Preterm Placenta Research Articles

Novel placental biomarker shows predictive potential for spontaneous preterm labor.

Human parturition involve many events among mother, fetus, and placenta, and the initiation of these events is the consequence of activation of a series of endocrine and immune responses. Multiple underlying pathways account for the cascade of events that culminate in spontaneous preterm labor. In this study, we aimed to characterize these signaling pathways of placental origin at molecular levels. We used single-cell RNA-sequencing (sc-RNA-seq) analysis to probe transcriptional heterogeneity in human placenta delivered at preterm or term and then used RNA in situ hybridization (RNA-ISH) assay on formalin-fixed paraffin-embedded placental tissues to validate these results. By using sc-RNA-seq on villous cytotrophoblast isolated from a preterm placenta, we found that signaling pathways implicated in initiation of term or preterm labor including ferroptosis, kisspeptin, and senescence were constitutively activated in distinct cellular clusters of these trophoblastic stem cells. RNA-ISH-based spatial gene expression profiling in formalin-fixed paraffin-embedded tissues revealed that Pregnancy Specific beta-1-Glycoprotein 4 (PSG4), a potent molecular driver for cellular aging, was significantly increased in preterm placentas (N=30) compared to their full-term counterparts (N=9). Furthermore, PSG4 mRNA signals were predominantly detected in the villous syncytiotrophoblast and the discontinuous monolayer of cytotrophoblast as well as the intervillous space where maternal blood circulates. Our study provides strong support for PSG4 overexpression serving as a biomarker for pregnant women at risk for preterm delivery, which can allow for development of timely and clinical preventive strategies.

Association between adenomyosis volume and adverse perinatal outcomes: multicenter cohort study.

To assess the association between adenomyosis volume, as a reflection of its severity, and the risk of adverse perinatal outcomes. This multicenter retrospective cohort study was conducted at a comprehensive tertiary care institution and a tertiary maternal and child healthcare hospital, which are the main types of hospital providing maternal medical care in China. The study included pregnant women without adenomyosis (non-AD cohort) who delivered between 1 January 2021 and 31 December 2021, and women with pregnancy complicated by adenomyosis (AD cohort) who delivered between 1 January 2020 and 31 December 2022. Adenomyosis was diagnosed and measured using transvaginal or transabdominal ultrasound up to 14 weeks of gestation. The adenomyosis volume (V) was calculated based on the sonographic measurement of three dimensions, using the formula V = (length × width × thickness) × 4/3π. Univariate and multivariate logistic regression analyses were conducted to assess the association between adenomyosis and the risk of pregnancy complications. We also performed a sensitivity analysis among 226 pregnancies complicated by adenomyosis that had volume measurements available and 10 507 pregnancies without adenomyosis, using as a threshold for severe adenomyosis the 3rd quartile of adenomyosis volume. The study group included 10 507 pregnant women in the non-AD cohort and 321 in the AD cohort. Pregnancies complicated by adenomyosis had an increased risk of preterm birth < 37 weeks of gestation (adjusted odds ratio (aOR), 2.39 (95% CI, 1.65-3.48)), spontaneous preterm birth < 37 weeks of gestation (aOR, 2.57 (95% CI, 1.54-4.28)), placenta previa (aOR, 2.57 (95% CI, 1.41-4.67)), cervical incompetence (aOR, 9.70 (95% CI, 4.00-23.55)) and abnormal fetal presentation (aOR, 2.04 (95% CI, 1.39-3.00)), and there was also a non-significant trend toward increased risk of pre-eclampsia (aOR, 1.64 (95% CI, 0.94-2.85)). Sensitivity analysis revealed there was a greater risk in pregnancies with severe (≥ 757.5 cm3) vs mild adenomyosis of preterm birth < 37 weeks of gestation (aOR, 5.50 (95% CI, 2.80-10.82) vs aOR, 1.73 (95% CI, 0.98-3.05)), pre-eclampsia (aOR, 4.94 (95% CI, 2.11-11.58) vs aOR, 1.03 (95% CI, 0.41-2.58)), placenta previa (aOR, 6.37 (95% CI, 2.39-17.04) vs aOR, 1.58 (95% CI, 0.60-4.19)) and cervical incompetence (aOR, 12.79 (95% CI, 2.87-56.93) vs aOR, 4.97 (95% CI, 1.25-19.77)) compared to pregnancies without adenomyosis. The risk of spontaneous preterm birth < 37 weeks and the risk of abnormal fetal presentation was similar between the two subgroups. Pregnancies complicated by adenomyosis, particularly those with severe adenomyosis, have an increased risk of pregnancy complications, including preterm birth, spontaneous preterm birth, placenta previa, cervical incompetence and abnormal fetal presentation. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

Identification of key metabolism-related genes and pathways in spontaneous preterm birth: combining bioinformatic analysis and machine learning.

