Maternal Vascular Malperfusion Research Articles

COVID-19 as an independent risk factor for subclinical placental dysfunction

BackgroundThe 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. ObjectiveThe 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 designThis 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. ResultsThe 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. ConclusionsAsymptomatic 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.

Histologic Chorioamnionitis in Pregnancies Complicated by Preeclampsia and the Effect on Neonatal Outcomes.

Histological chorioamnionitis (HC) is a common placental finding that represents acute/chronic inflammation and can affect neonatal outcomes. We aimed to examine the effect of HC on neonatal outcomes in pregnancies complicated by preeclampsia. All pregnancies with the diagnosis of preeclampsia at 24-42weeks between 2008 and 2019 were reviewed. Placental lesions were classified according to the "Amsterdam" criteria. Composite adverse neonatal outcome included ≥1 early complication. Maternal and neonatal outcomes were compared between cases with and without HC. Multivariable regression analysis was performed to identify independent associations with adverse neonatal outcome. Compared to preeclampsia without HC (n=517), preeclampsia with HC (n=55) was characterized by a more advanced gestational age (p<0.001) and a higher rate of nulliparity (p=0.02). Diabetes was more prevalent in preeclampsia without HC (p=0.039) as was a history of previous preeclampsia (p=0.048). Neonates in the preeclampsia with HC group had higher rates of adverse neonatal outcome (p<0.001) and Apgar scores <7 at 5min (p=0.034) despite a higher birthweight (p=0.005). Preeclampsia without HC was associated with smaller placentas and a higher rate of placental maternal vascular malperfusion lesions (p=0.014 and p<0.001 respectively). By multivariate analysis, gestational age and HC were independently associated with adverse neonatal outcome (aOR 0.88 95% CI 0.76-0.96, and aOR 1.33, 95% CI 1.11-3.09, respectively). In preeclampsia, concomitant HC was associated with adverse neonatal outcome despite a more advanced gestational age and higher neonatal birthweight. This inflammatory mechanism probably plays a role in a more severe subgroup of preeclampsia cases, causing an additional risk for the developing fetus.

Placental pathology of the third trimester pregnant women from COVID-19

AimsTo explore the clinical characteristics and placental pathological changes of pregnant women with 2019 novel coronavirus (CoV) disease (COVID-19) in the third trimester, and to assess the possibility of vertical transmission.Methods and resultsThe placenta tissues were evaluated by using immunohistochemistry for inflammatory cells and Hofbauer cells, and using severe acute respiratory syndrome (SARS) CoV-2 RNA Fluorescence In-Situ Hybridization (FISH) and SARS-CoV-2 spike protein immunofluorescence (IF) double staining. All eight placentas from the third trimester pregnancy women were studied. All patients were cured, no clinical or serological evidence pointed to vertical transmission of SARS-CoV-2. Features of maternal vascular malperfusion (MVM) such as increased syncytial knots were present in all 8 cases (8/8), and increased focal perivillous fibrin depositions were presented in 7 cases (7/8). No significate chronic histiocytic intervillositis was noted in the placenta. The number of macrophages and inflammatory cells such as T cells, B cells and plasma cells in the placental villous was not significantly increased in all cases. Moreover, all of eight cases demonstrated negative results by FISH using a SARS-CoV-2 virus RNA probe and by IF using a monoclonal antibody against SARS-CoV-2 spike protein.ConclusionsWe found no evidence of vertical transmission and adverse maternal-fetal outcomes in the placentas of third trimester COVID-19 pregnancy women, which provided further information for the clinical management of those women in the third trimester. However, further studies are still needed for patients with infections in different stage of gestation, especially in first and second trimester.

