Preeclampsia Pregnancy Research Articles

Role and expression of miRNAs (miRNA 548e_5p, miRNA 873_5p, miRNA 378b) in fetal development and incidence of Preeclampsia in pregnancy

Role and expression of miRNAs (miRNA 548e_5p, miRNA 873_5p, miRNA 378b) in fetal development and incidence of Preeclampsia in pregnancy

Adding on Addison’s: A Case Report of Rare Co-Existent Pathology Complicating Acute Pre-Eclampsia (PET) in Pregnancy

Addison’s disease is a rare condition, which world-wide, may affect many millions of people. In pregnancy however, it has been rarely reported and, in this setting, remains poorly understood. What we do know, is that it is an endocrine disorder characterized by adrenal insufficiency leading to decreased production of cortical hormones including most notably, cortisol, but also the androgens and aldosterone. The sequaelae may be varied but most significantly, can lead to a loss of the body’s normal resilience to stress and injury. We present the case of a 35-year-old woman who presented in late pregnancy with signs and symptoms of fulminating pre-eclampsia (PET). Paradoxically, she was found to have electrolyte abnormalities which persisted despite appropriate treatment. These were suggestive of an underlying endocrine disorder and she was subsequently diagnosed with atypical Addison’s disease. With appropriate management, she was stabilized and delivered safely. We report this as a rare example of newly diagnosed Addison’s disease discovered for the first time in late pregnancy. It highlights that although rarely diagnosed, early identification can help avoid potentially life-threatening sequalae such as acute adrenal insufficiency as well as complications including preterm birth, neonatal hypoglycaemia and prolonged hospital admission. This calls for ongoing vigilance in clinical care, and the continuous improvement of shared knowledge through collaborative communication and awareness of evidence based, best practice guidelines.

Is arginine supplementation effective in preventing preeclampsia in pregnant women?

Objectives: The objective of this study was to review data from randomized controlled trials to assess whether or not the supplementation of L-Arginine (L-Arg) is effective in reducing the incidence of preeclampsia (PE) in pregnancies at risk of developing the disorder. Methods: We aimed to systematic review randomized controlled trials, including those which compared L-Arg supplementation with placebo in pregnant women at high risk of PE development, analyzing PE incidence as the main outcome. Data were collected from MEDLINE/ Pubmed, EMBASE/ Elsevier, LILACS/ BVS and Cochrane. Results: A total of 46 papers were identified in the primary search. After analysis of eligibility, inclusion and exclusion criteria, two articles (which respected in detail all the stages of evaluation) were included in the present review. A risk of bias assessment was performed. Data analysis revealed that the incidence of PE was significantly lower in both studies, and no major adverse effects were reported. The limitations of this study were the lack of standardization between the trials analyzed and the relative low number of studies included. Conclusions: The supplementation with L-Arg appears to reduce the incidence of PE in pregnant women with high risk for its development.

Endothelial Cell Mineralocorticoid Receptor (ECMR) deletion improves fetal growth and vascular function in the RUPP mouse model of preeclampsia