Spontaneous preterm birth (sPTB) is a global disease that is a leading cause of death in neonates and children younger than 5 years of age. However, the etiology of sPTB remains poorly understood. Recent evidence has shown a strong association between metabolic disorders and sPTB. To determine the metabolic alterations in sPTB patients, we used various bioinformatics methods to analyze the abnormal changes in metabolic pathways in the preterm placenta via existing datasets. In this study, we integrated two datasets (GSE203507 and GSE174415) from the NCBI GEO database for the following analysis. We utilized the "Deseq2" R package and WGCNA for differentially expressed genes (DEGs) analysis; the identified DEGs were subsequently compared with metabolism-related genes. To identify the altered metabolism-related pathways and hub genes in sPTB patients, we performed multiple functional enrichment analysis and applied three machine learning algorithms, LASSO, SVM-RFE, and RF, with the hub genes that were verified by immunohistochemistry. Additionally, we conducted single-sample gene set enrichment analysis to assess immune infiltration in the placenta. We identified 228 sPTB-related DEGs that were enriched in pathways such as arachidonic acid and glutathione metabolism. A total of 3 metabolism-related hub genes, namely, ANPEP, CKMT1B, and PLA2G4A, were identified and validated in external datasets and experiments. A nomogram model was developed and evaluated with 3 hub genes; the model could reliably distinguish sPTB patients and term labor patients with an area under the curve (AUC) > 0.75 for both the training and validation sets. Immune infiltration analysis revealed immune dysregulation in sPTB patients. Three potential hub genes that influence the occurrence of sPTB through shadow participation in placental metabolism were identified; these results provide a new perspective for the development and targeting of treatments for sPTB.

Arachidonic acid metabolism regulates the development of retinopathy of prematurity among preterm infants.

Extremely preterm infants are at risk of developing retinopathy of prematurity (ROP), characterized by neovascularization and neuroinflammation leading to blindness. Polyunsaturated fatty acid (PUFA) supplementation is recommended in preterm infants to lower the risk of ROP, however, with no significant improvement in visual acuity. Reasonably, this could be as a result of the non-consideration of PUFA metabolizing enzymes. We hypothesize that abnormal metabolism of the arachidonic acid (AA) pathway may contribute to severe stages of ROP. The present study investigated the AA-metabolizing enzymes in ROP pathogenesis by a targeted gene expression analysis of blood (severe ROP = 70, No/Mild = 56), placenta (preterm placenta = 6, full term placenta = 3), and human primary retinal cell cultures and further confirmed at the protein level by performing IHC in sections of ROP retina. The lipid metabolites were identified by LC-MS in the vitreous humor (VH; severe ROP = 15, control = 15). Prostaglandins D2 (p = 0.02), leukotrienes B5 (p = 0.0001), 11,12-epoxyeicosatrienoic acid (p = 0.01), and lipid-metabolizing enzymes of the AA pathway such as CYP1B1, CYP2C8, COX2, and ALOX15 were significantly upregulated while EPHX2 was significantly (0.04) downregulated in ROP cases. Genes involved in hypoxic stress, angiogenesis, and apoptosis showed increased expression in ROP. An increase in the metabolic intermediates generated from the AA metabolism pathway further confirmed the role of these enzymes in ROP, while metabolites for EPHX2 activity were low in abundance. Inflammatory lipid intermediates were higher compared to anti-inflammatory lipids in VH and showed an association with enzyme activity. Both the placenta of preterm infants who developed ROP and hypoxic retinal cultures showed a reduced expression of EPHX2. These findings suggested a strong involvement of EPHX2 in regulating retinal neovascularization and inflammation. The study results underscore the role of arachidonic acid metabolism in the development of ROP and as a potential target for preventing vision loss among preterm-born infants.