The Causes of Stillbirths in South Asia: Results from a Prospective Study in India and Pakistan (PURPOSe)

Background: South Asia contributes more than one-third of all global stillbirths, yet the cause of stillbirth remains largely unstudied in this region. New investigations, including novel assessment of placental and fetal tissues, facilitate more precise determination of the underlying causes of stillbirth. We sought to assess underlying and contributing causes of stillbirth from settings in India and Pakistan. Methods: The Project to Understand and Reduce Stillbirth and Preterm birth in Southeast Asia (PURPOSe) was established in hospitals in central India and south Pakistan to collect standardized, prospective data from women delivering in those health facilities to better understand causes of stillbirth and causes of death in preterm newborns. Here, we analyzed data from stillbirths. An expert panel reviewed available data for all stillbirths eligible for the study to determine the primary and contributing maternal, placental, and fetal causes of death. Findings: Between September 2018 and February 2020, 981 eligible stillbirths were enrolled and, of those, 611 had their cases reviewed by the expert panel. The primary maternal causes of stillbirth were hypertensive disease (36·1%), followed by severe anemia (10·8%) while the primary placental causes were maternal and fetal vascular malperfusion (47·9%). The primary fetal cause of stillbirth was intrauterine hypoxia (71·5%). When we assessed the overlap of main causes, 18·9% of all stillbirths had intrauterine hypoxia, placental malperfusion, and eclampsia/pre-eclampsia indicated as primary causes of death. Infection, including of the placenta, its membranes and in the fetus, as well as congenital anomalies also were causative for stillbirth. Interpretation: In South Asia, fetal asphyxia is the major cause of stillbirth. Several placental lesions, especially those associated with maternal and fetal vascular malperfusion and placental abruption play an important role in the pathway through asphyxia to fetal death. Maternal hypertension and especially preeclampsia is often the primary maternal condition associated with this pathway. Funding: Bill & Melinda Gates Foundation Declaration of Interest: The authors declare no conflict of interest. Ethical Approval: The study was reviewed and approved by the ethics review committees at the Aga Khan University (Karachi, Pakistan), KLE Academy of Higher Education and Research (Belagavi, India), J.J.M. Medical College (Davangere, India), and RTI International (Durham, NC US). All women provided informed written consent prior to participation in the study.

Association between proteinuria and placental pathology in preeclampsia: A retrospective study.

Introduction:Preeclampsia develops due to placental insufficiency and systemic proinflammatory and antiangiogenic mediator release, with ensuing systemic endothelial dysfunction. Nephrotic-range proteinuria appears to be associated with worse pregnancy outcomes. The relationship between differing degrees of proteinuria and the severity of placental alterations has not been studied.Methods:This is a single-centre retrospective comparison of 150 singleton pregnancies complicated by preeclampsia and varying degrees of proteinuria. Maternal demographic, obstetrical and fetal outcome data were obtained from chart review. The placental histologic evaluations were performed by a placental pathologist blinded to all other clinical information.Results:Preeclamptic women with massive proteinuria had evidence of more severe maternal vascular malperfusion lesions. The severity of the lesions was progressive through mild, moderate and massive proteinuria. Women with massive proteinuria had a higher incidence of renal dysfunction and severe hypertension, and had earlier preterm deliveries compared to preeclamptic women with mild and moderate proteinuria (p < 0.05).Conclusion:Preeclampsia with more severe proteinuria is associated with a higher prevalence of placental maternal vascular malperfusion.

Pathological investigation of placentas in preeclampsia (the PEARL study)

ABSTRACT INTRODUCTION: Preeclampsia (PE), but mainly preterm PE, is associated with deep placentation disorders. We aimed to compare placental pathologies in pregnancies affected by term and preterm PE compared to normal pregnancies. METHODS: We performed a prospective case-cohort study. Low-risk nulliparous women were recruited in the first trimester and women who developed PE were recruited at diagnosis. Placental pathologies were reported according to the Amsterdam Placental Workshop Group Consensus Statement and were compared between cases and controls. PE cases stratified as term (≥37 weeks) and preterm PE (<37 weeks). Our primary outcome was maternal vascular malperfusion (MVM). RESULTS: Twenty-four women who developed preterm PE were compared to 10 women who developed term PE and 41 women without PE. Preterm PE (92%) was associated with more MVM than term PE (10%, p < 0.01) and controls (4%, p < 0.01), but the rate of MVM was similar between term PE and controls (p = 0.56). Preterm PE was also associated with more placental infarcts (65% vs. 20% vs. 15%); advanced villous maturation (91% vs. 30% vs. 1%); and hypoplastic villous maturation (70% vs. 10% vs. 3%); and moderate to severe decidual vasculopathy (56% vs. 10% vs. 3%) than term PE and controls (all p < 0.05). CONCLUSION: Most cases of preterm PE are associated with MVM, placental infarcts, advanced and/or hypoplastic villous maturation, and moderate to severe decidual vasculopathy, while it is infrequent in term PE and pregnancies without PE. Preterm and term preeclampsia have a different pathologic process that should be considered for their prevention and clinical management.

