Pregnancy-related Disorders Research Articles

The association of activity patterns on female reproductive diseases: a prospective cohort study of UK biobank

ObjectiveLittle is known about the role of timing of physical activity in female reproductive disorders. These disorders include polycystic ovary syndrome (PCOS), heavy menstrual bleeding (HMB), endometriosis, infertility, and pregnancy-related disorders. This study aims to investigate the associations of activity patterns with female reproductive diseases.MethodsA total of 49,540 female participants from the UK Biobank with valid accelerometer data were enrolled at baseline. Activity patterns were defined based on the timing of moderate-to-vigorous intensity physical activity (MVPA) throughout the day. Participants were categorized into four groups according to the timing of their MVPA: “morning, evening, mixed, midday-afternoon”, with the midday-afternoon group serving as the reference. Cox proportional hazards models were utilized to evaluate the association between activity patterns and female reproductive diseases.ResultsDuring a median follow-up of 12.6 years, a total of 1044 cases of female reproductive diseases were documented. After adjustment for potential confounders, compared to women with midday-afternoon exercise, women with morning exercise and mixed-timing exercise were associated with lower risks for female reproductive diseases (HRmorning=0.81, 95% CI: 0.67–0.98; HRmixed=0.79, 95% CI: 0.69–0.91, P-trend < 0.05). Moreover, morning exercise and mixed-timing exercise had lower risks of PCOS (HRmorning=0.38, 95% CI: 0.15–0.97; HRmixed=0.27, 95% CI: 0.13–0.57, P-trend<0.001), and mixed-timing exercise was associated with a lower risk for HMB (HRmixed=0.81, 95% CI: 0.70–0.95, P-trend < 0.05), compared with the reference group.ConclusionsCompared with midday-afternoon group, morning and mixed MVPA timing groups, but not evening group, were associated with decreased risks for female reproductive diseases and PCOS. In addition, we found that women with mixed MVPA timing exercise had a lower risk of HMB, compared with the reference group.

Determine the Connection Between Endometriosis and Hypertensive Disorders During Pregnancy: A Systematic Review

This study is designed to explore the correlation between endometriosis and hypertensive disorders during pregnancy. We looked through the Cochrane Library, PubMed and Scopus, for pertinent papers to the end of 2023. Included were full-text qualitative research studies that were published in English and provided a definitive diagnosis of endometriosis. While pregnant women without a prior endometriosis diagnosis made up the control group, pregnant women having an endometriosis diagnosis at any stage were included in the case group. The data was separately extracted and examined by two authors. A third author reviewed the entire manuscript to resolve disagreements. Data extraction and screening were done using Endnote X9. Review Manager 5.3's fixed and random effects models were employed to examine the combined data. The Downs and Black checklist were used to evaluate the included studies' quality. This analysis found that pregnancy-related hypertension disorder in 3116 endometriosis-affected women. The study confirmed that endometriosis may raise the risk of pregnancy-induced hypertension and conditions related to hypertension. Raising knowledge of hypertension diseases during pregnancy will help create screening and early diagnosis strategies that are effective.

The role of placenta Hofbauer cells during pregnancy and pregnancy complications.

Placental Hofbauer cells (HBCs) are specialized macrophages present in the human placenta that play a crucial role in maintaining a healthy pregnancy. These cells are derived from the fetal mesoderm and are responsible for various functions, including immune regulation, angiogenesis, and nutrient transport. In normal pregnancies, HBCs primarily exhibit an M2 or immunomodulatory phenotype, which helps maintain a tolerant and anti-inflammatory environment at the maternal-fetal interface. However, in pregnancies complicated by conditions such as immunological disorders, inflammation, or infection, the phenotype and function of HBCs may be altered. Although emerging evidence has highlighted the vital role of HBCs in both normal pregnancies and those with complications, such as chorioamnionitis, gestational diabetes, preeclampsia, and viral infections, their role remains unclear. Recent research also suggests a relationship between HBCs and the development of diseases in offspring. Understanding the role of HBCs in pregnancy could provide insights into the pathophysiology of various pregnancy-related disorders and offer potential therapeutic targets for improving maternal and fetal outcomes. This review explores the functions of HBCs in normal pregnancy and their involvement in complications, emphasizing their potential as biomarkers or targets for interventions aimed at reducing the incidence of adverse pregnancy outcomes. Additionally, we reviewed their potential for perinatal research in recent studies.

