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BACKGROUND The placenta is a unique and pivotal organ in reproduction, controlling crucial growth and cell differentiation processes that ensure a successful pregnancy. Placental development is a tightly regulated and dynamic process, in which the transforming growth factor beta (TGFβ) superfamily plays a central role. This family of pleiotropic growth factors is heavily involved in regulating various aspects of reproductive biology, particularly in trophoblast differentiation during the first trimester of pregnancy. TGFβ signalling precisely regulates trophoblast invasion and the cell transition from cytotrophoblasts to extravillous trophoblasts, which is an epithelial-to-mesenchymal transition-like process. Later in pregnancy, TGFβ signalling ensures proper vascularization and angiogenesis in placental endothelial cells. Beyond its role in trophoblasts and endothelial cells, TGFβ signalling contributes to the polarization and function of placental and decidual macrophages by promoting maternal tolerance of the semi-allogeneic foetus. Disturbances in early placental development have been associated with several pregnancy complications, including preeclampsia (PE) which is one of the severe complications. Emerging evidence suggests that TGFβ is involved in the pathogenesis of PE, thereby offering a potential target for intervention in the human placenta. OBJECTIVE AND RATIONALE This comprehensive review aims to explore and elucidate the roles of the major members of the TGFβ superfamily, including TGFβs, bone morphogenetic proteins (BMPs), activins, inhibins, nodals, and growth differentiation factors (GDFs), in the context of placental development and function. The review focusses on their interactions within the major cell types of the placenta, namely trophoblasts, endothelial cells, and immune cells, in both normal pregnancies and pregnancies complicated by PE throughout pregnancy. SEARCH METHODS A literature search was carried out using PubMed and Google Scholar, searching terms: 'TGF signalling preeclampsia', 'pregnancy TGF signalling', 'preeclampsia tgfβ', 'preeclampsia bmp', 'preeclampsia gdf', 'preeclampsia activin', 'endoglin preeclampsia', 'endoglin pregnancy', 'tgfβ signalling pregnancy', 'bmp signalling pregnancy', 'gdf signalling pregnancy', 'activin signalling pregnancy', 'Hofbauer cell tgfβ signalling', 'placental macrophages tgfβ', 'endothelial cells tgfβ', 'endothelium tgfβ signalling', 'trophoblast invasion tgfβ signalling', 'trophoblast invasion Smad', 'trophoblast invasion bmp', 'trophoblast invasion tgfβ', 'tgfβ preeclampsia', 'tgfβ placental development', 'TGFβ placental function', 'endothelial dysfunction preeclampsia tgfβ signalling', 'vascular remodelling placenta TGFβ', 'inflammation pregnancy tgfβ', 'immune response pregnancy tgfβ', 'immune tolerance pregnancy tgfβ', 'TGFβ pregnancy NK cells', 'bmp pregnancy NK cells', 'bmp pregnancy tregs', 'tgfβ pregnancy tregs', 'TGFβ placenta NK cells', 'TGFβ placenta tregs', 'NK cells preeclampsia', 'Tregs preeclampsia'. Only articles published in English until 2023 were used. OUTCOMES A comprehensive understanding of TGFβ signalling and its role in regulating interconnected cell functions of the main placental cell types provides valuable insights into the processes essential for successful placental development and growth of the foetus during pregnancy. By orchestrating trophoblast invasion, vascularization, immune tolerance, and tissue remodelling, TGFβ ligands contribute to the proper functioning of a healthy maternal–foetal interface. However, dysregulation of TGFβ signalling has been implicated in the pathogenesis of PE, where the shallow trophoblast invasion, defective vascular remodelling, decreased uteroplacental perfusion, and endothelial cell and immune dysfunction observed in PE, are all affected by an altered TGFβ signalling. WIDER IMPLICATIONS The dysregulation of TGFβ signalling in PE has important implications for research and clinical practice. Further investigation is required to understand the underlying mechanisms, including the role of different ligands and their regulation under pathophysiological conditions, in order to discover new therapeutic targets. Distinguishing between clinically manifested subtypes of PE and studying TGFβ signalling in different placental cell types holistically is an important first step. To put this knowledge into practice, pre-clinical animal models combined with new technologies are needed. This may also lead to improved human research models and identify potential therapeutic targets, ultimately improving outcomes for affected pregnancies and reducing the burden of PE. [ABSTRACT FROM AUTHOR]

BACKGROUND With increasing significance of developmental programming effects associated with placental dysfunction, more investigations are devoted to improving the characterization and understanding of placental signatures in health and disease. The placenta is a transitory but dynamic organ adapting to the shifting demands of fetal development and available resources of the maternal supply throughout pregnancy. Trophoblasts (cytotrophoblasts, syncytiotrophoblasts, and extravillous trophoblasts) are placental-specific cell types responsible for the main placental exchanges and adaptations. Transcriptomic studies with single-cell resolution have led to advances in understanding the placenta's role in health and disease. These studies, however, often show discrepancies in characterization of the different placental cell types. OBJECTIVE AND RATIONALE We aim to review the knowledge regarding placental structure and function gained from the use of single-cell RNA sequencing (scRNAseq), followed by comparing cell-type-specific genes, highlighting their similarities and differences. Moreover, we intend to identify consensus marker genes for the various trophoblast cell types across studies. Finally, we will discuss the contributions and potential applications of scRNAseq in studying pregnancy-related diseases. SEARCH METHODS We conducted a comprehensive systematic literature review to identify different cell types and their functions at the human maternal–fetal interface, focusing on all original scRNAseq studies on placentas published before March 2023 and published reviews (total of 28 studies identified) using PubMed search. Our approach involved curating cell types and subtypes that had previously been defined using scRNAseq and comparing the genes used as markers or identified as potential new markers. Next, we reanalyzed expression matrices from the six available scRNAseq raw datasets with cell annotations (four from first trimester and two at term), using Wilcoxon rank-sum tests to compare gene expression among studies and annotate trophoblast cell markers in both first trimester and term placentas. Furthermore, we integrated scRNAseq raw data available from 18 healthy first trimester and nine term placentas, and performed clustering and differential gene expression analysis. We further compared markers obtained with the analysis of annotated and raw datasets with the literature to obtain a common signature gene list for major placental cell types. OUTCOMES Variations in the sampling site, gestational age, fetal sex, and subsequent sequencing and analysis methods were observed between the studies. Although their proportions varied, the three trophoblast types were consistently identified across all scRNAseq studies, unlike other non-trophoblast cell types. Notably, no marker genes were shared by all studies for any of the investigated cell types. Moreover, most of the newly defined markers in one study were not observed in other studies. These discrepancies were confirmed by our analysis on trophoblast cell types, where hundreds of potential marker genes were identified in each study but with little overlap across studies. From 35 461 and 23 378 cells of high quality in the first trimester and term placentas, respectively, we obtained major placental cell types, including perivascular cells that previously had not been identified in the first trimester. Importantly, our meta-analysis provides marker genes for major placental cell types based on our extensive curation. WIDER IMPLICATIONS This review and meta-analysis emphasizes the need for establishing a consensus for annotating placental cell types from scRNAseq data. The marker genes identified here can be deployed for defining human placental cell types, thereby facilitating and improving the reproducibility of trophoblast cell annotation. [ABSTRACT FROM AUTHOR]

Background We examined the relationship between placental histopathology and transplacental antibody transfer in pregnant patients after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Methods Differences in plasma concentrations of anti-receptor biding domain (RBD) immunoglobulin (Ig)G antibodies in maternal and cord blood were analyzed according to presence of placental injury. Results Median anti-RBD IgG concentrations in cord blood with placental injury (n = 7) did not differ significantly from those without injury (n = 16) (median 2.7 [interquartile range {IQR}, 1.8–3.6] vs 2.7 [IQR, 2.4–2.9], P = 0.59). However, they were associated with lower transfer ratios (median 0.77 [IQR, 0.61–0.97] vs 0.97 [IQR, 0.80–1.01], P = 0.05). Conclusions SARS-CoV-2 placental injury may mediate reduced maternal-fetal antibody transfer. [ABSTRACT FROM AUTHOR]