Maternal Hematologic Neoplasms during Pregnancy: Histologic Findings in the Placenta

Placental metastasis of maternal neoplasms is well documented in solid tumors, unlike hematologic neoplasms. We reviewed placental findings from deliveries complicated by maternal hematologic neoplasms exploring the prevalence and patterns of placental transmission and insufficiency. In the 8-yr study period, 11 cases were analyzed. Acute myeloid leukemia was the most common diagnosis (4/11, 36%). Seven cases (63%) showed no evidence of placental spread of neoplasm, while four cases (36%) showed placental spread, restricted to the maternal compartment. Maternal vascular malperfusion was documented in 8/11 (72%) cases. Neonatal follow up was available in 10 cases, all children were alive and well.

The spectrum of placental pathology in a public v. private laboratory practice in Gauteng Province, South Africa

Background. Laboratory information systems have a wealth of patient and health data that can be made available for research. These data can serve to better inform healthcare delivery and formulation of policies. The placenta is just one histopathology laboratory specimen that can provide such insight, particularly with regard to maternal and neonatal healthcare. Objectives. To describe the spectrum of placental pathology in a private and public laboratory and to ascertain implications for improved maternal and neonatal healthcare and policies. Methods. We conducted a retrospective descriptive study of placental histopathology reports from Lancet Laboratories and the National Health Laboratory Service (NHLS) in Johannesburg over a 1-year period (August 2017 - July 2018). The reports were categorised according to the 2014 Amsterdam Placental Workshop Group Consensus Statement and the percentages of each diagnostic entity compared between the two laboratories. These diagnostic categories included ascending infection, maternal vascular malperfusion (MVM), fetal vascular malperfusion, haematogenous infection, chronic villitis of unknown aetiology, retroplacental haemorrhage, no specific pathological changes and ‘other’. Differences in maternal age and gestational age were also compared. Results. There were 1 172 and 946 placentas that were entered into the study at Lancet and NHLS, respectively. MVM was the most prevalent pathology seen in both laboratories (40.6% and 47.7%; p =0.3193). Mean maternal and gestational age were both higher in the private system (both p &lt;0.0000). Conclusion. Differences in placental pathology were multifactorial and reasons may include differences in socioeconomic status and resources, clinical and laboratory policies and practices, as well as pathologist training and expertise. Clear clinical guidelines for the submission and histopathological examination of the placenta are required to better inform neonatal and maternal healthcare and policies. In our divided healthcare system, collaborative medical research is not only possible between the public and private sectors but also necessary to achieve better healthcare and equity for patients in South Africa.

Adverse Outcome in a Near Term, High-Risk Twin Pregnancy Complicated by COVID-19: A case report

Background: COVID-19 affecting the outcome of pregnancy is still under investigation. Here we report a case of primigravida with monochorionic diamniotic twin pregnancy with superimposed preeclampsia who develop symptoms of COVID-19 infection on her near term pregnancy and was confirmed later on as COVID-19 positive after cesarean section. The pregnancy was terminated abdominally due to the intrauterine fetal demise of both twins using COVID-19 standard equipment.Case Presentation: A 29-year-old female, gravida 1, para 0 presented with a twin pregnancy at the gestational age of 36 weeks was referred to our emergency department for further management of intrauterine fetal death of both twins. Six days before admitted to our emergency department, she has been experienced a remittent fever which followed by a mild cough. Four days before admission, she complained of decrease movement of the babies. She went to the Secondary Hospital to check her pregnancy and both fetal heart rates were not found. The patient is obese (BMI 49.2 kg/m2) and had prior uncontrolled hypertension but no other medical history, including epilepsy, allergies, asthma, heart disease as well as Diabetes Mellitus.Conclusion: A research about placental pathology in pregnancy with confirmed case of COVID-19 infection showed no pathognomonic feature in the histopathologic examination but mostly, there were maternal vascular malperfusion (decidual arteriopathy in particular) and intervillous thrombi. In the end, a further examination is suggested to evaluate the course and causal factors pertaining to this case.