Preeclampsia (PE), a hypertensive disorder of pregnancy, induces adverse pregnancy outcomes including fetal growth restriction (FGR) and afflicts ~5‐10% of pregnancies. Compelling clinical data indicate that PE risk and severity in pregnant women is strongly associated with endothelial dysfunction. Previous work by our group shows that deletion of endothelial cell mineralocorticoid receptors (ECMR) improves endothelial function in premenopausal hypertensive female mice, however whether ECMR promotes endothelial dysfunction in PE is unknown. We tested the hypothesis that ECMR deletion improves FGR and endothelial function in a mouse model of PE, the reduced uterine perfusion pressure (RUPP) mouse. Pregnant ECMR‐intact (WT) and ECMR‐deficient (KO) mice were randomized to RUPP or sham surgery on GD13 and sacrificed on GD18 (WT Sham=6, WT RUPP=5, KO Sham=7, KO RUPP=6). Vascular function was measured via wire myography on 2nd order mesenteric arteries. Conscious blood pressure was measured by radiotelemetry throughout pregnancy in a subset of mice. RUPP surgery did not decrease maternal weights in either WT or KO mice (P>0.05) at GD18. RUPP surgery significantly decreased GD18 pup weight, a measure of FGR, (726±20mg WT+Sham vs 660±11mg WT+RUPP, *P<0.05) and trended to decrease placental efficiency (pup/placenta weight) (8.23±0.23 WT+Sham vs 7.45±0.22 WT+RUPP P=0.13) in WT pregnant mice. ECMR deletion protected pregnant mice both from RUPP‐induced reductions in pup weight (710±20mg KO+Sham vs 690±20mg KO+RUPP) and decreases in placental efficiency (7.63±0.19 KO+Sham vs 7.76±0.31 KO+RUPP). RUPP reduced acetylcholine‐mediated relaxation (10‐9‐3x10‐5 M) in mesenteric arteries of WT pregnant mice but not KO pregnant mice (*P<0.05, 2‐way ANOVA, repeated measures), indicating RUPP induced endothelial dysfunction in WT mice only. Preincubation with nitric oxide (NO) synthase inhibitor LNAME ablated differences in Ach‐mediated relaxation between WT+sham and WT+RUPP mice (P>0.05), indicating that reductions in endothelial function in WT+RUPP mice were mediated by reduced NO. However, ECMR deletion as a variable increased Ach‐mediated relaxation in the presence of LNAME in both Sham and RUPP mice (*P<0.05). Therefore, ECMR deletion may have protected pregnant mice from endothelial dysfunction via a non‐NO mechanism. RUPP did not increase a‐receptor agonist phenylephrine (Phe)‐induced constriction in WT mice, however, ECMR deletion as a variable decreased Phe‐mediated constriction independent of RUPP surgery indicating that ECMR deletion reduces smooth muscle‐mediated vasoconstriction in pregnant sham and RUPP mice. These data indicate that specific deletion of ECMR improves vascular function to increase vasodilation and prevent constriction in PE pregnancy. Preliminary data further indicates that systolic blood pressure increased from GD8‐18 (pre‐post RUPP) in WT+RUPP but decreased in KO+RUPP pregnant mice (2.7 vs ‐8.6 DmmHg, respectively, N=1). Lastly RUPP surgery trended to increase plasma levels of the ECMR agonist corticosterone in WT pregnant mice (2.03±0.4pg/ml WT+Sham vs 3.33±0.95pg/ml WT+RUPP). Collectively, these data indicate that ECMR activation promotes FGR, vascular dysfunction and hypertension in the RUPP model of PE which may lead to clinical studies for the consideration of specific MR antagonists as therapeutic options for PE pregnancies.

The Remediable Metarteriole - Chorangioma

Chorioangioma is a benign, non-trophoblastic, vascular neoplasm arising from the placenta. Chorangioma is associated with features such as advanced maternal age, diabetes mellitus, hypertension, preeclampsia, multiple gestations or high-altitude pregnancy. The miniature, asymptomatic chorangioma is incidentally discovered whereas giant chorangioma exceeding >4 centimeters magnitude exemplifies adverse perinatal and foetal outcomes and is associated with intrauterine growth restriction (IUGR), polyhydramnios, preterm labour, arteriovenous shunts, foetal cardiomegaly or foetal heart failure, hydrops foetalis, foetal thrombocytopenia and maternal mirror syndrome. Tumefaction is composed of foetal capillaries circumscribed by stroma and trophoblastic tissue. Foci of tumor infarction, fibrosis, hyalinization, calcification and deposition of hemosiderin pigment are observed. Chorangioma requires a segregation from chorangiosis, chorangiomatosis, inflammatory myofibroblastictumor, Leiomyoma, placental infarct, intervillous thrombus or chorangiocarcinoma. Chorangioma or giant chorioangioma can be suitably discerned with ultrasonography. Treatment options such as draining excessive amniotic fluid or surgical intervention of chorioangioma with laser coagulation and electrosurgical maneuvers may be adopted.

Interleukin-6 and its correlations with maternal characteristics and echocardiographic parameters in pre-eclampsia, gestational hypertension and normotensive pregnancy.

Pre-eclampsia and gestational hypertension are pregnancy-related disorders with major maternal cardiovascular implications later in life. The aim of this study was to determine interleukin-6 levels in women with pre-eclampsia and gestational hypertension and in healthy pregnant controls, and to examine their correlations with characteristics of the women and echocardiographic findings. The ELISA method was used to determine serum interleukin-6 in 36 women with gestational hypertension, 37 women with pre-eclampsia and 50 pregnant controls. The echocardiographic examination was performed according to current recommendations by the European Association of Cardiovascular Imaging and the American Society of Echocardiography. Mean serum interleukin-6 levels were 2.77 pg/ml in the controls, 5.08 pg/ml in the gestational hypertension group and 8.06 pg/ml in the pre-eclampsia group. A significant difference in these levels was present between the controls and both hypertensive groups, but not between the two hypertensive groups. Higher levels correlated with heart chamber enlargement and worse ventricular function. Interleukin-6 levels in gestational hypertension and pre-eclampsia were significantly elevated compared to those in healthy pregnancy. Higher levels also corresponded to echocardiographical changes.

