Pregnancy-specific Disorder Research Articles

Approach to Altered Mental Status in Pregnancy and Postpartum.

The evaluation and diagnosis of altered mental status in the pregnant or postpartum patient largely parallels the approach used for any other patient; however, there are several critical differences including that some neuroobstetric diagnoses require emergent delivery of the fetus. Being familiar with the physiological changes and medical complications of pregnancy and delivery is therefore essential. This review first addresses pregnancy-specific disorders that may result in altered mental status, such as the hypertensive disorders of pregnancy and pregnancy-related metabolic and endocrinopathies. The focus then shifts to the complex physiologic changes in pregnancy and how these changes contribute to the distinct epidemiology of pregnancy-related cerebrovascular complications like intracranial hemorrhage, ischemic stroke, and reversible cerebral vasoconstriction syndrome. Medical disorders that are not unique to pregnancy, such as infections and autoimmune conditions, may present de novo or worsen during pregnancy and the peripartum period and require a thoughtful approach to diagnosis and management. Finally, the unique nervous system complications of obstetric anesthesia are explored. In each section, there is a focus not only on diagnosis and syndrome recognition but also on the emergent treatment needed to reverse these complications, bearing in mind the unique physiology of the pregnant patient.

Alpha 1,3 N-Acetylgalactosaminyl Transferase (GTA) Impairs Invasion Potential of Trophoblast Cells in Preeclampsia.

Preeclampsia (PE) is a pregnancy-specific disorder associated with shallow invasion of the trophoblast cells and insufficient remodeling of the uterine spiral artery. Protein glycosylation plays an important role in trophoblast cell invasion. However, the glycobiological mechanism of PE has not been fully elucidated. In the current study, employing the Lectin array, we found that soybean agglutinin (SBA), which recognizes the terminal N-acetylgalactosamine α1,3-galactose (GalNAc α1,3 Gal) glycotype, was significantly increased in placental trophoblast cells from PE patients compared with third-trimester pregnant controls. Upregulating the expression of the key enzyme α1,3 N-acetylgalactosaminyl transferase (GTA) promoted the biosynthesis of terminal GalNAc α1,3 Gal and inhibited the migration/invasion of HTR8/SVneo trophoblast cells. Moreover, the methylation status of GTA promoter in placental tissues from PE patients was lower than that in the third trimester by methylation-specific PCR (MSP) and bisulfite sequencing PCR (BSP) analysis. Elevated GTA expression in combination with the DNA methylation inhibitor 5-azacytidine (5-AzaC) treatment increased the glycotype biosynthesis and impaired the invasion potential of trophoblast cells, leading to preeclampsia. This study suggests that elevated terminal GalNAc α1,3 Gal biosynthesis and GTA expression may be applied as the new markers for evaluating placental function and the auxiliary diagnosis of preeclampsia.

Characteristics and outcome of pregnancy-related acute kidney injury in a teaching hospital in a low-resource setting: a five-year retrospective review.

