Trophoblast organoids with physiological polarity model placental structure and function.

Human trophoblast organoids (TOs) are a three-dimensional ex vivo culture model that can be used to study various aspects of placental development, physiology and pathology. However, standard culturing of TOs does not recapitulate the cellular orientation of chorionic villi in vivo given that the multi-nucleated syncytiotrophoblast (STB) develops largely within the inner facing surfaces of these organoids (STBin). Here, we developed a method to culture TOs under conditions that recapitulate the cellular orientation of chorionic villi in vivo. We show that culturing STBin TOs in suspension with gentle agitation leads to the development of TOs containing the STB on the outer surface (STBout). Using membrane capacitance measurements, we determined that the outermost surface of STBout organoids contain large syncytia comprising >50 nuclei, whereas STBin organoids contain small syncytia (<10 nuclei) and mononuclear cells. The growth of TOs under conditions that mimic the cellular orientation of chorionic villi in vivo thus allows for the study of a variety of aspects of placental biology under physiological conditions.

Bushen Antai recipe ameliorates immune microenvironment and maternal-fetal vascularization in STAT3-deficient abortion-prone mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Spontaneous abortion (SA) is an intricate disorder affecting women of reproductive age. Previous studies have confirmed the indispensable role of signal transducer and activator of transcription (STAT) 3 in normal pregnancy. Bushen Antai recipe (BAR) is a satisfactory formula commonly used in practice, based on the rationale of traditional Chinese medicine (TCM) for SA. AIM OF THE STUDY: The current study explores the potential therapeutic effects and mechanistic insights of BAR in STAT3-deficient abortion-prone mice. MATERIALS AND METHODS: A STAT3-deficient abortion-prone mouse model was developed using intraperitoneal injection of stattic from embryo day (ED) 5.5 to ED9.5 among pregnant females (C57BL/6). We separately administered BAR1 (5.7 g/kg), BAR2 (11.4 g/kg), progesterone (P4), or distilled water at 10 ml/kg/day from ED0.5 until ED10.5. The embryo resorption rate and placenta-uterus structure were observed on ED10.5. The systemic immune status was examined by analyzing the frequency of immunosuppressive myeloid-derived suppressor cells (MDSCs), the ratio of two macrophage (M) subtypes, and the protein expression of associated molecules. Morphological observation, immunohistochemistry, and western blotting were used to evaluate the vascularization conditions at the maternal-fetal interface. RESULTS: BAR1, BAR2, or P4 treatment exerted remarkable effects in alleviating embryo resorption rate and disordered placental-uterus structure in STAT3-deficient abortion-prone mice. Western blotting indicated the deficiency of phosphorylated STAT3 and two prime target molecules, PR and HIF-1α, at the maternal-fetal interface under STAT3 inhibition. Simultaneously, BAR2 treatment significantly upregulated their expression levels. The systemic immune environment was disrupted, indicated by the reduced serum cytokine concentrations, MDSCs frequency, M2/M1 ratio, and the expression of immunomodulatory factors. Nonetheless, BAR2 or P4 treatment revived the immune tolerance for semi-allogenic embryos by enhancing the immune cells and factors. Besides, the western blot and immunohistochemistry results revealed that BAR2 or P4 treatment upregulated VEGFA/FGF2 and activated ERK/AKT phosphorylation. Therefore, BAR2 or P4 facilitated vascularization at the maternal-fetal interface in STAT3-deficient abortion-prone mice. CONCLUSIONS: BAR sustained pregnancy by reviving the systemic immune environment and promoting angiogenesis at the maternal-fetal interface in STAT3-deficient abortion-prone mice.

Maternal COVID-19 causing intrauterine foetal demise with microthrombotic placental insufficiency: a case report.

BACKGROUND: Pregnant women have an increased risk of getting infected with SARS-CoV-2 and are more prone to severe illness. Data on foetal demise in affected pregnancies and its underlying aetiology is scarce and pathomechanisms remain largely unclear. CASE: Herein we present the case of a pregnant woman with COVID-19 and intrauterine foetal demise. She had no previous obstetric or gynaecological history, and presented with mild symptoms at 34 + 3 weeks and no signs of foetal distress. At 35 + 6 weeks intrauterine foetal death was diagnosed. In the placental histopathology evaluation, we found inter- and perivillous fibrin depositions including viral particles in areas of degraded placental anatomy without presence of viral entry receptors and SARS-CoV-2 infection of the placenta. CONCLUSION: This case demonstrates that maternal SARS-CoV-2 infection in the third trimester may lead to an unfavourable outcome for the foetus due to placental fibrin deposition in maternal COVID-19 disease possibly via a thrombogenic microenvironment, even when the foetus itself is not infected.