Abnormal microRNA expression profile at early stages of gestation in pregnancies destined to develop placenta previa.

Placenta previa is the abnormal implantation of the placenta into the lower segment of the uterus, is associated with adverse maternal and fetal outcomes such as placenta accreta spectrum disorders, antepartum and postpartum hemorrhage, fetal growth restriction, prematurity, stillbirth and neonatal death, thrombophlebitis, and septicemia. The aim of the study was to assess retrospectively how the later onset of placenta previa affects the microRNA expression profile in the whole peripheral blood during the first trimester of gestation. Regarding the occurrence of the association between aberrant microRNA expression profiles at early stages of gestation and later onset of various pregnancy-related complications, we selected for the study pregnancies developing placenta previa as the only pregnancy-related disorder. In total, 24 singleton pregnancies diagnosed with placenta previa that underwent first-trimester prenatal screening and delivered on-site within the period November 2012-May 2018 were included in the study. Overall, 80 normal pregnancies that delivered appropriate-for-gestational age newborns after completing 37 weeks of gestation were selected as the control group based on the equality of the length of biological sample storage. Downregulation of multiple microRNAs (miR-20b-5p, miR-24-3p, miR-26a-5p, miR-92a-3p, miR-103a-3p, miR-130b-3p, miR-133a-3p, miR-145-5p, miR-146a-5p, miR-155-5p, miR-181a-5p, miR-195-5p, miR-210-3p, miR-342-3p, and miR-574-3p) was observed in pregnancies destined to develop placenta previa. The combination of seven microRNAs (miR-130b-3p, miR-145-5p, miR-155-5p, miR-181a-5p, miR-210-3p, miR-342-3p, and miR-574-3p) showed the highest accuracy (AUC 0.937, p < 0.001, 100.0% sensitivity, 83.75% specificity) to differentiate, at early stages of gestation, between pregnancies with a normal course of gestation and those with placenta previa diagnosed in the second half of pregnancy. Overall, 75% of pregnancies destined to develop placenta previa were correctly identified at 10.0% FPR. Consecutive large-scale analyses must be performed to verify the reliability of the proposed novel early predictive model for placenta previa occurring as the only pregnancy-related disorder.

Exercise Intervention to Mitigate the Cardiovascular Sequence of Pregnancy Complications.

Pregnancy issues such as gestational hypertension, preeclampsia, and gestational diabetes mellitus (GDM) are significant contributors to long-term cardiovascular diseases (CVDs) in women. Recent research has proved the impact of exercise on improving cardiovascular outcomes, particularly in women with pregnancy-related disorders. This review explores the outcomes of various exercise interventions on cardiovascular health in pregnant women. Among these, aerobic exercise has been widely studied, with results from observational studies and randomized controlled trials (RCTs) showing its positive outcomes on cardiovascular health in pregnant women, especially with complications. It has been found that regular aerobic exercise has been associated with reduced hypertension and improved endothelial function, particularly in women with a history of preeclampsia. Evidently, aerobic exercise results in better blood pressure regulation and enhanced vascular health that directly attends to the risk of cardiovascular diseases associated with pregnancy complications. Another form of exercise is resistance training, which despite being studied less, has shown potential benefits as well. Some advantages of resistance exercise have been found to improve muscle strength and overall enhancement in metabolic control. This is important, especially in women with GDM whereby improvement in insulin sensitivity reduces the overall risk of type 2 diabetes and future CVDs. Combined exercise that incorporates both aerobic and resistance elementshas been known to offer the most comprehensive benefits. Various studies suggest that a combinatory approach maximizes the positive cardiovascular effects. Practicing women have experienced better overall heart health, with improved blood pressure regulation, enhanced endothelial function, and reduced metabolic risks. However, despite these findings, there are challenges such as small sample sizes and limited follow-up durations that hinder the generalizability of current research. Importantly, previous studies targeting exercise interventions for women experiencing complications during pregnancy have been limited in evidence by small sample sizes, short follow-ups, and lack of diversity. Such broader, more diverse populations were needed to reflect the various health risks and responses to exercise. Future research must include multi-center RCTs, diverse exercise regimens, and digital health tools for monitoring exercise adherence. This warrants future large-scale, multicenter trials that are necessary to establish more definitive evidence. Additionally, clinicians should consider including tailored exercise programs in care plans for women with pregnancy complications to mitigate long-term cardiovascular risks.