Pregnancy-related kidney injury contributes to a high burden of acute kidney injury in low-resource settings and causes maternal and perinatal morbidity and mortality. Few studies have examined the impact of acute kidney injury in resource-limited countries, with very limited research on pregnancy-specific disorders in Ethiopia. This study aimed to determine the characteristics of pregnancy-related acute kidney injury, outcomes and associated factors. A retrospective study was conducted to evaluate the clinical profile and maternal-fetal outcome of pregnancy-related acute kidney injury at Ayder Comprehensive Specialized Hospital in Tigray, Ethiopia, from January 1, 2017, to December 31, 2021. Maternal and fetal outcomes were analyzed using descriptive statistics. Multivariate logistic regression was used to determine the association between the dependent and independent variables. Of 27,350 mothers who delivered at Ayder Comprehensive Specialized Hospital between January 1, 2017, and December 31, 2021, a total of 187 women developed pregnancy-related acute kidney injury, a prevalence rate of 68 per 100,000 births. Preeclampsia, sepsis and pre-renal causes due to dehydration and hemorrhage were the most common causes of pregnancy-related acute kidney injury in this study. Hemodialysis was needed in 8.6% (n = 16) of patients. Of the 187 pregnancy-related acute kidney injuries, 143 (76.5%) recovered completely and 30 (16%) partially. The mortality rate was 7.5%. Preexisting chronic kidney disease (AOR = 30.13; 95% CI: 2.92, 310.84), use of vasoactive agents (AOR = 5.77; 95% CI: 1.47, 22.67), increase in creatinine per unit (AOR = 1.65; 95% CI: 1.11, 2.45) and complications related to acute kidney injury (AOR = 5.26; 95% CI: 1.73, 16.00) were determinants of the composite endpoints (partial renal recovery and death). This study emphasizes acute kidney injury in resource-limited settings is a significant cause of maternal and fetal morbidity and mortality. The vast majority of patients with pregnancy-related acute kidney injury recovered completely from kidney injury. The main causes of pregnancy-related acute kidney injury were preeclampsia, sepsis and pre-renal associated with hemorrhage and dehydration. Preexisting renal disease, use of vasopressors, increase in creatinine per unit and complications associated with acute kidney injury were determining factors for concomitant fetomaternal mortality. Appropriate preventive strategies during prenatal care and prompt treatment are needed for pregnancy-related acute kidney injury.

Longitudinal Assessment of Oxidative Stress Markers in Women with Preeclampsia.

Preeclampsia (PE) is a pregnancy-specific disorder and a major contributor to maternal and fetal morbidity and mortality. Role of oxidative stress in early pregnancy with the pathophysiology of the disorder is unclear. The current study aims to analyse maternal levels of oxidative stress markers (MDA and protein carbonyl) longitudinally across gestation and placental levels of oxidative stress markers (MDA, protein carbonyl and 8-oxo-2'-deoxyguanosine) in women with PE and compare them with non-PE women. 324 pregnant women (216 non-PE and 108 PE women) were longitudinally followed during pregnancy. Women with preeclampsia were stratified as early onset preeclampsia (EOP) and late onset preeclampsia (LOP) Maternal blood at four time points across gestation (11-14weeks, 18-22weeks, 26-28weeks, and at delivery) and placenta were collected. Maternal and placental levels of oxidative stress markers were assessed using commercially available kits. Maternal plasma MDA and protein carbonyl levels were comparable between the PE and non-PE group at all timepoints across gestation. Maternal plasma MDA were significantly higher levels at 26-28weeks in EOP women when compared to non-PE women (p < 0.05). Placental 8-oxo-dG levels were lower in the EOP group as compared to non-PE (p < 0.05). Elevated plasma MDA levels were positively associated with birth length at 18-22weeks and 26-28weeks in the PE group (p < 0.05 for both). Maternal plasma MDA levels were positively associated with systolic blood pressure at 18-22weeks. Oxidative stress in early pregnancy is not associated with risk of PE.

Skin Care in Pregnancy and the Postnatal Period

A great deal of advice around maintaining health is focused on nutrition and exercise – in particular what to do and what not to do. Little focus is on the importance of skin care. Just like the heart and lungs, the skin is an organ of the body. In fact it is the largest of all of the organs. It has many functions, many of which support us to maintain health and wellbeing through a complex eco system of the microbiome where it provides protections against pathogens, supports vitamin synthesis, metabolism and immune development.1 In pregnancy, the body’s organs undergo a myriad of physiological changes affecting each system differently.2 There are three categories of skin conditions in pregnancy, benign hormone-related changes such as hyperpigmentation and striae gravidarum, pre-existing skin conditions, such as acne and psoriasis, and pregnancy-specific disorders such as atopic eruption of pregnancy.3 Each will require different treatment or care to minimise discomfort or irritation.

Protein Misfolding in Pregnancy: Current Insights, Potential Mechanisms, and Implications for the Pathogenesis of Preeclampsia.