Investigation of maternal serum endocan concentrations in pregnant women with gestational diabetes mellitus; a prospective case-control study.

OBJECTIVE: We aimed to investigate the maternal serum endocan concentrations in pregnant women diagnosed with Gestational Diabetes Mellitus (GDM) and to investigate the usability of serum endocan in GDM screening. METHODS: This prospective case-control study was conducted with 160 pregnant women. The GDM group consisted of 80 pregnant women who had 75 g OGTT between the 24th and 28th weeks of pregnancy and were diagnosed with GDM. The control group consisted of 80 healthy pregnant women who were matched with the GDM group in terms of age and body mass index (BMI) and had a normal 75 g OGTT result. Serum endocan concentrations were evaluated between 24 and 28 weeks of gestation in all participants and the groups were compared in terms of serum endocan concentrations. RESULTS: The median maternal serum endocan concentration was found to be significantly higher in the GDM group than in the control group (498 ng/L, and 467 ng/L, respectively, p = 0.024). In the subgroup analysis according to the BMI of the participants, the highest median maternal serum endocan concentration (513 ng/L) was found in the overweight GDM group. ROC analysis was performed to determine the value of maternal serum endocan concentration in predicting GDM. AUC analysis of maternal serum endocan for estimation of GDM was 0.603 (p = 0.024, 95% CI = 0.515 - 0.691). The optimal threshold value for maternal serum endocan concentration was determined as 376 ng/L with 88.75% sensitivity and 32.5% specificity. CONCLUSION: Although serum endocan does not have high enough specificity to be used as an alternative to OGTT in GDM screening between 24 and 28 weeks of gestation, we think that it is somehow involved in the pathogenesis of GDM. The contribution of placental endocan expression to the serum concentration and the effect of blood glucose regulation on serum endocan concentration in GDM remain to be investigated.

Antigen-specific decidual CD8+ T cells include distinct effector memory and tissue-resident memory cells.

Maternal decidual CD8+ T cells must integrate the antithetical demands of providing immunity to infection while maintaining immune tolerance for fetal and placental antigens. Human decidual CD8+ T cells were shown to be highly differentiated memory T cells with mixed signatures of dysfunction, activation, and effector function. However, no information is present on how specificity for microbial or fetal antigens relates to their function or dysfunction. In addition, a key question, whether decidual CD8+ T cells include unique tissue-resident memory T cells (Trm) or also effector memory T cell (Tem) types shared with peripheral blood populations, is unknown. Here, high-dimensional flow cytometry of decidual and blood CD8+ T cells identified 2 Tem populations shared in blood and decidua and 9 functionally distinct Trm clusters uniquely found in decidua. Interestingly, fetus- and virus-specific decidual CD8+ Trm cells had similar features of inhibition and cytotoxicity, with no significant differences in their expression of activation, inhibitory, and cytotoxic molecules, suggesting that not all fetus-specific CD8+ T cell responses are suppressed at the maternal-fetal interface. Understanding how decidual CD8+ T cell specificity relates to their function and tissue residency is crucial in advancing understanding of their contribution to placental inflammation and control of congenital infections.

Trauma in pregnancy: An analysis of the adverse perinatal outcomes and the injury severity score.

BACKGROUND: Trauma during pregnancy is one of the most important causes of non-obstetric maternal and fetal mortality and morbidity. The aim of our study is to evaluate the adverse perinatal outcomes that may occur according to the type and severity of the trauma. METHODS: In this retrospective cohort study, pregnant traumatized women aged 18-50 years and referred for consultation to the Prof. Dr. Cemil Tascioglu City Hospital's emergency services of the departments of gynecology and obstetrics, between January 1, 2017, and December 31, 2022, were evaluated. Demographic characteristics, trauma findings, Injury Severity Scoring (ISS), and obstet-ric outcomes were recorded. RESULTS: A total of 1825 trauma patients, including 900 pregnants were referred to our emergency gynecology clinic for consulta-tion. One hundred and fifty three pregnant patients, whose birth information we reached, were selected as the study group. The mean age of the patients was 25.56±5.99 years and the mean gestational week at the time of trauma was 21.59±9.89 weeks, the patients had fallen (67.97%), had been exposed to violence (30.07%), and had a traffic accient (1.96%). The patient's delivery and hospitalization status on the day of trauma, fracture and ISS ≥9 were statistically significantly at a higher rate in the 3rd trimester. Rates of hospitaliza-tion and 3rd trimester traumas were found to be significantly higher in the ISS ≥9 group. (P=0.0001, P=0.028, respectively). CONCLUSION: Compared to the general population, the rates of preterm premature rupture of membranes-premature rupture of membranes, fetal death, fetal distress, cesarean delivery, placental abruption, and preterm delivery increased in traumatized pregnant women. Patients with low ISS scores should also be followed closely during pregnancy in terms of perinatal complications, as well as the severe trauma group.

