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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.

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.

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.

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.

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.

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.

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.

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.

The incidence of placenta accreta spectrum (PAS) is increasing and will become more commonly encountered by obstetric anaesthetists in the elective and emergency settings. Significant maternal and neonatal morbidity is associated with these disorders, and hence it is important for anaesthetists to have early involvement in perioperative planning. Major haemorrhage should be anticipated and requires robust perioperative preparation including Patient Blood Management (PBM) and use of intraoperative strategies for haemorrhage management wherever possible. Several institutions have demonstrated good outcomes with regional anaesthesia alone, but the choice of anaesthetic technique requires individualised planning considering patient, anaesthetic and surgical factors. Optimisation of postoperative analgesia needs additional consideration; it is key to good recovery, minimising the impact on quality of life and reducing the risk of persistent post-surgical pain. Further research is required to ascertain the optimal multi-modal analgesic regime including the role of peripheral nerve blockade.

Objectives To determine the causes of fetal death among the stillbirths using two classification systems from 22 weeks of gestation in a period of three years in high-risk pregnancies. This is a retrospective observational study. Methods The National Institute of Perinatal Health in Mexico City is a Level 3 care referral center attending high-risk pregnancies from throughout the country. The population consisted of patients with fetal death during a three-year period. Between January 2016 and December 2018, all stillbirths were examined in the Pathology Department by a pathologist and a medical geneticist. Stillbirth was defined as a fetal death occurring after 22 weeks of gestation. Results Main outcome measures: Causal analysis of fetal death using the International Statistical Classification of Disease and Related Health Problems-Perinatal Mortality (ICD-PM) and initial causes of fetal death (INCODE) classification systems. A total of 297 stillborn neonates were studied. The distribution of gestational age in antepartum stillbirths (55.2%) showed a bimodal curve, 36% occurred between 24 and 27 weeks and 32% between 32 and 36 weeks. In comparison, the majority (86%) of intrapartum deaths (44.8%) were less than 28 weeks of gestation. Of the 273 women enrolled, 93 (34%) consented to a complete fetal autopsy. The INCODE system showed a present cause in 42%, a possible cause in 54% and a probable cause in 93% of patients. Conclusions The principal causes of antepartum death were fetal abnormalities and pathologic placental conditions and the principal causes of intrapartum death were complications of pregnancy which caused a premature labor and infections.

Normal placental development and function is of key importance to fetal growth. Conversely aberrations of placental structure and function are evident in pregnancy complications including fetal growth restriction (FGR) and preeclampsia. Although trophoblast turnover and function is altered in these conditions, their underlying aetiologies and pathophysiology remains unclear, which hampers development of therapeutic interventions. Here we review evidence that supports a role for estrogen related receptor-gamma (ESRRG) in the development of placental dysfunction in FGR and preeclampsia. This relationship deserves particular consideration because ESRRG is highly expressed in normal placenta, is reduced in FGR and preeclampsia and its expression is altered by hypoxia, which is thought to result from deficient placentation seen in FGR and preeclampsia. Several studies have also found microRNA (miRNA) or other potential upstream regulators of ESRRG negatively influence trophoblast function which could contribute to placental dysfunction seen in FGR and preeclampsia. Interestingly, miRNAs regulate ESRRG expression in human trophoblast. Thus, if ESRRG is pivotally associated with the abnormal trophoblast turnover and function it may be targeted by microRNAs or other possible upstream regulators in the placenta. This review explores altered expression of ESRRG and upstream regulation of ESRRG-mediated pathways resulting in the trophoblast turnover, placental vascularisation, and placental metabolism underlying placental dysfunctions. This demonstrates that the ESRRG pathway merits further investigation as a potential therapeutic target in FGR and preeclampsia.