Insights into the pathogenesis of gestational and hepatic diseases: the impact of ferroptosis.

Ferroptosis, a distinct form of non-apoptotic cell death characterized by iron dependency and lipid peroxidation, is increasingly linked to various pathological conditions in pregnancy and liver diseases. It plays a critical role throughout pregnancy, influencing processes such as embryogenesis, implantation, and the maintenance of gestation. A growing body of evidence indicates that disruptions in these processes can precipitate pregnancy-related disorders, including pre-eclampsia (PE), gestational diabetes mellitus (GDM), and intrahepatic cholestasis of pregnancy (ICP). Notably, while ICP is primarily associated with elevated maternal serum bile acid levels, its precise etiology remains elusive. Oxidative stress induced by bile acid accumulation is believed to be a significant factor in ICP pathogenesis. Similarly, the liver's susceptibility to oxidative damage underscores the importance of lipid metabolism dysregulation and impaired iron homeostasis in the progression of liver diseases such as alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), cholestatic liver injury, autoimmune hepatitis (AIH), acute liver injury, viral hepatitis, liver fibrosis, and hepatocellular carcinoma (HCC). This review discusses the shared signaling mechanisms of ferroptosis in gestational and hepatic diseases, and explores recent advances in understanding the mechanisms of ferroptosis and its potential role in the pathogenesis of gestational and hepatic disorders, with the aim of identifying viable therapeutic targets.

A Systematic Review of the Association of Low Platelet Counts and Preeclampsia

Introduction: Preeclampsia is a serious pregnancy-related disorder that affects women worldwide; representing as a main cause of feto-maternal morbidity and mortality. Objectives: The present systematic review aims to evaluate the reported values of platelet count differences in preeclamptic women and compare them to normotensive pregnant women as controls.Methods: Pubmed-NCBI, Web of Science and Google scholar Database were searched till November 2023 using the keywords “Preeclampsia OR eclampsia AND platelet count". Cohort, case-control, and cross-sectional studies reporting data on platelet count in preeclampsia in comparison to normotensive pregnant women were included. Results: Ten articles were included, with a total of 870 preeclampsia cases and 1409 controls. The mean (SD) of the platelets count was significantly lower in preeclamptic women compared to normotensive pregnant women [195.2 (55.7) % vs. 249.4 (52.5) %, P &lt; 0.001]. The mean difference was 55.18, 95% CI = 38.33–72.04. However, it was insignificantly lower in women with severe preeclampsia compared to those with mild preeclampsia [178(42.11) vs. 216 (48.69), respectively, P =0.76]. The mean difference was 40.6, 95% CI = 34.24–46.95. Conclusions: The platelets count is low in preeclampsia and can be considered as a promising laboratory marker for the detection and follow-up of pregnant women who develop preeclampsia.

Genetic study of intrahepatic cholestasis of pregnancy in Chinese women unveils East Asian etiology linked to historic HBV epidemic

