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Introduction: While many placental lesions have been identified and defined, the significance of multiple overlapping lesions has not been addressed. The purpose of our analysis was to evaluate overlapping patterns of placental pathology and determine meaningful phenotypes associated with adverse birth outcomes., Methods: Placental pathology reports were obtained from a single hospital between 2009 and 2018. Placental lesions were grouped into four major categories: acute inflammation (AI), chronic inflammation (CI), maternal vascular malperfusion (MVM), and fetal vascular malperfusion (FVM). Within each category, lesions were classified as not present, low grade or high grade. Combinations of pathologies were evaluated in relation to preterm birth (<37 weeks) and small for gestational age (SGA) infant (birthweight <10th percentile)., Results: During the study period, 19,027 placentas were reviewed by pathologists. Results from interaction models indicate that MVM and MVM in combination with CI and/or FVM are associated with the greatest odds of SGA infant and PTB. When incorporating grade, we identified 21 phenotype groups, each with characteristic associations with the SGA infant and patterns of PTB., Discussion: We have developed a comprehensive and meaningful placental phenotype that incorporates severity and multiplicity of placental lesions. We have also developed a web application to facilitate phenotype determination (https://placentaexpression.shinyapps.io/phenotype).

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.

Chronic intervillositis of unknown etiology (CIUE) is a rare placental disease characterized by intervillous infiltration of maternal macrophages and associated with poor pregnancy outcomes and a high risk of recurrence in subsequent pregnancies. Its pathophysiology remains unclear and prognostic factors have not yet been established. In addition, clear relationships between the histologic extent of lesions and the severity of perinatal outcomes have not been demonstrated. Our objectives were to validate a CIUE classification system based on the gradation of macrophagic infiltration of the intervillous space, and to attempt to correlate these results with perinatal outcomes. For this multicenter retrospective study, 3 pathologists reviewed all cases diagnosed with "intervillositis" between 1997 and 2018. Confirmed CIUE cases were semiquantitatively graded based on the percentage of macrophagic infiltrate in the intervillous space: grade 1 (5% to 10%), grade 2 (10% to 50%), and grade 3 (>50%). Multiple pregnancies and pregnancies with medical follow-up completed outside of the study centers were excluded. In total, 122 cases of CIUE in 102 patients were included in the study. Microscopic classification based on one criterion was easy to perform, and interobserver correlation was good. Grade 3 infiltration was strongly associated with poor perinatal outcomes and fetal growth restriction (P<0.0001). After delivery, only 16.1% of newborns from the grade 3 CIUE group were alive, compared with 59% from the grade 2 and 86.5% from the grade 1 group (P=0.0002). Recurrence risk was associated with CIUE gradation of the index case (P=0.004), with 95% of recurrent CIUE cases being from patients with grades 2 and 3 CIUE. In this study, conducted with the largest CIUE cohort to date, a classification based only on the degree of macrophagic infiltration of the intervillous space was validated, and this classification was shown to be strongly associated with poor perinatal outcomes and risk of recurrence.

Objective Morbidly adherent placenta (MAP) is a clinical condition the prevalance of which is steadily increasing. It is described as the invasion of the placenta into the uterine wall through the myometrium and beyond. Several studies have shown that intercellular adhesion molecule-1 (ICAM-1) increases the invasion capability of tumor cells and placental cells. In our study, we investigated the expression of ICAM-1 in MAP cases. Methods This is a prospective case-control study. Eighty-nine patients who were diagnosed with MAP and 96 patients, without adherent placenta, as a control group were included in the study. ICAM-1 staining was examined by immuno-histochemical staining in placental samples. Results Of the 89 patients in the MAP group, 72 (80.8%) showed positive staining, while 26 (27%) did so in the control group. ICAM-1 positive staining in the MAP group was statistically significantly higher (P=0.03). Conclusion This is the first study investigating the relationship between MAP and ICAM-1 in the literature. In our study, we showed that ICAM-1 expression increased in the MAP group.