We investigated the relationships between syndromic manifestations of defective placentation and the incidence of intellectual disability (ID) in offspring by conducting a population-based cohort study of 1,581,200 nonmalformed, live singleton infants born in Sweden between 1998 and 2014. Exposures were: 1) placental abruption, 2) preterm preeclampsia (<34 weeks of gestation), 3) preeclampsia combined with infant being small for gestational age (SGA) at birth, and 4) spontaneous preterm birth. The outcome was an ID diagnosis after 3 years of age. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for each syndrome using Cox regression and robust variances. There were 9,451 children with ID (5.5 per 10,000 child-years). ID incidence rates increased with placental abruption (HR = 2.8, 95% CI: 2.3, 3.5), preterm preeclampsia (HR = 3.7, 95% CI: 2.9, 4.7), preeclampsia combined with SGA (HR = 3.3, 95% CI: 2.6, 4.1), and spontaneous preterm birth (for 32–36 and 22–31 weeks, respectively, HR = 1.6 (95% CI: 1.4, 1.8) and 5.2 (95% CI: 4.3, 6.2)). The same pattern of results was evident in sibling-controlled analyses among 1,043,158 full siblings. The strength of associations increased with ID severity. Preterm birth only partly explained the associations of placental abruption, preeclampsia, or SGA with ID. We conclude that defective placentation is related to increased incidence of ID in the offspring. [ABSTRACT FROM AUTHOR]

We observed an increased frequency of massive perivillous fibrin deposition (MPFD) during the second coronavirus disease 2019 (COVID-19) pandemic wave dominated by the Alpha variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). MPFD associated with 100% reverse transcription polymerase chain reaction (RT-PCR) positivity for SARS-CoV-2 and detection by immunohistochemistry. The Alpha variant was identified in all placentas with MPFD that could be sequenced. [ABSTRACT FROM AUTHOR]

Opioids affect placental development and function in animal models, but human data on their association with ischemic placental disease are limited. Using a cohort of pregnant women in the US nationwide Medicaid Analytic eXtract (2000–2014), we compared women with ≥2 opioid dispensings in pregnancy with unexposed women. Given an uncertain etiologically relevant window, we assessed exposure occurring in early pregnancy, late and not early pregnancy, and both early and late pregnancy. For placental abruption, preterm delivery, small for gestational age (SGA), and preeclampsia, we estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) using Cox proportional hazard models adjusting for demographic factors, indications/comorbidities, and medications. Among 1,833,871 eligible pregnancies, ≥2 opioid dispensings were filled in 6.5%. We observed an early exposure aHR of 1.34 (95% CI: 1.26, 1.43) for placental abruption, 1.21 (95% CI: 1.18, 1.23) for preterm delivery, 1.13 (95% CI: 1.09, 1.17) for SGA, and 0.95 (0.91, 0.98) for preeclampsia. Estimates for late exposure were attenuated. Early and late exposure was associated with higher aHRs for placental abruption, 1.62 (95% CI: 1.47, 1.78); preterm delivery, 1.37 (95% CI: 1.33, 1.42); and SGA, 1.26 (95% CI: 1.19, 1.33); but not preeclampsia, 0.99 (95% CI: 0.93, 1.05). Prescription opioids may modestly increase risk of placental abruption, preterm birth and SGA, but they do not appear to be associated with preeclampsia. [ABSTRACT FROM AUTHOR]

Discomfort and, to a lesser extent, pain are common complaints during pregnancy, and some patients may turn to opioids for pain relief. Esposito et al. (Am J Epidemiol. 2022;191(5):759–768) report associations between intermittent exposure to opioids during pregnancy and the risk of ischemic placental disease—a syndrome that includes preeclampsia, placental abruption, births that are small for gestational age, and preterm delivery. They found that early opioid exposure in pregnancy was associated with a modestly increased risk for abruption, births that are small for gestational age, and preterm delivery, and both early and late exposures were associated with the greatest risk for these outcomes. Surprisingly, preeclampsia was not associated with opioid use. Through quantitative bias analysis, the authors cleverly tackle a number of biases to assess their roles in explaining the associations, including unmeasured confounding, outcome misclassification, and residual confounding; none exerted strong influences on the associations. Although the findings appear fairly robust on the surface, the lack of association between intermittent opioid use and preeclampsia, and important differences in characteristics of patients in the opioid-exposed group compared with the unexposed group, suggest that further study is needed to clarify the relationship between intermittent opioid use, lifestyle factors, and ischemic placental disease risk. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Stanniocalcin-1 (STC-1) is a widely expressed glycoprotein hormone involved in a diverse spectrum of physiological and pathophysiological processes including angiogenesis, mineral homeostasis, cell proliferation, inflammation and apoptosis. Over the last 20 years, numerous studies have reported STC-1 expression within female reproductive tissues including the uterus, ovaries and placenta and implicated STC-1 in processes such as ovarian follicular development, blastocyst implantation, vascular remodelling in early pregnancy and placental development. Notably, dysregulation of STC-1 within reproductive tissues has been linked to the onset of severe reproductive disorders including endometriosis, polycystic ovary syndrome, poor trophoblast invasion and placental perfusion in early pregnancy. Furthermore, significant changes in tissue expression and in maternal systemic concentration take place throughout pregnancy and further substantiate the vital role of this protein in reproductive health and disease.Objective and Rationale: Our aim is to provide a comprehensive overview of the existing literature, to summarise the expression profile and roles of STC-1 within the female reproductive system and its associated pathologies. We highlight the gaps in the current knowledge and suggest potential avenues for future research.Search Methods: Relevant studies were identified through searching the PubMed database using the following search terms: 'stanniocalcin-1', 'placenta', 'ovary', 'endometrium', 'pregnancy', 'reproduction', 'early gestation'. Only English language papers published between 1995 and 2020 were included.Outcomes: This review provides compelling evidence of the vital function that STC-1 plays within the female reproductive system. The literature presented summarise the wide expression profile of STC-1 within female reproductive organs, as well as highlighting the putative roles of STC-1 in various functions in the reproductive system. Moreover, the observed link between altered STC-1 expression and the onset of various reproductive pathologies is presented, including those in pregnancy whose aetiology occurs in the first trimester. This summary emphasises the requirement for further studies on the mechanisms underlying the regulation of STC-1 expression and function.Wider Implications: STC-1 is a pleiotropic hormone involved in the regulation of a number of important biological functions needed to maintain female reproductive health. There is also growing evidence that dysregulation of STC-1 is implicated in common reproductive and obstetric disorders. Greater understanding of the physiology and biochemistry of STC-1 within the field may therefore identify possible targets for therapeutic intervention and/or diagnosis. [ABSTRACT FROM AUTHOR]

Background: Villous cytotrophoblast (vCTB) is a precursor cell population that supports the development of syncytiotrophoblast (vSTB), the high surface area barrier epithelium of the placental villus, and the primary interface between maternal and fetal tissue. In light of increasing evidence that the placenta can adapt to changing maternal environments or, under stress, can trigger maternal disease, we consider what properties of these cells empower them to exert a controlling influence on pregnancy progression and outcome.Objective and Rationale: How are cytotrophoblast proliferation and differentiation regulated in the human placental villus to allow for the increasing demands of the fetal and environmental challenges and stresses that may arise during pregnancy?Search Methods: PubMed was interrogated using relevant keywords and word roots combining trophoblast, villus/villous, syncytio/syncytium, placenta, stem, transcription factor (and the individual genes), signalling, apoptosis, autophagy (and the respective genes) from 1960 to the present. Since removal of trophoblast from its tissue environment is known to fundamentally change cell growth and differentiation kinetics, research that relied exclusively on cell culture has not been the main focus of this review, though it is mentioned where appropriate. Work on non-human placenta is not systematically covered, though mention is made where relevant hypotheses have emerged.Outcomes: The synthesis of data from the literature has led to a new hypothesis for vCTB dynamics. We propose that a reversible transition can occur from a reserve population in G0 to a mitotically active state. Cells from the in-cycle population can then differentiate irreversibly to intermediate cells that leave the cycle and turn on genes that confer the capacity to fuse with the overlying vSTB as well as other functions associated with syncytial barrier and transport function. We speculate that alterations in the rate of entry to the cell cycle, or return of cells in the mitotic fraction to G0, can occur in response to environmental challenge. We also review evidence on the life cycle of trophoblast from the time that fusion occurs, and point to gaps in knowledge of how large quantities of fetal DNA arrive in maternal circulation. We critique historical methodology and make a case for research to re-address questions about trophoblast lifecycle and dynamics in normal pregnancy and the common diseases of pre-eclampsia and fetal growth restriction, where altered trophoblast kinetics have long been postulated.Wider Implications: The hypothesis requires experimental testing, moving research away from currently accepted methodology towards a new standard that includes representative cell and tissue sampling, assessment of cell cycle and differentiation parameters, and robust classification of cell subpopulations in villous trophoblast, with due attention to gestational age, maternal and fetal phenotype, disease and outcome. [ABSTRACT FROM AUTHOR]

