE patients. Conclusions This study demonstrates that downregulation of EGF can lead to poor trophoblast cell invasion by increasing KISS1 expression which subsequently contributes to the pathogenesis of PE.

SARS-CoV-2 has emerged as a major pandemic of the century and little is known about the impact of maternal infection on placental histopathology. Histopathologic examination of placental tissue can contribute to significant information regarding the pathophysiology of the disease and how it affects the fetal outcome.This was a cross-sectional study conducted at the Department of Pathology, Government Doon Medical College and Hospital, Dehradun, on the placenta of 50 coronavirus disease 2019 (COVID-19)-positive pregnant females confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) from August 2020 to October 2020. Fifty term historical placentas were taken as control. Placenta sections were fixed in formalin, processed into paraffin blocks, stained with hematoxylin and eosin (H and E) stain, and visualized for any abnormality.The most prominent histological finding in the placenta of pregnant women affected by COVID-19 was chorangiosis, which is a feature of fetal vascular malperfusion seen in 28 (56%) cases. Other features included maternal vascular malperfusions (MVM) such as villous crowding and agglutination in 12 (24%) cases. Tenney-Parker change was seen in 13 (26%) patients. Intervillous fibrinoid deposition and intervillous hemorrhage were seen in 37 (74%) patients and 7 (14%) patients showed significant calcification. Other findings observed were less common.Infection with SARS-CoV-2 may be associated with a significant impact on fetal and maternal circulation causing features of fetal and maternal malperfusion such as chorangiosis, villous crowding, and agglutination. Indicating that the infection could cause a potential rise in the risk of adverse perinatal outcomes such as intrauterine fetal growth retardation, preterm birth, or stillbirth.

Context.— Case reports and rare case series have demonstrated variable placental pathology in the setting of maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In rare small studies demonstrating infection of the placental parenchyma, histologic manifestations have included variable degrees of histiocytic intervillositis, perivillous fibrin deposition, and syncytiotrophoblast necrosis. Objective.— To characterize the placental pathologic features of SARS-CoV-2–infected placentas, irrespective of fetal-maternal transmission, and to examine the frequency of C4d activation in such cases. Design.— A retrospective study of 7 placentas from mothers with active SARS-CoV-2 infection and placental infection as demonstrated by RNA in situ hybridization was conducted. Results.— There were 6 placentas from live-born neonates (5 singletons, 1 nonfused diamniotic-dichorionic twin placenta), and 1 was from a stillbirth. A total of 5 of the 8 neonates (including the stillbirth) tested negative for SARS-CoV-2, and all were negative for neonatal infection. The remaining 3 neonates were well at time of discharge. All placentas were positive for SARS-CoV-2 infection by RNA in situ hybridization and demonstrated variable degrees of histiocytic intervillositis, perivillous fibrin deposition, and trophoblast necrosis. Three cases demonstrated features of fetal vascular malperfusion. CD68 highlighted intervillous histiocytes. C4d expression was present along the villous borders in 6 of 7 cases. Conclusions.— SARS-CoV-2 placentitis is defined by the triad of histiocytic intervillositis, perivillous fibrin deposition, and trophoblast necrosis. The features may occur in cases without confirmed transplacental transmission. The damage caused by SARS-CoV-2 placentitis is likely mediated by complement activation.