Folic Acid Levels During Pregnancy Regulate Trophoblast Invasive Behavior and the Possible Development of Preeclampsia.

BackgroundOne of the unique features of placentation is its similarity to tumorigenesis yet being very well regulated. It allows rapid proliferation, migration, and invasion of mononuclear trophoblast cells into the maternal uterus and remodeling the maternal vasculature. This pseudomalignant nature of trophoblastic cells is strictly regulated and its importance becomes evident in abnormal pregnancies that are characterized by aberrant trophoblast proliferation/invasion like preeclampsia. In addition to this, the importance of folic acid supplementation during pregnancy is well documented. We aimed to analyze the molecular and epigenetic regulation of the pseudomalignant nature of placentation via folic acid levels.MethodsPlacental tissue samples were collected from different pregnancies in three different gestational stages. We estimated the impact of folic acid levels on global methylation, LINE1 methylation, and expression of DNMTs in all three gestational stages in pregnant women and preeclampsia pregnancies. We also analyzed the effect of folic acid supplementation on trophoblastic invasion using placental derived cells viz, JEG-3 and HTR-8/SVneo cell line and verified the molecular and epigenetic mechanisms involved in this regulation.ResultsDevelopment of preeclampsia was observed to be associated with lower folate levels in placental tissue, higher global methylation level, and higher expression of DNMT1and DNMT3A. Folic acid supplementation was found to increase the invasive potential of placental trophoblasts by almost two folds which were associated with the decreased expression of tumor suppressor genes and tissue inhibitors of matrix metalloproteinases; and increased expression of oncogenes, telomerase gene, and matrix metalloproteinases. These folic acid-mediated changes were observed to be regulated by CpG methylation in the case of many genes. Folic acid supplementation was also observed to significantly decrease global methylation in placental trophoblasts related to decreasing expression of DNMT1 and DNMT3A.ConclusionLower folic acid levels are associated with preeclampsia development and folic acid supplementation regulates the invasive potential of placental trophoblasts as mediated by various epigenetic changes in the placenta suggesting the protective effect of folic acid against preeclampsia.

Identifying preeclampsia-associated genes using a control theory method

Preeclampsia is a pregnancy-specific disease that can have serious effects on the health of both mothers and their offspring. Predicting which women will develop preeclampsia in early pregnancy with high accuracy will allow for improved management. The clinical symptoms of preeclampsia are well recognized, however, the precise molecular mechanisms leading to the disorder are poorly understood. This is compounded by the heterogeneous nature of preeclampsia onset, timing and severity. Indeed a multitude of poorly defined causes including genetic components implicates etiologic factors, such as immune maladaptation, placental ischemia and increased oxidative stress. Large datasets generated by microarray and next-generation sequencing have enabled the comprehensive study of preeclampsia at the molecular level. However, computational approaches to simultaneously analyze the preeclampsia transcriptomic and network data and identify clinically relevant information are currently limited. In this paper, we proposed a control theory method to identify potential preeclampsia-associated genes based on both transcriptomic and network data. First, we built a preeclampsia gene regulatory network and analyzed its controllability. We then defined two types of critical preeclampsia-associated genes that play important roles in the constructed preeclampsia-specific network. Benchmarking against differential expression, betweenness centrality and hub analysis we demonstrated that the proposed method may offer novel insights compared with other standard approaches. Next, we investigated subtype specific genes for early and late onset preeclampsia. This control theory approach could contribute to a further understanding of the molecular mechanisms contributing to preeclampsia.