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) and organophosphate flame retardants (OPFRs) are chemicals that may contribute to placenta-mediated complications and adverse maternal-fetal health risks. Few studies have investigated these chemicals in relation to biomarkers of effect during pregnancy. We measured 12 PFASs and four urinary OPFR metabolites in 132 healthy pregnant women during mid-gestation and examined a subset with biomarkers of placental development and disease (n  =   62). Molecular biomarkers included integrin alpha-1 (ITGA1), vascular endothelial-cadherin (CDH5), and matrix metalloproteinase-1 (MMP1). Morphological endpoints included potential indicators of placental stress and the extent of cytotrophoblast (CTB)-mediated uterine artery remodeling. Serum PFASs and urinary OPFR metabolites were detected in ∼50%–100% of samples. The most prevalent PFASs were perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), and perfluorooctane sulfonic acid (PFOS), with geometric mean (GM) levels of ∼1.3–2.8 (95% confidence limits from 1.2–3.1) ng/ml compared to ≤0.5 ng/ml for other PFASs. Diphenyl phosphate (DPhP) and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) were the most prevalent OPFR metabolites, with GMs of 2.9 (95% CI: 2.5–3.4) and 3.6 (95% CI: 2.2–3.1) ng/ml, respectively, compared to <1 ng/ml for bis(2-chloroethyl) phosphate (BCEP) and bis(1-chloro-2-propyl) phosphate (BCIPP). We found inverse associations of PFASs or OPFRs with ITGA1 or CDH5 immunoreactivity and positive associations with indicators of placental stress in multiple basal plate regions, indicating these chemicals may contribute to abnormal placentation and future health risks. Associations with blood pressure and lipid concentrations warrant further examination. This is the first study of these chemicals with placental biomarkers measured directly in human tissues and suggests specific biomarkers are sensitive indicators of exposure during a vulnerable developmental period. [ABSTRACT FROM AUTHOR]

Background In general, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy is not considered to be an increased risk for severe maternal outcomes but has been associated with an increased risk for fetal distress. Maternal-fetal transmission of SARS-CoV-2 was initially deemed uncertain; however, recently a few cases of vertical transmission have been reported. The intrauterine mechanisms, besides direct vertical transmission, leading to the perinatal adverse outcomes are not well understood. Methods Multiple maternal, placental, and neonatal swabs were collected for the detection of SARS-CoV-2 using real-time quantitative polymerase chain reaction (RT-qPCR). Serology of immunoglobulins against SARS-CoV-2 was tested in maternal, umbilical cord, and neonatal blood. Placental examination included immunohistochemical investigation against SARS-CoV-2 antigen expression, with SARS-CoV-2 ribonucleic acid (RNA) in situ hybridization and transmission electron microscopy. Results RT-qPCRs of the oropharynx, maternal blood, vagina, placenta, and urine were all positive over a period of 6 days, while breast milk, feces, and all neonatal samples tested negative. Placental findings showed the presence of SARS-CoV-2 particles with generalized inflammation characterized by histiocytic intervillositis with diffuse perivillous fibrin depositions with damage to the syncytiotrophoblasts. Conclusions Placental infection by SARS-CoV-2 leads to fibrin depositions hampering fetal-maternal gas exchange with resulting fetal distress necessitating a premature emergency cesarean section. Postpartum, the neonate showed a fetal or pediatric inflammatory multisystem-like syndrome with coronary artery ectasia temporarily associated with SARS-CoV-2 for which admittance and care on the neonatal intensive care unit (NICU) were required, despite being negative for SARS-CoV-2. This highlights the need for awareness of adverse fetal and neonatal outcomes during the current coronavirus disease 2019 pandemic, especially considering that the majority of pregnant women appear asymptomatic. [ABSTRACT FROM AUTHOR]

Preeclampsia, new onset hypertension in pregnancy, affects ~5%–10% of the world's population. Preeclampsia is the leading cause of morbidity and mortality for both the mother and fetus. As of today, there is no cure for this disease except for delivery of the fetal–placental unit. The exact causation and onset of the disease are unknown. However, recent studies have shown a strong correlation between mitochondrial dysfunction and preeclampsia. Circulating mitochondrial DNA, elevated reactive oxygen species, angiotensin II type 1 receptor agonistic autoantibodies (AT1-AA), activated natural killer cells, and upregulated inflammatory responses all contribute to mitochondrial dysfunction and the pathophysiology of preeclampsia. This review summarizes the current literature of both experimental and clinical observations that support the hypothesis that mitochondrial dysfunction contributes to the pathophysiology of preeclampsia and may be a precursor to the disease onset. This review will also address the use of therapies to improve mitochondrial dysfunction in preeclampsia. [ABSTRACT FROM AUTHOR]

Objective The objective of the study was to evaluate the rates of pathological placental lesions among pregnant subjects positive for aPL antibodies. Methods 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. Results 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)]. Conclusion 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. [ABSTRACT FROM AUTHOR]

Background: Haem oxygenases (HO) catabolise haem, which is the prosthetic group of numerous haemoproteins. Thus, multiple primary cellular pathways and functions rely on haem availability. HO exists in two isoforms, both expressed in the placenta, namely HO-1 and HO-2, the first being inducible. Haem oxygenases, particularly HO-1, have garnered specific interest in the field of physiological and pathological placental function. These enzymes mediate haem degradation by cleaving the alpha methene bridge to produce biliverdin, which is subsequently converted to bilirubin, carbon monoxide and iron. HO-1 has anti-inflammatory and antioxidant activities.Search Methods: An initial literature analysis was performed using PubMed on 3 October 2018 using key terms such as 'haem oxygenase and pregnancy', 'haem oxygenase and placenta', 'HO-1 and pregnancy', 'HO-1 and placenta', 'HO and placenta', 'HO and pregnancy', 'genetic variant and HO', 'CO and pregnancy', 'CO and placenta', 'Bilirubin and pregnancy', 'Iron and pregnancy' and 'PPAR and Haem', selecting consensus conferences, recommendations, meta-analyses, practical recommendations and reviews. A second literature analysis was performed, including notable miscarriages, foetal loss and diabetes mellitus, on 20 December 2019. The three authors studied the publications independently to decipher whether they should be included in the manuscript.Objective and Rationale: This review aimed to summarise current pieces of knowledge of haem oxygenase location, function and regulation in the placenta, either in healthy pregnancies or those associated with miscarriages and foetal loss, pre-eclampsia, foetal growth restriction and diabetes mellitus.Outcomes: HO-1 exerts some protective effects on the placentation, probably by a combination of factors, including its interrelation with the PGC-1α/PPAR pathway and the sFlt1/PlGF balance, and through its primary metabolites, notably carbon monoxide and bilirubin. Its protective role has been highlighted in numerous pregnancy conditions, including pre-eclampsia, foetal growth restriction, gestational diabetes mellitus and miscarriages.Wider Implications: HO-1 is a crucial enzyme in physiological and pathological placentation. This protective enzyme is currently considered a potential therapeutic target in various pregnancy diseases. [ABSTRACT FROM AUTHOR]

Objectives: Obesity is an increasing health problem that has become a common medical disorder among women of childbearing age, representing worldwide a risk factor for stillbirth. The aim of the study is to evaluate the association between placental histopathologic findings and obesity in stillbirth.Methods: Placentas were analyzed according to the Amsterdam consensus statement. Histologic findings in stillbirth from obese and lean mothers were analyzed and compared with those observed in liveborn controls.Results: Stillbirth in obese mothers displayed placental pathology in all gestational ages, mostly at term of pregnancy. The most observed placental lesions were those consistent with maternal vascular malperfusion of the placental bed. Decidual arteriopathy and placental infarcts appeared specifically associated with maternal obesity. Moreover, obese women with stillbirth showed the highest cumulative number of placental lesions.Conclusions: Considering the significant association between stillbirth, maternal obesity, and placental histopathologic findings, health care providers should be aware about the importance of placental examination in obese women, especially in stillborn cases. The high prevalence of lesions consistent with vascular malperfusion of the placental bed suggests that stillbirth prevention strategies in obese women should rely on the development of tools to study and improve decidual artery functioning early in pregnancy. [ABSTRACT FROM AUTHOR]

Objectives: To describe histopathologic findings in the placentas of women with coronavirus disease 2019 (COVID-19) during pregnancy.Methods: Pregnant women with COVID-19 delivering between March 18, 2020, and May 5, 2020, were identified. Placentas were examined and compared to historical controls and women with placental evaluation for a history of melanoma.Results: Sixteen placentas from patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were examined (15 with live birth in the third trimester, 1 delivered in the second trimester after intrauterine fetal demise). Compared to controls, third trimester placentas were significantly more likely to show at least one feature of maternal vascular malperfusion (MVM), particularly abnormal or injured maternal vessels, and intervillous thrombi. Rates of acute and chronic inflammation were not increased.The placenta from the patient with intrauterine fetal demise showed villous edema and a retroplacental hematoma.Conclusions: Relative to controls, COVID-19 placentas show increased prevalence of decidual arteriopathy and other features of MVM, a pattern of placental injury reflecting abnormalities in oxygenation within the intervillous space associated with adverse perinatal outcomes. Only 1 COVID-19 patient was hypertensive despite the association of MVM with hypertensive disorders and preeclampsia. These changes may reflect a systemic inflammatory or hypercoagulable state influencing placental physiology. [ABSTRACT FROM AUTHOR]