Protein misfolding disorders are a group of diseases characterized by supra-physiologic accumulation and aggregation of pathogenic proteoforms resulting from improper protein folding and/or insufficiency in clearance mechanisms. Although these processes have been historically linked to neurodegenerative disorders, such as Alzheimer's disease, evidence linking protein misfolding to other pathologies continues to emerge. Indeed, the deposition of toxic protein aggregates in the form of oligomers or large amyloid fibrils has been linked to type 2 diabetes, various types of cancer, and, in more recent years, to preeclampsia, a life-threatening pregnancy-specific disorder. While extensive physiological mechanisms are in place to maintain proteostasis, processes, such as aging, genetic factors, or environmental stress in the form of hypoxia, nutrient deprivation or xenobiotic exposures can induce failure in these systems. As such, pregnancy, a natural physical state that already places the maternal body under significant physiological stress, creates an environment with a lower threshold for aberrant aggregation. In this review, we set out to discuss current evidence of protein misfolding in pregnancy and potential mechanisms supporting a key role for this process in preeclampsia pathogenesis. Improving our understanding of this emerging pathophysiological process in preeclampsia can lead to vital discoveries that can be harnessed to create better diagnoses and treatment modalities for the disorder.

Novel cuproptosis-related prognostic gene profiles in preeclampsia

BackgroundPreeclampsia (PE) is a pregnancy-specific disorder with complex pathogenesis. Cuproptosis is a novel identified form of programmed cell death, however, the link between cuproptosis and clinical outcomes in PE is still not fully understood. In this study, we searched for cuproptosis-related genes (CRGs) in the placental tissues of normal and PE patients to clarify the importance of cuproptosis in the development of PE and provide potential predictive indicators for the occurrence of PE.MethodsUsing RNA sequencing data in the GEO database, we conducted functional enrichment analysis of Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA), supported by linear regression model and operating characteristic curve (ROC) curve analysis, and summarized the role of CRGs in preeclampsia.ResultsA total of 2831 differentially expressed genes related to PE were screened through multiple database analyses. After further intersection with 19 reported CRGs, 5 CRGs have been closely associated with the pathogenesis of PE, including NFE2L2, PDHA1, PDHB, DLD and GLS. NFE2L2 was identified as a key central gene. Pearson correlation analysis showed that CRGs could be related to several maternal and fetal outcome factors, including the highest pregnancy blood pressure, placenta weight, umbilical blood flow pulsatility index (PI), and neonatal weight. Linear regression equation revealed that the expression of NFE2L2 is negatively correlated with the highest pregnancy blood pressure and umbilical blood flow PI but positively correlated with placental weight and neonatal weight. QRT-PCR showed that the expression of these CRGs was significantly lower in placental tissues.ConclusionsThis cuproptosis pattern may be a potential prognostic factor in patients with PE and could provide new insights into disease progression.