Until delivery, the placenta plays an important mediator role between mother and fetus. This unit is affected by peristatic conditions, such as acute or chronic maternal diseases, malnutrition, drugs, and others. But also genetic factors and fetal malformations due to embryonic developmental disorders may contribute to macroscopically visible changes and functional disorders of the placenta. In a constantly ongoing progress of maturation, the placenta records and saves changes due to fetal distress partly as maturation disorders. Understanding of maturation disorders might, therefore, be an important contribution to a better understanding of influences on villous differentiation and might improve follow up and fetal outcome to reduce recurrence risk. However, an internationally unified classification system of maturation disorders does not exist. In this review, terminology, trials, and classifications of villous maturation disorders are summed up and compared, to pinpoint the need of agreement on an international unified and reproducible classification of maturation disorders., (© 2018 APMIS. Published by John Wiley & Sons Ltd.)

Aim: Placental invasion is a life-threatening obstetric complication. The aim of this study was to identify the optimal ultrasonographic (US) criteria for placenta increta/percreta in order to improve diagnostic accuracy., Methods: In a retrospective diagnostic study, all 116 patients at Peking University Third Hospital who had been diagnosed with placental invasion from October 2006 to October 2013 were included. Depending on their clinical and/or histopathological diagnosis, the study was divided into two groups: the Placenta Accreta Group (63 cases) and the Placenta Increta/Percreta Group (53 cases). The US images were analyzed for differences between placenta accreta and placenta increta/percreta., Results: The sonographic criteria found to have predictive value for placenta increta/percreta using a regression model were: deficiency of retroplacental sonolucent zone and/or segmental retroplacental myometrial thinning less than 1 mm, multiple vascular lacunae presenting a 'moth hole' appearance, and placenta previa. Using a cut-off point of 0.589, the sensitivity and specificity were 81.1% and 77.8%, respectively. The area under the receiver-operator curve was 0.848 (P < 0.001)., Conclusion: US diagnosis not only allows the detection of placental invasion, but also facilitates preliminary classification. The three aforementioned criteria facilitate the identification of placenta increta/percreta for precise and comprehensive clinical decision-making., (© 2017 Japan Society of Obstetrics and Gynecology.)

Background: Stillbirth is the mayor contributor to perinatal mortality., Aim: To report a system for classification of fetal deaths., Material and Methods: Retrospective cohort study of 29,916 births with 258 fetal deaths that occurred in a public hospital. Data were obtained from audit reports of stillbirths. The method for classification “obstetric condition relevant to the death” was applied, based on obstetric and placental pathological findings analyzed exclusively by a single obstetrician and a single pathologist., Results: Ninety two percent of obstetric conditions causing fetal death were identified. The most commonly reported were ascending bacterial infection in 26%, congenital anomalies in 19%, arterial hypertension in 12% and placental pathology in 12%. Fetal growth restriction was identified in 50% of stillbirths. Ninety percent were secondary to a primary obstetric condition and 10% had an unexplained cause. Placental abruption as the final cause of fetal death was identified in 60% of cases with arterial hypertension, 43% of cases with placental pathology and 37% of ascending infections. Fetal deaths occurred during pregnancy in 82% of cases and during labor in 17%. Intrapartum asphyxia occurred in 0.8% of stillbirths and presented in term pregnancies., Conclusions: The “obstetric condition relevant to the death” method for classification of fetal death is effective to identify the originating obstetric cause of stillbirth and reduces the impact of fetal growth restriction and intrapartum asphyxia as the leading causes of death.