“Maternal and Perinatal Outcome in Preterm Placenta Praevia”

Introduction: Placenta previa (PP) is a significant cause of maternal and fetal morbidity and mortality worldwide. However, there is limited data from developing countries on the maternal and fetal outcomes and complications associated with placenta previa. Aim of the study: The aim of this study was to evaluate maternal and perinatal outcome in preterm placenta praevia. Methods: This prospective observational study was conducted in the Department of Gynae and Obstetrics of Dhaka Medical College Hospital, Dhaka, Bangladesh during the period from March 2010 to August 1010. Result: Total 66 patients were diagnosed with placenta previa. We found, the majority (42%) of participants were aged between 26-30 years and with lower socio-economic status significantly associated with higher prevalence due to lack of regular antenatal care. The majority were admitted at 35-37 weeks gestation, with the highest perinatal loss occurring before 30 weeks. Initial bleeding was generally small, and many presented with labor pain and anemia. Ultrasonography diagnosed 55% of cases, with cesarean sections frequently used, leading to better outcomes compared to vaginal deliveries. Severe postpartum complications like hemorrhage and urinary tract infections were common in more severe cases. Conclusion: Placenta previa is a major cause of maternal and perinatal morbidity and mortality. Early registration, regular antenatal care, early detection of high-risk cases, and timely referral to higher centers with good NICU services and blood bank facilities can help prevent these adverse outcomes.

The role of placental kisspeptin in trophoblast invasion and migration: an assessment in Kiss1r knockout mice, BeWo cell lines and human term placenta.

Context There is mounting evidence implicating kisspeptin signalling in placental development and function. Aims This study aimed to elucidate kisspeptin's role in trophoblast invasion and migration using three experimental models. Methods First, we examined the mouse fetus and placenta in a kisspeptin receptor (Kiss1r) knockout (KO) model. Fetal/placental weights and gene expression (quantitative polymerase chain reaction) were assessed. Second, we determined kisspeptin effects on a human trophoblast (BeWo) cell line in vitro . Third, we examined KISS1 and KISS1R gene expression in human placenta from term and pre-term pregnancies. Key results No difference was found in fetal or placental weight between Kiss1r KO and wildtype mice. However, expression of the trophoblast invasion marker, Mmp2 mRNA, was greater in the placental labyrinth zone of Kiss1r KO mice. BeWo cell models of villus cytotrophoblast and syncytiotrophoblast cells exhibited kisspeptin protein expression, with greater expression in syncytiotrophoblast, consistent with KISS1 mRNA. Kisspeptin treatment inhibited the migratory potential of cytotrophoblast-like cells. Finally, while no difference was seen in KISS1 and KISS1R mRNA between term and pre-term placentas, we saw a difference in the relative expression of each gene pre-term. We also observed a positive correlation between KISS1 expression and maternal body mass index. Conclusions Our results indicate that kisspeptin may inhibit trophoblast invasion. Implications Further investigation is required to clarify specific regulatory mechanisms.

A genome scale transcriptional regulatory model of the human placenta.

Gene regulation is essential to placental function and fetal development. We built a genome-scale transcriptional regulatory network (TRN) of the human placenta using digital genomic footprinting and transcriptomic data. We integrated 475 transcriptomes and 12 DNase hypersensitivity datasets from placental samples to globally and quantitatively map transcription factor (TF)-target gene interactions. In an independent dataset, the TRN model predicted target gene expression with an out-of-sample R2 greater than 0.25 for 73% of target genes. We performed siRNA knockdowns of four TFs and achieved concordance between the predicted gene targets in our TRN and differences in expression of knockdowns with an accuracy of >0.7 for three of the four TFs. Our final model contained 113,158 interactions across 391 TFs and 7712 target genes and is publicly available. We identified 29 TFs which were significantly enriched as regulators for genes previously associated with preterm birth, and eight of these TFs were decreased in preterm placentas.

Gestational Age, Infection, and Suboptimal Maternal Prepregnancy BMI Independently Associate with Placental Histopathology in a Cohort of Pregnancies without Major Maternal Comorbidities.