Summary: The innate immune response in the placenta depends on the ability of maternal immune cells and fetal trophoblast cells to detect and eliminate invading pathogens through germline‐encoded pattern recognition receptors (PRRs). In the present study, we analysed the transcripts and protein expression of interferon (IFN)‐inducible protein (IFI)16, melanoma differentiation‐associated protein 5 (MDA5), RIG‐I‐like receptor (RIG‐I) and Toll‐like receptor (TLR)‐3 in third‐trimester human placentas and investigated cytokine profiles generated during herpes simplex type 1 (HSV‐1) infection. Decidual and chorionic villous biopsies (38–42 weeks of gestation) were obtained from healthy women immediately after a caesarean section. The expression of the DDX58 (RIG‐I), IFIH1 (MDA5), IFI16 and TLR3 transcripts was measured using quantitative real‐time polymerase chain reaction (qRT–PCR). Extracellular cytokine and PRRs levels were then quantified by enzyme‐linked immunosorbent assays (ELISAs). All examined PRRs genes, including DDX58, IFIH1, IFI16 and TLR3, were expressed constitutively at the mRNA and protein levels in the placental biopsies. The concentration of the IFI16 protein was increased in HSV‐1‐infected decidual and chorionic villous explants compared to those of mock‐infected tissues (P = 0·029). Higher protein expression levels of RIG‐I in both the maternal and fetal parts of the placenta were found (P = 0·009 and P = 0·004, respectively). In addition, increased production of IFN‐β by HSV‐1‐infected tissues was noticed (P = 0·004 for decidua, P = 0·032 for chorionic villi). No significant differences in the IFN‐α, interleukin (IL)‐6 and IL‐8 levels were found. These results showed that HSV‐1 infection can enhance the expression of IFI16 and RIG‐I proteins in the human term placenta. [ABSTRACT FROM AUTHOR]

Dupuytren's disease (DD) is a rare connective tissue disorder resulting in progressive fibrosis and thickening of the palmar fascia, and contracture of the fingers due to excessive collagen deposition. Staged surgical interventions are reserved for severe cases, yet worsening of fibrosis and contracture of fingers post-surgery, has been reported to have a recurrence rate as high as 85%. Here, the authors report on use of viable cryopreserved placental membrane (vCPM) allograft as an adjunct to open fasciectomy. In a patient with debilitating bilateral DD contractures of >20 years duration, this novel approach resulted in a 34.8% range of motion (ROM) improvement and ability to fully extend all digits of the right hand. No adverse events were recorded. At 1 year post-surgery, the patient has no decrease in ROM. Results indicate that vCPM incorporation in open fasciectomy may provide benefit in reducing contracture recurrence in DD patients. [ABSTRACT FROM AUTHOR]

Collagen is one of the most important components of the extracellular matrix that is involved in the strength of tissues, cell adhesion and cell proliferation. Mutations in several collagen and posttranslational modification enzyme genes cause Ehlers-Danlos syndrome (EDS) characterized by joint and skin hyperextensibility as well as fragility of various organs. Carbohydrate sulfotransferase 14/dermatan 4-O-sulfotransferase-1 (CHST14/D4ST1) is a critical enzyme for biosynthesis of dermatan sulfate, a side chain of various proteoglycans including biglycan that regulates collagen fibrils through their interaction. Mutations in CHST14 were found to cause a new form of EDS, named musculocontractural type EDS (mcEDS-CHST14). Large subcutaneous hematomas are one of the most serious complications accompanied by decreased quality of life and potential lethality. In this study, Chst14 gene-deleted mice were expected to be an animal model of the vascular abnormalities of mcEDS-CHST14. However, only limited numbers of adult mice were generated because of perinatal lethality in most Chst14 gene-deleted homozygote (Chst14−/−) mice. Therefore, we investigated the placentas of these fetuses. The placentas of Chst14−/− fetuses showed a reduced weight, alterations in the vascular structure, and ischemic and/or necrotic-like changes. Electron microscopy demonstrated an abnormal structure of the basement membrane of capillaries in the placental villus. These findings suggest that Chst14 is essential for placental vascular development and perinatal survival of fetuses. Furthermore, placentas of Chst14−/− fetuses could be a useful model for vascular manifestations in mcEDS-CHST14, such as the large subcutaneous hematomas. [ABSTRACT FROM AUTHOR]

The placenta is a highly specialized organ that is formed during human gestation for conferring protection and generating an optimal microenvironment to maintain the equilibrium between immunological and biochemical factors for fetal development. Diverse pathogens, including viruses, can infect several cellular components of the placenta, such as trophoblasts, syncytiotrophoblasts and other hematopoietic cells. Viral infections during pregnancy have been associated with fetal malformation and pregnancy complications such as preterm labor. In this minireview, we describe the most recent findings regarding virus-host interactions at the placental interface and investigate the mechanisms through which viruses may access trophoblasts and the pathogenic processes involved in viral dissemination at the maternal-fetal interface. [ABSTRACT FROM AUTHOR]

Pregnancy-associated Plasmodium falciparum infection impacts the health of mothers and newborns, but little is known about the effects of these infections on infant susceptibility to malaria. We followed 473 mother-infant pairs during pregnancy and through 2 years of age. We observed that children born to mothers with placental malaria, but not those born to mothers with peripheral infection without evidence of placental sequestration, had increased risk of malaria during the first year of life compared with children born to mothers with no malaria during pregnancy. Malaria infections with placental sequestration have long-lasting impact on infant susceptibility to malaria infection. [ABSTRACT FROM AUTHOR]

Study Question: Can the baboon uterus support a gestation to livebirth with an angiosome using microsurgically anastomosed utero-ovarian vessels and lacking uterine arteries and veins?Summary Answer: Our angiosome model allows healthy livebirth albeit with risk of fetal growth restriction and stillbirth.What Is Known Already: Uterine transplant can provide livebirth in humans, but requires a living donor to undergo a prolonged laparotomy for hysterectomy. In an attempt to avoid the time-consuming dissection of the uterine vein, our group has previously shown maintenance of baboon uterine menstrual function after ligation of the uterine vein and after ligation of both the uterine artery and uterine vein.Study Design, Size, Duration: In a 19-month timespan, three baboons underwent laparotomy to surgically alter uterine perfusion, and pregnancy outcomes were monitored after spontaneous mating in a breeding colony.Participants/materials, Setting, Methods: Three nulligravid female Papio hamadryas baboons in a breeding colony underwent laparotomy to ligate uterine arteries and veins along with colpotomy and cervico-vaginal anastomosis. During the same surgery, the utero-ovarian arteries and veins were microsurgically transected and re-anastomosed to themselves. Intraoperative organ perfusion was confirmed with laser angiography. After a recovery period, monitoring of menstrual cycling via menstrual blood flow and sex-skin cycling occurred, as well as uterine viability via sonography and cervical biopsy. Each baboon was released to the breeding colony for spontaneous mating and pregnancies dated by menstrual calendar and compared with early ultrasound. Delivery outcomes were monitored in each including neonate weight and placental pathology. In the event of a stillbirth, the animal was returned to the breeding colony for repeat mating attempts. After achieving a livebirth, the maternal baboon was removed from the study.Main Results and the Role Of Chance: Each baboon in the trial underwent successful surgery with all uteri demonstrating viability and return of menstrual function within 10 weeks of surgery. Pregnancies occurred within two menstrual cycles in breeding colony. Baboons one and two initially had vaginal breech stillbirths, both with appearance of placental insufficiency, and one with fetal growth restriction. Baboon three underwent scheduled cesarean delivery resulting in a normally grown livebirth. Baboon one had a subsequent pregnancy resulting in a livebirth via cesarean delivery.Limitations, Reasons For Caution: Stillbirth in two of four gestations, and fetal growth restriction in one of four, are the largest concerns in our perfusion model. It remains uncertain whether the stillbirths resulted from placental insufficiency, or birth trauma from breech deliveries.Wider Implications Of the Findings: The success of two livebirths warrants further attempts at improving consistency of our proposed uterine angiosome. This may allow living uterine donors to undergo less-invasive and shorter donor hysterectomy procedures.Study Funding/competing Interest(s): The study had no external sponsors, and was supported by the Cleveland Clinic Foundation. Some equipment was loaned without cost to the research team including a laser angiography system courtesy of Novadaq Technologies, Inc. (Missaugua, ON, Canada) and a surgical microscope courtesy of DB Surgical (Coral Springs, FL, USA). B.B., K.A., M.S., K.R., M.M., P.F.E., A.T. and T.F. have no conflicts of interest. M.L.S. and S.Z. report activity as consultants for Medtronic-Covidien, and S.Z. also is a consultant to Applied Medical. [ABSTRACT FROM AUTHOR]