Funding: This paper presents independent research supported by the National Funding: Institute for Health Research (NIHR) Clinical Research Facility and the NIHR Biomedical Research Centre based at Imperial College Healthcare NHS Trust. AA is supported by an NIHR Clinician Scientist award (CS‐2018‐18‐ST2‐002). MAM is funded by the Tommy’s National Centre for Miscarriage Research. MP is supported by an NIHR Academic Clinical Lectureship. CI-E is supported by an Imperial College-BRC IPPRF Fellowship. SAC is supported by an NIHR Academic Clinical Lectureship. EGM is supported by an MRC clinical training fellowship (MR/T006242/1). LY is supported by an MRC clinical training fellowship (MR/R000484/1). ANC is supported by the NHS and BRC. TB is supported by the NIHR Biomedical Research Centre based at Imperial College Healthcare NHS Trust. WSD is supported by an NIHR Research Professorship (RP-2014-05-001). Context: Antenatal complications such as hypertensive disorders of pregnancy (HDP), fetal growth restriction (FGR), gestational diabetes (GDM), and preterm birth (PTB) are associated with placental dysfunction. Kisspeptin has emerged as a putative marker of placental function, but limited data exist describing circulating kisspeptin levels across all three trimesters in women with antenatal complications. Objective: To assess whether kisspeptin levels are altered in women with antenatal complications. Methods: Women with antenatal complications (n = 105) and those with uncomplicated pregnancies (n = 265) underwent serial ultrasound scans and blood sampling at the Early Pregnancy Assessment Unit at Hammersmith Hospital, UK, at least once during each trimester (March 2014 to March 2017). The women with antenatal complications (HDP [n = 32], FGR [n = 17], GDM [n = 35], PTB [n = 11], and multiple complications [n=10]) provided 373 blood samples and the controls provided 930 samples. Differences in circulating kisspeptin levels were assessed. Participants: Women with antenatal complications: HDP (n=32), FGR (n=17), GDM (n=35) and PTB (n=11), and 10 women with multiple complications, provided 373 blood samples, and a further 265 controls provided 930 samples. Results: Third-trimester kisspeptin levels were higher than controls in HDP but lower in FGR. The odds of HDP adjusted for gestational age, maternal age, ethnicity, BMI, smoking, and parity were increased by 30% (95% CI, 16%-47%; P

Introduction Gastroschisis is a congenital malformation characterized by intestinal herniation through an abdominal wall defect. Despite its unknown pathogenesis, known risk factors include maternal smoking, alcohol use, and young maternal age. Previous work has shown that gastroschisis is associated with placental delayed villous maturation, and the goal of this study was to assess for additional associated placental pathologies that may help clarify the pathogenesis of gastroschisis. Methods We conducted a retrospective slide review of 29 placentas of neonates with gastroschisis. Additionally, we reviewed pathology reports from one control group of 30 placentas with other congenital malformations. Gross and histological data were collected based on a standardized rubric. Results Gastroschisis was associated with increased placental fetal vascular malperfusion (FVM) in 62% of cases (versus 0% of controls, p Conclusion Our study demonstrates an association between gastroschisis and FVM. While FVM could be the consequence of vascular disruption due to the ventral location of gastroschisis, it could also reflect estrogen-induced thrombosis in early pregnancy. Further research is needed to separate these possibilities and determine the cause of the placental FVM observed in gastroschisis.

Objective This study aimed to compare the risks of amniocentesis between anteriorly located placentas and placentas in other locations and assess the factors that cause procedure-related complications. Materials and methods We prospectively studied women with singleton pregnancies who underwent amniocentesis between 2014 and 2020. The amniocentesis puncture sites were determined using ultrasonography. Women were classified into two groups according to their placental location. Medical records were retrospectively reviewed and characteristics and complications were compared between the groups of patients with different placental locations. Results During the study period, 629 women underwent amniocentesis. Three cases (0.5%) of premature rupture of membranes and one case (0.3%) of fetal loss within four weeks of amniocentesis were found. Puncture failure was observed in 14 cases (2.2%). Puncture failure included procedures with failure to obtain an adequate sample and procedures requiring more than three needle insertions. There was no significant difference in the frequency of puncture failure between the two groups. Logistic regression analysis revealed that uterine myoma (odds ratio [OR] 11.92; 95% CI, 3.04–45.17) and tenting membrane (OR 33.57; 95% CI, 6.45–178.41) were associated with puncture failure. Conclusion Anteriorly located placenta is not a risk factor for amniocentesis-related adverse outcomes. Instead, puncture failure frequently occurs in case of uterine myoma and tenting membrane. If puncture failure occurs, or if the puncture is difficult to perform, then the procedure should be considered technically difficult and postponed until it can be more easily performed.