The SARS-CoV-2 receptor, angiotensin-converting enzyme 2, is required for human endometrial stromal cell decidualization†.

The coronavirus disease 2019 (COVID-19) first appeared in December 2019 and rapidly spread throughout the world. The SARS-CoV-2 virus enters the host cells by binding to the angiotensin-converting enzyme 2 (ACE2). Although much of the focus is on respiratory symptoms, recent reports suggest that SARS-CoV-2 can cause pregnancy complications such as pre-term birth and miscarriages; and women with COVID-19 have had maternal vascular malperfusion and decidual arteriopathy in their placentas. Here, we report that the ACE2 protein is expressed in both endometrial epithelial and stromal cells in the proliferative phase of the menstrual cycle, and the expression increases in stromal cells in the secretory phase. It was observed that the ACE2 mRNA and protein abundance increased during primary human endometrial stromal cell (HESC) decidualization. Furthermore, HESCs transfected with ACE2-targeting siRNA impaired the full decidualization response, as evidenced by a lack of morphology change and lower expression of the decidualization markers PRL and IGFBP1. Additionally, in mice during pregnancy, the ACE2 protein was expressed in the uterine epithelial cells, and stromal cells increased through day 6 of pregnancy. Finally, progesterone induced Ace2 mRNA expression in mouse uteri more than vehicle or estrogen. These data establish a role for ACE2 in endometrial physiology, suggesting that SARS-CoV-2 may be able to enter endometrial stromal cells and elicit pathological manifestations in women with COVID-19, including an increased risk of early pregnancy loss.

Abstract 16839: Maternal Placental Vascular Malperfusion Lesions Associated With Increased Cardiometabolic Risk and Reduced Microvascular Density in Women a Decade After Delivery: Which Placental Features Matter?

Introduction: Maternal vascular malperfusion (MVM) lesions in the placenta are commonly found in women with adverse pregnancy outcomes associated with increased CVD in later life. Minimal criteria for MVM include vasculopathy, accelerated villous maturation and increased syncytial knots, and villous infarction upon pathologic examination; expanded definitions have included presence of fibrin deposition (intervillous or perivillous) or low placental weight (&lt;10 th %). Hypothesis: Women with a history of MVM lesions would have evidence of cardiometabolic risk factors and peripheral microvascular changes a decade after delivery independent of pregnancy outcome. Methods: A total of 469 women with placental pathology data available were evaluated at 8-10 years postpartum. Placental specimens were reviewed by a perinatal pathologist. Cardiometabolic variables were measured at the time of the study visit. Sidestream dark field imaging was used to assess the sublingual microcirculation. We compared the median size (diameter) of microvessels, density (total length of perfused microvessels/mm 2 ) and penetration of red cells into the glycocalyx of vessels 5-25μm diameter (perfused boundary region, PBR) in women 8-10 years after pregnancy, using the minimal MVM criteria (compared to none). Expanded criteria were examined alone. Significance =*p&lt;0.05 vs no MVM lesions. Results: Women with minimally defined MVM lesions in their placentas had higher diastolic blood pressure (79mmHg MVM vs. 75 mmHg No MVM*), LDL (111mg/dL MVM vs. 101 mg/dL No MVM*), Cholesterol (185 mg/dL MVM vs. 175mg/dL No MVM*) and insulin (14mg/dL MVM vs. 12mg/dL No MVM*), along with smaller-sized microvessels (median 8.75±1.1 μM vs. 9.06±0.7 μM*), and a lower density of perfused microvessels compared to women without MVM lesions (3590±1260mm/mm 2 MVM vs. 3970±820 mm/mm 2 No MVM*) a decade after delivery. Glycocalyx PBR was smaller in women with prior MVM vs. women without lesions (2.01±0.23μm vs. 2.09±0.15μm, P=0.02). Similar results were not seen in subjects with either presence of fibrin or small placenta in the absence of other MVM criteria. Discussion: Using minimal criteria MVM was associated most strongly with maternal cardiometabolic and microvascular differences a decade later.