Effects of Gestational Arsenic Exposures on Placental and Fetal Development in Mice: The Role of Cyr61 m6A.

BACKGROUND: Several epidemiological investigations demonstrated that maternal arsenic (As) exposure elevated risk of fetal growth restriction (FGR), but the mechanism remains unclear. OBJECTIVES: This study aimed to investigate the effects of gestational As exposure on placental and fetal development and its underlying mechanism. METHODS: Dams were exposed to 0.15, 1.5, and 15mg/L NaAsO2 throughout pregnancy via drinking water. Sizes of fetuses and placentas, placental histopathology, and glycogen content were measured. Placental RNA sequencing was conducted. Human trophoblasts were exposed to NaAsO2 (2µM) to establish an in vitro model of As exposure. The mRNA stability and protein level of genes identified through RNA sequencing were measured. N6-Methyladenosine (m6A) modification was detected by methylated RNA immunoprecipitation-quantitative real-time polymerase chain reason (qPCR). The binding ability of insulin-like growth factor 2 binding protein 2 to the gene of interest was detected by RNA-binding protein immunoprecipitation-qPCR. Intracellular S-adenosylmethionine (SAM) and methyltransferase activity were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and colorimetry, respectively. In vitro As+3 methyltransferase (As3MT) knockdown or SAM supplementation and in vivo folic acid (FA) supplementation were used to evaluate the protective effect. A case-control study verified the findings. RESULTS: Sizes of fetuses (exposed to 1.5 and 15mg/L NaAsO2) and placentas (exposed to 15mg/L NaAsO2) were lower in As-exposed mice. More glycogen+ trophoblasts accumulated and the expression of markers of interstitial invasion was lower in the 15mg/L NaAsO2-exposed mouse group in comparison with control. Placental RNA sequencing identified cysteine-rich angiogenic inducer 61 (Cyr61) as a candidate gene of interest. Mechanistically, mice and cells exposed to As had lower protein expression of CYR61, and this was attributed to a lower incidence of Cyr61 m6A. Furthermore, cells exposed to As had lower methyltransferase activity, suggesting that this could be the mechanism by which Cyr61 m6A was affected. Depletion of intracellular SAM, a cofactor for m6A methyltransferase catalytic domain, partially contributed to As-induced methyltransferase activity reduction. Either As3MT knockdown or SAM supplementation attenuated As-induced Cyr61 m6A down-regulation. In mice, FA supplementation rescued As-induced defective trophoblastic invasion and FGR. In humans, a negative correlation between maternal urinary As and plasma CYR61 was observed in infants who were small for gestational age. DISCUSSION: Using in vitro and in vivo models, we found that intracellular SAM depletion-mediated Cyr61 m6A down-regulation partially contributed to As-induced defective trophoblastic invasion and FGR. https://doi.org/10.1289/EHP12207.

Associations between velamentous or marginal cord insertion and risk of adverse perinatal outcomes in twin pregnancies: a retrospective cohort study.

BACKGROUND: Velamentous cord insertion (VCI) and marginal cord insertion (MCI) are well-known risk factors for adverse perinatal outcomes in singleton pregnancies. However, the potential links between VCI or MCI and perinatal outcomes in twin pregnancies have yet to be systematically evaluated. This study aimed to investigate the relationships between VCI or MCI and perinatal outcomes in twin pregnancies. METHODS: This retrospective single-center cohort study included women with twin pregnancies who gave birth in a tertiary hospital in Southwest, China between January 2017 and December 2022. VCI and MCI were identified by abdominal ultrasound and confirmed after placental delivery. Logistic regression, multinomial logit regression and generalized estimation equation models were used to evaluate the association between VCI or MCI and perinatal outcomes. RESULTS: A total of 3682 twin pregnancies were included, including 100 (2.7%) pregnancies with VCI and 149 (4.0%) pregnancies with MCI. Compared to pregnancies with normal cord insertion, both monochorionic and dichorionic pregnancies with VCI were associated with an increased risk of preterm delivery 32-34 weeks (aRRR 2.94, 95% CI 1.03-8.39; aRRR 2.55, 95% CI 1.19-5.46, respectively), while pregnancies with MCI were not associated with preterm delivery. VCI was associated with a higher incidence of placental previa (aOR 6.36, 95% CI 1.92-21.04) in monochorionic pregnancies and placental accreta (aOR 1.85, 95% CI 1.06-3.23) in dichorionic pregnancies. MCI was associated with an increased risk of preeclampsia (aOR 3.07, 95% CI 1.49-6.32), intertwin birthweight discordance ≥ 20% (aOR 2.40, 95% CI 1.08-5.60) and selective fetal growth restriction (aOR 2.46, 95% CI 1.08-5.60) in monochorionic pregnancies and small-for-gestational age neonates (aOR 1.97, 95% CI 1.24-3.14) in dichorionic pregnancies. CONCLUSIONS: VCI was associated with an increased risk of preterm delivery in twin pregnancies irrespective of chorionicity, whereas MCI was associated with an increased preeclampsia risk, significant intertwin birthweight discordance in monochorionic pregnancies and small-for-gestational age neonates in dichorionic pregnancies.