The placenta plays a fundamental role during pregnancy for fetal growth and development. A suboptimal placental function may result in severe consequences during the infant’s first years of life. In recent years, a new field known as neuroplacentology has emerged and it focuses on the role of the placenta in fetal and neonatal brain development. Because of the limited data, our aim was to provide a narrative review of the most recent knowledge about the relation between placental lesions and fetal and newborn neurological development. Papers published online from 2000 until February 2022 were taken into consideration and particular attention was given to articles in which placental lesions were related to neonatal morbidity and short-term and long-term neurological outcome. Most research regarding the role of placental lesions in neurodevelopment has been conducted on fetal growth restriction and preterm infants. Principal neurological outcomes investigated were periventricular leukomalacia, intraventricular hemorrhages, neonatal encephalopathy and autism spectrum disorder. No consequences in motor development were found. All the considered studies agree about the crucial role played by placenta in fetal and neonatal neurological development and outcome. However, the causal mechanisms remain largely unknown. Knowledge on the pathophysiological mechanisms and on placenta-related risks for neurological problems may provide clues for early interventions aiming to improve neurological outcomes, especially among pediatricians and child psychiatrists.

Objective: Peripartum hysterectomy is a life-saving procedure performed during and after vaginal delivery or cesarean section. The incidence of placental invasion anomaly is increasing in parallel with the increase in the number of births by cesarean section. It was aimed to evaluate the frequency, risk factors and outcomes of peripartum hysterectomy performed in a tertiary hospital. Materials and methods: Research data were obtained by a retrospective review of patient files. Patients who underwent peripartum hysterectomy because of postpartum hemorrhage in the Gynecology and Obstetrics Clinic of Trabzon Kanuni Training and Research Hospital, University of Health Sciences, Turkey, were included in the present study. The patients were divided into two groups as those who underwent emergency peripartum hysterectomy (EPH) and those who did not. Demographic variables, fetal and maternal mortality, EPH indications, additional surgeries performed during EPH, and intra- or postoperative complications were collected. Pearson chi-square test was used for statistical analysis. Results: There were 22,464 deliveries, of which 13,514 were delivered vaginally and 8,950 by cesarean section. Peripartum hysterectomy was performed on 42 patients (vaginal 16, cesarean section 26). The most common EPH indications in both groups were placenta accreta spectrum (42.9/3.2%), followed by uterine atony (38.1/2.5%). The most common risk factor for EPH was found to be a history of previous cesarean sections. Conclusion: Placental invasion anomalies that cause severe postpartum hemorrhage are due to increased cesarean rates. Currently, the most common indication of EPH is placental invasion anomalies. Key words: peripartum hysterectomy – placental invasion anomaly – postpartum hemorrhage

Relatamos o caso de uma grávida de 31 anos, na sua terceira gestação, com antecedentes de morbilidade obstétrica grave, referenciada para estudo de patologia protrombótica. No estudo efetuado, não foi detetada trombofilia, contudo salienta-se elevação isolada da fosfatase alcalina (10 vezes superior ao valor máximo de referência). A elevação da fosfatase alcalina durante a gravidez, até duas vezes o valor máximo de referência, é considerada normal no último trimestre. A elevação acima desse valor implica o diagnóstico diferencial com patologia hepatobiliar, óssea e renal. Foi efetuada terapêutica antitrombótica profilática off-label durante a totalidade da gravidez, que decorreu favoravelmente, com nascimento de nado-vivo saudável. A avaliação anátomo- -patológica da placenta nesta gravidez revelou a presença de intervilite crónica com predomínio de histiócitos, uma entidade rara não completamente esclarecida ligada a fenómenos autoimunes da placenta, na qual a fosfatase alcalina é apontada como possível marcador., Medicina Interna, Vol. 24 N.º 4 (2017): Outubro/ Dezembro