Abstract 16048: Placental Pathology in Pregnancies Complicated by Maternal Cardiac Disease: A Study From the Standardized Outcomes in Reproductive Cardiovascular Care (STORCC) Initiative

Background: The incidence of pregnancy in women with cardiovascular disease (CVD) has increased, yet there is little known about placental pathology in these women. Objective: To describe placental pathology in pregnancies carried by women with CVD and to compare placental findings between categories of maternal CVD. Methods: We identified live births within the prospective, single-center Standardized Outcomes in Reproductive Cardiovascular Care cohort for which the placenta underwent histopathologic examination. Pathology reports were reviewed by an experienced placental pathologist (BJQ) for prespecified pathologic findings that were then compared against maternal characteristics. Results: 271 placentas (Table 1) were identified from pregnancies associated with maternal congenital heart disease (CHD) (65%), arrhythmia (16%), cardiomyopathy (8%), connective tissue disease (7%), and valvular heart disease (4%). Median maternal age at delivery was 32 years (range 19-49). Median gestational age at delivery was 39 weeks (range 25-41). Anatomic pathology, mostly in the form of small placenta by weight, was most common, affecting 43% of placentas. Vascular pathology, mostly maternal vascular malperfusion or fetal flow restriction, was seen in 41% of placentas. Infectious (acute chorioamnionitis) and inflammatory (chronic villitis) pathology was seen in 23% and 10% of placentas, respectively. Inflammatory pathology was more common in maternal CHD than in other CVD categories (14.9% vs. 2.1%, p=0.001), while anatomic, infectious, and vascular pathology were seen at similar rates across all CVD categories. Conclusion: Pregnancies among women with CVD commonly demonstrate abnormal placental findings, especially anatomic and vascular pathology. Chronic villitis was more common in women with CHD compared to other types of CVD. Otherwise, the incidence of specific pathology findings did not differ significantly based on maternal characteristics.

The association between first trimester placental biomarkers and placental lesions of maternal vascular malperfusion

IntroductionAbnormal levels of first trimester placental biomarkers are associated with the development of placental syndrome (PS). However, prediction performance is moderate, possibly explained by the clinical heterogeneity of PS. Aim of this study is to investigate the association between first trimester biomarkers and the presence of maternal vascular malperfusion (MVM), as a marker for placental insufficiency. MethodsThis retrospective study included 195 women with available first trimester blood sample and placenta histological sections for examination at the Maastricht University Medical Centre. Women were divided into 4 groups, based on the presence of having MVM lesions and/or PS. Levels of PAPP-A, PlGF and sFlt-1 were measured and MVM lesions were classified according to the Amsterdam Placental Workshop Group Consensus Statement. ResultsMVM occurrence was observed in 32% of the uncomplicated pregnancies. Women with MVM (regardless of the PS) had lower levels of PAPP-A (p = 0.038) and sFLt-1 (p = 0.006), and a non-significant trend for lower PlGF and sFlt-1/PlGF ratio compared to women without MVM. Low PAPP-A levels individually and in combination with the presence of PS was significantly associated with MVM lesions (aOR = 3.0 and 6.1, respectively), as did the combination of low PlGF levels and PS (aOR = 4.6). In women with PS, having MVM increased the incidence of fetal growth restriction, small for gestational age neonates, lower birthweight and adverse neonatal outcome. DiscussionOur findings suggest that MVM lesions were found to be associated with increased obstetric risks due to early placental dysfunction that can potentially be predicted by the use of first trimester biomarkers.