A comprehensive study of unusual cases of placental pathology may provide insight into mechanisms of normal human fertilization and early embryonic development by examining the exception to the rule. A gravida three para two 39-year-old woman was monitored by ultrasound from 16 weeks of gestation for cystic placenta. A female newborn was born at 36 weeks gestation. Pathologic examination of the partially cystic placenta revealed a singleton placenta comprised of 2/3 normal placenta and 1/3 complete hydatidiform mole, largely degenerated. Immunostaining for p57 was negative in stromal cells of the molar villi. Chromogenic in-situ hybridization revealed diploidy in both normal and molar parts. A total of 16 microsatellites were studied by short tandem repeat analysis, 11 of which were informative. The analysis revealed bipaternal molar tissue of dispermic origin. The paternal monospermic contribution to the normal part was different from that in the molar part, thus resulting in tripaternal contribution to the conceptus. A chimera is a single organism composed of two or more different populations of genetically distinct cells that originated from different zygotes (tetragametic) whereas mosaic is a mixture of two cell lines in one organism originating from one zygote. The possible mechanisms leading to the formation of chimeric/mosaic placenta in our case (one of the components being complete hydatidiform mole), including twinning, fusion at an early embryonic stage and diploidization of triploids, are discussed. [ABSTRACT FROM AUTHOR]

Background: A mother's infection with placental malaria (PM) can affect her child's susceptibility to malaria, although the mechanism remains unclear. The fetus acquires a small amount of maternal cells and DNA known as maternal microchimerism (MMc), and we hypothesized that PM increases MMc and that MMc alters risk of Plasmodium falciparum malaria during infancy.Methods: In a nested cohort from Muheza, Tanzania, we evaluated the presence and level of cord blood MMc in offspring of women with and without PM. A maternal-specific polymorphism was identified for each maternal-infant pair, and MMc was assayed by quantitative polymerase chain reaction. The ability of MMc to predict malaria outcomes during early childhood was evaluated in longitudinal models.Results: Inflammatory PM increased the detection rate of MMc among offspring of primigravidae and secundigravidae, and both noninflammatory and inflammatory PM increased the level of MMc. Detectable MMc predicted increased risk of positive blood smear but, interestingly, decreased risk of symptomatic malaria and malaria hospitalization.Conclusions: The acquisition of MMc may result in increased malaria infection but protection from malaria disease. Future studies should be directed at the cellular component of MMc, with attention to its ability to directly or indirectly coordinate anti-malarial immune responses in the offspring. [ABSTRACT FROM AUTHOR]

Background: Since the first successful use of donated oocytes in 1984, the number of oocyte donation cycles in Europe and the USA has dramatically increased. Consequently, there has been increasing interest in the impact of oocyte donation on maternal and fetal outcomes.Objective and Rationale: The aim of this review was to summarize the literature regarding maternal and fetal outcomes from pregnancies conceived through oocyte donation.Search Methods: Identification of relevant publications was through research within the Embase Medline and PubMed databases, the Google-indexed scientific literature and periodic specialized magazines from the on-line Library Service of the University of Milan.Outcomes: Oocyte donation seems to be independently associated with a higher rate of pregnancy-induced hypertension and pre-eclampsia. An explanatory hypothesis is that an immunological maladaptation causes placenta-mediated disorders in oocyte donation pregnancies. The risks are even higher in twin pregnancies. Oocyte donation also seems to be associated with lower fetal birthweight. However, after adjusting for obstetric complications, most studies report less pronounced differences in birthweight or no dissimilarities. The incidence of cesarean section is increased without clear clinical indications.Wider Implications: Oocyte donation pregnancies are associated with a higher rate of placental disorders of pregnancy, such as gestational hypertension and pre-eclampsia. The risk of poorer neonatal outcomes is increased in oocyte donation pregnancies compared to other in-vitro fertilization pregnancies. Poorer outcomes have been demonstrated especially for twin pregnancies and in association with previous chronic pathologies or the development of obstetrics complications. [ABSTRACT FROM AUTHOR]

Objective: The human Ureaplasma species are the microbes most frequently isolated from placentae of women who deliver preterm. The role of Ureaplasma species has been investigated in pregnancies at <32 weeks of gestation, but currently no studies have determined the prevalence of ureaplasmas in moderately preterm and late-preterm (hereafter, "moderate/late preterm") infants, the largest cohort of preterm infants.Methods: Women delivering moderate/late preterm infants (n = 477) and their infants/placentae (n = 535) were recruited, and swab specimens of chorioamnion tissue, chorioamnion tissue specimens, and cord blood specimens were obtained at delivery. Swab and tissue specimens were cultured and analyzed by 16S ribosomal RNA polymerase chain reaction (PCR) for the presence of microorganisms, while cord blood specimens were analyzed for the presence of cytokines, chemokines, and growth factors.Results: We detected microorganisms in 10.6% of 535 placentae (443 were delivered late preterm and 92 were delivered at term). Significantly, Ureaplasma species were the most prevalent microorganisms, and their presence alone was associated with histologically confirmed chorioamnionitis in moderate/late preterm and term placentae (P < .001). The presence of ureaplasmas in the chorioamnion was also associated with elevated levels of granulocyte colony-stimulating factor (P = .02).Conclusions: These findings have important implications for infection and adverse pregnancy outcomes throughout gestation and should be of major consideration for obstetricians and neonatologists. [ABSTRACT FROM AUTHOR]

Background: Passively acquired respiratory syncytial virus (RSV) neutralizing antibody protects against RSV-associated lower respiratory infections, but placental malaria (PM) and maternal hypergammaglobulinemia might interfere with transplacental immunoglobulin transport.Methods: We measured RSV plaque-reduction neutralization (PRN) antibody in 300 full-term maternal/cord serum pairs in 2 cohorts in malaria-endemic Papua New Guinea: Alexishafen (2005-2008) and the Fetal Immunity Study (FIS) (2011-2013). We defined impaired transport as a cord-to-maternal titer ratio <1.0 and a protective RSV PRN titer (PRNT) ≥1:200.Results: PM and hypergammaglobulinemia occurred in 60% and 54% of Alexishafen mothers versus 8% and 9% of FIS mothers, respectively. 34% of Alexishafen and 32% of FIS pairs demonstrated impaired transport. Multivariate modeling revealed significant associations between increasing maternal IgG (log2) and impaired transport (adjusted OR, Alexishafen: 2.68 [1.17-6.14], FIS: 6.94 [1.94-24.8]) but no association with PM. 34% of Alexishafen and 31% of FIS cord PRNTs were <1:200.Conclusions: Impaired RSV antibody transport was observed in approximately one-third of maternal/cord pairs. Hypergammaglobulinemia, but not PM, was associated with impaired transport, particularly among women with low RSV PRNT. Detection of RSV PRNT <1:200 in one-third of cord sera confirms the need to increase levels of RSV neutralizing antibody in pregnant women through maternal immunization. [ABSTRACT FROM AUTHOR]