Background Late onset intra-uterine growth restriction (IUGR) refers to impaired growth and development of the fetus, characterized by placental morphological abnormalities that affect the fetus supply of nutrients. Human Leukocyte Antigen-G (HLA-G) is physiologically expressed during pregnancy, but in normal placenta decreased during the last weeks of gestation possibly inducing childbirth. Several viruses involved in congenital infection, such as herpesviruses, exploit HLA-G expression as an immune-escape mechanism. To date, despite different congenital herpetic infections have been associated with late IUGR, no direct implication of HHV-6 infection, has been reported. Methods We evaluated HLA-G expression and HHV-6 infection in 11 placentas from late onset IUGR newborns and 11 placentas from uncomplicated pregnancies by histopathological and immunohistochemistry analysis. Results We found higher levels of HLA-G expression and HHV-6 presence in IUGR placenta samples compared with control placenta samples. Conclusions We report HHV-6 staining in IUGR placenta samples, characterized by high HLA-G expression. These preliminary data suggest a possible involvement of HHV-6 infection in HLA-G deregulation that might affect vessel remodeling and prevent the correct pregnancy outcome in IUGR condition. This article is protected by copyright. All rights reserved.

Cervical remodeling is a critical component in both term and preterm labor in eutherian mammals. However, the molecular mechanisms underlying cervical remodeling remain poorly understood in the mare. The current study compared the transcriptome of the equine cervix (cervical mucosa (CM) and stroma (CS)) during placentitis (placentitis group, n = 5) and normal prepartum mares (prepartum group, n = 3) to normal pregnant mares (control group, n = 4). Transcriptome analysis identified differentially expressed genes (DEGs) during placentitis (5310 in CM and 907 in CS) and during the normal prepartum period (189 in CM and 78 in CS). Our study revealed that cervical remodeling during placentitis was dominated by inflammatory signaling as reflected by the overrepresented toll-like receptor signaling, interleukin signaling, T cell activation, and B cell activation pathways. These pathways were accompanied by upregulation of several proteases, including matrix metalloproteinases (MMP1, MMP2, and MMP9), cathepsins (CTSB, CTSC, and CTSD) and a disintegrin and metalloproteinase with thrombospondin type 1 motifs (ADAMTS1, ADAMTS4, and ADAMTS5), which are crucial for degradation of cervical collagens during remodeling. Cervical remodeling during placentitis was also associated with upregulation of water channel-related transcripts (AQP9 and RLN), angiogenesis-related transcripts (NOS3, ENG1, THBS1, and RAC2), and aggrecan (ACAN), a hydrophilic glucosaminoglycan, with subsequent cervical hydration. The normal prepartum cervix was associated with upregulation of ADAMTS1, ADAMTS4, NOS3 and THBS1, which might reflect an early stage of cervical remodeling taking place in preparation for labor. In conclusion, our findings revealed the possible key regulators and mechanisms underlying equine cervical remodeling during placentitis and the normal prepartum period.

The Amsterdam classification system defines four major patterns of placental injury, maternal vascular malperfusion, fetal vascular malperfusion, acute chorioamnionitis, and villitis of unknown etiology, and lists the histologic findings that characterize each. However, there continues to be uncertainty regarding specific definitions, histologic mimics, grading and staging, and what combination of findings is required to diagnose each pattern of injury in a reproducible fashion. The purpose of this review is to clarify some of these issues by suggesting a stepwise approach to more fully realize the potential of this new classification system. In our view, the critical steps for correctly identifying and communicating each pattern of injury are (1) familiarity with the underlying pathophysiology and known clinical associations, (2) incorporation of important gross findings, (3) learning to recognize underlying architectural alterations and defining features at low power, (4) using higher magnification to narrow the differential diagnosis and assess severity (grading) and duration (staging), and (5) adopting a template for generating standardized placental reports that succinctly provide useful information for patient care and research applications.