The difference of platelet-white blood cell ratio in severe preeclampsia and normotensive pregnancy

Background: Inflammation is believed to play a role in preeclampsia. Leukocytes increase due to inflammatory response. Endothelial damage in preeclampsia induces platelet aggregation, triggers platelet consumption, and decreases platelet. Therefore, preeclampsia could alter the platelet-white blood cell ratio, which can be used as a marker for preeclampsia. This study examines the difference of platelet-white blood cell ratio in severe preeclampsia and normotensive pregnancy. Methods: This study used the medical records of pregnant women in Dr. Kariadi General Hospital Semarang from 2019 to 2020. Samples were collected using a consecutive sampling method. Data were analyzed using an independent t-test and Mann-Whitney. Results: There was a significant difference in platelet count (p=0.011) and leukocyte count (p=0.018) between severe preeclampsia and normotensive pregnancy. Therefore, a difference (p<0.01) in platelet-white blood cell ratio between severe preeclampsia and normotensive pregnancy was observed. Conclusion: Platelet-white blood cell ratio in severe preeclampsia is 0.7 times lower than in normotensive pregnancy.

A New Model for the Predicting the Risk of Preeclampsia in Twin Pregnancy

ObjectiveWe aimed to develop an effective nomogram model for predicting the risk of preeclampsia in twin pregnancies.MethodsThe study was a retrospective cohort study of women pregnant with twins who attended antenatal care and labored between January 2015 and December 2020 at the Fujian Maternity and Child Health Hospital, China. We extracted maternal demographic data and clinical characteristics. Then we performed the least absolute shrinkage and selection operator regression combined with clinical significance to screen variables. Thereafter, multivariate logistic regression was used to construct a nomogram that predicted the risk of preeclampsia in twin pregnancies. Finally, the nomogram was validated using C-statistics (C-index) and calibration curves.ResultsA total of 2,469 women with twin pregnancies were included, of whom 325 (13.16%) had preeclampsia. Multivariate logistic regression models revealed that serum creatinine, uric acid, mean platelet volume, high-density lipoprotein, lactate dehydrogenase, fibrinogen, primiparity, pre-pregnancy body mass index, and regular prenatal were independently associated with preeclampsia in twin pregnancies. The constructed predictive model exhibited a good discrimination and predictive ability for preeclampsia in twin pregnancies (concordance index 0.821).ConclusionThe model for the prediction of preeclampsia in twin pregnancies has high accuracy and specificity. It can be used to assess the risk of preeclampsia in twin pregnancies.

Impairment of mitochondrial respiration in platelets and placentas: a pilot study in preeclamptic pregnancies

Preeclampsia (PE) is a major complication of pregnancy with partially elucidated pathophysiology. Placental mitochondrial dysfunction has been increasingly studied as major pathomechanism in both early- and late-onset PE. Impairment of mitochondrial respiration in platelets has recently emerged as a peripheral biomarker that may mirror organ mitochondrial dysfunction in several acute and chronic pathologies. The present study was purported to assess mitochondrial respiratory dys/function in both platelets and placental mitochondria in PE pregnancies. To this aim, a high-resolution respirometry SUIT (Substrate-Uncoupler-Inhibitor-Titration) protocol was adapted to assess complex I (glutamate + malate)- and complex II (succinate)-supported respiration. A decrease in all respiratory parameters (basal, coupled, and maximal uncoupled respiration) in peripheral platelets was found in preeclamptic as compared to healthy pregnancies. At variance, placental mitochondria showed a dichotomous behavior in preeclampsia in relation to the fetal birth weight. PE pregnancies with fetal growth restriction were associated with decreased in coupled respiration (oxidative phosphorylation/OXPHOS capacity) and maximal uncoupled respiration (electron transfer/ET capacity). At variance, these respiratory parameters were increased for both complex I- and II-supported respiration in PE pregnancies with normal weight fetuses. Large randomized controlled clinical studies are needed in order to advance our understanding of mitochondrial adaptive vs. pathological changes in preeclampsia.

Assessment of Protein Oxidation Status and Its Correlation with Antioxidant Potential in Preeclampsia

Objective: The objective of the study is to assess protein oxidation status and its correlation with antioxidant potential in serum during preeclampsia (PE). Materials and Methods: A casecontrol study was performed on 63 pregnant subjects (mean age = 30 tential in serpreeclamptic and 32 age-matched normotensive (control) pregnant women. Serum samples were analyzed for total protein, globulin, albumin, protein carbonyls (PCO), advanced oxidation protein products (AOPP), and ferric reducing antioxidant potential. Results: Compared to the control pregnant subjects, a compromised serum protein pattern, elevated PCO (P < 0.01), and AOPP (P < 0.02) were observed in PE pregnant women that were correlated significantly with the total antioxidant potential of serum. Conclusion: The results of the study suggest that PE pregnancies are susceptible to protein oxidation which may be due to diminished antioxidant potential during PE. The study concludes that oxidative modulation of proteins may be one of the major causative factors in complicating the maternal and fetal conditions during PE.