Placental pathology can be useful in a variety of ways including immediate diagnosis of important conditions affecting the mother or infant, identifying conditions that are likely to recur in subsequent pregnancies, separating clinical syndromes into distinct pathological phenotypes for further investigation, and uncovering the underlying cause of unexpected adverse outcomes. Classification of placental lesions has evolved from being a purely descriptive exercise through a stage in which the major pathophysiological processes such as disorders of maternal implantation and the amniotic fluid infection syndrome were first described to a recently proposed comprehensive classification system that includes all of the major maternal and fetal vascular and infectious and idiopathic/immune inflammatory processes (Amsterdam Placental Workshop Group). Implementation of this unified system with reproducible grading and staging should help establish evidence-based recommendations for placental submission and facilitate progress in studying the pathogenesis, diagnosis, and treatment of obstetric disorders with an underlying placental etiology., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To determine the opinion of clinical obstetricians regarding interpretation of placental reports, including a recently proposed Norwegian classification system., Methods: Paper and online surveys were circulated to practicing obstetricians in Ireland. Data on clinician experience, clinical workload, and exposure to placental pathology reporting were collated. Additionally, clinicians' opinions regarding the Norwegian classification system were sought. Statistical analysis was performed using Statsdirect version 2.7.8., Results: Sixty-two practicing clinical obstetricians completed the survey. Overall, 47 (75.8%) respondents had at least 5 years of experience in clinical obstetrics. The population surveyed had a high level of clinicopathologic exposure, with 55 (88.7%) regularly attending a perinatal morbidity conference and 57 (91.9%) reading placental pathology reports. A significantly higher proportion of experienced clinicians read placental pathology reports (46/47 [97.9%]) compared with clinicians with less experience (11/15 [73.3%]; P=0.01). Overall, 51 (82.3%) obstetricians believed that introduction of the Norwegian classification would improve interpretation of placental findings; this high acceptance rate was similar for both experienced and less experienced clinicians (P>0.99)., Conclusion: The Norwegian classification system is a clinician-friendly system for placental pathology reporting., (Copyright © 2013 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: obstetric haemorrhage remains a significant cause of maternal morbidity and mortality worldwide and is significant in terms of patient safety and quality of care. One drastic outcome of haemorrhage is the need for peripartum hysterectomy. A classification system that can be used to audit severe events such as peripartum hysterectomy would be a useful adjunct to patient safety systems, but it would need to account for pre-existing risk factors, such as previous caesarean section. One system that accounts for important risk factors is the Robson Ten Group Classification System (TGCS). The aim of this study was to examine whether the TGCS could be extended in a novel way to classify who required peripartum hysterectomy., Setting: population-based matched case-control study data from the UK Obstetric Surveillance System was used. All eligible UK hospitals participated., Participants: women who underwent peripartum hysterectomy between February 2005 and February 2006 and their matched controls., Methods: cases and controls were categorised using the TGCS. The odds of having a peripartum hysterectomy in each classification group were calculated using logistic regression. An adjusted analysis was undertaken controlling for potential confounders., Findings: 307 of the 315 women who had a peripartum hysterectomy were classified into one of the 10 groups; 606 of the 608 control women were classified. Women who underwent a peripartum hysterectomy were predominantly from the more complex classification groups. After adjusting for age, ethnicity and socio-economic status, the groups with an increased odds of peripartum hysterectomy were those who had a previous caesarean section., Conclusions: the TGCS can be used in a novel way, that is, to examine an outcome other than caesarean section, and could be part of a new system to monitor patient safety. Population-based data were used as an example of how an existing classification system could be used in a different way from that for which it was created, and could make comparisons across institutions and countries while adjusting for case mix in a simple manner. The TGCS may not necessarily be a useful way to monitor other events in childbirth. Further work is needed to develop other classification systems which could be used as a benchmarking tools to monitor patient safety in maternity care., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The differential diagnosis of villous forms of gestational trophoblastic disease (GTD) includes hydropic abortion, complete and partial hytatidiform mole and placental mesenchymal dysplasia. In addition to histologic criteria, p57(KIP2) immunohistochemistry might be helpful. Choriocarcinoma represents the most immature form of GTD. This and downregulation of HSP-27 might contribute to the high chemosensitivity, compared to placental site (PSTT) and epitheloid trophoblastic tumor (ETT). Within the differential diagnosis of the non-villous forms of GTD an algorithmic approach of immunohistochemistry is very helpful. With an incidence of 1.6% of all abortions within the first trimester the exaggerated placental site reaction (EPS) is rare. There is no molecular indication that the EPS represents a precursor lesion of PSTT. The morphologic prediction of the behaviour of PSTT is not well established. Factors which might be associated with adverse outcome are age >35 years, interval since last pregnancy >2 years, growth outside the uterus, deep myometrial invasion, destructive growth, extensive coagulative necrosis, presence of cells with clear cytoplasm, high mitotic rate and a Ki-67 labeling index >50%. Recent molecular data suggest a neoplastic transformation of (cyto-) trophoblastic stem cells, within the pathogenesis of (non-villous) GTD. The detection of target molecules for a targeted therapy is currently irrelevant.