Introduction Salmonella foodborne disease during pregnancy causes a significant fetal loss in domestic livestock and preterm birth, chorioamnionitis and miscarriage in humans. These complications could be associated with alterations in placental structure. This study was aimed to determine how a low dose of Salmonella Enteritidis during late gestation affects placental histomorphometric in mice. Methods We used a self-limiting enterocolitis murine model. BALB/c pregnant animals received a low dose of Salmonella Enteritidis (3–4 x 102 CFU/mouse) on gestational day (GD) 15. At day 3 post infection bacterial loads, serum cytokines expression and placental histomorphometrics parameters were analyzed. Results We found that a sub-lethal infection with Salmonella induced a significant drop in fetal weight -to-placental weight-ratio and an increase in the placental coefficient. After bacterial inoculation maternal organs were colonized, inducing placental morphometric alterations, including increased placental thickness, reduced surface area, and diminished major and minor diameters. Also, foci of necrosis accompanied by acute leukocyte infiltration in decidual zone, reduction of vascular spaces and vascular congestion in labyrinth zone, were also evident in placentas from infected females on GD 18. Our data shows that placentas from infected mothers are phenotypically different from control ones. Furthermore, expression of IFN-gamma and IL-6 was up regulated in response to Salmonella in maternal serum. Discussion Our findings demonstrate that a low dose of Salmonella during late gestation alters the placental morphometry leading to negative consequences on pregnancy outcome such as significant reduction in fetal body weight.

ObjectiveCorrelation of BPD with placental pathology is important for clarification of the multifactorial pathogenesis of BPD; however, previous reports have yielded varying results. We report placental findings in no/mild BPD compared to moderate/severe BPD, and with and without pulmonary hypertension (PH).MethodsEligible infants were 230/7-276/7weeks gestational age. BPD was defined by the need for oxygen at ≥28 days with severity based on need for respiratory support at ≥36 weeks. Acute and chronic inflammatory placental lesions and lesions of maternal and fetal vascular malperfusion were examined.ResultsOf 246 eligible infants, 146 (59%) developed moderate/severe BPD. Thirty-four (23%) infants developed PH, all but 1 being in the moderate/severe BPD group. Chronic deciduitis (32% vs 16%, P = .003), chronic chorioamnionitis (23% vs 12%, P = .014), and ≥ 2 chronic inflammatory lesions (13% vs 3%, P = .007) were more frequent in the moderate/severe BPD group. Development of PH was associated with placental villous lesions of maternal vascular malperfusion (30% vs 15%, P = .047).ConclusionsThe association of chronic inflammatory placental lesions with BPD severity has not been previously reported. This supports the injury responsible for BPD as beginning before birth in some neonates, possibly related to cytokines associated with these chronic inflammatory lesions.

Background Placental malaria has been associated with increased cord blood maternal microchimerism (MMc), which in turn may affect susceptibility to malaria in the offspring. We sought to determine the impact of maternal peripheral Plasmodium falciparum parasitemia during pregnancy on MMc and to determine whether maternal cells expand during primary parasitemia in the offspring. Methods We conducted a nested cohort study of maternal-infant pairs from a prior pregnancy malaria chemoprevention study. Maternal microchimerism was measured by quantitative polymerase chain reaction targeting a maternal-specific marker in genomic DNA from cord blood, first P falciparum parasitemia, and preparasitemia. Logistic and negative binomial regression were used to assess the impact of maternal peripheral parasitemia, symptomatic malaria, and placental malaria on cord blood MMc. Generalized estimating equations were used to assess predictors of MMc during infancy. Results Early maternal parasitemia was associated with increased detection of cord blood MMc (adjusted odds ratio = 3.91, P = .03), whereas late parasitemia, symptomatic malaria, and placental malaria were not. The first parasitemia episode in the infant was not associated with increased MMc relative to preparasitemia. Conclusions Maternal parasitemia early in pregnancy may increase the amount of MMc acquired by the fetus. Future work should investigate the impact of this MMc on immune responses in the offspring.