Placenta accreta spectrum disorders are among the leading causes of maternal morbidity and mortality and their prevalence is likely to increase in the future. The risk of placenta accreta spectrum disorders is highest in cases of placenta previa overlying a previous cesarean section scar. Few studies have evaluated placenta accreta spectrum disorders in Portugal. The aim of this study was to review the cases of placenta accreta spectrum overlying a cesarean section scar managed in a Portuguese tertiary center over the last decade.Retrospective, cross-sectional study, with data collected from hospital databases. Only cases with histopathological confirmation of placenta accreta spectrum were included.During the study period, 15 cases of placenta accreta spectrum overlying a cesarean section scar were diagnosed (prevalence 0.6/1000). All cases were diagnosed antenatally. A transverse cesarean section was present in all cases; 13 were managed by a scheduled multidisciplinary approach, while two required emergent management. Total or subtotal hysterectomy was performed in 12 cases. There were no cases of maternal or neonatal death. Histopathological evaluation confirmed nine cases of placenta accreta, three cases of placenta increta and three cases of placenta percreta.Early antenatal diagnosis is important for a programmed multidisciplinary management of these cases, which may reduce potential morbidity and mortality and ensure better obstetric outcomes.This case series of placenta accreta spectrum overlying a cesarean section scar reports the reality of a tertiary-care perinatal center in Portugal, in which no maternal or neonatal mortality due to placenta accreta spectrum was registered over the last decade; this may be attributed to prenatal diagnosis and a coordinated multidisciplinary team approach.Introdução: O acretismo placentário está entre as principais causas de morbilidade e mortalidade materna, sendo provável que a sua prevalência venha a aumentar. O risco é máximo em casos de placenta prévia sobre cicatriz de cesariana. Existem poucos estudos sobre esta realidade em Portugal. O objetivo deste estudo foi rever os casos de acretismo placentário sobre cicatriz de cesariana prévia, ocorridos ao longo da última década num centro terciário português. Material e Métodos: Estudo retrospetivo, transversal, com dados recolhidos de bases de dados hospitalares; foram incluídos apenas casos com confirmação histopatológica de acretismo placentário. Resultados: Foram diagnosticados 15 casos durante o período do estudo (prevalência 0,6 / 1000). Todos os casos foram diagnosticados durante a gravidez. Em todos os casos foi realizada cesariana; 13 foram agendadas com base numa abordagem multidisciplinar, e duas foram emergentes. Em 12 casos foi realizada histerectomia total ou subtotal. Não se registaram casos de mortalidade materna ou neonatal. O estudo histopatológico confirmou nove casos de placenta acreta, três de placenta increta e três de placenta percreta. Discussão: O diagnóstico pré-natal precoce é fundamental para um planeamento multidisciplinar que permita reduzir a potencial morbilidade e mortalidade e garantir melhores desfechos obstétricos. Conclusão: Esta série de casos de acretismo placentário sobre cicatriz de cesariana relata a realidade de um centro de assistência perinatal terciário em Portugal, no qual não se registou mortalidade materna ou neonatal ao longo da última década; esta situação é atribuível ao diagnóstico pré-natal eficiente e à abordagem coordenada por uma equipa multidisciplinar.

BACKGROUND General and allied health practitioners caring for pregnant women and neonates often encounter placental histopathological reports with esoteric diagnostic entities of contentious clinical significance such as chronic villitis, massive perivillous fibrin deposition, chronic histiocytic intervillositis, materno-fetal vascular malperfusion and delayed villous maturation. These lesions may recur in subsequent pregnancies. OBJECTIVE The aim of this article is to review the status quo of placental pathology and research with an emphasis on clinical management implications for some of these most often reported but less understood recurrent clinicopathological entities of the placenta. An update on the current nomenclature and classification of placental conditions is also provided. DISCUSSION When reported adequately and interpreted correctly, placental histopathology provides useful information that may explain adverse pregnancy outcomes and guides further management of the mother, newborn or future pregnancy. Empirical treatments for immune-mediated placental conditions with prednisolone, aspirin, heparin and intravenous immunoglobulins have been reported. However, evidence-based guidelines for management of these conditions are lacking, and more research, including clinical trials, is in order.

Placental ischemia in preeclampsia (PE) results in hypertension and intrauterine growth restriction (IUGR). Stimulation of soluble guanylate cyclase (sGC) reduces blood pressure in the clinically relevant reduced uterine perfusion pressure (RUPP) rat model of PE, implicating involvement in RUPP-induced hypertension. However, the contribution of sGC in the development of IUGR in PE is not known. Thus, this study demonstrated the efficacy of Riociguat, an sGC stimulator, in IUGR reversion in the RUPP rat model of PE, and tested the hypothesis that improvement in fetal weight occurs in association with improvement in placental perfusion, placental morphology, and placental nutrient transport protein expression. Sham or RUPP surgery was performed at gestational day 14 (G14) with administration of vehicle (Sham or RUPP) or the sGC stimulator (Riociguat, 10 mg/kg/day sc; sGC-treated) until G20. Fetal weight was reduced ( P = 0.004) at G20 in RUPP but not in sGC-treated RUPP compared with Sham, the control group. At G20, uterine artery resistance index (UARI) was increased ( P = 0.010) in RUPP, indicating poor placental perfusion; proportional junctional zone surface area was elevated ( P = 0.035), indicating impaired placental development. These effects were ameliorated in sGC-treated RUPP. Placental protein expression of nutrient transporter heart fatty acid-binding protein (hFABP) was increased ( P = 0.008) in RUPP but not in sGC-treated RUPP, suggesting a compensatory mechanism to maintain normal neurodevelopment. Yet, UARI ( P < 0.001), proportional junctional zone surface area ( P = 0.013), and placental hFABP protein expression ( P = 0.008) were increased in sGC-treated Sham, suggesting a potential adverse effect of Riociguat. Collectively, these results suggest sGC contributes to IUGR in PE.