Pathological Study of Stillbirths Placentas at Muhimbili National Hospital, Tanzania

Abstract Introduction/Objective Stillbirth is defined as fetal death that occurs at gestational age of ≥28 weeks. In our setting clinical assessment is the only method used to determine cause of stillbirths, with no reported proportion of unknown clinical diagnosis. Studies showed that unknown cause of stillbirths can be reduced by examination of placenta. Causal identification aids in the mourning process and identifying recurrence risks. The study aimed to describe pathological changes in the placentas of stillbirths which have risk to cause fetal death Methods A descriptive cross-sectional study done for the period of 6 months, it involved examination of 80 placentas of stillbirths born at gestational age of ≥ 28 weeks, placentas were fixed in 10% neutral buffered formalin for 8–12 hours. Grossing and interpretation of placenta pathology was according to Amsterdam Placental Workshop Group Consensus Statement. Results Out of 80 stillbirths, 32(40%) had unknown clinical diagnosis. Majority of stillbirth placentas 71(91%) found with either one or combined pathologies with the risk to cause stillbirth. Maternal vascular malperfusion was the commonest pathology and was significantly associated with preterm stillbirths. Maternal floor infarction, a placenta pathology with risk to cause fetal death and high risk of recurrence was among the pathologies found, was seen in 4(5%) of stillbirth placentas. Conclusion Findings in this study clearly indicated the importance of pathological examination of placenta in determining cause of stillbirth. Placenta examination in stillbirths can identify more pathology related to stillbirths than clinical assessment alone.

Does macroscopic estimation of the extent of placental abruption correlate with pregnancy outcomes?

IntroductionWe aimed to study the correlation between the extent of placental abruption (PA), as grossly estimated immediately after delivery, and pregnancy outcomes, in correlation with placental histopathology. Materials and MethodsPregnancy and placental reports of all pregnancies complicated by PA (clinically diagnosed) between 11/2008-12/2018 were reviewed.We compared maternal background, pregnancy outcomes, and placental histopathology between cases of PA divided into three groups according to the extent of abruption: Group 1-<30 %, Group 2-30−49 %, and Group 3->50 % of placental surface.Placental lesions were classified according to the current "Amsterdam" criteria.The primary outcome was defined as a composite of severe neonatal morbidity and included ≥ 1 of the following complications: seizures, intraventricular hemorrhage, hypoxic-ischemic encephalopathy, periventricular leukomalacia, blood transfusion, necrotizing enterocolitis, intrauterine fetal demise, or neonatal death. ResultsA total of 260 PA cases were included: 111 (42.7 %) in Group 1, 94 (36.2 %) in Group 2, and 55 (21.1 %) in Group 3. The rate of the primary outcome (7.2 % vs. 11.7 % vs. 27.3 %, p = 0.02) was associated with the degree of PA as well as maternal heavy smoking (p = 0.04), DIC (p = 0.03), umbilical artery Ph <7.1 (p = 0.02), 5-minute Apgar scores <7 (p = 0.03), NICU admissions, placental maternal vascular malperfusion lesions (p = 0.04), and neonatal weights <5th percentile (0.04). In multivariable analysis severe adverse neonatal outcome was independently associated with the percentage of PA (aOR = 1.4, 95 % CI = 1.3–3.9). ConclusionThe extent of placental abruption, as estimated by the examiner, correlated with DIC and severe neonatal outcomes and may serve as an early alarming sign in deliveries complicated by PA.

Maternal and foetal placental vascular malperfusion in pregnancies with anti-phospholipid antibodies.

The objective of the study was to evaluate the rates of pathological placental lesions among pregnant subjects positive for aPL antibodies. We performed a longitudinal case-control study including 27 subjects with primary APS, 51 with non-criteria APS, 24 with aPL antibodies associated with other well-known CTDs enrolled at the end of the first trimester of pregnancy and 107 healthy controls. Compared with controls and after correction for multiple comparisons, primary, non-criteria APS and aPL associated to CTD, subjects had lower placental weight, volume and area. After penalized logistic regression analysis to correct for potential confounders, placental lesions suggesting severe maternal vascular malperfusion (MVM) were more common among primary [odds ratio (OR) 11.7 (95% CI 1.3, 108)] and non-criteria APS [OR 8.5 (95% CI 1.6, 45.9)] compared with controls. The risk of foetal vascular malperfusion (FVM) was higher in primary APS [OR 4.5 (95% CI 1.2, 16.4)], aPL associated with CTDs [OR 3.1 (95% CI 1.5, 6.7)] and non-criteria APS [OR 5.9 (95% CI 1.7, 20.1)] compared with controls. Among clinical and laboratory criteria of APS, first trimester aCL IgG >40 UI/ml [OR 4.4 (95% CI 1.3, 14.4)], LA positivity [OR 6.5 (95% CI 1.3, 33.3)] and a history of pre-eclampsia at <34 weeks [OR 32.4 (95% CI 6.5, 161)] were the best independent first trimester predictors of severe MVM [area under the curve 0.74 (95% CI 0.6, 0.87)]. Compared with healthy controls, pregnant subjects with aPL antibodies have an increased risk of placental lesions, suggesting MVM and FVM. First-trimester variables such as aCL IgG >40 UI/ml and a history of pre-eclampsia were significant predictors of both severe MVM and FVM.