Placental, Foetal, and Maternal Serum Metabolomic Profiles in Pregnancy-Associated Cancer: Walker-256 Tumour Model in a Time-Course Analysis.

Cancer during pregnancy presents a delicate coexistence, imposing ethical and professional challenges on both the patient and medical team. In this study, we aimed to explore in a pre-clinical model the impact of tumour evolution in serum, placental and foetal metabolomics profiles during pregnancy in a time-course manner. Pregnant Wistar rats were distributed into two experimental groups: Control (C) and Walker-256 tumour-bearing (W). The rats were euthanised on three different gestational periods: at 12 days post-conception (dpc), at 16 dpc, and at 19 dpc. Serum, placenta and foetal metabolomic profiles were performed by 1H-NMR spectra following the analyses using Chenomx NMR Analysis Software V8.3. The tumour evolution was exponential, affecting the placental metabolomic profile during all the pregnancy stages. The placental tissue in tumour-bearing dams developed at a lower speed, decreasing the foetus's weight. Associated with the serum metabolomic changes related to tumour growth, the placental metabolomic alterations impacted many metabolic pathways related to energy provision, protein synthesis and signalling, which directly harmed the foetus's development. The development of the foetus is clearly affected by the damage induced by the tumour evolution, which alters the metabolic profile of both the serum and the placenta, impairing early embryonic development.

Prenatal Alcohol Exposure Impairs the Placenta-Cortex Transcriptomic Signature, Leading to Dysregulation of Angiogenic Pathways.

Although alcohol consumption during pregnancy is a major cause of behavioral and learning disabilities, most FASD infants are late- or even misdiagnosed due to clinician's difficulties achieving early detection of alcohol-induced neurodevelopmental impairments. Neuroplacentology has emerged as a new field of research focusing on the role of the placenta in fetal brain development. Several studies have reported that prenatal alcohol exposure (PAE) dysregulates a functional placenta-cortex axis, which is involved in the control of angiogenesis and leads to neurovascular-related defects. However, these studies were focused on PlGF, a pro-angiogenic factor. The aim of the present study is to provide the first transcriptomic "placenta-cortex" signature of the effects of PAE on fetal angiogenesis. Whole mouse genome microarrays of paired placentas and cortices were performed to establish the transcriptomic inter-organ "placenta-cortex" signature in control and PAE groups at gestational day 20. Genespring comparison of the control and PAE signatures revealed that 895 and 1501 genes were only detected in one of two placenta-cortex expression profiles, respectively. Gene ontology analysis indicated that 107 of these genes were associated with vascular development, and String protein-protein interaction analysis showed that they were associated with three functional clusters. PANTHER functional classification analysis indicated that "intercellular communication" was a significantly enriched biological process, and 27 genes were encoded for neuroactive ligand/receptors interactors. Protein validation experiments involving Western blot for one ligand-receptor couple (Agt/AGTR1/2) confirmed the transcriptomic data, and Pearson statistical analysis of paired placentas and fetal cortices revealed a negative correlation between placental Atg and cortical AGTR1, which was significantly impacted by PAE. In humans, a comparison of a 38WG control placenta with a 36WG alcohol-exposed placenta revealed low Agt immunolabeling in the syncytiotrophoblast layer of the alcohol case. In conclusion, this study establishes the first transcriptomic placenta-cortex signature of a developing mouse. The data show that PAE markedly unbalances this inter-organ signature; in particular, several ligands and/or receptors involved in the control of angiogenesis. These data support that PAE modifies the existing communication between the two organs and opens new research avenues regarding the impact of placental dysfunction on the neurovascular development of fetuses. Such a signature would present a clinical value for early diagnosis of brain defects in FASD.