Aim This study aimed to evaluate the clinical features and pregnancy outcomes of placental mesenchymal dysplasia (PMD) in Japan. Methods We requested detailed clinical information and placental tissue of PMD cases in 2000-2018 from Japanese facilities with departments of obstetrics and gynecology and analyzed the pregnancy course and neonatal outcomes. Results We collected 49 cases of PMD. Of 18 patients with measured maternal serum alpha-fetoprotein (MSAFP) levels, 15 (83.3%) had elevated levels. Maternal serum human chorionic gonadotropin (MShCG) levels were transiently elevated in five (17.8%) of 28 patients. Forty-seven patients continued their pregnancies. All pregnancies were singleton and 40 (85.1%) were associated with adverse events including fetal growth restriction (FGR), threatened premature delivery, fetal demise, and hypertensive disorder of pregnancy in 34 (72.3%), 14 (29.8%), eight (17.0%), and six (12.8%) patients, respectively. Of 47 infants, there were eight stillbirths. There were 40 (85.1%) female infants, and eight (17.0%) had Beckwith-Wiedemann syndrome. Of 39 live births, 23 (59.0%) were associated with premature induction of labor or cesarean section for obstetric indications related to FGR. Eighteen (46.2%) neonates had complications. PMD-affected placentas were pathologically heterogeneous in both grossly PMD-affected and non-affected areas. Conclusions Our study included the largest number of PMD cases with detailed clinical information. PMD is a high-risk condition for both the mother and the child. Elevated MSAFP levels with normal MShCG levels indicate PMD. Conventional perinatal management of FGR in Japan might be effective in reducing the fetal mortality rate.

Objectives Spontaneous preterm labor is an obstetrical syndrome accounting for approximately 65–70% of preterm births, the latter being the most frequent cause of neonatal death and the second most frequent cause of death in children less than five years of age worldwide. The purpose of this study was to determine and compare to uncomplicated pregnancies (1) the frequency of placental disorders of villous maturation in spontaneous preterm labor; (2) the frequency of other placental morphologic characteristics associated with the preterm labor syndrome; and (3) the distribution of these lesions according to gestational age at delivery and their severity. Methods A case-control study of singleton pregnant women was conducted that included (1) uncomplicated pregnancies (controls, n=944) and (2) pregnancies with spontaneous preterm labor (cases, n=438). All placentas underwent histopathologic examination. Patients with chronic maternal diseases (e.g., chronic hypertension, diabetes mellitus, renal disease, thyroid disease, asthma, autoimmune disease, and coagulopathies), fetal malformations, chromosomal abnormalities, multifetal gestation, preeclampsia, eclampsia, preterm prelabor rupture of the fetal membranes, gestational hypertension, gestational diabetes mellitus, and HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome were excluded from the study. Results Compared to the controls, the most prevalent placental lesions among the cases were the disorders of villous maturation (31.8% [106/333] including delayed villous maturation 18.6% [62/333] vs. 1.4% [6/442], q Conclusions Disorders of villous maturation are present in nearly one-third of the cases of spontaneous preterm labor.

Placental villitis is characterized by the presence of inflammatory infiltrate in the placental villous. The objective of this study was to characterize in villitis of unknown etiology (VUE) of the human placentas the subpopulation of M1, important effector cells, and M2 macrophages, immunoregulatory cells.Sixteen cases of VUE and three control placentas were examined using immunohistochemistry with antibodies for CD3, CD68, CD11c, and CD163.CD11c appeared predominantly in the inflamed villi when compared to the normal areas (We conclude that the almost exclusive presence of M1 macrophages in the inflamed areas suggests the influence of these cells in the pathogenesis VUE. The greater amount of M2 in villitis and normal areas suggests a possible immunoregulatory mechanism of the inflammatory process in VUE.

Background: Placental hepatic heterotopia is a benign lesion with unclear histogenesis hypothesized to be of hepatocytic differentiation of yolk sac elements. Of the 14 hepatic heterotopia cases pr...

From the start of the global COVID‐19 pandemic, a lot of attention has been focused on how SARS‐CoV‐2 (severe acute respiratory syndrome coronavirus type 2) impacts pregnancy. The current evidence suggests that pregnant women may be at an increased risk for more severe COVID‐19 disease and an increase in maternal death rate has been observed worldwide (1,2).