Different classification systems for the cause of intra-uterine fetal death (IUFD) are used internationally. About two thirds of these deaths are reported as unexplained and placental causes are often not addressed. Differences between systems could have consequences for the validity of vital statistics, for targeting preventive strategies and for counselling parents on recurrence risks. Our objective was to compare use of the Tulip classification with other currently used classification systems for causes of IUFD. We selected the extended Wigglesworth classification, modified Aberdeen and the classifications by Hey, Hovatta, de Galan-Roosen and Morrison. We also selected the ReCoDe system for relevant conditions, comparable to contributing factors in the Tulip classification. Panel classification for 485 IUFD cases in the different systems was performed by assessors after individual investigation of structured patient information. Distribution of cases into cause of death groups for the different systems varied, most of all for the placental and unknown groups. Systems with a high percentage of cases with an unknown cause of death and death groups consisting of clinical manifestations only are not discriminatory. Our largest cause of death group was placental pathology and classification systems without placental cause of death groups or minimal subdivision of this group are not useful in modern perinatal audit as loss of information occurs. The most frequent contributing factor was growth restriction. This illustrates the vital role of the placenta in determination of optimal fetal development. In the Tulip classification, mother, fetus and placenta are addressed together. The system has a clear defined subclassification of the placenta group, a low percentage of unknown causes and is easily applied by a multidisciplinary team. A useful classification aids future research into placental causes of IUFD.

In areas of high malaria endemicity, women have increased susceptibility to malaria during pregnancy characterized by placental parasitemia. Our previous studies in children with malaria demonstrate that suppression of leukocyte-derived prostaglandin-E(2) (PGE(2)) is associated with enhanced pathogenesis. To examine the role of PGE(2) as an immunoregulatory molecule in placental malaria, PGE(2) was determined in cultured intervillous blood mononuclear cells (IVBMCs) from aparasitemic and parasitemic women. PGE(2) was significantly lower in parasitemic women at all gravidities. Women with a positive antenatal peripheral parasitemia who were negative for placental malaria (PM) at term produced the highest PGE(2) levels. Suppression of PGE(2) was associated with increasing amounts of hemozoin (malarial pigment) acquired during the natural infection. PGE(2) regulatory cytokines, tumor necrosis factor (TNF)-alpha and interleukin (IL)-10, were non-significantly increased in IVBMC containing an intermediate amount of hemozoin and significantly suppressed in IVBMC with high levels of hemozoin. Results presented here show that in vivo acquisition of high levels of hemozoin by IVBMC leads to decreased synthesis of PGE(2), IL-10, and TNF-alpha.

Our objective was to use factor analysis as a data reduction tool to organize a large number of placental pathologic features into useful aggregates. We examined 1146 placentas of live-born infants with a birth weight of 500-1500 g. We then conducted analyses of pairs of characteristics and multiple characteristics to identify "associated groups" and "factors," respectively. We found an associated group and factor that had placental features associated with acute inflammation and another associated group and factor that had features associated with vasculopathy. Acute umbilical vasculitis had the strongest correlation with other features of the acute inflammation associated group and factor. Gross evidence of acute inflammation (opacification and green appearance of membrane) was eliminated in the reduction from associated group to factor. Infarcts and syncytial knots were strongly dissociated with features of acute inflammation. The multiple pathologic features of the very low birthweight placenta can be aggregated into two associated groups or two factors. Lack of membrane opacification cannot be used as a criterion for declining microscopic examination. The absence of infarcts and syncytial knots should prompt a search for features of acute inflammation. If a placenta has two or more findings from the acute inflammation factor or the vasculopathy factor, it is unlikely to demonstrate features from the other factor.