Changes in Lipid Profile in Preeclampsia

Background &amp; objective: Preeclampsia is an age-old pregnancy-specific disorder. Numerous theories and ideas have been advanced on its etiology, pathophysiology, and complications, but commendable progress in preventing this long-standing disorder has not yet been made. The relationship between altered blood lipid levels and preeclampsia is currently a topic of discussion. The present study was to ascertain whether serum lipid levels are associated with preeclampsia. Methods: The present case-control study was carried out at the Department of Obstetrics &amp; Gynaecology, Dhaka Medical College Hospital and Department of Obstetrics &amp; Gynaecology, BSMMU, Dhaka over a period of one year between January 2011 to December 2011. Pregnant women in their 3rd trimester with preeclampsia were included as cases, while normal pregnant women at term without preeclampsia were included as controls. An equal number of cases (n = 75) and controls (n = 75) were selected consecutively. While the exposure variable was preeclampsia, the outcome variable was dyslipidaemia, which was defined as either total cholesterol:HDL ratio&gt;4.5 or triglyceride:HDL ratio &gt; 3.5. Result: The cases and the controls were almost identical in terms of age. The gestational age was also comparable between groups. The preeclamptic patients were predominantly primigravidae (57.3%) and overweight or obese (85.3%). Past history of PET was found in 12% cases as opposed to none in the controls. The prevalences of elevated serum total cholesterol (TC), LDL-C, and triglycerides (Tg) were considerably higher in the case group than those in the control group, although the differences were not statistically significant. However, the prevalence of low HDL-C was significantly higher in the former group than that in the latter group (56% vs. 14.7%, p &lt; 0.001). The incidences of raised total cholesterol and HDL ratio &gt; 4.5 and raised triglyceride and HDL ratio &gt; 3.5 were observed to be significantly higher in the case group than those in the control group(p&lt; 0.001 and p &lt; 0.001 respectively). The likelihood of having raised TC:HDL ratio was estimated to be 10.1(95% CI = 4.2 - 23.9) times higher and that of raised TG:HDL ratio was 3.7(95% CI = 1.9 - 7.4) times higher in the case group than those in the control group. Conclusion: The total cholesterol:HDL ratio and triglyceride:HDL ratio increase significantly in preeclamptic women compared to that in normal pregnant women. However, the alteration is presumably caused by a significant lowering of HDL cholesterol, the total cholesterol and triglyceride do not experience any significant change. Ibrahim Card Med J 2022;12(2):53-58

Circulating chemerin levels in preeclampsia: a systematic review and meta-analysis

BackgroundPreeclampsia (PE) is a new-onset pregnancy-specific disorder with a high prevalence that leads to over 70 000 maternal and 500 000 foetal fatalities worldwide each year. The level of chemerin, a newly identified adipokine, is increased in diabetic and obese patients. Currently, there are several studies describing the relationship between maternal circulating chemerin levels and PE. Therefore, this study aimed to assess their association in pooled samples.MethodsFour databases were systematically searched to identify potential studies that reported circulating chemerin levels in PE and normal pregnancy groups. Standardized mean differences (SMDs), 95% confidence intervals (CIs), and 95% prediction intervals (PIs) were calculated using a random-effects meta-analysis. The probability of heterogeneity was also investigated by sensitivity analysis, subgroup analysis, and meta-regression.ResultsThirteen studies in 11 articles with a total of 860 PE patients and 1309 women with normal pregnancies met the inclusion criteria. The results of the meta-analysis revealed that circulating chemerin, which levels in PE patients were considerably higher than those in controls (SMD = 1.39, 95% CI: 1.02, 1.77, 95% PI: -0.07, 2.86). Moreover, sensitivity analysis determined that the outcomes of the overall pooled results were not affected after the elimination of any study. Notably, subgroup analysis demonstrated a similar expression pattern irrespective of geographic location, severity, timing of sampling, and sample size. Last, there were no factors that significantly impacted the overall estimate, according to meta-regression.ConclusionsThis meta-analysis is the first to assess circulating chemerin levels in PE patients. The findings indicate that circulating chemerin levels may be a potential marker to diagnose PE.

Single-cell profiling reveals immune disturbances landscape and HLA-F-mediated immune tolerance at the maternal-fetal interface in preeclampsia.