Maternal floor infarction (MFI) and massive perivillous fibrin deposition (MPFD) are uncommon, related placental conditions secondary to trophoblastic cell damage. The etiology is unknown but MPFD/...

Bacterial placentitis in horses commonly results in abortion, premature birth or compromised neonatal foal health. Although mycobacterial infections are generally uncommon in horses, 10 equine abortion cases caused by Mycobacterium avium subsp. hominissuis (MAH) infections occurred between 2018 and 2019 in Japan. They occurred on seven Thoroughbred horse farms in the Hidaka district of Hokkaido, but direct contact among the mares on different farms was not recorded. Most cases were characterized by extensive pathological lesions of the placenta, which are not typical in cases of common pathogenic bacteria such as Streptococcus zooepidemicus and Escherichia coli. All abortions featured white–yellow exudates on the surface of the placenta. Mycobacterial granuloma formations were histologically found in the placenta and fetal organs, and acid‐fast bacteria were isolated from the placenta, fetal samples (heart, lung, liver, kidney, spleen and stomach contents) or uterine lavage fluid. The greatest number of bacteria was isolated from necrotic lesions on the placenta, which could be an important site for bacterial isolation in mycobacterial equine abortions. The isolates were identified as MAH based on internal genome sequences. In variable number tandem repeat analysis, all patterns of the strains were identical. Single nucleotide polymorphism analysis of the core genome grouped all strains in the II‐a/SC3 subcluster. Both results reveal that these strains share the same genetic background, suggesting that the horses had been infected by the same unknown contagious source., This article reports 10 equine abortions cases caused by Mycobacterial avium subsp. hominissuis infections. We confirmed the isolated strains shared the same genetic background, suggesting that the horses had been infected by the same contagious source.

Improved understanding of the molecular mechanisms underlying ascending equine placentitis holds the potential for the development of new diagnostic tools and therapies to forestall placentitis-induced preterm labor. The current study characterized the equine placental transcriptome (chorioallantois [CA] and endometrium [EN]) during placentitis (placentitis group, n = 6) in comparison to gestationally-matched controls (control group, n = 6). Transcriptome analysis identified 2953 and 805 differentially expressed genes in CA and EN during placentitis, respectively. Upstream regulator analysis revealed the central role of toll-like receptors (TLRs) in triggering the inflammatory signaling, and consequent immune-cell chemotaxis. Placentitis was associated with the upregulation of matrix metalloproteinase (MMP1, MMP2, and MMP9) and apoptosis-related genes such as caspases (CASP3, CASP4, and CASP7) in CA. Also, placentitis was associated with downregulation of transcripts coding for proteins essential for placental steroidogenesis (SRD5A1 and AKR1C1), progestin signaling (PGRMC1 and PXR) angiogenesis (VEGFA, VEGFR2, and VEGFR3), and nutrient transport (GLUT12 and SLC1A4), as well as upregulation of hypoxia-related genes (HIF1A and EGLN3), which could explain placental insufficiency during placentitis. Placentitis was also associated with aberrant expression of several placenta-regulatory genes, such as PLAC8, PAPPA, LGALS1, ABCG2, GCM1, and TEPP, which could negatively affect placental functions. In conclusion, our findings revealed for the first time the key regulators and mechanisms underlying placental inflammation, separation, and insufficiency during equine placentitis, which might lead to the development of efficacious therapies or diagnostic aids by targeting the key molecular pathways.Summary sentenceThis is the first study to characterize the equine placenta transcriptome to identify the key regulators and pathways underlying placental inflammation, separation, and insufficiency during the equine ascending placentitis.Graphical Abstract

In this paper we start illustrating our experience of multifocal chorangiomatosis with the newborn affected by massive umbilical vein thrombosis, disseminated intravascular coagulopathy and hydrops, going to a literature review of cases available.Our clinical case and the review of literature highlight how multifocal chorangiomatosis, within the three subgroups identified, is the rarer form with distinct placental features and the worst outcomes for neonates. No cases of multifocal chorangiomatosis have never been described prenatally and, for further studies, could be reasonable investigate the involvement of some growth factors like vascular endothelial growth factor and placental growth factor that could lead to a detection of a subgroup of patient at higher risk to manifest placental vascular lesions and the follow fetal and maternal complications.