A structured review of placental morphology and histopathological lesions associated with SARS-CoV-2 infection

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, was first identified after a cluster of cases in Wuhan, China in December 2019. Whether vertical transmission or placental pathology might occur following maternal infection during pregnancy remains unknown. This review aimed to summarise all studies that examined the placenta or neonates following infection with SARS-CoV-2, or closely related highly pathogenic coronavirus (SARS-CoV-1, or the Middle East respiratory syndrome coronavirus (MERS-CoV)). Structured literature searches found 50 studies that met the inclusion criteria.Twenty studies reported placental histopathology findings in third trimester placentas following maternal SARS-CoV-2 infection. Using the Amsterdam Consensus criteria to categorise the histopathology results, evidence of both fetal vascular malperfusion (35.3% of cases; 95% Confidence Interval (CI) 27.7–43.0%) and maternal vascular malperfusion (46% of cases; 95% CI 38.0–54.0%) were reported, along with evidence of inflammation in the placentas (villitis 8.7% cases, intervillositis 5.3% of cases, chorioamnionitis 6% of cases). The placental pathologies observed in SARS-CoV-2 were consistent with findings following maternal SARS-CoV-1 infection. Of those tested, a minority of neonates (2%) and placental samples tested positive for SARS-CoV-2 infection (21%).Limited conclusions can be drawn about the effect of maternal SARS-CoV-2 infection on placental pathology as most lack control groups and the majority of reports followed third trimester infection. Collaboration to maximise the number of samples examined will increase the reliability and generalisability of findings. A better understanding of the association between maternal SARS-CoV-2 infection and placental pathology will inform maternity care during the coronavirus pandemic.

Altered Levels of Decidual Immune Cell Subsets in Fetal Growth Restriction, Stillbirth, and Placental Pathology.

Immune cells are critically involved in placental development and functioning, and inadequate regulation of the maternal immune system is associated with placental pathology and pregnancy complications. This study aimed to explore numbers of decidual immune cells in pregnancies complicated with fetal growth restriction (FGR) and stillbirth (SB), and in placentas with histopathological lesions: maternal vascular malperfusion (MVM), fetal vascular malperfusion (FVM), delayed villous maturation (DVM), chorioamnionitis (CA), and villitis of unknown etiology (VUE). Placental tissue from FGR (n = 250), SB (n = 64), and healthy pregnancies (n = 42) was included. Histopathological lesions were classified according to criteria developed by the Amsterdam Placental Workshop Group. Tissue slides were stained for CD68 (macrophages), CD206 (M2-like macrophages), CD3 (T cells), FOXP3 [regulatory T (Treg) cells], and CD56 [natural killer (NK) cells]. Cell numbers were analyzed in the decidua basalis using computerized morphometry. The Mann-Whitney U-test and Kruskal Wallis test with the Dunn's as post-hoc test were used for statistical analysis. Numbers of CD68+ macrophages were higher in FGR compared to healthy pregnancies (p < 0.001), accompanied by lower CD206+/CD68+ ratios (p < 0.01). In addition, in FGR higher numbers of FOXP3+ Treg cells were seen (p < 0.01) with elevated FOXP3+/CD3+ ratios (p < 0.01). Similarly, in SB elevated FOXP3+ Treg cells were found (p < 0.05) with a higher FOXP3+/CD3+ ratio (p < 0.01). Furthermore, a trend toward higher numbers of CD68+ macrophages was found (p < 0.1) in SB. Numbers of CD3+ and FOXP3+ cells were higher in placentas with VUE compared to placentas without lesions (p < 0.01 and p < 0.001), accompanied by higher FOXP3+/CD3+ ratios (p < 0.01). Elevated numbers of macrophages with a lower M2/total macrophage ratio in FGR suggest a role for a macrophage surplus in its pathogenesis and could specifically indicate involvement of inflammatory macrophages. Higher numbers of FOXP3+ Treg cells with higher Treg/total T cell ratios in VUE may be associated with impaired maternal-fetal tolerance and a compensatory response of Treg cells. The abundant presence of placental lesions in the FGR and SB cohorts might explain the increase of Treg/total T cell ratios in these groups. More functionality studies of the observed altered immune cell subsets are needed.