Preeclampsia is a pregnancy-specific disorder that always causes maternal and fetal serious adverse outcome. Disturbances in maternal immune tolerance to embryo at the maternal-fetal interface (MFI) may be associated with preeclampsia onset. Recent studies have revealed the reduced expression pattern of HLA-F at the MFI in preeclampsia, while the mechanism of it mediating maternal fetal immune tolerance has not been revealed. Single-cell RNA sequencing on placental decidua was performed to reveal the immune disturbances landscape at the MFI in preeclampsia. Human Jar cells and NK-92MI cells were employed to study the role of HLA-F in trophoblasts and lymphocyte. A total of 101,250 cells were classified into 22 cell clusters. Disease-related IGFBP1+SPP1+ extracellular villus trophoblast (EVT) was identified in the preeclamptic placental decidua, accompanied by newly discovered immune cellular dysfunction such as reduced ribosomal functions of NK populations and abnormal expression of antigen-presenting molecules in most cell clusters. Certain genes that are characteristic of the intermediate stage of myeloid or EVT cell differentiation were found to have unexplored but important functions in the pathogenesis of preeclampsia; specifically, we detected enhanced cell cross-talk between IGFBP1+SPP1+ EVT2 or SPP1+M1 cells and their receptor cell populations at the MFI of PE patients compared to controls. With respect to HLA-F, mIF staining confirmed its reduced expression in PE samples compared to controls. Over-expression of HLA-F in Jar cells promoted cell proliferation, invasion, and migration while under-expression had the opposite effect. In NK-92MI cells, over-expression of HLA-F increased the secretion of immunoregulation cytokines such as CSF1 and CCL22, and promoted adaptive NKG2C+NK cell transformation. We revealed the immune disturbance landscape at the MFI in preeclampsia. Our findings regarding cellular heterogeneity and immune cellular dysfunction, as revealed by scRNA-seq, and the function of HLA-F in cells provide new perspectives for further investigation of their roles in the pathogenesis of preeclampsia, and then provide potential new therapeutic target.

Microglia activation in paraventricular nucleus of hypothalamus: A self-help strategy for fetus born to preeclamptic mother

Preeclampsia (PE) is a life-threatening pregnancy-specific disorder, characterized by new-onset hypertension after 20 weeks of gestation. It has been generally acknowledged that failure of uterine spiral arteries remodeling, imbalance of pro-angiogenic and anti-angiogenic substances are engaged in the early stage of PE. Nevertheless, the exact pathogenesis remains poorly understood. Recent evidence shows that microglial activation in the paraventricular nucleus of hypothalamus (PVN) is associated with neuroinflammation and enhanced sympathetic excitation, which contribute to the hypertensive status in many diseases with PE included. In our recent work, we sequenced fetus-derived exosomal microRNA (miRNA) profiles and found that 181 miRNAs were significantly downregulated in women with PE. Among these miRNAs, miR-216a-5p exhibited the most significant fold change and may regulate CCCTC-binding factor (ctcf), the pivotal molecule in microglia activation. In conclusion, we hypothesize that fetuses under compromised uteroplacental environment may release exosomal miRNAs, activate microglia in maternal PVN, enhance sympathetic excitation and result in elevated maternal blood pressure, which participate in the occurrence and development of PE, however, guarantee the adequate blood supply to fetuses themselves. More basic research regarding this hypothesis may open up a new direction for the study of the pathogenesis of PE and is expected to provide a new theoretical basis for early diagnosis and treatment of PE. One day, would the changes of specific miRNAs be discovered through portable device may help the early diagnosis of PE or be the marker of prognosis of worsened PE.

Two distinct molecular faces of preeclampsia revealed by single-cell transcriptomics

Preeclampsia is a multisystemic, pregnancy-specific disorder united by new-onset hypertension but with considerable variation in clinical manifestation, onset, and severity. For symptoms to regress, delivery of the placenta is required. For symptoms to regress, delivery of the placenta is required, making the placenta central to preeclampsia pathophysiology. To dissect which placental functions were impacted intwo forms ofpreeclampsia, we studied molecular changes across the cell types of the placenta. We performed a transcriptomic survey of single-cells and single-nuclei on cases of early- and late-onset preeclampsia with gestation-matched controls. Our data revealed massive dysregulation of gene expression in all cell classes that was almost exclusive to early preeclampsia. For example, an important known receptor/ligand imbalance hallmarking angiogenic disfunction, sFLT1/placental growth factor (PGF), was reflected in striking, cell-autonomous dysregulation of FLT1 and PGF transcription in the syncytium in early preeclampsia only. Stromal cells and vasculature echoed an inflamed, stressed, anti-angiogenic environment. Finally, the placental immune niche set the tone for inflammation in early but not late preeclampsia. Here, fetal-origin Hofbauer and maternal-origin TREM2 macrophages were revealed as surprising main actors, while local cells of the adaptive immune system were largely unaffected. Late preeclampsia showed minimal cellular impact on the placenta. Our survey provides systematic molecular evidence for two distinct diseases. We resolved systematic molecular dysregulation to individual cell types with strong implications for definition, early detection, diagnosis, and treatment. Funded by the Preeclampsia Foundation through the Peter Joseph Pappas Research Grant.