Objective To analyze all the variables in women who received fibrinogen for postpartum hemorrhage (PPH) using hierarchical cluster analysis, to provide greater insight into the risk variables involved in these women. Methods This retrospective study of women with at least 500 mL of bleeding at birth or during the postpartum period and treated with fibrinogen was conducted at the Department of Obstetrics and Gynecology, Ataturk University School of Medicine from January 2013 to January 2018. Data on the women were obtained from medical records and various risk variables were recorded and analyzed using hierarchical cluster analysis. Results A total of 114 women with PPH were included in the study. Based on a dendrogram, three main clusters of similar quality variables were created: 1) gravida, parity, age, cervical/vaginal hematoma, laparotomy, hypogastric artery ligation, uterine artery embolization, uterine artery ligation, uterine atony, distance from outer center, lowest hemoglobin, preoperative platelets, endometritis, preoperative white blood cells; 2) lowest fibrinogen, highest fibrinogen, type of birth, placenta invasion anomaly, Bakri balloon tamponade, postpartum hysterectomy, preoperative activated partial thromboplastin time (APTT), preoperative international normalized ratio (INR), placental abruption, in-utero ex fetus; 3) postoperative APTT, postoperative INR, maternal mortality, erythrocyte transfusion, plasma transfusion, hospital stay time, disseminated intravascular coagulation/HELLP syndrome, highest hemoglobin, blood group, postoperative platelets, platelet transfusion, pre-eclampsia/eclampsia, fibrinogen extract. Conclusion According to the cluster analysis, we should keep fibrinogen extract in the foreground especially in the treatment of hemorrhage in patients with variable conditions. As a result, we can determine whether fibrinogen extract, which has a high economic cost, should be kept at each center. We can also direct which patient will be referred in accordance with the referral steps.

Objective The aim of the current review is to present a systematic evaluation of reported human placental findings in cases of zika virus (ZIKV) infection. Data sources We reviewed the EMBASE, PUBMED, and SCIELO databases until June 2019, without language restrictions. Selection of studies The search terms placenta AND zika virus were used. The inclusion criteria of the studies were studies that reported placental findings in humans. Experimental studies, reviews, notes or editorials were excluded. A total of 436 studies were retrieved; after duplicate exclusion, 243 articles had their titles screened, and 128 had their abstract read; of those, 32 were included in the final analysis (18 case reports, 10 case series, and 4 cohorts) Data collection We collected data concerning the author, year of publication, study design, number of participants, number of placental samples, onset of symptoms, perinatal outcomes, and main findings on histological analysis. Data synthesis The placental pathologic findings were described as mild and nonspecific, similar to those of other placental infections, including chronic placentitis, chronic villitis, increased Hofbauer cells, irregular fibrin deposits, increased mononuclear cells in the villus stroma, villous immaturity, edema, hypervascularization, stromal fibrosis, calcification, and focal necrosis of syncytiotrophoblasts. Conclusion Zika infection presents unspecific placental findings, similar to other infections in the toxoplasmosis, other agents, rubella, cytomegalovirus, and herpes (TORCH)group. Characterizing and standardizing placental findings after zika virus infection is key to understanding the mechanisms of congenital diseases. Resumo Objetivo O objetivo desta revisão é apresentar uma avaliação sistemática dos achados relacionados à infecção por zika vírus (ZIKV) na placenta humana. Fontes de dados As bases de dados EMBASE, PUBMED, e SCIELO foram pesquisadas, até junho de 2019, sem qualquer restrição de língua. Seleção dos estudos Os termos placenta E zika virus foram utilizados na busca. Foram incluídos estudos que reportassem achados placentários de infecção em seres humanos, enquanto estudos experimentais, revisões, notas e editoriais foram excluídos. Um total de 436 estudos foram identificados, e 243 tiveram seus títulos lidos após a exclusão de duplicatas. Cento e vinte e oito artigos tiveram seus resumos avaliados, dos quais 32 foram incluídos na análise final (18 relatos de caso, 10 séries de casos, e 4 estudos de coorte). Dados obtidos Foram pesquisados dados relativos ao autor, ano da publicação, desenho do estudo, número de participantes, número de amostras de placenta, início dos sintomas, desfechos perinatais, e principais achados histológicos. Síntese dos dados Os principais achados placentários descritos foram leves e inespecíficos, similares a outras infecções placentárias, incluindo infecção placentária crônica, vilosite crônica, aumento das células de Hofbauer, depósitos irregulares de fibrina, aumento das células mononucleares no estroma viloso, imaturidade vilosa, edema, hipervascularização, fibrose estromal, calcificação, e necrose focal dos sincicitrofoblastos. Conclusão Infecções por ZIKV têm achados placentários inespecíficos, similares aos de outras infecções do grupo toxoplasmose, rubéola, citomegalovírus e herpes (TORCH). Caracterizar e padronizar os achados placentários após infecção por ZIKV é fundamental para entender o mecanismo das infecções congênitas.