Effect of newborn gender on placental histopathology and perinatal outcome in singleton live births following IVF

Research question: Does newborn gender affect placental histopathology pattern and perinatal outcome in singleton live births following IVF treatment?Design: Retrospective cohort study evaluating data of all live births from one academic tertiary hospital following IVF treatment during 2009–2017. All patients had placentas sent for pathological evaluation irrelevant of maternal and fetal complications status. Exclusion criteria were abnormal uterine cavity findings, previous uterine surgery, in-vitro maturation cycles, gestational carrier cycles, oocyte recipient cycles, preimplantation genetic diagnosis cycles and multiple pregnancies. The primary outcomes included anatomical, inflammation, vascular malperfusion and villous maturation placental features. The secondary outcomes included fetal, maternal, perinatal and delivery complications. A multivariate analysis was conducted to adjust the results for factors potentially associated with placental pathology features.Results: A total of 1057 live births were included in the final analysis and were allocated to the study groups according to fetal gender: males (n = 527) and females (n = 530). After adjustment for potential confounding factors, male gender was significantly associated with villous agglutination (odds ratio [OR] 9.8; 95% confidence interval [CI] 1.4–78.2), avascular villi (OR 4.1; 95% CI 1.3–12.6) and maternal vascular malperfusion (OR 1.8; 95% CI 1.2–2.7). Female gender was significantly associated with bilobed placenta (OR 0.2; 95% CI 0.06–0.8) and subchorionic thrombi (OR 0.5; 95% CI 0.3–0.9). The prevalence of adverse fetal, maternal and delivery outcomes was similar between the groups.Conclusions: Newborn gender has a significant impact on the placental histopathology pattern, which can contribute to the development of adverse perinatal outcomes.

Fibrinogen-Like Protein 2-Associated Transcriptional and Histopathological Features of Immunological Preeclampsia.

Preeclampsia is a multifactorial hypertensive disorder of pregnancy, with variable presentation in both maternal and fetal factors, such that no treatment or marker is currently universal to all cases. Here, we demonstrate that the prothrombinase and immunomodulatory secreted factor FGL-2 (fibrinogen-like protein 2) is differentially expressed across previously characterized gene expression clusters containing clinically relevant disease subtypes. FGL2 is low in a cluster consistent with the traditional paradigm of the pathology of preeclampsia (canonical preeclampsia) and high in a cluster exhibiting evidence of immune activation (immunological preeclampsia). We show that it is part of an immunoregulatory gene module integral to the transcriptional profile and placental pathology specific to immunological preeclampsia. We determine that FGL2 associates positively with chronic inflammation lesions of the placenta while associating negatively with maternal vascular malperfusion lesions. The transcriptional profiles of maternal vascular malperfusion lesions show downregulation of FGL2 and upregulation of previously investigated preeclampsia biomarkers, such as FLT1 (Fms Related Receptor Tyrosine Kinase 1) and ENG (endoglin). Conversely, the profiles of chronic inflammation lesions show an interesting downregulation of these genes, but an upregulation of FGL2 and of FGL2-correlated immunoregulatory genes, suggesting it is upregulated downstream of major inflammatory mediators such as TNF (tumor necrosis factor)-α and IFN (interferon)-γ, hallmarks of the immunological preeclampsia subtype. This work, overall, demonstrates that FGL-2 expression levels in the term placenta reflect the unique pathophysiology that leads to immunological preeclampsia, leading to its potential as a subtype-specific biomarker.