New Ideas for the Prevention and Treatment of Preeclampsia and Their Molecular Inspirations.

Preeclampsia (PE) is a pregnancy-specific disorder affecting 4-10% of all expectant women. It greatly increases the risk of maternal and foetal death. Although the main symptoms generally appear after week 20 of gestation, scientific studies indicate that the mechanism underpinning PE is initiated at the beginning of gestation. It is known that the pathomechanism of preeclampsia is strongly related to inflammation and oxidative stress, which influence placentation and provoke endothelial dysfunction in the mother. However, as of yet, no "key players" regulating all these processes have been discovered. This might be why current therapeutic strategies intended for prevention or treatment are not fully effective, and the only effective method to stop the disease is the premature induction of delivery, mostly by caesarean section. Therefore, there is a need for further research into new pharmacological strategies for the treatment and prevention of preeclampsia. This review presents new preventive methods and therapies for PE not yet recommended by obstetrical and gynaecological societies. As many of these therapies are in preclinical studies or under evaluation in clinical trials, this paper reports the molecular targets of the tested agents or methods.

Circulating extracellular vesicles of neurovascular origin are elevated in women with severe preeclampsia years after their affected pregnancies

AbstractBackgroundPreeclampsia (PE), a pregnancy specific hypertensive disorder, has been associated with elevated risk for strokes, cognitive decline, and smaller brain volumes later in life. As severe PE has been associated with the highest risks for cerebrovascular disease, we hypothesized that circulating extracellular vesicles (EVs) of neurovascular origin will be detectable in women years after severe PE as a marker of persistent neurovascular damage and amyloid‐β.MethodA cohort of 40 women with histories of normotensive pregnancies (control group) and age‐ and parity‐matched to 40 women with history of mild (n = 33) and severe (n = 7) PE were identified using the Rochester Epidemiology Project. Diagnosis of severe PE was ascertained based on clinical criteria (Table). While none of the women had any major cardiovascular events, our previous study of this cohort has demonstrated that total gray matter volumes were smaller in women with a history of preeclampsia and late‐life hypertension compared with the other groups. Blood‐borne EVs derived from neurovascular cellular activation were determined by standardized digital flow cytometry. Plasma concentration of amyloid‐β was measured by ELISA. Differences among the groups were tested by ANOVA, with the least difference test for pos hoc analysis. The association between EVs and MRI brain imaging was assessed by Pearson correlation coefficient.ResultWomen with history of severe PE had a significantly higher concentration of amyloid‐β carrying EVs compared to controls (p = 0.003). EVs positive for the markers of blood‐brain barrier‐ endothelial damage (LDL‐R) and inflammatory coagulation pathway activator (tissue factor), were significantly higher in women with history of severe PE compared to controls (p = 0.008 and p = 0.002, respectively), as well as to the women with history of mild PE. Plasma concentration of total amyloid‐β was also significantly greater in women with history of severe vs. mild PE (p = 0.037) (Table). The number of tissue factor positive EVs was negatively correlated with total gray matter volume (cm3) (p&lt;0.05).ConclusionWomen with a history of severe PE demonstrate elevated levels of markers of neuroinflammation and neurovascular damage, as well as greater amyloid‐β secretion. Excessive inflammation may contribute to previously described brain atrophy in these women.