Background: The placenta undergoes morphological and functional adaptations to adverse exposures during pregnancy. The effects ofsuboptimal maternal body mass index (BMI), preterm birth, and infection on placental histopathological phenotypes are not yet well understood, despite the association between these conditions and poor offspring outcomes. We hypothesized that suboptimal maternal prepregnancy BMI and preterm birth (with and without infection) would associate with altered placental maturity and morphometry, and that altered placental maturity would associate with poor birth outcomes. Methods: Clinical data and human placentae were collected from 96 pregnancies where mothers were underweight, normal weight, overweight, or obese, without other major complications. Placental histopathological characteristics were scored by an anatomical pathologist. Associations between maternal BMI, placental pathology (immaturity and hypermaturity), placental morphometry, and infant outcomes were investigated for term and preterm births with and without infection. Results: Fetal capillary volumetric proportion was decreased, whereas the villous stromal volumetric proportion was increased in placentae from preterm pregnancies with chorioamnionitis compared to preterm placentae without chorioamnionitis. At term and preterm, pregnancies with maternal overweight and obesity had a high percentage increase in proportion of immature placentae compared to normal weight. Placental maturity did not associate with infant birth outcomes. We observed placental hypermaturity and altered placental morphometry among preterm pregnancies with chorioamnionitis, suggestive of altered placental development, which may inform about pregnancies susceptible to preterm birth and infection. Conclusions: Our data increase our understanding of how common metabolic exposures and preterm birth, in the absence of other comorbidities or complications, potentially contribute to poor pregnancy outcomes and developmental programming.

Characterisation of ciclesonide metabolism in human placentae across gestation

IntroductionCurrent clinical management of pregnancies at risk of preterm delivery includes maternal antenatal corticosteroid (ACS) treatment. ACS activate the glucocorticoid receptor (GR) in all fetal tissues, maturing the lungs at the cost of impaired brain development, creating a need for novel treatments. The prodrug ciclesonide (CIC) activates the GR only when converted to des-CIC by specific enzymes, including acetylcholinesterase (ACHE) and carboxylesterase 1 and 2 (CES1, CES2). Importantly, the human placenta expresses ACHE and CES, and could potentially produce des-CIC, resulting in systemic fetal exposure and GR activation in all fetal tissues. We therefore investigated CES gene expression and conversion of CIC to des-CIC in human placentae collected during the second trimester (Tri2), and at preterm and term birth. MethodsDifferential expression analysis was performed in Tri2 (n = 27), preterm (n = 34), and term (n = 40) placentae using the DESeq2 R-package. Conversion of CIC to des-CIC was measured in a subset of placenta samples (Tri2 n = 7, preterm n = 26, term n = 20) using functional assays. ResultsACHE mRNA expression was higher in Tri2 male than preterm and term male placentae only, whereas CES1 mRNA expression was higher in Tri2 than preterm or term placentae of both sexes. Conversion of CIC to des-CIC did not differ between gestational ages. DiscussionConversion of CIC to des-CIC by the human placenta may preclude its use as a novel GR-agonist in threatened preterm birth. In vivo studies are required to confirm the extent to which placental activation occurs after maternal treatment.

Effects of COVID-19 Vaccination on Nebraska Maternal Health Outcomes [ID 2683619

INTRODUCTION: When the COVID-19 vaccine was developed, there were many concerns about the risk–benefit profile, especially in pregnancy. The purpose of this study was to elucidate the effect of COVID-19 vaccination on maternal health outcomes. METHODS: An IRB-approved, retrospective analysis was performed using data from CHI Nebraska's 2021 EPIC health records to determine whether maternal COVID-19 vaccination prior to delivery in previously healthy, primigravid women aged 18–35 affected maternal health outcomes. The outcomes studied included preterm delivery, eclampsia, gestational diabetes, preeclampsia, placental abruption, placenta previa, and postpartum hemorrhage. RESULTS: Of the 7,997 patients analyzed, 1,220 were vaccinated for COVID-19 prior to their delivery date. Compared to patients that were not vaccinated, vaccinated patients had statistically significant increased rates of gestational diabetes and preeclampsia (odds ratio [OR] 1.31; P=.02103; OR 1.47, P=.00589). Vaccinated patients were also found to have increased rates of eclampsia, placenta previa, preterm delivery, and postpartum hemorrhage, but these were not statistically significant. Clinically, these differences between vaccinated and nonvaccinated patients were small for all outcomes tested, all being less than 2%. CONCLUSION: Although our research was restricted by accessibility of the vaccine in early 2021, it illustrated that vaccinated individuals did not experience any significant increase in eclampsia, placenta previa, postpartum hemorrhage, or preterm delivery compared to the unvaccinated. We found that history of COVID-19 vaccination correlated with a small, yet significant increased rate of gestational diabetes and preeclampsia. Further research should be done to further elucidate how the vaccination affects health outcomes as they pertain to pregnancy.