Background & AimsIntrahepatic cholestasis of pregnancy (ICP) is the most common and high-risk liver disorder during pregnancy, with varying prevalence across populations. Our understanding of the mechanisms underlying ICP and its population difference remains limited. This study delves into the genetic etiology of ICP in East Asians, drawing comparisons with Europeans to comprehend ICP etiology in the context of genetic background and evolution. MethodsWe conducted the hitherto largest-scale genome-wide association studies (GWAS) on fasting total serum bile acids (TBA) and ICP in 98,269 Chinese pregnancies. The findings were replicated in three cohorts and compared with European populations. Additionally, phenome-wide association and spatio-temporal evolution analyses were employed to investigate the function and evolutionary patterns of ICP-associated loci. ResultsWe identified eight loci for fasting TBA and four for ICP, including ten novel loci. Notably, we discovered an East-Asian-specific locus within a 0.4Mbp region at 14q24.1, which increases fasting TBA by 6.12 μmol/L and ICP risk by 16.56-fold per risk allele (95% CI: 16.43 to 16.69, P = 7.06×10-381). Phenome-wide association and spatial-temporal evolution analyses revealed that this 14q24.1 ICP risk locus confers resistance to hepatitis B and has become prevalent in East and Southeast Asia within the last 3,000 years. ConclusionsWe uncovered a distinct genetic etiology of ICP in East Asians, likely linked to a historic HBV epidemic in East and Southeast Asia within the last 3,000 years. These findings enhance our understanding of ICP pathophysiology and offer potential for more precise detection, assessment, and treatment of the disorder. Impact and implicationsThis study provides novel insights into the genetic basis of intrahepatic cholestasis of pregnancy (ICP) in East Asian populations, where little was previously known. The identification of the East-Asian-specific 14q24.1 locus, associated with both fasting TBA and ICP, and its connection to a historical hepatitis B epidemic emphasize the importance of incorporating population-specific history into disease research. These findings are crucial for researchers studying pregnancy-related liver disorders and clinicians providing care to pregnant women, enabling more accurate screening, risk assessment, and targeted interventions for ICP.

Decoding Apelin: Its Role in Metabolic Programming, Fetal Growth, and Gestational Complications.

Placental insufficiency and gestational diabetes, which are both serious pregnancy complications, are linked to altered fetal growth, whether restricted or excessive, and result in metabolic dysfunction, hypoxic/oxidative injury, and adverse perinatal outcomes. Although much research has been carried out in this field, the underlying pathogenetic mechanisms have not as yet been fully elucidated. Particularly because of the role it plays in cardiovascular performance, glucose metabolism, inflammation, and oxidative stress, the adipokine apelin was recently shown to be a potential regulator of fetal growth and metabolic programming. This review investigated the numerous biological actions of apelin in utero and aimed to shed more light on its role in fetal growth and metabolic programming. The expression of the apelinergic system in a number of tissues indicates its involvement in many physiological mechanisms, including angiogenesis, cell proliferation, energy metabolism, inflammation, and oxidative stress. Moreover, it appears that apelin has a major function in disorders such as diabetes mellitus, fetal growth abnormalities, fetal hypoxia, and preeclampsia. We herein describe in detail the regulatory effects exerted by the adipokine apelin on fetal growth and metabolic programming while stressing the necessity for additional research into the therapeutic potential of apelin and its mechanisms of action in pregnancy-related disorders.

12440 Exploring The Potential Protective Role Of The Bacterial-derived Metabolite Indole-3-propionic Acid Against Obesogenic Insults In Placenta Cell Lines

Abstract Disclosure: J. Ernst: None. L. Conlon: None. R. Gupta: None. L. Kang: None. M.E. Heard-Lipsmeyer: None. Obesity during pregnancy is associated with detrimental changes in placental function that lead to the development of complications such as gestational diabetes and preeclampsia as well as altered metabolism in the offspring. With the incidence of obesity reaching epidemic levels world-wide, it is imperative to find mechanisms to mitigate these risks during pregnancy. The gut-microbiome is a diverse system that regulates numerous body functions through the secretion of specific metabolites. Gut dysbiosis has recently emerged as one mechanism that contributes to placental dysfunction and clear associations between obesity and gut dysbiosis are evident. Indole-3-propionic acid (IPA) is a gut microbiome-derived metabolite that has anti-inflammatory, anti-oxidative stress and glucose regulatory functions, all of which are dysregulated in obesity. Previous studies have found diminished levels of IPA in serum of women with overweight/obesity. However, it remains unknown what the physiological functions of IPA are in the placenta and if it could have potential protective effects against perturbations caused by obesity. The objective of this study is to determine what physiological role IPA plays in the placenta and if IPA can protect against obesogenic insults that contribute to placental pathology. For this study, we developed an in vitro model of obesity where two human placental cell lines, BeWo (choriocarcinoma) and HTR8 (normal immortalized trophoblasts) were cultured in media conditioned by mature human adipocytes (ACM). RNA sequencing (RNAseq) analysis was used to determine acute effects of IPA treatment after 24 hours in the presence and absence of ACM. We further examined the influence of IPA on insulin signaling with physiological and hyperinsulinemia levels of insulin at 24 and 72 hours utilizing QPCR and western blot analyses. RNAseq analysis revealed treatment with physiological levels of IPA induced changes in genes associated with normal placental function, autophagy and inflammatory mediated processes and other pathways. Our RNAseq analysis offers initial insight into the molecular mechanisms of IPA in placental cells. Future analyses will investigate the potential role of insulin signaling, glucose homeostasis and oxidative stress. Collectively, this study highlights the importance of a healthy gut microbiome and potentially serves as a window of opportunity to mitigate the onset or severity of pregnancy-related disorders such as gestational diabetes by enhancing the gut microbiome prior to pregnancy. Presentation: 6/1/2024