Frequency of Preeclampsia in Pregnant Women Presenting in A Tertiary Hospital

Preeclampsia is pregnancy specific disorder that involves endothelial dysfunction and vasospam, so it needs prompt diagnosis and expert management as both mother and fetus are at risk. Objective: To determine the frequency of preeclampsia in pregnant women presenting in a tertiary hospital. Methods: This Cross-Sectional study was done in Department of Obstetrics and Gynecology, Unit-II ward-9, Jinnah Postgraduate Medical Centre, Karachi from 6th April 2018- 10th November 2018. We included 340 pregnant females fulfilling the inclusion criteria. Informed consent was taken. The data were collected on prepared performa. Results: A total of 340 pregnant women were included in this study, mean age of patients was 28.3 ± 3.5 (16-30) years and mean gestational age in patients was 33.6 ± 5.2 in weeks. 49(14.4%) patients had pre-eclampsia while 291(85.6%) pregnant women were normotensive. Conclusions: Our results show patient with preeclampsia are at increased risk for morbidity and mortality of both new born and mother, so proper antenatal workup is required.

Gut microbiota alters host bile acid metabolism to contribute to intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy (ICP) is a female pregnancy-specific disorder that is characterized by increased serum bile acid and adverse fetal outcomes. The aetiology and mechanism of ICP are poorly understood; thus, existing therapies have been largely empiric. Here we show that the gut microbiome differed significantly between individuals with ICP and healthy pregnant women, and that colonization with gut microbiome from ICP patients was sufficient to induce cholestasis in mice. The gut microbiomes of ICP patients were primarily characterized by Bacteroides fragilis (B. fragilis), and B. fragilis was able to promote ICP by inhibiting FXR signaling via its BSH activity to modulate bile acid metabolism. B. fragilis-mediated FXR signaling inhibition was responsible for excessive bile acid synthesis and interrupted hepatic bile excretion to ultimately promote the initiation of ICP. We propose that modulation of the gut microbiota-bile acid-FXR axis may be of value for ICP treatment.

MiR-141-3p promotes hypoxia-induced autophagy in human placental trophoblast cells.

Preeclampsia (PE) is a pregnancy-specific disorder and a significant contributor to maternal, fetal and neonatal morbidity and mortality worldwide. Its pathogenesis is generally accepted as insufficient trophoblast invasion of the maternal endometrium and inadequate remodeling of the maternal spiral arteries. These impairments lead to elevated levels of hypoxia and oxidative stress. Autophagy has become a highly researched field in obstetrics, and this process may be essential for preimplantation development beyond the four- and eight-cell stages, and for blastocyst survival, extra-villous trophoblast functions, invasion and vascular remodeling. Several studies have shown that autophagy activation, shown by an increase in autophagy vacuoles or microtubule-associated protein 1A/1B-light chain 3 (LC3) dots, was more common in PE than in normal pregnancy. Thus, changes in autophagic status are seen in preeclamptic placentas. MicroRNA-141-3p (miR-141-3p), a multifunctional miRNA, is involved in a variety of physiological and pathological processes, including PE and autophagy. However, the influence of miR-141-3p on autophagy regulation in trophoblast cells has yet to be described. Therefore, the objective of our study was to investigate the role of miR-141-3p in autophagy induced by hypoxia in human placental trophoblast cells. Our results found that hypoxia induced autophagy in trophoblast cells and dramatically elevated the expression of miR-141-3p. Overexpression of miR-141-3p improved autophagic activity, whereas low expression of miR-141-3p inhibited autophagic activity. Therefore, our data demonstrated that miR-141-3p promoted hypoxia-induced autophagy in placental trophoblast cells, which may be related to the development of preeclampsia.

Hematological Markers: Testing a new diagnostic modality for Intrahepatic Cholestasis of pregnancy