Targeting Mitochondrial Oxidative Stress to Protect Against Preterm Birth and Fetal Brain Injury via Nrf2 Induction.

Aims: Preterm birth (PTB), recognized as delivery before 37 weeks of gestation, is a multifactorial syndrome characterizing as the main cause of neonatal mortality. Reactive oxygen species (ROS) have been identified as proinflammatory factors to cause placental inflammation, thereby resulting in several pregnancy outcomes. To date, limited knowledge regarding the underlying mechanisms of ROS-induced PTB has been reported. In this study, we aimed to investigate the role of oxidative stress in PTB and the protective effects of mitochondria-targeted antioxidant MitoTEMPO (MT) on preterm labor and offspring mice. Results: In this study, we found that preterm placentas had abnormal mitochondrial function, oxidative stress, and inflammatory response. In the lipopolysaccharide (LPS)-induced PTB mouse model, MT inhibited PTB by ameliorating maternal oxidative stress and inflammation, especially in placentas, thus improving placental function to maintain pregnancy. Antenatal administration of MT prevented LPS-induced fetal brain damage in acute phase and improved long-term neurodevelopmental impairments. Furthermore, our in vitro investigations validated that MT retarded the ROS accumulation and inflammatory response in LPS-stimulated trophoblast cells by promoting Kelch-like ECH-associated protein 1 (Keap1) degradation and subsequently activating nuclear factor erythroid 2-related factor 2 (Nrf2). By inhibiting Nrf2 activation, we discovered that the anti-inflammation and protective characteristics of MT were Nrf2/ARE pathway dependent. Innovation and Conclusion: MT inhibited PTB and fetal brain injury by inhibiting maternal inflammation and improving placental function through Keap1/Nrf2/antioxidant response element signaling pathway. Our findings provide a novel therapeutic strategy for PTB. Antioxid. Redox Signal. 41, 597-615.

Prevalence of Fetal Inflammatory Response Syndrome and Villitis of Unknown Etiology in the Placenta of Saudi Women and Their Association with Baby Sex.

Long-term health consequences are influenced by circumstances that occur during pregnancy. The convergence of the maternal and fetal circulations occurs in the placenta, which is the first organ to develop. Placental pathology provides an accurate diagnosis of amniotic sac inflammation, and pathological alterations in preterm placentas provide evidence for the causes of numerous perinatal pathologies, including spontaneous preterm births. This retrospective study aimed to re-examine placentas regarded as normal by the Obstetrics and Gynecology Department at our institution. Thirty-seven male and forty-seven female placentas were collected following full-term delivery, and the grading and staging of any evident inflammatory responses were evaluated and correlated with the babies' sex. Full-thickness placental samples that were considered normal and not sent to the histopathology department were obtained from the central and marginal regions of placental discs. Morphological examination of the fresh placenta was conducted, and fetal and maternal inflammatory response syndromes were assessed. In addition, placental villitis of unknown etiology (VUE) and chronic deciduitis were evaluated. Immunohistochemistry was performed to evaluate the patterns of inflammation in the placenta using anti-CD8 and anti-CD68 antibodies. The correlation between silent pathologies and clinical complications or the development of fetal inflammatory response syndrome was measured. In this study, 17 (20%) maternal and 10 (12%) fetal samples showed inflammatory responses. The frequencies of chronic deciduitis and VUE were higher among pregnant Saudi women than previously reported, probably because fetal inflammatory response syndrome goes unnoticed in Saudi Arabia. In addition, the prevalence of fetal and maternal inflammatory responses was higher in the placentas of the mothers of males than in those of females, suggesting that differences occur in the inflammatory response in the placenta depending on the sex of the newborn. Grading placental inflammation (in cases of VUE) typically predicts the degree of maternal anti-fetal cellular rejection; therefore, increasing the number of placental samples sent for microscopic inspection may be preferable because of their significance in identifying the causes of chronic disorders.