Sex-Specific Effects of Prenatal Hypoxia and a Placental Antioxidant Treatment on Cardiac Mitochondrial Function in the Young Adult Offspring.

Prenatal hypoxia is associated with placental oxidative stress, leading to impaired fetal growth and an increased risk of cardiovascular disease in the adult offspring; however, the mechanisms are unknown. Alterations in mitochondrial function may result in impaired cardiac function in offspring. In this study, we hypothesized that cardiac mitochondrial function is impaired in adult offspring exposed to intrauterine hypoxia, which can be prevented by placental treatment with a nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ). Cardiac mitochondrial respiration was assessed in 4-month-old rat offspring exposed to prenatal hypoxia (11% O2) from gestational day (GD)15-21 receiving either saline or nMitoQ on GD 15. Prenatal hypoxia did not alter cardiac mitochondrial oxidative phosphorylation capacity in the male offspring. In females, the NADH + succinate pathway capacity decreased by prenatal hypoxia and tended to be increased by nMitoQ. Prenatal hypoxia also decreased the succinate pathway capacity in females. nMitoQ treatment increased respiratory coupling efficiency in prenatal hypoxia-exposed female offspring. In conclusion, prenatal hypoxia impaired cardiac mitochondrial function in adult female offspring only, which was improved with prenatal nMitoQ treatment. Therefore, treatment strategies targeting placental oxidative stress in prenatal hypoxia may reduce the risk of cardiovascular disease in adult offspring by improving cardiac mitochondrial function in a sex-specific manner.

Metabolic and molecular effects of dietary extra virgin olive oil in blood and placenta of women with GDM.

Gestational diabetes mellitus (GDM) increases the risks of maternal, placental, and neonatal complications. Previously, we found that a diet enriched in extra virgin olive oil (EVOO) prevents increased maternal triglyceridemia and placental proinflammatory markers in a cohort of GDM patients. The aim of this work was to evaluate maternal circulating markers of insulin resistance, placental collagen, glycogen and lipid levels, and placental levels of proteins, mRNAs, and a microRNA involved in the endocytic pathway in the same cohort of control women and women with GDM who received or did not receive a diet enriched in EVOO (36 g/day) from weeks 24 to 28 of pregnancy until term. Results: At term, the TG/HDL cholesterol ratio, fatty acid binding protein 4 circulating levels, and maternal BMI were increased in the GDM patients, alterations prevented by the maternal diet enriched in EVOO. Although there were no changes in placental lipid levels and lipid profile, GDM placentas were thicker than controls and showed increased glycogen and collagen content, alterations prevented by the EVOO enriched diet. GDM placentas showed increases in megalin levels, in the expression of several genes involved in the endocytic pathway, and in miR-199, which targets these genes, alterations prevented by the maternal diet enriched in EVOO. Conclusions: We identified novel beneficial effects of an EVOO-enriched diet in GDM women, a diet capable of regulating maternal insulin resistance, the structure and metabolism of the placenta, and the placental endocytic pathway, suggesting effects that may be beneficial for fetal development.

Is placental glutathione S-Transferase (GST-P) a suitable biomarker for oral carcinogenesis: A scoping review.

Placental Glutathione S-Transferase (GST-P) can be considered a useful marker of not only of preneoplastic lesion in rat hepatocarcinogenesis and hamster pancreatic carcinogen but also as a potential marker for premalignant and malignant lesions in cases of buccal pouch mucosa. In this context, the aim of this review is to elucidate the following question whether the GST-P is a suitable biomarker for oral carcinogenesis. A total of 16 studies were carefully selected. Our results demonstrate that GST-P expression is a useful and coherent marker for oral carcinogenesis. Regarding the samples, most studies evaluated hamsters, two evaluated GST-P expression in rats and three evaluated GST-P expression in human cells. All studies demonstrated positive findings allowing us to consider such studies reliable. In summary, our conclusion is that GST-P can be a suitable biomarker for oral carcinogenesis.

The influence of embryo stage on obstetric complications and perinatal outcomes following programmed compared to natural frozen-thawed embryo transfer cycles: a systematic review and meta-analysis.