12440 Exploring The Potential Protective Role Of The Bacterial-derived Metabolite Indole-3-propionic Acid Against Obesogenic Insults In Placenta Cell Lines

Abstract Disclosure: J. Ernst: None. L. Conlon: None. R. Gupta: None. L. Kang: None. M.E. Heard-Lipsmeyer: None. Obesity during pregnancy is associated with detrimental changes in placental function that lead to the development of complications such as gestational diabetes and preeclampsia as well as altered metabolism in the offspring. With the incidence of obesity reaching epidemic levels world-wide, it is imperative to find mechanisms to mitigate these risks during pregnancy. The gut-microbiome is a diverse system that regulates numerous body functions through the secretion of specific metabolites. Gut dysbiosis has recently emerged as one mechanism that contributes to placental dysfunction and clear associations between obesity and gut dysbiosis are evident. Indole-3-propionic acid (IPA) is a gut microbiome-derived metabolite that has anti-inflammatory, anti-oxidative stress and glucose regulatory functions, all of which are dysregulated in obesity. Previous studies have found diminished levels of IPA in serum of women with overweight/obesity. However, it remains unknown what the physiological functions of IPA are in the placenta and if it could have potential protective effects against perturbations caused by obesity. The objective of this study is to determine what physiological role IPA plays in the placenta and if IPA can protect against obesogenic insults that contribute to placental pathology. For this study, we developed an in vitro model of obesity where two human placental cell lines, BeWo (choriocarcinoma) and HTR8 (normal immortalized trophoblasts) were cultured in media conditioned by mature human adipocytes (ACM). RNA sequencing (RNAseq) analysis was used to determine acute effects of IPA treatment after 24 hours in the presence and absence of ACM. We further examined the influence of IPA on insulin signaling with physiological and hyperinsulinemia levels of insulin at 24 and 72 hours utilizing QPCR and western blot analyses. RNAseq analysis revealed treatment with physiological levels of IPA induced changes in genes associated with normal placental function, autophagy and inflammatory mediated processes and other pathways. Our RNAseq analysis offers initial insight into the molecular mechanisms of IPA in placental cells. Future analyses will investigate the potential role of insulin signaling, glucose homeostasis and oxidative stress. Collectively, this study highlights the importance of a healthy gut microbiome and potentially serves as a window of opportunity to mitigate the onset or severity of pregnancy-related disorders such as gestational diabetes by enhancing the gut microbiome prior to pregnancy. Presentation: 6/1/2024

Economic analysis of the use of the Flt-1/PlGF preeclampsia ratio compared to the standard of care in Uruguay

Preeclampsia (PE) is a pregnancyrelated hypertensive disorder that can lead to severe complications and adverse maternal and fetal outcomes. This study aimed to estimate the economic impact of integrating the sFlt-1/PlGF ratio into Uruguay's healthcare system as part of routine clinical practice for diagnosing. A decision tree model was used to estimate the annual economic impact on the Uruguayan healthcare system for a hypothetical cohort of women with suspected PE. This included relevant costs associated with diagnosis, monitoring, and treatment from the initial presentation of suspected PE until childbirth. The study analyzed the annual costs under two scenarios: the standard of care and a scenario incorporating the sFlt-1/PlGF ratio for PE, using 2022 as the reference year. Various deterministic and probabilistic sensitivity analyses were performed. The economic model estimated that the implementation of the sFlt-1/PlGF ratio could save the Uruguayan healthcare system $95,432,678 Uruguayan pesos (2,320,269 United States Dollars [USD]) annually, representing a 5 % reduction in costs compared with the standard of care. These savings were primarily due to a reduction in hospitalizations of women with suspected PE. The estimated economic impact equated to an annual net saving of approximately $10,602 Uruguayan pesos (258 USD) per patient. The introduction of the sFlt-1/PlGF ratio into the Uruguayan healthcare system is likely to generate savings due to the optimization of the management of hospitalizations for women with suspected preeclampsia (PE). However, the potential for savings will primarily depend on the current hospitalization rate of these women (the efficiency of managing high-risk PE pregnancies) and the length of stay for hospitalized women.