Bacterial Diversity in Placentas from Complicated Pregnancies Using 16s rRNA Gene Sequencing

Introduction: The ‘sterile womb paradigm’ is currently under debate and the advent of next generation 16S rRNA gene sequencing is driving the characterization of microbes associated with the amniotic cavity during pregnancy. Objective: To characterize the bacterial diversity in placentas from preterm and term births using next generation 16S rRNA gene sequencing in association with adverse pregnancy outcomes and histopathology studies. Methods: In this prospective study, placentas were collected consecutively from patients attending a public tertiary referral hospital in South Africa, delivering preterm (n=42; 28-34 weeks gestational age) and term (n=20; &gt;37 weeks gestational age). Placentas underwent histopathology tests and next generation 16S rRNA gene sequencing. Results: Analysis of microbial diversity in the placenta showed a significantly higher alpha diversity in term placentas compared to preterm placentas (P=0.000075), in placentas with acute chorioamnionitis compared to placentas without acute chorioamnionitis (P=0.0061), between HIV negative term births and both HIV negative and HIV positive preterm births (P=0.0118 and P=0.0008), respectively. Beta diversity was significantly different between preterm and term births (unweighted UniFrac distance, P=0.003996; Jaccard distance, P=0.03696) and Escherichia/Shigella, Shuttleworthia, Anaeroglobus and Megasphaera were differentially expressed. Conclusion: This is the first South African study to characterize the bacterial diversity in placentas from complicated pregnancies using next generation 16S rRNA gene sequencing in conjunction with full placental histology. Microbial diversity differs between preterm and term placentas where HIV may act as a cofactor associated with decreased bacterial alpha diversity in placentas from preterm birth.

Clinical and Histological Associations of Chronic Inflammatory Lesions in Preterm Placentas: Uncovering the Hidden Dangers.

Chronic placental inflammatory lesions (CPIL) include chronic deciduitis (CD), villitis of unknown etiology (VUE), and chronic chorioamnionitis (CCA). The frequency of these lesions and their relationship with various clinicopathological parameters in preterm birth (PTB) is presented. Preterm placentas from April 2018 to December 2020 were reviewed for presence of CPIL. PTB was classified as spontaneous, indicated, or mixed phenotype. The association of CPIL with clinical parameters like gestational age, birth weight, obstetric complications, and placental parameters like placental dimensions, weight, vascular malperfusion, acute inflammatory lesions, and basal plate myometrial fibers were analyzed. The study included 538 preterm placentas with 54.3% from indicated PTB. CD was more common (28.4%) than VUE (17.8%) and CCA (12.6%). CD showed significant association with VUE and CCA (both P = .0001) and VUE with CCA (P = .0001). CD was more common in indicated PTB (33.8%, P = .002) and associated with lower birth weight (1591 g vs 1705 g, P = .003), lower placental weight (270.7 g vs 296.9 g, P = .004), length (14.2 cm vs 14.8 cm, P = .006), breadth (11.7 cm vs 12.2 cm, P = .007), maternal vascular malperfusion (P = .004), and basal plate myometrial fibers (P = .02). High-grade and multifocal low-grade VUE was associated with reduced placental length (13.9 cm vs 14.6 cm, P = .02)and breadth (11.5 cm vs 12.1 cm, P = .01). CCA did not show any other association. CPIL are common in PTB and their coexistence suggested a common pathogenic mechanism. Placental examination is the only definite way to identify as they lack clinical signs and symptoms. The smaller placental size associated with these lesions may suggest alter mechanisms for adverse pregnancy outcomes.

Rosiglitazone-Mediated Activation of PPARγ Restores HO1 Expression in the Human Preeclamptic Placenta.

Preeclampsia is a hypertensive disorder of pregnancy characterized by chronic placental ischemia and suppression of proangiogenic proteins, causing oxidative stress, hypertension, and maternal systemic organ damage. The transcription factor, PPARγ (peroxisome proliferator-activated receptor-γ) promotes healthy trophoblast differentiation but is dysregulated in the preeclampsia placenta. Our study identifies the beneficial impact of Rosiglitazone-mediated PPARγ-activation in the stressed preeclampsia placenta. We used first trimester placentas, preeclamptic and preterm control placentas, and human trophoblast cell lines to study PPARγ activation. Induction of PPARγ activates cell growth and antioxidative stress pathways, including the gene, heme oxygenase 1 (Hmox1). Protein expression of both PPARγ and HO1 (heme oxygenase 1) are reduced in preeclamptic placentas, but Rosiglitazone restores HO1 signaling in a PPARγ-dependent manner. Restoring disrupted pathways by PPARγ in preeclampsia offers a potential therapeutic pathway to reverse placental damage, extending pregnancy duration, and reduce maternal sequelae. Future research should aim to understand the full scope of impaired PPARγ signaling in the human placenta and focus on compounds for safe use during pregnancy to prevent severe perinatal morbidity and mortality.