Increased carotid artery stiffness after preeclampsia in a cross-sectional study of postpartum women.

Preeclampsia (PE) is a hypertensive obstetrical complication associated with increased cardiovascular disease risk. Carotid artery functional assessments allow for identification of subclinical vascular dysfunction. This cross‐sectional study measured carotid artery functional indices in healthy women with a recent pregnancy complicated by PE, versus women with a prior uncomplicated pregnancy. Women with a history of PE (N = 30) or an uncomplicated pregnancy (N = 30), were recruited between 6 months and 5 years postpartum. Left and right carotid artery ultrasound measured carotid intima media thickness, plaque burden, peak systolic velocity, end diastolic flow velocity and carotid far‐wall circumferential strain (FWCS). Carotid FWCS is inversely related to vessel stiffness, where a decrease in FWCS indicates increased vessel stiffness. Right‐side FWCS did not differ between women with a history of PE versus normotensive pregnancy. Left carotid artery FWCS was lower in formerly preeclamptic women after adjustment for diameter, pulse pressure, and heart rate compared to women following an uncomplicated pregnancy (3.35 ± 1.08 × 10−3 vs. 4.46 ± 1.40 × 10−3; p = 0.003). Those with prior severe PE had the greatest decrease in FWCS adjusted to diameter, pulse pressure, and heart rate compared to healthy controls (p = 0.02). Adjusted FWCS and total serum cholesterol were independent indicators of PE history when present in a logistic regression model with confounding variables including age, body mass index, and resting blood pressure. Further investigation is needed to elucidate if FWCS can be used as a risk stratification tool for future cardiovascular disease following a pregnancy complicated by PE. A history of PE is associated with decreased left FWCS (increased left carotid artery stiffness).

Circulating Levels of Anti-C1q and Anti-Factor H Autoantibodies and Their Targets in Normal Pregnancy and Preeclampsia.

Preeclampsia (PE) generally manifests in the second half of pregnancy with hypertension and proteinuria. The understanding of the origin and mechanism behind PE is incomplete, although there is clearly an immune component to this disorder. The placenta constitutes a complicated immune interface between fetal and maternal cells, where regulation and tolerance are key. Stress factors from placental dysfunction in PE are released to the maternal circulation evoking the maternal response. Several complement factors play a role within this intricate landscape, including C1q in vascular remodeling and Factor H (FH) as the key regulator of alternative pathway complement activation. We hypothesize that decreased levels of C1q or FH, or disturbance of their function by autoantibodies, may be associated with PE. Autoantibodies against C1q and FH and the concentrations of C1q and FH were measured by ELISA in maternal sera from women with preeclamptic and normal pregnancies. Samples originated from cohorts collected in the Netherlands (n=63 PE; n=174 control pregnancies, n=51 nonpregnant), Finland (n=181 PE; n=63 control pregnancies) and Norway (n=59 PE; n=27 control pregnancies). Serum C1q and FH concentrations were higher in control pregnancy than in nonpregnant women. No significant differences were observed for serum C1q between preeclamptic and control pregnancy in any of the three cohorts. Serum levels of FH were lower in preeclamptic pregnancies compared to control pregnancies in two of the cohorts, this effect was driven by the early onset PE cases. Neither anti-C1q autoantibodies nor anti-FH autoantibodies levels differed between women with PE and normal pregnancies. In conclusion, levels of anti-C1q and anti-FH autoantibodies are not increased in PE. C1q and FH are increased in pregnancy, but importantly, a decrease in FH concentration is associated with PE.