Maternal Plasma miRNAs as Early Biomarkers of Moderate-to-Late-Preterm Birth.

Globally, preterm birth (PTB) is a primary cause of mortality and morbidity in infants, with PTB rates increasing worldwide over the last two decades. Biomarkers for accurate early prediction of PTB before the clinical event do not currently exist. Given their roles in the development and progression of many disease states, there has been increasing interest in the utility of microRNAs (miRNAs) as early biomarkers for pregnancy-related disorders, including PTB. The present study was designed to examine potential differences in miRNA abundances in maternal plasma from mothers with infants born following a moderate to late (28-36 weeks' gestation, n = 54) spontaneous PTB (SPTB) compared to mothers with matched term infants (n = 54). Maternal plasma collected at 15 weeks' gestation were utilised from the Auckland and Adelaide cohorts from the Screening for Pregnancy Endpoints (SCOPE) study. miRNAs in plasma were quantified using the NanoString nCounter expression panel (800 miRNAs). The top four most abundant miRNAs were significantly decreased in the plasma of mothers in the SPTB group with results consistent across both cohorts and pathway analysis was undertaken to examine the biological processes linked to the dysregulated miRNAs. The top candidate miRNAs (miRs-451a, -223-3p, let-7a-5p, and -126-3p) were linked to gene pathways associated with inflammation, apoptosis, and mitochondrial biogenesis. Moreover, miRNAs were consistently less abundant in the plasma of mothers of preterm infants across both sites, suggesting potential global dysregulation in miRNA biogenesis. This was supported by a significant downregulation in expression of key genes that are involved in miRNA biogenesis (DROSHA, DICER, and AGO2) across both sites in the SPTB group. In summary, the present study has identified miRNAs in maternal plasma that may provide predictive utility as early biomarkers for the risk of later SPTB. Importantly, these observations were conserved across two independent cohorts. Further, our data provide evidence for a persistent decrease in miRNA abundance in mothers who later experienced an SPTB, which is likely to have widespread consequences for gene regulation and epigenetic processes.

Abstract P195: Vascular MAPK/ERK Activation in sFTL-1-Induced Preeclampsia In Vivo

Vascular endothelial growth factor (VEGF) inhibition is linked to the development of hypertension and proteinuria in preeclampsia. This occurs as anti-angiogenic factors from the placenta contribute to pregnancy-related hypertension disorder. Soluble VEGF receptor fms-like tyrosine kinase-1 (sFLT-1) is an anti-angiogenic factor that counteracts VEGF. Levels of sFLT-1 are three times higher in preeclamptic placentas compared to those from normotensive pregnancies, and plasma sFLT-1 levels increase with the severity of preeclampsia. Infusing sFLT-1 in rodents induces hypertension, proteinuria, and glomerular endotheliosis, resembling the human condition of preeclampsia. Currently, there is no effective pharmacological treatment of preeclampsia, and in severe cases, early delivery is often the only effective treatment. In this study, we aim to determine how sFLT-1 exposure affects the activation of the vascular MAPK/ERK pathway and the contractility of the aorta ex-vivo using wire myography, to assess if the MAPK/ERK pathway can be a therapeutic target in preeclampsia. To this end, we treated pregnant female C57BL/6 mice from embryonic day E7.5 to E18.5 with either sFLT-1 (3.7mg/kg/day) or vehicle (phosphate-buffered saline) delivered by osmotic minipumps (intraperitoneal) and carried out non-invasive tail-cuff blood pressure measurements. After sacrifice, we isolated descending thoracic aorta for isometric tension measurements in a wire myograph. Infusion of sFLT-1 resulted in marked systolic blood pressure (SBP) elevation (D increase of 14 mmHg, P=0.0003) and augmented aortic phosphorylated-ERK activation (2-fold increase, P=0.040) by western blot and displayed impaired acetylcholine-induced endothelial relaxation in thoracic aortic segments (P&lt;0.05), providing in vivo evidence of increased vascular p-ERK activation, accompanied by higher SBP and endothelial dysfunction in sFLT-1 - indued mouse model of preeclampsia. Future experiments are aimed to test the effect of pharmacological ERK inhibition in sFLT-1 infusion in vivo . We hypothesize that sFLT-1-induced rise in SBP and vascular p-ERK could be prevented in vivo by treatment with the pharmacological ERK inhibitor.