Aim To determine which genes are important in placenta by network analysis. Methods Placenta expressing genes were screened from RNA-Seq data. Protein-protein interaction data were downloaded from STRING (v11.0) database. Google PageRank (PR) algorithm was used to identify important placental genes from protein interaction network. Six placental disease-related datasets were downloaded from NCBI GEO database, and the differential expression of the 99 genes was identified. Results We calculated PR for each placenta expressing gene and defined the top 99 genes with high PR as important genes. GAPDH has the highest PR. The 99 genes had different expression pattern in placental cell types. FN1 is up-regulated in 8 w EVT compared to 8 w CTB and 24 w EVT compared to 8 w EVT. HSPA4 is down-regulated in 8 w EVT compared to 8 w CTB and 24 w EVT compared to 8 w EVT. MIB2, TLR4, and UBB are consistently changed in preeclampsia (PE). UBB and ACTG1 were identified to be down-regulated in fetal growth restriction (FGR). SOD1 is down-regulated in preterm birth placenta. Conclusion Our findings confirmed that the importance of these genes in placenta-related diseases, and provide new candidates (MIB2, UBB, ACTG1, and SOD1) for placenta-related disease diagnosis and treatment.

Introduction Assisted reproductive technology including in vitro fertilization (IVF) and oocyte donation (OD) may increase risk for placenta-mediated diseases. Comprehensive analysis of histopathological placental lesions according to source of oocytes used in the IVF procedure – recipient derived (RD-IVF) vs oocyte donation (OD-IVF), has not been conducted in a population with a hypertensive disorder of pregnancy (HDP) and/or intrauterine growth restriction (IUGR). Methods A retrospective cohort study of archived placenta specimens from RD-IVF and OD-IVF pregnancies affected by HDP and/or IUGR was conducted with blinded histopathological placental examination. Three categories of lesions were differentiated and defined as main outcomes: maternal vascular malperfusion (MVM), chronic inflammation, and fetal vascular malperfusion (FVM). To determine the relationship between conception method and placental lesions, multivariable regressions were performed with maternal age, gestational age, HDP, birth and placental weight percentiles as model covariates. Results 115 placentas were included 83 (72.2%) RD-IVF, 32 (27.8%) OD-IVF. Adjusted OR (aOR) for conception method was 5.05 (95%CI 0.58–43.90, p=0.142) for MVM, 1.87 (95%CI 0.68–5.15, p=0.228) for chronic inflammatory and 0.61 (95%CI 0.15–2.37, p=0.471) for FVM lesions. Multiple gestation demonstrated borderline association with MVM (aOR=0.24, 95%CI 0.04–1.51, p=0.129) and total pathology score (aRR=0.79, 95%CI 0.62–1.01, p=0.058). Subgroup analysis suggested greater odds of villitis of unknown etiology (VUE) for OD-IVF (aOR=2.98, 95%CI 1.12–7.93, p=0.029). Discussion Source of oocyte derivation demonstrated no evidence of association with main outcomes in cases of HDP and/or IUGR. Subgroup analysis demonstrated increased rates of inflammatory lesions for OD-IVF. Multiple gestation may be associated with decreased MVM and total lesions.

Background Women with human immunodeficiency virus (HIV) (WHIV) are at higher risk of adverse birth outcomes. Proposed mechanisms for the increased risk include placental arteriopathy (vasculopathy) and maternal vascular malperfusion (MVM) due to antiretroviral therapy and medical comorbid conditions. However, these features and their underlying pathophysiologic mechanisms have not been well characterized in WHIV. Methods We performed gross and histologic examination and immunohistochemistry staining for vascular endothelial growth factor A (VEGF-A), a key angiogenic factor, on placentas from women with ≥1 MVM risk factors including: weight below the fifth percentile, histologic infarct or distal villous hypoplasia, nevirapine-based antiretroviral therapy, hypertension, and preeclampsia/eclampsia during pregnancy. We compared pathologic characteristics by maternal HIV serostatus. Results Twenty-seven of 41 (placentas 66%) assessed for VEGF-A were from WHIV. Mean maternal age was 27 years. Among WHIV, median CD4 T-cell count was 440/µL, and the HIV viral load was undetectable in 74%. Of VEGF-A–stained placentas, both decidua and villous endothelium tissue layers were present in 36 (88%). VEGF-A was detected in 31 of 36 (86%) with decidua present, and 39 of 40 (98%) with villous endothelium present. There were no differences in VEGF-A presence in any tissue type by maternal HIV serostatus (P = .28 to >.99). MVM was more common in placentas selected for VEGF-A staining (51 vs 8%; P Conclusions VEGF-A immunostaining was highly prevalent, and staining patterns did not differ by maternal HIV serostatus among those with MVM risk factors, indicating that the role of VEGF-A in placental vasculopathy may not differ by maternal HIV serostatus.