Aspirin and calcium as a preventive therapy of early and late preeclampsia

Annotation. Preeclampsia and fetal growth restriction are major causes of perinatal death and handicap in survivors. Indications for aspirin during pregnancy are a matter of debate. The optimum dosage, from 75mg/day to 150mg/day, needs to be determined. The aim of the research was to estimate the impact of low-dose aspirin and calcium on prevention of preeclampsia. During the research there was conducted a prospective analysis of the effectiveness of aspirin and calcium in pregnant women with preeclampsia from VMCM hospital №1, in a period from 2016 till 2018. 88 women participated, they were divided into two investigated groups: I – 36 women with early preeclampsia (EP), and II group – 52 women with late preeclampsia (LP). In EP group 28 women were taking aspirin in dose of 75 mg, in LP – 36. Also, in EP group 12 women were taking low doses of calcium (˂1g/day), and 26 in LP group (tab. 1). Main diagnostically significant indexes were determined, which later underwent comparative analysis for all groups. Statistical processing of the obtained results was performed by odds ratio, its standard error and 95% confidence interval were calculated according to Altman, 1991. We didn’t define significant preventive differences in preeclampsia phenotype compared subgroups. Aspirin in dose of 75 mg/day and Calcium ˂1g/day is ineffective, also taking to account irregular intake – for 4-5-6 times per week. Preventive therapy requires definite period of beginning – 12 weeks of gestation and systemic everyday intake of drugs. In future, we need to explore a perfect dose of aspirin and calcium supplementation to prevent preeclampsia and hypertensive disorders in pregnancy.

Differences and similarities in endothelial and angiogenic profiles of preeclampsia and COVID-19 in pregnancy

BackgroundCOVID-19 presents a spectrum of signs and symptoms in pregnant women that might resemble preeclampsia. Differentiation between severe COVID-19 and preeclampsia is difficult in some cases.ObjectiveTo study biomarkers of endothelial damage, coagulation, innate immune response, and angiogenesis in preeclampsia and COVID-19 in pregnancy in addition to in vitro alterations in endothelial cells exposed to sera from pregnant women with preeclampsia and COVID-19.Study DesignPlasma and sera samples were obtained from pregnant women with COVID-19 infection classified into mild (n=10) or severe (n=9) and from women with normotensive pregnancies as controls (n=10) and patients with preeclampsia (n=13). A panel of plasmatic biomarkers was assessed, including vascular cell adhesion molecule-1, soluble tumor necrosis factor-receptor I, heparan sulfate, von Willebrand factor antigen (activity and multimeric pattern), α2-antiplasmin, C5b9, neutrophil extracellular traps, placental growth factor, soluble fms-like tyrosine kinase-1, and angiopoietin 2. In addition, microvascular endothelial cells were exposed to patients’ sera, and changes in the cell expression of intercellular adhesion molecule 1 on cell membranes and von Willebrand factor release to the extracellular matrix were evaluated through immunofluorescence. Changes in inflammation cell signaling pathways were also assessed by of p38 mitogen-activated protein kinase phosphorylation. Statistical analysis included univariate and multivariate methods.ResultsBiomarker profiles of patients with mild COVID-19 were similar to those of controls. Both preeclampsia and severe COVID-19 showed significant alterations in most circulating biomarkers with distinctive profiles. Whereas severe COVID-19 exhibited higher concentrations of vascular cell adhesion molecule-1, soluble tumor necrosis factor-α receptor I, heparan sulfate, von Willebrand factor antigen, and neutrophil extracellular traps, with a significant reduction of placental growth factor compared with controls, preeclampsia presented a marked increase in vascular cell adhesion molecule-1 and soluble tumor necrosis factor-α receptor I (significantly increased compared with controls and patients with severe COVID-19), with a striking reduction in von Willebrand factor antigen, von Willebrand factor activity, and α2-antiplasmin. As expected, reduced placental growth factor, increased soluble fms-like tyrosine kinase-1 and angiopoietin 2, and a very high soluble fms-like tyrosine kinase-1 to placental growth factor ratio were also observed in preeclampsia. In addition, a significant increase in C5b9 and neutrophil extracellular traps was also detected in preeclampsia compared with controls. Principal component analysis demonstrated a clear separation between patients with preeclampsia and the other groups (first and second components explained 42.2% and 13.5% of the variance), mainly differentiated by variables related to von Willebrand factor, soluble tumor necrosis factor-receptor I, heparan sulfate, and soluble fms-like tyrosine kinase-1. Von Willebrand factor multimeric analysis revealed the absence of von Willebrand factor high-molecular-weight multimers in preeclampsia (similar profile to von Willebrand disease type 2A), whereas in healthy pregnancies and COVID-19 patients, von Willebrand factor multimeric pattern was normal.Sera from both preeclampsia and severe COVID-19 patients induced an overexpression of intercellular adhesion molecule 1 and von Willebrand factor in endothelial cells in culture compared with controls. However, the effect of preeclampsia was less pronounced than the that of severe COVID-19. Immunoblots of lysates from endothelial cells exposed to mild and severe COVID-19 and preeclampsia sera showed an increase in p38 mitogen-activated protein kinase phosphorylation. Patients with severe COVID-19 and preeclampsia were statistically different from controls, suggesting that both severe COVID-19 and preeclampsia sera can activate inflammatory signaling pathways.ConclusionAlthough similar in in vitro endothelial dysfunction, preeclampsia and severe COVID-19 exhibit distinctive profiles of circulating biomarkers related to endothelial damage, coagulopathy, and angiogenic imbalance that could aid in the differential diagnosis of these entities.