Antioxidant Defenses, Oxidative Stress Responses, and Apoptosis Modulation in Spontaneous Abortion: An Immunohistochemistry Analysis of First-Trimester Chorionic Villi.

Oxidative stress (OS) and apoptosis are critical factors in placental development and function. Their interplay influences trophoblast proliferation, differentiation, and invasion, as well as vascular development. An imbalance between these processes can lead to pregnancy-related disorders such as preeclampsia, intrauterine growth restriction, and even spontaneous abortion. Our study seeks to elucidate the associations between preventive antioxidant/protective OS response factors-glutathione (GSH), MutT Homolog 1 (MTH1), and apoptotic regulation modulators-tumor protein p53 and B-cell lymphoma (Bcl-2) transcripts, in the context of spontaneous abortion (30 samples) versus elective termination of pregnancy (20 samples), using immunohistochemistry (IHC) to determine their proteomic expression in chorionic villi within abortive fetal placenta tissue samples. Herein, comparative statistical analyses revealed that both OS response factors, GSH and MTH1, were significantly under-expressed in spontaneous abortion cases as compared to elective. Conversely, for apoptotic regulators, p53 expression was significantly higher in spontaneous abortion cases, whereas Bcl-2 expression was significantly lower in spontaneous abortion cases. These findings suggest that a strong pro-apoptotic signal is prevalent within spontaneous abortion samples, alongside reduced anti-apoptotic protection, depleted antioxidant defenses and compromised oxidative DNA damage prevention/repair, as compared to elective abortion controls. Herein, our hypothesis that OS and apoptosis are closely linked processes contributing to placental dysfunction and spontaneous abortion was thus seemingly corroborated. Our results further highlight the importance of maintaining redox homeostasis and apoptotic regulation for a successful pregnancy. Understanding the mechanisms underlying this interplay is essential for developing potential therapies to manage OS, promote placentation, and avoid unwanted apoptosis, ultimately improving pregnancy outcomes. Antioxidant supplementation, modulation of p53 activity, and the enhancement of DNA repair mechanisms may represent potential approaches to mitigate OS and apoptosis in the placenta. Further research is needed to explore these strategies and their efficacy in preventing spontaneous abortion.

The Roles of Obesity and ASB4 in Preeclampsia Pathogenesis.

Preeclampsia is a complex pregnancy-related hypertensive disorder which poses significant risks for both maternal and fetal health. Preeclampsia affects 5-8% of pregnancies in the United States, causing a significant public health and economic burden. Despite extensive research, the etiology and pathogenesis of preeclampsia remain elusive, but have been correlated with maternal conditions such as obesity. In recent decades, the incidence of preeclampsia increased along with the prevalence of obesity among women of reproductive age. Maternal obesity has been shown to negatively affect pregnancy in almost all aspects. However, the precise mechanisms by which obesity influences preeclampsia are unclear. Ankyrin repeat and SOCS Box Containing protein 4 (ASB4) is an E3 ubiquitin ligase that can promote the degradation of a wide range of target proteins. ASB4-null mice display a full spectrum of preeclampsia-like phenotypes during pregnancy including hypertension, proteinuria, and decreased litter size. Furthermore, maternal obesity induced by a high-fat diet aggravates preeclampsia-like phenotypes in pregnant mice lacking ASB4. Variants in the ASB4 gene have been associated with obesity in humans, and a functional connection between the ASB4 gene and obesity has been established in mice. This review discusses the connections between preeclampsia, obesity, and ASB4.