Placental chronic deciduitis is a lesion consistent with the presence of plasma cells within the placental basal plate. It could be associated with adverse pregnancy outcomes, including stillbirth.We retrospectively evaluated a cohort of 180 antepartum stillborn cases from singleton pregnancies, with the aim of investigating the clinical-histopathological relationship. Placental slides were reviewed following the standard protocol proposed by the "Amsterdam consensus statement".We observed an association between chronic deciduitis and lesions consistent with maternal vascular malperfusion, delayed villous maturation, villitis of unknown etiology and maternal autoimmunity.The observed clinical-histopathological associations suggest that an extensive maternal investigation could improve the comprehension of factors interfering with the placental development and the increasing risk of adverse pregnancy outcomes. HighlightsChronic deciduitis is associated with lesions consistent with maternal vascular malperfusionChronic deciduitis is associated with delayed villous maturationChronic deciduitis is associated with villitis of unknown etiologyChronic deciduitis is associated with maternal autoimmunity.

Background Rare nodules of heterotopic adrenocortical and hepatic tissue are reported in the placenta. A mechanism for adrenocortical tissue in the placenta has been perplexing, while hepatic tissue is generally considered related to yolk sac primordia. The clear cell morphology of these nodules is similar to the adrenal cortex of the adult; however, the fetal adrenal gland does not usually display clear cells. Methods We stained 9 placental nodules, histologically identical to “adrenocortical” heterotopia of the placenta, to determine whether adrenocortical differentiation could be confirmed. These cases include 3 archival cases initially diagnosed as “adrenocortical” heterotopia. Results Immunohistochemical staining with steroid factor-1 (SF-1), HepPar-1, and Arginase-1 showed that these nodules of clear cells are actually hepatic (SF-1 negative, HepPar-1, and Arginase-1 positive). PAS staining suggests that glycogen accumulation is responsible for the clear cytoplasm. In contrast, a nodule of adrenocortical heterotopia near the testis and the adrenal gland from a 38-week-old neonatal autopsy case confirm SF-1 reactivity as expected. Conclusion We propose that adrenocortical heterotopia in the placenta is a misnomer, and that these subchorionic nodules of clear cells demonstrate hepatic differentiation.

Third stage placental complications (TSPC) including partially or complete retained placenta, are a common obstetric complication. Previous studies have underlined risk factors for TSPC in heterogenous populations of women, whereas data regarding primigravid term women are scarce. We aimed to identify the factors associated with TSPC in this subset of parturients.A retrospective cohort study including all primigravid women who delivered vaginally a term, live-singleton neonate between 2011 and 2019. Women who underwent revision of the uterine cavity due to TSPC were compared with those who did not. Univariate and multivariate regression analyses were performed in order to identify the risk factors for TSPC.Overall, 16,867 deliveries met the study inclusion criteria. Of those, 1097 (6.5%) deliveries were complicated by TSPC. Women with TSPC were older (p 0.001) and with a higher proportion of lateral and fundal placental location (p 0.001). In a multivariate regression analysis, the following factors were positively independently associated with TSPC: maternal age (aOR [95% CI] 1.26 (1.17-1.36), p 0.001), the use of assisted reproduction technologies (aOR [95% CI] 1.26 (1.06-1.49), p = 0.007), preeclampsia (aOR [95% CI] 3.39 (1.89-6.10), p 0.001), thrombocytopenia (aOR [95% CI] 1.83 (1.34-2.48), p 0.001), oxytocin administration (aOR [95% CI] 1.29 (1.12-1.48), p 0.001) and longer second stage duration (aOR [95% CI] 1.03 (1.003-1.05), p = 0.02). Fetal male gender was negatively associated with TSPC (aOR [95% CI] 0.80 (0.70-0.92), p = 0.002).We have identified multiple independent risk factors for TSPC among primigravid women. This information can aid in patient counseling and delivery management in these subset of parturients.

Objective The placental development has been shown to be compromised in pregnancies affected by fetal congenital heart defects (CHD). This study aimed to investigate the frequency of complications related to utero-placental insufficiency in pregnancies with and without major CHD. Method This retrospective case-control study was conducted at a Fetal Echocardiography Center in Milan. The following outcomes were compared between the two groups: preeclampsia (PE), small for gestational age (SGA), placental disorders and preterm birth (PTB). The logistic regression analysis was adjusted for maternal age, parity, co-morbidities and mode of conception. Results The CHD group (n = 480) showed significantly increased incidence of PE (2.9% vs 0.9%; aOR, 6.50; 95% CI, 1.39-30.41; P = .017) as compared to the control group (n = 456). Placental disorders occurred more frequently in the CHD than in controls, but the increased risk showed only a borderline significance (4.5% vs 3.3%; aOR, 2.56; 95% CI, 0.99-1.02; P = .046). There was a significantly higher risk of SGA in CHD than in controls (8.7% vs 3.9%; aOR, 3.37; 95% CI, 1.51-7.51; P = .003). PTB occurred in 65/477 (13.6%) cases and in 39/447 (8.7%) controls (P = .022) (aOR, 2.17; 95% CI, 1.24-3.81; P = .007). Conclusion Major CHD are significantly associated with the risk of PE, SGA and PTB.