Objective: To investigate the effect of embryo stage at the time of transfer on obstetric and perinatal outcomes in programmed frozen-thawed embryo transfer (FET) versus natural FET cycles. Design: Systematic review and meta-analysis. Setting: Not applicable. Patients: Women with programmed frozen-thawed embryo transfer (FET) and natural FET. Interventions: The PubMed, MEDLINE, and EMBASE databases and the Cochrane Central Register of Controlled Trials (CCRT) were searched from 1983 to October 2022. Twenty-three observational studies were included. Primary outcome measure: The primary outcomes were hypertensive disorders of pregnancy (HDPs), gestational hypertension and preeclampsia (PE). The secondary outcomes were gestational diabetes mellitus (GDM), placenta previa, postpartum haemorrhage (PPH), placental abruption, preterm premature rupture of membranes (PPROM), large for gestational age (LGA), small for gestational age (SGA), macrosomia, and preterm delivery (PTD). Results: The risk of HDP (14 studies, odds ratio (OR) 2.17; 95% confidence interval (CI) 1.95-2.41; P<0.00001; I2 = 43%), gestational hypertension (11 studies, OR 1.38; 95% CI 1.15-1.66; P=0.0006; I2 = 19%), PE (12 studies, OR 2.09; 95% CI 1.88-2.32; P<0.00001; I2 = 0%), GDM (20 studies, OR 1.09; 95% CI 1.02-1.17; P=0.02; I2 = 8%), LGA (18 studies, OR 1.11; 95% CI 1.07-1.15; P<0.00001; I2 = 46%), macrosomia (12 studies, OR 1.15; 95% CI 1.07-1.24; P=0.0002; I2 = 31%), PTD (22 studies, OR 1.21; 95% CI 1.15-1.27; P<0.00001; I2 = 49%), placenta previa (17 studies, OR 1.2; 95% CI 1.02-1.41; P=0.03; I2 = 11%), PPROM (9 studies, OR 1.19; 95% CI 1.02-1.39; P=0.02; I2 = 40%), and PPH (12 studies, OR 2.27; 95% CI 2.02-2.55; P <0.00001; I2 = 55%) were increased in programmed FET cycles versus natural FET cycles with overall embryo transfer. Blastocyst transfer had a higher risk of HDP (6 studies, OR 2.48; 95% CI 2.12-2.91; P<0.00001; I2 = 39%), gestational hypertension (5 studies, OR 1.87; 95% CI 1.27-2.75; P=0.002; I2 = 25%), PE (6 studies, OR 2.23; 95% CI 1.93-2.56; P<0.00001; I2 = 0%), GDM (10 studies, OR 1.13; 95% CI 1.04-1.23; P=0.005; I2 = 39%), LGA (6 studies, OR 1.14; 95% CI 1.07-1.21; P<0.0001; I2 = 9%), macrosomia (4 studies, OR 1.15; 95% CI 1.05-1.26; P<0.002; I2 = 68%), PTD (9 studies, OR 1.43; 95% CI 1.31-1.57; P<0.00001; I2 = 22%), PPH (6 studies, OR 1.92; 95% CI 1.46-2.51; P<0.00001; I2 = 55%), and PPROM (4 studies, OR 1.45; 95% CI 1.14-1.83; P=0.002; I2 = 46%) in programmed FET cycles than in natural FET cycles. Cleavage-stage embryo transfers revealed no difference in HDPs (1 study, OR 0.81; 95% CI 0.32-2.02; P=0.65; I2 not applicable), gestational hypertension (2 studies, OR 0.85; 95% CI 0.48-1.51; P=0.59; I2 = 0%), PE (1 study, OR 1.19; 95% CI 0.58-2.42; P=0.64; I2not applicable), GDM (3 study, OR 0.79; 95% CI 0.52-1.20; P=0.27; I2 = 21%), LGA (1 study, OR 1.15; 95% CI 0.62-2.11; P=0.66; I2not applicable), macrosomia (1 study, OR 1.22; 95% CI 0.54-2.77; P=0.64; I2 not applicable), PTD (2 studies, OR 1.05; 95% CI 0.74-1.49; P=0.79; I2 = 0%), PPH (1 study, OR 1.49; 95% CI 0.85-2.62; P=0.17; I2not applicable), or PPROM (2 studies, OR 0.74; 95% CI 0.46-1.21; P=0.23; I2 = 0%) between programmed FET cycles and natural FET cycles. Conclusions: The risks of HDPs, gestational hypertension, PE, GDM, LGA, macrosomia, SGA, PTD, placenta previa, PPROM, and PPH were increased in programmed FET cycles versus natural FET cycles with overall embryo transfer and blastocyst transfer, but the risks were not clear for cleavage-stage embryo transfer.

Ferroptosis and its potential role in gestational diabetes mellitus: updated evidence from pathogenesis to therapy.