Introduction Chronic villitis of unknown etiology (VUE) is a chronic inflammatory lesion of third trimester placenta, which contributes to major adverse obstetric outcomes. However, the inciting factors and mechanisms by which VUE contributes to adverse outcomes are poorly understood. This limits our ability to develop preventions or interventions. Our goals were to determine whether viruses can be detected in placental tissues with VUE and to determine whether gene expression profiles support an antiviral response. Methods We extracted RNA and DNA from 20 placentas with high-grade chronic villitis and 20 control placentas without inflammation. Viruses were assessed using ViroCap viral nucleic acid enrichment coupled with metagenomic sequencing. RNA sequencing was used to evaluate the inflammatory gene expression profiles in each placenta. Results We detected at least 1 virus in 50% of the samples tested. We found that herpesviruses, were found more frequently in cases compared with controls (P = 0.01). Antiviral pathways, including defense response to virus, interferon gamma response, and IFN alpha/beta response, were upregulated in cases. We observed two clusters of gene expression profiles in the VUE cases, suggesting multiple inflammatory profiles are associated with VUE. Discussion These data support a viral etiology for some cases of VUE. Furthermore, gene expression profiles suggest the possibility of more than one cause or manifestation of VUE. Viral mechanisms should be explored as potential targets for prevention or intervention in VUE.

Background The pandemic of the severe acute respiratory distress syndrome-associated Coronavirus-2 (SARS-CoV-2) has affected millions around the world. In pregnancy the dangers to the mother and fetus are still being explored. SARS-CoV2 can potentially compromise maternal and neonatal outcomes and this may be dependent on the pregnancy stage during which the infection occurs. Objective The present study was done to find the histopathological alterations in the placenta of SARS-CoV-2 positive pregnancies with either no symptoms or mild coronavirus disease (COVID)-19 related symptoms and its association with neonatal outcomes. Study design This was a prospective analytical study. Twenty seven asymptomatic or mildly symptomatic SARS-CoV-2 positive pregnant women with a singleton pregnancy delivered between 1st July 2020 and 15th September 2020, were included as cases. An equal number of SARS-CoV-2 negative singleton pregnancies matched for maternal and gestational age during the same period were included as controls. After delivery the histopathological examination of the placenta of these women was done and the findings recorded on a predesigned proforma based on the Amsterdam consensus criteria for evidence of maternal and fetal vascular malperfusion changes. Results The baseline characteristics were comparable between the cases and controls. The following features of maternal vascular malperfusion (MVM) were significantly higher in the placentae of COVID-19 positive pregnancies: retroplacental hematomas (RPH), accelerated villous maturation (AVM), distal villous hyperplasia (DVH), atherosis, fibrinoid necrosis, mural hypertrophy of membrane arterioles (MHMA), vessel ectasia and persistence of intramural endovascular trophoblast (PIEVT). Fetal vascular malperfusion (FVM) significantly associated with the positive pregnancies were chorioangiosis, thrombosis of the fetal chorionic plate (TFCP), intramural fibrin deposition (IMFD) and vascular ectasia. Additionally, perivillous fibrin deposition was also significantly higher in the placentae of cases. The percentage of spontaneously delivered women was comparable in the two groups. The sex and weight of the newborn and the number of live births were comparable between the two groups. Conclusions Asymptomatic or mildly symptomatic SARS-CoV-2 positive pregnant women, with otherwise uncomplicated pregnancies, show evidence of placental injury at a microscopic level. Similar findings have been demonstrated in other studies too. This placental injury apparently does not lead to poor pregnancy outcomes. The extent of this injury in symptomatic cases of COVID-19 pregnancies and its consequences on the outcomes need to be analysed.