Pregnancy management and outcome after uterus transplantation.

Uterus transplantation is a novel approach in women whose uterus is absent or severely abnormal. However, it is still an experimental procedure that poses risks to both mother and baby. To date, 32 live births after uterus transplantation have been reported in peer-reviewed journals, with several maternal, fetal and neonatal complications. The most common complications were preterm delivery, hypertensive disorders and placenta previa. Four patients experienced episodes of transplant rejection during pregnancy. The appropriate management of complicated and non-complicated pregnancies following uterus transplantation is still unresolved. In this review, obstetric outcomes after uterus transplantation and optimal management during pregnancy are discussed in light of the available data. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Comparison of Placental Pathology Reports From Spontaneous Preterm Births Finalized by General Surgical Pathologists Versus Perinatal Pathologist: A Call to Action.

Placental examination, frequently performed by general surgical pathologists, plays an important role in understanding patient outcomes and explaining the underlying mechanisms leading to preterm birth (PTB). This secondary analysis of a larger study recurrent PTB aimed to compare diagnoses between general surgical pathologists (GSP) and a perinatal pathologist (PP) in preterm placentas examined between 2009 and 2018 at a single institution. Pathology diagnoses were coded into 4 categories (acute inflammation [AI], chronic inflammation, fetal vascular malperfusion, maternal vascular malperfusion) based on original reports for the GSP and second review by the single PP. A total of 331 placentas were included, representing placentas finalized by 17 GSPs. The prevalence of all 4 placental diagnostic categories was higher for the PP, and nearly half (49.2%) of placentas finalized by GSP had no diagnostic findings. Agreement was highest for AI at κ=0.50 (weak agreement). However, there was no agreement for maternal vascular malperfusion (κ=0.063), chronic inflammation (κ=0.0026), and fetal vascular malperfusion (κ = -0.018). Chronic basal deciduitis with plasma cells had the highest false-negative rate (missed in 107 cases by GSP). Villous infarction had the highest false-positive rate (overcalled in 28/41 [68%] cases) with the majority of the "infarcts" representing intervillous thrombi. In conclusion, there is no agreement between GSP and PP when assessing placental pathology other than AI, and weak agreement even for AI. These findings are a call to action to implement educational efforts and structural/organizational changes to improve consistency of placental pathology reporting.

Association between proNGF receptors and apoptotic factors in human placentae

IntroductionEarlier studies have shown higher apoptosis in the pre-term placenta as compared to term. However, the exact mechanisms triggering these are not completely understood. Studies in neuronal and non-neuronal tissues have shown that the precursor form of NGF (proNGF) triggers apoptosis through preferential activation of p75NTR and sortilin receptors. We therefore, investigated placental expression of proNGF, mature NGF, p75NTR, co-receptor sortilin and their association with apoptosis. We further compared the levels of pro-protein convertase, furin between samples having high and low proNGF: mature NGF ratio. MethodsPlacenta samples were collected from women delivering at term (≥37 weeks; n = 41) and preterm (<37 weeks; n = 44). The protein levels of NGF, proNGF, p75NTR, Bax, Bcl-2 and furin were estimated by ELISA. Mean values of variables between different groups were compared using the independent sample t-test and associations were studied by Pearson correlation analysis. ResultsThe placental mature NGF, proNGF and p75NTR protein levels were comparable between groups. Bax: Bcl-2 ratio was higher in preterm (p < 0.05) compared to term placenta. p75NTR was positively associated with Bax levels and sortilin levels were positively associated with p75NTR in whole cohort as well as individual groups. DiscussionThe higher Bax: Bcl-2 ratio in preterm placenta suggests the sensitivity to apoptosis. There were no differences in levels of NGF, proNGF, p75NTR, sortilin, and furin between groups. The observed associations between p75NTR, sortilin and Bax suggest that p75NTR and sortilin mediated signalling may be involved in the mechanisms leading to higher apoptosis in preterm placentae.