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

Low‐lying placentas, placenta previa and abnormally invasive placentas are the most frequently occurring placental abnormalities in location and anatomy. These conditions can have serious consequences for mother and fetus mainly due to excessive blood loss before, during or after delivery. The incidence of such abnormalities is increasing, but treatment options and preventive strategies are limited. Therefore, it is crucial to understand the etiology of placental abnormalities in location and anatomy. Placental formation already starts at implantation and therefore disorders during implantation may cause these abnormalities. Understanding of the normal placental structure and development is essential to comprehend the etiology of placental abnormalities in location and anatomy, to diagnose the affected women and to guide future research for treatment and preventive strategies. We reviewed the literature on the structure and development of the normal placenta and the placental development resulting in low‐lying placentas, placenta previa and abnormally invasive placentas.

Objective This study aimed to assess the association of preimplantation genetic testing (PGT) with abnormal placentation among a cohort of pregnancies conceived after frozen embryo transfer (FET). Study Design This is a retrospective cohort study of women who conceived via FET at the University of California, San Francisco from 2012 to 2016 with resultant delivery at the same institution. The primary outcome was abnormal placentation, including placenta accreta, retained placenta, abruption, placenta previa, vasa previa, marginal or velamentous cord insertion, circumvallate placenta, circummarginate placenta, placenta membranacea, bipartite placenta, and placenta succenturiata. Diagnosis was confirmed by reviewing imaging, delivery, and pathology reports. Our secondary outcome was hypertensive disease of pregnancy. Results A total of 311 pregnancies were included in analysis; 158 (50.8%) underwent PGT. Baseline demographic characteristics were similar between groups except for age at conception and infertility diagnosis. Women with PGT were more likely to undergo single embryo transfer (82.3 vs. 64.1%, p Conclusion Among pregnancies conceived after FET, PGT is not associated with a statistically significant increased risk of abnormal placentation or hypertensive disorders of pregnancy. Key Points

Ultrasound Doppler method of Superb Microvascular Imaging (SMI) can significantly visualize low-velocity blood flow using a unique algorithm. We scanned placenta antenatally using SMI and compared those findings with histological findings after delivery in cases with placental abnormalities. In normal, SMI expresses stem villous vessels connecting to the tertiary villous vessels which are sharply diminished, and expresses intervillous blood flow as "scatter." Placental infarction was expressed as an anechoic area in SMI. Avascular villi was expressed as absent villous blood trees in a background scatter flow in SMI. In this report, we demonstrated typical SMI findings of the pathologic placenta as a pilot study.

What are the clinical characteristics of pregnancies complicated by fetal growth restriction (FGR) and preeclampsia in patients who have undergone IVF, and what is the correlation between these complications and histopathological placental findings in such pregnancies.A retrospective cohort of patients who had delivered their babies at our institution who had been diagnosed with preeclampsia, whose babies had been diagnosed with FGR, or both. Deliveries in which the placenta was sent for histopathological examination were included. Computerized files and pathological reports were reviewed, and maternal, obstetric, neonatal outcomes and placental histopathological reports were compared between pregnancies conceived by IVF and controls. Placental lesions were classified according to the Amsterdam criteria.Between December 2008 and December 2018, the placentas of 1114 singleton babies who had received a diagnosis of FGR, whose mothers had received a diagnosis of preeclampisa, or both, were examined. A total of 105 patients conceived with IVF and 1009 were conceived spontaneously. The IVF group was older, of lower parity and had a higher rate of diabetes and chronic hypertension. Deliveries occurred at an earlier gestational age, although birth weight was not significantly different between the groups. The rate of neonatal adverse composite outcome among IVF deliveries was significantly lower (59.0% versus 76.7%; P0.001). On placental examination, placental weight, maternal and fetal vascular malperfusion lesions were similar between the groups, whereas villitis of unknown etiology was significantly more common among the IVF group (16.2% versus 8.3%; P = 0.007).Neonatal outcome is relatively favourable in IVF patients with placental-related diseases. Placental chronic villitis is more common in IVF patients, pointing to an additive immunological cause.