Background: Studies have demonstrated that high iron status is positively associated with gestational diabetes mellitus (GDM), implying that iron overload and ferroptosis play important roles in the development of GDM. The aim of this study was to explore effective therapeutic drugs from traditional Chinese medicine (TCM)formulas for the treatment of GDM based on ferroptosis. Methods: In this study, the presence of ferroptosis in the placenta was verified through clinical and experimental data, and key genes were subsequently screened for association with ferroptosis in the development of GDM. The analysis was based on transcriptome sequencing of datasets combined with differentially expressed genes (DEGs) analysis and weighted gene correlation network analysis (WGCNA); functional enrichment analysis was also performed. A protein-protein interaction (PPI) network was constructed and pivotal genes were identified using Cytoscape. Finally, traditional Chinese medicine (TCM)formulas related to treating GDM were collected, then the proteins corresponding to the key genes were molecularly docked with the small molecular structures of clinically proven effective herbal tonics, and molecular dynamic simulations were performed to select the best candidates for pharmacological compounds. Results: Elevated ferritin levels in patients with GDM were verified using clinical data. The presence of ferroptosis in placental tissues of patients with GDM was confirmed using electron microscopy and western blotting. Ninety-nine key genes with the highest correlation with ferroptosis were identified from DEGs and weighted gene co-expression network analysis (WGCNA). Analysis using the Kyoto Encyclopedia of Genes and Genomes demonstrated that the DEGs were primarily involved in the oxidative phosphorylation pathway. The key genes were further screened by PPI; two key genes, SF3B14 and BABAM1, were identified by combining the gene corresponding to protein structure and function, followed by molecular docking and molecular dynamic simulation. Coptis chinensis was proposed as the best candidate for herbal treatment at the molecular level. Conclusion: This data revealed the presence of ferroptosis in patients with GDM and identified possible modulatory roles of ferroptosis-related genes involved in the molecular mechanisms of GDM, providing new insights into the pathogenesis of GDM, which also provided new directions for the systematic optimization of TCM formulas for the management and targeted treatment of GDM.

Cis P-tau is a central circulating and placental etiologic driver and therapeutic target of preeclampsia.

Preeclampsia (PE) is the leading cause of maternal and fetal mortality globally and may trigger dementia later in life in mothers and their offspring. However, the etiological drivers remain elusive. Cis P-tau is an early etiological driver and blood biomarker in pre-clinical Alzheimer's and after vascular or traumatic brain injury, which can be targeted by stereo-specific antibody, with clinical trials ongoing. Here we find significant cis P-tau in the placenta and serum of PE patients, and in primary human trophoblasts exposed to hypoxia or sera from PE patients due to Pin1 inactivation. Depletion of cis P-tau from PE patient sera by the antibody prevents their ability to disrupt trophoblast invasion and endovascular activity and to cause the PE-like pathological and clinical features in pregnant humanized tau mice. Our studies uncover that cis P-tau is a central circulating etiological driver and its stereo-specific antibody is valuable for early PE diagnosis and treatment.

Integrated unbiased multiomics defines disease-independent placental clusters in common obstetrical syndromes.

BACKGROUND: Placental dysfunction, a root cause of common syndromes affecting human pregnancy, such as preeclampsia (PE), fetal growth restriction (FGR), and spontaneous preterm delivery (sPTD), remains poorly defined. These common, yet clinically disparate obstetrical syndromes share similar placental histopathologic patterns, while individuals within each syndrome present distinct molecular changes, challenging our understanding and hindering our ability to prevent and treat these syndromes. METHODS: Using our extensive biobank, we identified women with severe PE (n = 75), FGR (n = 40), FGR with a hypertensive disorder (FGR + HDP; n = 33), sPTD (n = 72), and two uncomplicated control groups, term (n = 113), and preterm without PE, FGR, or sPTD (n = 16). We used placental biopsies for transcriptomics, proteomics, metabolomics data, and histological evaluation. After conventional pairwise comparison, we deployed an unbiased, AI-based similarity network fusion (SNF) to integrate the datatypes and identify omics-defined placental clusters. We used Bayesian model selection to compare the association between the histopathological features and disease conditions vs SNF clusters. RESULTS: Pairwise, disease-based comparisons exhibited relatively few differences, likely reflecting the heterogeneity of the clinical syndromes. Therefore, we deployed the unbiased, omics-based SNF method. Our analysis resulted in four distinct clusters, which were mostly dominated by a specific syndrome. Notably, the cluster dominated by early-onset PE exhibited strong placental dysfunction patterns, with weaker injury patterns in the cluster dominated by sPTD. The SNF-defined clusters exhibited better correlation with the histopathology than the predefined disease groups. CONCLUSIONS: Our results demonstrate that integrated omics-based SNF distinctively reclassifies placental dysfunction patterns underlying the common obstetrical syndromes, improves our understanding of the pathological processes, and could promote a search for more personalized interventions.