Objectives: Triploidy (69, XXX; 69, XXY; 69, XYY) accounts for 1% of conceptions, but the affected fetus often does not survive past the first trimester. Fetal development in triploidy is rare. A consecutive series was used to describe the fetal and placental phenotypes and compare them with previous publications. Methods: Fifty-four triploid fetuses were identified in the Active Malformations Surveillance Program between 1972 and 2012 at Brigham andWomen's Hospital in Boston. The phenotype was described from prenatal imaging and autopsy findings. Results: The diagnosis was confirmed by chromosome analysis in 53 of the 54 fetuses. Twenty-seven (50%) of the affected fetuses were identified during pregnancy. The abnormalities identified by prenatal ultrasound included renal malformations, heart defects, hydrocephalus, holoprosencephaly, and myelomeningocele. At autopsy, syndactyly, usually between fingers 3 and 4, was identified in 37 (69%) of the fetuses. Thirteen (24%) of the infants had the histologic features of a partial hydatidiform mole in the placenta. Conclusions: The presence of major malformations and growth restriction during pregnancy makes triploidy a potential diagnosis. There are no obligate clinical features in triploidy. Syndactyly, especially 3-4 syndactyly of the hands, is a distinctive feature. Cystic changes in the placenta can be seen by ultrasound during pregnancy. There was no difference in the phenotype between triploid infants associated with partial moles and those with nonmolar placentas. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Does polycystic ovary syndrome (PCOS) in women without pregnancy complications affect placental signal transducer and activator of transcription 3 (STAT3) and mechanistic target of rapamycin (mTOR) signaling? SUMMARY ANSWER Placental STAT3 signaling is activated but mTOR signaling is unaffected in PCOS. WHAT IS KNOWN ALREADY Women with PCOS have increased risk of poor pregnancy outcomes (e.g. restricted or accelerated fetal growth), indicating placental dysfunction. Placental STAT3 and mTOR pathways regulate placental function and indirectly affect fetal growth. STUDY DESIGN, SIZE, DURATION In a case–control study, placental tissue and maternal blood were collected at delivery from 40 control pregnant women and 38 PCOS women with uncomplicated pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS Women with PCOS were recruited at two medical centers and pregnant controls were recruited at one of these centers. Placental mRNA expression of genes encoding proteins related to steroid action, metabolic pathways and cytokines was analyzed by quantitative RT–PCR. Phosphorylated placental STAT3 (P-STAT3) and mTOR targets was measured by western blot. Levels of sex steroids in serum were determined by mass spectrometry. MAIN RESULTS AND THE ROLE OF CHANCE Placental P-STAT3 (Tyr-705) was increased in women with PCOS (P < 0.05) versus controls. Placental mTOR signaling was not affected in PCOS women when compared with controls. Circulating levels of androstenedione, androst-5-ene-3β, 17β-diol, testosterone, 5α-dihydrotestosterone and etiocholanolone glucuronide were higher and estradiol lower in women with PCOS than in controls (all P < 0.05). No correlation between sex steroid levels in serum and P-STAT3 was observed. LIMITATIONS, REASONS FOR CAUTION Women with PCOS and pregnancy complications were excluded to avoid the confounding effects of placental pathologies, which could modify STAT3 and mTOR signaling. Moreover, 97.4% of women with PCOS in the study displayed oligoamenorrhea at diagnosis. Thus, the current findings could be restricted to PCOS women with the oligo-anovulatory phenotype without pregnancy complications. WIDER IMPLICATIONS OF THE FINDINGS Phosphorylation of STAT3 is increased in the placenta from women with PCOS and uncomplicated pregnancies, indicating that specific metabolic placental pathways are activated in the absence of obstetric and perinatal complications. STUDY FUNDING/COMPETING INTEREST(S) The work was supported by the Swedish Medical Research Council (Project No. 2011-2732 and 2014-2775); Jane and Dan Olsson Foundation, Wilhelm and Martina Lundgrens's Science Fund; Hjalmar Svensson Foundation (E.S.-V and M.M.); Adlerbert Research Foundation; Swedish federal government under the LUA/ALF agreement ALFFGBG-136481 and 429501 and the Regional Research and Development agreement (VGFOUREG-5171, -11296 and -7861). MM thanks the Becas Chile Programme (Chile) and University of Chile for financial support through a postdoctoral fellowship. There are no competing interests. [ABSTRACT FROM PUBLISHER]

A case of Couvelaire uterus with placenta accreta found during scheduled repeat low transverse Cesarean section will be discussed within this article. First described in the 1900s, Couvelaire syndrome, also known as uteroplacental apoplexy, is a rare form of nonfatal placenta abruption complication. The case involves a 30-year-old gravida 3 para 2 otherwise healthy female with an uncomplicated pregnancy and two previous cesarean deliveries without complication. She received routine prenatal care. During her pregnancy, she did not experience any symptoms such as vaginal bleeding or abdominal pain. After delivering a healthy female, there were several unsuccessful attempts to remove the placenta from the uterus. Upon inspection, the uterus was found have dark purple patches with ecchymosis and indurations, diagnostic of Couvelaire uterus. Furthermore, there was high clinical suspicion for placenta accreta as the 30-minute mark approached without placenta detachment. A telephonic emergency review with the wet desk radiologist of the 18-week ultrasound revealed high suspicion for placenta accreta. A Cesarean hysterectomy was performed for prevention of significant hemorrhage. This case report may be the first documented association of Couvelaire uterus with placenta accreta. Providers should be vigilant in monitoring for antenatal bleeding, timing of placenta separation, and postpartum hemorrhage. [ABSTRACT FROM AUTHOR]

Spontaneous abortion in early pregnancy due to unknown reasons is a common problem. The excess complement activation and consequent placental inflammation and anti-angiogenic milieu is emerging as an important associated factor in many pregnancy-related complications. In the present study we sought to examine the expression of complement inhibitory proteins at the feto-maternal interface and levels of complement split products in the circulation to understand their role in spontaneous abortion. Consenting pregnant women who either underwent elective abortion due to non-clinical reasons ( n = 13) or suffered miscarriage ( n = 14) were recruited for the study. Systemic levels of complement factors C3a and C5a were measured by enzyme-linked immunosorbent assay ( ELISA). Plasma C5 and C3 protein levels were examined by Western blot. Expressions of complement regulatory proteins such as CD46 and CD55 in the decidua were investigated by quantitative polymerase chain reaction ( PCR) and Western blot. The median of plasma C3a level was 82·83 ng/ml and 66·17 ng/ml in elective and spontaneous abortion patients, respectively. Medians of plasma C5a levels in elective and spontaneous abortion patients were 0·96 ng/ml and 1·14 ng/ml, respectively. Only plasma C5a levels but not C3a levels showed significant elevation in spontaneous abortion patients compared to elective abortion patients. Further, there was a threefold decrease in the mRNA expressions of complement inhibitory proteins CD46 and CD55 in the decidua obtained from spontaneous abortion patients compared to that of elective abortion patients. These data suggested that dysregulated complement cascade may be associated with spontaneous abortion. [ABSTRACT FROM AUTHOR]

The serotonin transporter (SERT) is a key regulatory molecule in serotonergic transmission implicated in numerous biological processes relevant to human disorders. Recently, it was shown that SERT expression is controlled by miR-16 in mouse brain. Here, we show that SERT expression is regulated additionally by miR-15a as well as miR-16 in human and rat tissues. This post-transcriptional regulation was observed and characterized in reporter assays and likewise when endogenous SERT expression was evaluated in human placental choriocarcinoma JAR cells and rat brain raphe RN46A cells - two cell lines that en-dogenously express SERT. Similar effects for miR-16 to those of miR-15a were found in both human and rat cell lines. The effects of miR-15a and miR-16 were comparable in extent to those originally reported for miR-16 in mice. These findings represent a novel layer of complexity for SERT expression regulation exerted by the mir-15a/16 cluster, whose genes are adjacently located at human chromosome 13ql4.3. [ABSTRACT FROM AUTHOR]

Background. Evidence of the presence of Plasmodium vivax in the placenta is scarce and inconclusive. This information is relevant to understanding whether P. vivax affects placental function and how it may contribute to poor pregnancy outcomes.Methods. Histopathologic examination of placental biopsies from 80 Papua New Guinean pregnant women was combined with quantitative polymerase chain reaction (qPCR) to confirm P. vivax infection and rule out coinfection with other Plasmodium species in placental and peripheral blood. Leukocytes and monocytes/macrophages were detected in placental sections by immunohistochemistry.Results. Monoinfection by P. vivax and Plasmodium falciparum was detected by qPCR in 8 and 10 placentas, respectively. Seven of the 8 women with P. vivax placental monoinfection were negative in peripheral blood. By histology, 3 placentas with P. vivax monoinfection showed parasitized erythrocytes in the intervillous space but no hemozoin in macrophages nor increased intervillous inflammatory cells. In contrast, 7 placentas positive for P. falciparum presented parasites and hemozoin in macrophages or fibrin as well as intervillous inflammatory infiltrates.Conclusions. Plasmodium vivax can be associated with placental infection. However, placental inflammation is not observed in P. vivax monoinfections, suggesting other causes of poor delivery outcomes associated with P. vivax infection. [ABSTRACT FROM AUTHOR]

Background. Plasmodium falciparum–infected erythrocytes (IEs) adhere to host cell receptors, allowing parasites to sequester into deep vascular beds of various organs. This defining phenomenon of malaria pathogenesis is key to the severe clinical complications associated with cerebral and placental malaria. The principal ligand associated with the binding to chondroitin sulfate A (CSA) that allows placental sequestration of IEs is a P. falciparum erythrocyte membrane protein 1 (PfEMP1) family member encoded by the var2csa gene.Methods. Here, we investigated the transcription pattern of var genes by real-time polymerase chain reaction, the expression of VAR2CSA, protein by flow cytometry, and the CSA-binding ability of IEs collected at different stages of pregnancy using a static-based Petri dish assay.Results. Through comparison with the profiles of isolates from nonpregnant hosts, we report several lines of evidence showing that parasites infecting women during pregnancy preferentially express VAR2CSA protein, and that selection for the capacity to adhere to CSA via VAR2CSA expression occurs early in pregnancy.Conclusions. Our data suggest that the placental tropism of P. falciparum is already established in the first trimester of pregnancy, with consequent implications for the development of the pathology associated with placental malaria. [ABSTRACT FROM AUTHOR]