Objective: To analyze the correlation between placenta related disease of pregnant women with antecedent hysteroscopic adhesiolysis due to intrauterine adhesions (IUA). Materials and methods: This is a single center, non-randomized, open-label, retrospective cohort Study. 74 patients who had adhesiolysis and hormone therapy for IUA and progressed into the third trimester were group A and 296 without IUA were group B. The main outcome measure is the incidence of placenta related disease including placenta accreta spectrum, placenta previa, placental abruption, intrauterine growth restriction (IUGR), and pregnancy-induced hypertension (PIH). The second outcome is the perinatal, and intrapartum complications. Results: Patients in group A had a higher frequency of prior pregnancy times (2.51 ± 1.56 vs.1.84 ± 1.06, p = 0.001) and lower frequency of prior delivery times (0.20 ± 0.41 vs. 1.30 ± 0.51, p

The placenta performs a range of crucial functions that support fetal growth during pregnancy, including facilitating the supply of oxygen and nutrients to the fetus, removal of waste products from the fetus and the endocrine modulation of maternal physiology. The placenta also stores glucose in the form of glycogen, the function of which remains unknown. Aberrant placental glycogen storage in humans is associated with maternal diabetes during pregnancy and pre-eclampsia, thus linking placental glycogen storage and metabolism to pathological pregnancies. To understand the role of placental glycogen in normal and complicated pregnancies, we must turn to animal models. Over 40 targeted mutations in mice demonstrate the defects in placental cells that store glycogen and suggest that placental glycogen represents a source of readily mobilized glucose required during periods of high fetal demand. However, direct functional evidence is currently lacking. Here, we evaluate these genetic mouse models with placental phenotypes that implicate glycogen trophoblast cell differentiation and function to illuminate the common molecular pathways that emerge and to better understand the relationship between placental glycogen and fetal growth. We highlight the current limitations in exploring the key questions regarding placental glycogen storage and metabolism and define how to experimentally overcome these constraints.

Purpose of review This review describes maternal and fetal anesthetic management for noncardiac fetal surgical procedures, including the management of lower urinary tract obstruction, congenital diaphragmatic hernia (CDH), myelomeningocele, sacrococcygeal teratoma, prenatally anticipated difficult airway and congenital lung lesions. Recent findings Fetal interventions range from minimally invasive fetoscopic procedures to mid-gestation open surgery, to ex-utero intrapartum treatment procedure. Anesthetic management depends on the fetal intervention and patient characteristics. Anesthesia for most minimally invasive procedures can consist of intravenous sedation and local anesthetic infiltration in clinically appropriate maternal patients. Open fetal and ex-utero intrapartum treatment procedures require maternal general anesthesia with volatile anesthetic and other medications to maintain uterine relaxation. Tracheal balloons are a promising therapy for CDH and can be inserted via minimally invasive techniques. Management of the prenatally anticipated difficult airway during delivery and removal of tracheal balloons from patients with CDH during delivery can be clinically dynamic and require flexibility, seamless communication and a high-functioning, multidisciplinary care team. Summary Maternal and fetal anesthetic management is tailored to the fetal intervention and the underlying health of the fetus and mother.

© 2020 Elsevier Ltd Introduction: Before using blood-oxygen-level-dependent magnetic resonance imaging (BOLD MRI) during maternal hyperoxia as a method to detect individual placental dysfunction, it is necessary to understand spatiotemporal variations that represent normal placental function. We investigated the effect of maternal position and Braxton-Hicks contractions on estimates obtained from BOLD MRI of the placenta during maternal hyperoxia. Methods: For 24 uncomplicated singleton pregnancies (gestational age 27–36 weeks), two separate BOLD MRI datasets were acquired, one in the supine and one in the left lateral maternal position. The maternal oxygenation was adjusted as 5 min of room air (21% O2), followed by 5 min of 100% FiO2. After datasets were corrected for signal non-uniformities and motion, global and regional BOLD signal changes in R2* and voxel-wise Time-To-Plateau (TTP) in the placenta were measured. The overall placental and uterine volume changes were determined across time to detect contractions. Results: In mothers without contractions, increases in global placental R2* in the supine position were larger compared to the left lateral position with maternal hyperoxia. Maternal position did not alter global TTP but did result in regional changes in TTP. 57% of the subjects had Braxton-Hicks contractions and 58% of these had global placental R2* decreases during the contraction. Conclusion: Both maternal position and Braxton-Hicks contractions significantly affect global and regional changes in placental R2* and regional TTP. This suggests that both factors must be taken into account in analyses when comparing placental BOLD signals over time within and between individuals.