The interobserver reliability of histopathological features in the placenta was examined. Two pathologists independently reviewed slides from 250 placentas. The pathologists were given a morphological description of the placenta, but were blinded to clinical status, gestational age and original diagnoses. A protocol for diagnosis and grading of features was first developed and pilot-tested. Definitions and criteria were refined and elaborated. A range of features was examined including inflammatory lesions, features indicative of reduced uterine blood flow and other miscellaneous histopathological changes. Weighted kappa coefficients were calculated. The effect of multiple features on reliability was examined by stratifying on the presence of a second feature and calculating stratum-specific kappa coefficients. Results indicated good to excellent agreement for diagnoses of chorioamnionitis, cord vasculitis, funisitis and villitis (kappa(w) range 0.70-0.83). Agreement between observers was more variable for the diagnosis of reduced uterine blood flow states. Excellent agreement was observed for the diagnosis of meconium staining of the placenta (kappaw = 0.79). In general, lower levels of agreement were observed for features in the presence of a second feature. Reproducible measures are a prerequisite to using placental histopathology for diagnostic and prognostic information. This study demonstrated reliable placental diagnoses can be achieved through a standardised protocol.

Pregnant women are more likely to contract malaria than their non-pregnant counterparts. The aim of this study was to develop a simple classification system for the histopathological diagnosis of placental malaria infection applicable to placentas collected in field conditions. The placentas were classified into four groups depending on the presence and distribution of parasites and malaria pigment: active infection, active-chronic infection, past-chronic infection, not infected. The frequency of parasitized placentas (26.4%) was in keeping with the prevalence of placental parasitaemia documented in epidemiological studies. An additional 29.8% placentas showed pigment in fibrin only, indicating past-chronic infection. Chronic placental malaria infection was most common in primigravidae, possibly reflecting ineffective clearance of parasites from the placenta. Seasonal fluctuations between infection categories support progression of placental infection with delayed clearance of pigment from fibrin. The proposed classification system has allowed diagnosis of different categories of placental malaria infection by two independent observers. A standardized method of diagnosis may enhance understanding of placental pathology and reduced birth weight in malaria infection during pregnancy.

Malaria in pregnancy is associated with reduced birth weight. Most pathological studies of placental malaria infection have focused on severe Plasmodium falciparum infection. In the present study of 121 placentas delivered in a rural area of The Gambia, malaria infection was diagnosed in tissue sections using a simple classification system and severity of pathology was ranked semiquantitatively. Deposition of malaria pigment in circulating cells was associated with active infections whereas pigment in fibrin was a feature of active-chronic infections. Primigravidae had higher levels of pigment at all sites, although these observations were not always significant. Thickening of the trophoblast basement membrane occurred in all infection categories but fibrinoid necrosis of chorionic villi was a feature of active and active-chronic infection. Both birth weight and placental weight were increased in infected placentas but widespread trophoblast basement membrane thickening was associated with decreased birth weight. Both birth weight and placental weight decreased with increased fibrinoid necrosis and cytotrophoblast prominence but the results were not significant. By this approach it has been possible to correlate placental pathology with different infection categories and to analyse the pathological features associated with decreased birth weight.

Vascular lesions, most often mediated by thrombi, are second only to infections as a cause of fetal injury in the later weeks of pregnancy. In our experience many pathologists who examine placentas fail to conduct a proper search for vascular lesions and some even fail to recognize those exposed by their examination. This review is intended to define the typical clinical background or circumstances that suggest the presence of significant vascular problems, to define techniques calculated to display them well, and to identify criteria for diagnosis. Further research is needed to evaluate the prevalence of maternal and fetal hypercoagulable states and thrombi as a cause of fetal injury.

Existing morphologic classifications of placenta immaturity are analyzed on the basis of stages of the placenta villi normal histogenesis. 6 variants of its pathologic immaturity are distinguished: mesenchymal, embryonal, intermediate and differentiated villi, variant of chaotic sclerotized villi, variant of precocious villi maturation. These variants result in the foetal hypotrophy or its death at all stages of its antenatal development. 2 variants comprise a relative placenta immaturity: variant of a dissociated development of kotiledons and that of deficiency of terminal specialized villi. They occur in both risk groups of newborns and in normal pregnancy. Revealing of the above variants allows one to determine the time of the antenatal damage of developing placenta.