Background: Intrahepatic Cholestasis of pregnancy (ICP) is the most common pregnancy specific liver disorder presenting usually in the 3rd trimester with unexplained pruritis, elevated serum bile acids and/or raised liver enzymes. ICP is associated with adverse perinatal outcomes. Serum total bile acids (TBA) are considered as a gold standard for diagnosis of ICP but are time consuming, expensive and not readily available everywhere. Neutrophil to Lymphocyte ratio (NLR), Mean Platelet Volume (MPV) and Red cell Distribution Width (RDW) are haematological inflammatory markers and are routinely available on a simple complete blood count test when asked for. Aims: To study the role of haematological inflammatory markers in Intrahepatic Cholestasis of Pregnancy (ICP) and their association with the severity of the disease. Methods: This prospective case-control study was done in a tertiary care setting in New Delhi, from January 2021- August 2022(20 months) wherein 82 women with ICP were recruited after a written and informed consent. NLR, MPV, RDW and TBA levels were done. 82 healthy women with uncomplicated pregnancies served as the control group. Results: Both cases &amp; controls were comparable in terms of sociodemographic characteristics. Mean TBA levels were 22.85+/-7.82 in mild cases(60 subjects) &amp; 66.20+/-26.97 (22 severe cases). Cases delivered earlier between 37–38 weeks. Majority of women delivered vaginally &amp; was statistically significant. Cases developed more fetal distress(42.7% vs 9.8%) NLR and MPV were significantly raised (p&lt;0.05) while RDW was lower in cases. The cut off for NLR &amp; MPV were statistically significant. Conclusion: MPV can serve as a good screening tool, a high sensitivity (95.1%) while NLR can serve as a confirmatory test as it has high specificity (96.3%) to make diagnosis of ICP, although further exploration with larger multicentric studies is required.

Alternative pathway activation in pregnancy, a measured amount "complements" a successful pregnancy, too much results in adverse events.

During pregnancy, the maternal host must adapt in order to enable growth of the fetus. These changes affect all organ systems and are designed both to protect the fetus and to minimize risk to the mother. One of the most prominent adaptations involves the immune system. The semi-allogenic fetoplacental unit has non-self components and must be protected against attack from the host. This requires both attenuation of adaptive immunity and protection from innate immune defense mechanisms. One of the key innate immune players is complement, and it is important that the fetoplacental unit is not identified as non-self and subjected to complement attack. Adaptation of the complement response must, however, be managed in such a way that maternal protection against infection is not compromised. As the complement system also plays a significant facilitating role in many of the stages of a normal pregnancy, it is also important that any necessary adaptation to accommodate the semi-allogenic aspects of the fetoplacental unit does not compromise this. In this review, both the physiological role of the alternative pathway of complement in facilitating a normal pregnancy, and its detrimental participation in pregnancy-specific disorders, are discussed.

Siglec-6 Signaling Uses Src Kinase Tyrosine Phosphorylation and SHP-2 Recruitment.

Preeclampsia is a pregnancy-specific disorder involving placental abnormalities. Elevated placental Sialic acid immunoglobulin-like lectin (Siglec)-6 expression has been correlated with preeclampsia. Siglec-6 is a transmembrane receptor, expressed predominantly by the trophoblast cells in the human placenta. It interacts with sialyl glycans such as sialyl-TN glycans as well as binds leptin. Siglec-6 overexpression has been shown to influence proliferation, apoptosis, and invasion in the trophoblast (BeWo) cell model. However, there is no direct evidence that Siglec-6 plays a role in preeclampsia pathogenesis and its signaling potential is still largely unexplored. Siglec-6 contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) and an ITIM-like motif in its cytoplasmic tail suggesting a signaling function. Site-directed mutagenesis and transfection were employed to create a series of Siglec-6 expressing HTR-8/SVneo trophoblastic cell lines with mutations in specific functional residues to explore the signaling potential of Siglec-6. Co-immunoprecipitation and inhibitory assays were utilized to investigate the association of Src-kinases and SH-2 domain-containing phosphatases with Siglec-6. In this study, we show that Siglec-6 is phosphorylated at ITIM and ITIM-like domains by Src family kinases. Phosphorylation of both ITIM and ITIM-like motifs is essential for the recruitment of phosphatases like Src homology region 2 containing protein tyrosine phosphatase 2 (SHP-2), which has downstream signaling capabilities. These findings suggest Siglec-6 as a signaling molecule in human trophoblasts. Further investigation is warranted to determine which signaling pathways are activated downstream to SHP-2 recruitment and how overexpression of Siglec-6 in preeclamptic placentas impacts pathogenesis.