Malaria placental infection was strongly associated with risk of nonmalaria infectious morbidity in 553 infants followed from birth to the age of 18 months in Benin.Background. Several studies have shown that the risk of malaria infection increases for children born to a mother with placental malaria infection. An immune tolerance phenomenon has been hypothesized. We addressed whether Plasmodium falciparum placental infection could additionally be associated with the risk of nonmalaria fevers in infants.Methods. From 2007 to 2009, 553 infants were followed up from birth to 18 months in Benin. The occurrence of fever was actively screened by trained community workers. Malaria fevers (temperature >37.5°C with positive results of rapid diagnostic test or thick blood smear) were excluded from analysis. The association between placental malaria infection and the number of total, gastrointestinal, and respiratory febrile episodes was explored using binomial negative regression, with adjustment for maternal age, parity, parents’ schooling, socioeconomic level, sex, village of birth, season of birth, prematurity, Apgar score and nutritional status.Results. The prevalence of placental malaria infection was 11.2%. During a median follow-up of 17.8 months, 624 nonmalaria fevers were registered. Placental malaria infection was associated with a higher risk of nonmalaria fever episodes (adjusted incidence rate ratio, 1.4; 95% confidence interval, 1.1–1.8) as well as gastrointestinal (1.6; 1.1–2.5) and respiratory (1.5; 1.1–2.1) febrile syndromes. The same pattern was obtained when considering consultations after the age of 6 months.Conclusions. These results suggest an association between placental malaria infection and nonmalaria infections in the first 18 months of life. Immune tolerance could lead to impaired immune development not specific to malaria infections in infants born to mothers with placental malaria infection, but further studies are needed. [ABSTRACT FROM AUTHOR]

The authors use recent methodology in causal inference to disentangle the direct and indirect effects that operate through a mediator in an exposure-response association paradigm. They demonstrate how total effects can be partitioned into direct and indirect effects even when the exposure and mediator interact. The impact of bias due to unmeasured confounding on the exposure-response association is assessed through a series of sensitivity analyses. These methods are applied to a problem in perinatal epidemiology to examine the extent to which the effect of abruption on perinatal mortality is mediated through preterm delivery. Data on over 26 million US singleton births (1995–2002) were utilized. Risks of mortality among abruption and nonabruption births were 102.7 and 6.2 per 1,000 births, respectively. Risk ratios of the natural direct and indirect (preterm delivery-mediated) effects of abruption on mortality were 10.18 (95% confidence interval: 9.80, 10.58) and 1.35 (95% confidence interval: 1.33, 1.38), respectively. The proportion of increased mortality risk mediated through preterm delivery was 28.1%, with even higher proportions associated with deliveries at earlier gestational ages. Sensitivity analyses underscore that the qualitative conclusions of some mediated effects and substantial direct effects are reasonably robust to unmeasured confounding of a fairly considerable magnitude. [ABSTRACT FROM AUTHOR]

BackgroundAbnormal activation and/or dysfunction of the maternal vascular endothelium have been implicated as a cause of the placental ischemia and oxidative damage associated with pregnancy-induced hypertension (PIH).MethodsTo clarify the relationship between systemic oxidative stress and placental damage induced by reactive oxygen species (ROS), we immunostained placentas from 27 PIH pregnancies and 41 normal pregnancies for 8-hydroxy-2-deoxyguanosine (8OHdG).ResultsPositive 8OHdG staining was significantly more frequent in the syncytiotrophoblasts from PIH pregnancies compared to normal pregnancies matched for maternal age/gestational age at delivery. Comparison of 8OHdG positive and negative PIH patients revealed that antenatal serum uric acid (UA) was significantly higher, gestational age at delivery was significantly lower and early onset PIH was more frequent in patients with 8OHdG positive staining in the placenta.ConclusionThese results suggest that ROS directly injures the placental syncytiotrophoblast in PIH patients and that elevated UA in PIH patients, at least partly, indicates placental damage induced by ROS. Moreover, the role and significance of ROS injury in the placenta may differ between early onset and late-onset type PIH.American Journal of Hypertension (2011). doi:10.1038/ajh.2011.40 [ABSTRACT FROM AUTHOR]

BACKGROUND Severe pre-eclampsia (sPE) causes significant maternal morbidity and intrauterine growth restriction as a result of severe placental dysfunction. Defects in the formation of both extra-villous and villous trophoblast are characteristic of this disease. The outer syncytiotrophoblast layer covering the placental villi develops syncytial knots and focal necrosis while reduced invasion of the extra-villous trophoblast results in a reduced maternal blood supply and ischemia of the placental villi. The transcription factor glial cell missing-1 (GCM1) regulates formation of both types of trophoblast. GCM1 expression is reduced in placental villi of women with sPE but the functional downstream consequences of reduced GCM1 expression are unknown. METHODS AND RESULTS In floating first trimester villous explants we demonstrated increased mRNA (2.5-fold, n = 12) and protein level (9.8-fold) of tissue inhibitor of metalloproteinase-4 (TIMP4) following repression of GCM1 (70 ± 7%) by small interfering-RNA, using RT–PCR and western blot, respectively. Similar increases in TIMP4 mRNA (4.2-fold, n = 7, P< 0.001 versus control) and protein levels were found following gene silencing of GCM1 in BeWo cells (<90% knock down of protein). TIMP4 protein was increased in placenta from women with sPE (3.5 ± 0.4 pg/µg, n = 8), compared with preterm (1.7 ± 0.17 pg/µg, n = 9) and term controls (1.6 ± 0.16 pg/µg, n = 9; P< 0.01; quantified by enzyme-linked immunosorbent assay and visualized using immunohistochemistry) with reduced GCM1 expression, mostly in the pathologic syncytial knots. CONCLUSIONS TIMP4 is a downstream target of GCM1 that may link the consequences of reduced GCM-1-directed trophoblast differentiation to histologic and functional components of disordered placentation in sPE. [ABSTRACT FROM PUBLISHER]

BACKGROUND Vascular endothelial growth factor (VEGF) is the most potent stimulator of angiogenesis. It mediates its activity through two membrane-bound receptors, VEGFR-1 and VEGFR-2, both expressed in the placenta. Beginning in early pregnancy, the soluble form of the first, sVEGFR-1, binds and inhibits most of the biological actions of circulating VEGF. After delivery, it disappears from the maternal circulation. METHODS We determined the biological elimination rate of endogenous sVEGFR-1 after term pregnancy in serial venous samples obtained during and after elective Caesarean sections (n=8), and we demonstrated the relationship between serum sVEGFR-1 and VEGF after mid-trimester legal termination of pregnancy (n = 5), by analysing their concentrations using immunoassays (ELISA). RESULTS The disappearance of sVEGFR-1 from circulation after Caesarean delivery was biphasic with a rapid half-life of 3.4 h (2.2–7.5 h; median, range) and a slow one of 29 h (17–94 h). After mid-trimester legal termination of pregnancy the sVEGFR-1 concentrations decreased and those of free VEGF simultaneously increased with a highly significant negative correlation with each other (r = −0.90, P < 0.0001). CONCLUSIONS The disappearance of endogenous sVEGFR-1 after pregnancy is biphasic, and it is associated with a simultaneous increase in free VEGF concentrations. [ABSTRACT FROM AUTHOR]

Background. A recent study has shown that preeclampsia is an important risk marker for end-stage renal disease (ESRD), but the underlying mechanisms are unclear. The present study investigated whether previous preeclampsia was associated with progression of established kidney disease.Material and methods. Data from the Norwegian Kidney Biopsy Registry and the Medical Birth Registry of Norway were linked. We included women who, after their last pregnancy, had had a representative kidney biopsy in 1988–2005. Women were followed up for the development of ESRD using data from the Norwegian Renal Registry. Baseline was set at the time of biopsy and Cox regression statistics were performed.Results. Of the 582 included women, 76 developed ESRD 3.9 ± 3.4 years (range, 0.08–16 years) after diagnosis. Mean age at first birth was 24.0 ± 4.8 years and at the time of diagnosis 41.3 ± 9.7 years. Women with clinically diagnosed preeclampsia in their first pregnancy had a relative risk of ESRD of 1.2 (95% CI, 0.63–2.4) and women with preterm birth had a relative risk of 2.1 (95% CI, 1.2–3.9). After extensive adjustments for clinical and histopathological variables at the time of diagnosis, the relative risks were 1.1 (95% CI, 0.50–2.6) and 2.4 (95% CI, 1.2–4.6), respectively. Compared to women with a first term birth without preeclampsia, women with term preeclampsia were diagnosed at a younger age (36 vs 42 years) and women with preterm birth without preeclampsia had a lower estimated glomerular filtration rate at diagnosis (48 vs 64 ml/min/1.73 m2).Conclusion. In women with kidney disease diagnosed at kidney biopsy, previous preeclampsia does not seem to be a risk marker for progression to ESRD. [ABSTRACT FROM AUTHOR]