An in vitro model for equine placental research

A fundamental understanding of placental development and its associated pathologies is crucial to mitigating the losses associated with placental disorders. Organoids are widely used to investigate the developmental biology of organs and in disease modeling. In humans, placental organoids have been successfully developed using trophoblast cells. In this study, we aimed to 1) develop placental organoids using pre-term and term equine placentae, 2) evaluate the organoid structures, 3) compare the organoid transcriptome with their respective chorioallantois (CA), and 4) evaluate organoids based on their starting material (pre-term vs term). The CA was collected from healthy placentae following elective abortion (80-100d of gestation) and following spontaneous term parturition. CA samples were processed for culture, fixed for histology, and stored in RNAlater. For culture, each CA sample was enzymatically digested to a single cell suspension and was seeded into 50µL Matrigel Matrix droplets surrounded by medium. Passage-3 organoids (P3) were used for histology (H&E), immunohistochemistry (IHC), and transcriptomic analysis. Steroid production and conversion were measured by mass spectrometry (MS) of culture media. After optimization of culture conditions, we produced 3D-organoids (Pre-Term, n=6 and Term, n=3). Organoids were passaged up to 12 times over ±3 months and were successfully frozen and re-cultured post-thaw. Total extracted RNA from initial CA samples and organoids was sequenced (150PE; ∼43 million reads/sample). The genes expressed in the organoidsclosely resemble those of the tissue of origin, 19.4% of the expressed genes were differentially expressed (DEGs) between the initial CA and P3 (n=3,949 genes; FDR<0.001). H&E staining of both CA and the organoids indicates the epithelial origin of the cells within the organoids. The enriched expression of trophoblast-specific genes PLAC8B, GATA3, KRT7, VGLL1, and EGFR, and the presence of the trophoblast-specific genes TFAP2A and TFAP2C, and GATA2 in the organoids confirm their trophoblast identity. The presence of SOX2 and OCT4, as demonstrated by IHC, confirms the pluripotency of the organoid cells. The SRD5A1 and SRD5A3 genes were expressed in all organoids and our preliminary MS analysis demonstrated the conversion of progesterone to 5α-DHP, further suggesting functional integrity. Comparison between Pre-Term and Term organoids revealed 552 DEGs (FDR<0.001), with downregulation of immune/inflammatory/defense responses and blood vessel development, and upregulation of molecule transport, development, and adhesion in the Pre-Term group. To conclude, this is the first report of placental organoids in domestic animals. The organoids show structural, transcriptomic, and functional similarities to the equine placenta in vivo and consequently could be used as an in vitro model to study placental development and associated pathologies. Funded by The Foundation for The Horse, GJCRF, UGent BOF, BAEF, L'Oréal-UNESCO FWO, and the Center for Equine Health at UC Davis.

Influence of ovarian reserves on assisted reproductive and perinatal outcomes in patients with endometriosis: a retrospective study.

To investigate the association between different ovarian reserves and reproductive and adverse perinatal outcomes in patients with endometriosis. Retrospective study. Reproductive Medicine Center in a hospital. Patients surgically diagnosed with endometriosis were divided into three groups according to their ovarian reserve: diminished ovarian reserve (DOR) group (n=66), normal ovarian reserve (NOR) group (n=160), and high ovarian reserve (HOR) group (n=141). None. Live birth rate (LBR), cumulative live birth rate (CLBR), and adverse perinatal outcome for singleton live births. There were significantly higher live birth and cumulative live birth rates in endometriosis patients with NOR or HOR than in those with DOR. For adverse perinatal outcomes, patients with NOR or HOR had no significant association with preterm birth, gestational hypertension, placenta previa, fetal malformation, abruptio placentae, macrosomia, or low birth weight, except for a decreased risk of gestational diabetes mellitus. Our study revealed that although patients with endometriosis with NOR and HOR had increased reproductive outcomes, patients with endometriosis with DOR had still an acceptable live birth rate and a similar cumulative live birth rate with available oocytes. Moreover, patients with NOR and HOR might not exhibit a decreased risk of abnormal perinatal outcomes, except for gestational diabetes mellitus. Multicenter prospective studies are needed to further clarify the relationship.