Alternative drug delivery systems for pregnancy related disorders: A focused review

Objectives: The objective of this review was to summarize currently developed advanced drug delivery systems that can be used for pregnancy related disorders along with their advantages and clinical relevance. Methods: This process used a defined search strategy of indexed publications from databases like Google scholar, PubMed, Embase, Medline, Scopus and UTMB library from 2000 to 2020 and included methods to assess the quality of the evidence retrieved. Results: Pregnancy is the unique physiological condition where some of the drugs will be lifesaving to mother, but they can be toxic to fetal tissue. It is mandatory to research on the novel drug delivery systems. Although there was a substantial quantity of research has been carried out on the maternal -placental-fetal drug uptake, transfer, and toxicity, therapeutic evaluations of advanced drug delivery systems in pregnancy remain in their infancy. Conclusions: In this review, we highlighted the physiological considerations of the placenta and summarized recent research work in advanced drug delivery systems used in pregnancy as well as their potential applications in clinical reality.

Hypertension and diabetes risk in patients with previous pregnancy-related disorders and the time to onset of the disease

Hypertension and diabetes risk in patients with previous pregnancy-related disorders and the time to onset of the disease

In vitro culture of cynomolgus monkey embryos from blastocyst to early organogenesis.

Human early embryonic development is the cornerstone of a healthy baby. Abnormal early embryonic development may lead to developmental and pregnancy-related disorders. Accordingly, understanding the developmental events and mechanisms of human early embryonic development is very important. However, attempts to reveal these events and mechanisms are greatly hindered by the extreme inaccessibility of in vivo early human embryos. Fortunately, the emergence of in vitro culture (IVC) systems for mammalian embryos provides an alternative strategy. In recent years, different two-dimensional and three-dimensional IVC systems have been developed for human embryos. Ethical limitations restrict the IVC of human embryos beyond 14 days, which makes non-human primate embryos an ideal model for studying primate developmental events. Different culture systems have supported the development of monkey embryos to days postfertilization 14 and 25, respectively. The successful recapitulation of in vivo developmental events by these IVC embryos has greatly enriched our understanding of human early embryonic development, which undoubtedly helps us to develop possible strategies to predict or treat various gestation-related diseases and birth defects. In this protocol, we establish different two-dimensional and three-dimensional IVC systems for primate embryos, provide step-by-step culture procedures and notes, and summarize the advantages and limitations of different culture systems. Replicating this protocol requires a moderate level of experience in mammalian embryo IVC, and the embryo culture requires strict adherence to the procedures we have described.

HLA-C expression in extravillous trophoblasts is determined by an ELF3–NLRP2/NLRP7 regulatory axis

The distinct human leukocyte antigen (HLA) class I expression pattern of human extravillous trophoblasts (EVT) endows them with unique tolerogenic properties that enable successful pregnancy. Nevertheless, how this process is elaborately regulated remains elusive. Previously, E74 like ETS transcription factor 3 (ELF3) was identified to govern high-level HLA-C expression in EVT. In the present study, ELF3 is found to bind to the enhancer region of two adjacent NOD-like receptor (NLR) genes, NLR family pyrin domain-containing 2 and 7 (NLRP2, NLRP7). Notably, our analysis of ELF3-deficient JEG-3 cells, a human choriocarcinoma cell line widely used to study EVT biology, suggests that ELF3 transactivates NLRP7 while suppressing the expression of NLRP2. Moreover, we find that NLRP2 and NLRP7 have opposing effects on HLA-C expression, thus implicating them in immune evasion at the maternal-fetal interface. We confirmed that NLRP2 suppresses HLA-C levels and described a unique role for NLRP7 in promoting HLA-C expression in JEG-3. These results suggest that these two NLR genes, which arose via gene duplication in primates, are fine-tuned by ELF3 yet have acquired divergent functions to enable proper expression levels of HLA-C in EVT, presumably through modulating the degradation kinetics of IkBα. Targeting the ELF3-NLRP2/NLRP7-HLA-C axis may hold therapeutic potential for managing pregnancy-related disorders, such as recurrent hydatidiform moles and fetal growth restriction, and thus improve placental development and pregnancy outcomes.