Dynamics of IgG antibody response against Plasmodium antigens among Nigerian infants and young children.

Background: Plasmodium falciparum malaria is a leading cause of child mortality in Nigeria. Neonates are born with maternal antibodies from placental transfer which may protect against malaria infection in the first months of life. The IgG dynamics of the transition from passively transferred antimalarial antibodies to actively acquired IgG from natural exposure have not been well elucidated. Methods: Blood samples collected during a 2018 Nigeria nationwide HIV/AIDS household survey were available for 9,443 children under 5 years of age, with a subset of infants under 2 months of age having maternal samples available (n=41). Samples were assayed for the P. falciparum HRP2 antigen and anti-malarial IgG antibodies. LOESS regression examined the dynamics in IgG response in the first 5 years of life. Correlation with maternal IgG levels was assessed for mother/child pairs. Results: Consistent decreases were observed in median IgG levels against all Plasmodium spp. antigen targets for the first months of life. At a population level, P. falciparum apical membrane antigen-1 (AMA1) and merozoite surface protein-1 19kD (PfMSP1) IgG decreased during the first 12 months of life before reaching a nadir, whereas IgGs to other targets only declined for the first 4 months of life. Seropositivity showed a similar decline with the lowest seropositivity against AMA1 and PfMSP1 at 10-12 months, though remaining above 50% during the first 2 years of life in higher transmission areas. No protective association was observed between IgG positivity and P. falciparum infection in infants. Maternal antibody levels showed a strong positive correlation with infant antibody levels for all P. falciparum antigens from birth to 2 months of age, but this correlation was lost by 6 months of age. Discussion: Maternally transferred anti-malarial IgG antibodies rapidly decline during the first 6 months of life, with variations among specific antigens and malaria transmission intensity. From 3-23 months of age, there was a wide range in IgG levels for the blood-stage antigens indicating high individual variation in antibody production as children are infected with malaria. Non-falciparum species-specific antigens showed similar patterns in waning immunity and correlation with paired mother's IgG levels compared to P. falciparum antigens.

The emerging role of ferroptosis in female reproductive disorders.

Iron, as an essential trace element for the organism, is vital for maintaining the organism's health. Excessive iron can promote reactive oxygen species (ROS) accumulation, thus damaging cells and tissues. Ferroptosis is a novel form of programmed cell death distinguished by iron overload and lipid peroxidation, which is unique from autophagy, apoptosis and necrosis, more and more studies are focusing on ferroptosis. Recent evidence suggests that ferroptosis is associated with the development of female reproductive disorders (FRDs), including polycystic ovary syndrome (PCOS), premature ovarian insufficiency (POI), endometriosis (EMs), ovarian cancer (OC), preeclampsia (PE) and spontaneous abortion (SA). Pathways and genes associated with ferroptosis may participate in processes that regulate granulosa cell proliferation and secretion, oocyte development, ovarian reserve function, early embryonic development and placental oxidative stress. However, its exact mechanism has not been fully revealed. Therefore, our review systematically elaborates the occurrence mechanism of ferroptosis and its research progress in the development of FRDs, with a view to providing literature references for clinical targeting of ferroptosis -related pathways and regulatory factors for the management of FRDs.

Current state of interventional procedures to treat pernicious placenta previa accompanied by placenta accreta spectrum: A review.

Pernicious placenta previa (PPP) accompanied by placenta accreta spectrum (PAS) is a life-threatening placental implantation that causes a variety of complications, including antepartum hemorrhage, postpartum hemorrhage, hemorrhagic shock, preterm birth, and neonatal asphyxia. Along with continuous improvements in medical technology, interventional procedures have been widely used to prevent intraoperative hemorrhage associated with PPP. The commonly used interventional procedures include abdominal aorta clamping, prophylactic balloon occlusion of the internal or common iliac arteries, and uterine artery embolization. The above-mentioned interventional procedures have their respective advantages and disadvantages. The best procedure for different situations continues to be debated considering the complex pattern of blood supply to the uterus in patients with PPP. The specific choice of interventional procedure depends on the clinical situation of the patient with PPP. For grade III PAS, the need for uterine artery embolization is assessed based on blood loss and preoperative hemostatic effect following abdominal aorta clamping. Repair or hysterectomy may be performed following uterine artery embolization if there is a hybrid operating room for grade III PAS patients with extensive sub-serosal penetration of the uterus and repair difficulty. For grade II PAS (shallow placental implantation), prophylactic balloon occlusion may not be necessary before surgery. Uterine artery embolization can be performed in case of postoperative hemorrhage.