Summary: A cross-sectional study was conducted during the period of August 2007–April 2008 at Al-Wahda Teaching Hospital in Yemen to investigate prevalence and risk factors for placental malaria and anaemia and their effects on birthweight. Sociodemographic characteristics were gathered, maternal haemoglobin was measured and blood films were examined for malaria. Newborn birthweight was recorded. Out of 900 parturient women, malaria blood films were positive in 32 (3.6%) cases: in six sets of peripheral, placental and cord samples; in 15 placental and cord samples; and in 11 placental samples only. Malaria was not associated with age and parity, but it was significantly associated with history of fever [odds ratio (OR) 8.5, 95% CI 3.7–19, P <0.001], rural residence (OR 2.5, 95% CI 1.1–5.3, P =0.01) and rainy season (OR 5.1, 95% CI 1.7–15.2, P =0.003). Overall, 694 (77.1%) out of these 900 women had anaemia (Hb<11g/dl) and 16 (1.8%) patients had severe anaemia (Hb<7g/dl). Anaemia was not associated with age, parity and malaria. Low birthweight was significantly associated with malaria (OR 5.7, 95% CI 1.7–18.5; P =0.004). Thus, preventive measures (bednets and intermittent preventive treatment) should be employed for pregnant women regardless of their age or parity. [Copyright &y& Elsevier]

Summary: Chagas disease is caused by Trypanosoma cruzi, which can be transmitted to the fetus via the transplacental route. Factors that may be involved in transplacental transmission include parasite strain and placental immunological competence. The aim of this work was to compare the biological differences between two subpopulations of T. cruzi with respect to their interaction with the human placenta in vitro. We found that the Tulahuen strain (sublineage TcIIe) and another strain isolated from a congenitally infected newborn child had similar rates of productive infection in human chorionic villi in vitro, with similar deleterious nitric oxide levels between the two strains. We also found that the congenital T. cruzi stock had a greater ability than the Tulahuen strain to survive in the placental deleterious media, with the difference acquiring more importance considering the low reproductive rate of both subpopulations of T. cruzi within placental cells. As the presence of T. cruzi is a necessary condition to produce congenital transmission, we propose that the different survival rates of strains of T. cruzi in an adverse placental environment offer an opportunity for the parasite to infect the placenta in order to produce a sustainable infection during pregnancy, with the subsequent possibility of infecting the fetus. [Copyright &y& Elsevier]

Historically, untreated disseminated coccidioidomycosis during pregnancy was thought to be associated with 100% maternal fatality and 50% fetal mortality and was the leading cause of maternal deaths in areas of endemicity. As recently as 1995, therapeutic abortions and early deliveries were advocated in certain contexts. This report describes an unrecognized case of disseminated coccidioidomycosis diagnosed at the time of placental examination in a woman who completed her pregnancy without significant maternofetal complications. This case suggests that abortion and early delivery may not be necessary, because the possibility of an uncomplicated pregnancy exists. It is likely that other similar cases exist but remain underreported or underdiagnosed because of the mild, nondescript nature of the illness and low clinical suspicion. Although this mother and infant had good clinical outcomes, thorough travel histories and consideration of the associated travel-related diseases are important because of the possibility of serious, potentially avoidable clinical consequences. [ABSTRACT FROM AUTHOR]

Background. Q fever is a zoonosis caused by Coxiella burnetii. During pregnancy, it may result in obstetric complications, such as spontaneous abortion, intrauterine growth retardation, intrauterine fetal death, and pre-mature delivery. Pregnant women are exposed to the risk of chronic Q fever. Methods. We included 53 pregnant women who received a diagnosis of Q fever. We compared the incidence of obstetric and maternal Q fever complications for women who received long-term cotrimoxazole treatment (n = 16) with that for women who did not receive long-term cotrimoxazole treatment (n = 37); long-term cotrimoxazole treatment was defined as oral administration of trimethoprim-sulfamethoxazole during at least 5 weeks of pregnancy. Results. Obstetric complications were observed in 81.1% of pregnant women who did not receive long-term cotrimoxazole therapy: 5 (13.5%) women experienced spontaneous abortions, 10 (27%) experienced intrauterine growth retardation, 10 (27%) experienced intrauterine fetal death, and 10 (27%) experienced premature delivery. Oligoamnios was observed in 4 patients (10.8%). Obstetric complications were found to occur significantly more often in patients infected during their first trimester of pregnancy than in those infected later (P = .032). The outcome of the pregnancy was found to depend on placental infection by C. burnetii (P = .013). Long-term cotrimoxazole treatment protected against maternal chronic Q fever (P = .001), placental infection (P = .038), and obstetric complications (P = .009), especially intrauterine fetal death (P .018), which was found to be related to placental infection (P = .008). Conclusions. Q fever during pregnancy results in severe obstetric complications, including oligoamnios. Because of its ability to protect against placental infection, intrauterine fetal death, and maternal chronic Q fever, long- term cotrimoxazole treatment should be used to treat pregnant women with Q fever. [ABSTRACT FROM AUTHOR]

Background. In clinical trials, maternal tetanus toxoid (TT) vaccination is effective in protecting newborns against tetanus infection, but inadequate placental transfer of tetanus antibodies may contribute to lower-than expected rates of protection in routine practice. We studied the effect of placental malaria and maternal human immunodeficiency virus (HIV) infection on placental transfer of antibodies to tetanus. Methods. A total of 704 maternal-cord paired serum samples were tested by ELISA for antibodies to tetanus. The HIV status of all women was determined by an immunoglobulin G antibody–capture particle-adherence test, and placental malaria was determined by placental biopsy. Maternal history of TT vaccination was recorded. Results. Tetanus antibody levels were reduced by 52% (95% confidence interval [CI], 30%-67%) in newborns of HIV-infected women and by 48% (95% CI, 26%-62%) in newborns whose mothers had active-chronic or past placental malaria. Thirty-seven mothers (5.3%) and 55 newborns (7.8%) had tetanus antibody levels <0.1 IU/mL (i.e., were seronegative). Mothers' self-reported history of lack of tetanus immunization was the strongest predictor of seronegativity and of tetanus antibody levels in maternal and cord serum. Conclusion. Malarial and HIV infections may hinder efforts to eliminate maternal and neonatal tetanus, making implementation of the current policy for mass vaccination of women of childbearing age an urgent prio [ABSTRACT FROM AUTHOR]

Background. Serological testing for primary maternal cytomegalovirus (CMV) infection during pregnancy is not routine, but ultrasound studies are routine. Therefore, we evaluated placental thickening in women with primary CMV infection during pregnancy. Methods. The study included 92 women with primary CMV infection during pregnancy and 73 CMV-seropositive pregnant women without primary CMV infection. Neonatal CMV transmission was determined by CMV culture of urine samples. Thirty-two women were treated with CMV hyperimmune globulin to either prevent or treat intrauterine CMV infection. Maximal placental thickness was measured by longitudinal (nonoblique) scanning with the ultrasound beam perpendicular to the chorial dish. Programmed placental ultrasound evaluations were performed from 16 to 36 weeks of gestation. Results. At each measurement between 16 and 36 weeks of gestation, women with primary CMV infection who had a fetus or newborn with CMV disease had placentas that were significantly thicker than those of women with primary CMV infection who did not have a diseased fetus or newborn (P < .0001); the latter group, in turn, had placentas that were significantly thicker than those of seropositive control subjects (P < .0001). For both women with and women without diseased fetuses or newborns, receipt of hyperimmune globulin after primary CMV infection was associated with statistically significant reductions in placental thickness (P < .001). Placental vertical thickness values, which are predictive of primary maternal infection, were observed at each measurement from 16 to 36 weeks of gestation, and cutoff values ranged from 22 mm to 35 mm, with the best sensitivity and specificity at 28 and 32 weeks of gestation. Conclusions. Primary maternal CMV infection and fetal or neonatal disease are associated with sonographically thickened placentas, which respond to administration of hyperimmune globulin. These observations suggest that many of the manifestations of fetal and neonatal disease are caused by placental insufficiency. [ABSTRACT FROM AUTHOR]