Maternal and child-health outcomes in different endometrial preparation methods for frozen-thawed embryo transfer: a retrospective study

The purpose of this study was to analyse the obstetric outcome after frozen embryo transfer depending on the protocol used. The endometrial preparation during frozen embryo transfer (FET) was performed in the natural cycle (NC) with timing based on monitoring of the naturally occurring luteinizing hormone (LH) peak or in human chorionic gonadotropin (hCG)-triggered modified natural cycles (MNC), artificial cycle (AC) with hormone replacement therapy cycle and cycle with ovulation induction (OI). A retrospective cohort study was conducted between 2018 and 2020. Pregnancy, perinatal complications and neonatal outcomes were compared among patients treated during AC or MNC or OI protocols. After adjusting for the effect of gravidity, parity, pre-pregnancy body mass index (BMI) and number of miscarriages, the AC group had higher but not significantly different rates of gestational hypertension, preeclampsia and intrahepatic cholestasis of pregnancy (ICP) than women in OI and MNC groups. Significant differences were observed in the rates of placental adherence (15.30% in AC vs. 9.24% in MNC, p = 0.004) and postpartum haemorrhage (PPH) (24.33% in AC vs. 13.07% in OI, p = 0.003, 24.33% in AC vs. 16.24% in MNC, p = 0.002) among the three groups. In singletons, significant differences were observed in the rates of placental adherence (14.09% in AC vs. 8.57% in MNC, p = 0.002), AC and MNC groups had higher risk of PPH compared with OI group (18.36% in AC vs. 12.38% in MNC, p = 0.042 and 7.69% in OI vs. 18.36% in AC, p = 0.013). Neonatal outcomes were similar among the three groups except risk of small for date infants (0.35% in AC vs. 1.44% in MNC, p = 0.008). These findings are important in view of increasing use of frozen cycles and new policy of freeze-all cycles in in vitro fertilization (IVF). The results suggest a link between the absence of corpus luteum and adverse obstetric outcomes.

Effect of Short-Time BelAgeTM Prescription on Pregnancy and Risk Preeclampsia

Introduction: The aim was to determine if one month taking BelAgeTM in the second trimester of pregnancy could reduce the risk of preeclampsia. Methods: From April 2019 to July 2020, a non-blinded, prospective, randomized, study was performed inviting women in the second trimester of pregnancy to take 3 g of BelAgeTM once daily for one month. The control group received only the nutritional assessment. Relative risk (RR) to develop preeclampsia with 95% confidence interval (CI) was calculated using the Social Science Statistics online software, considering a significant statistical value a P-value < 0.05. Results: 144 patients from the BelAgeTM group (mean age 23.6 ± 9.7), and 99 from the control group (mean age 22.1 ± 8.6) were included, finding differences basal systolic blood pressure (P = 0.03), final diastolic blood pressure (P = 0.002) and final mean blood pressure (P = 0.001). Preeclampsia was developed by 18 patients in the BelAgeTM group versus ten patients in the control group, RR 1.2 (95% CI, 0.60–2.57, P = 0.57). Conclusion: A short-time BelAgeTM prescription in the second trimester of pregnancy was enough to reduce the DBP, but did not reduce the risk of developing preeclampsia. Keywords: BelAgeTM diastolic blood pressure, preeclampsia, relative risk.

The feasibility of soluble Fms-Like Tyrosine kinase-1 (sFLT-1) and Placental Growth Factor (PlGF) ratio biomarker in predicting preeclampsia and adverse pregnancy outcomes among medium to high risk mothers in Kuala Lumpur, Malaysia.

Preeclampsia significantly contributes to maternal and perinatal morbidity and mortality. It is imperative to identify women at risk of developing preeclampsia in the effort to prevent adverse pregnancy outcomes through early intervention. Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) level changes are noticeable several weeks before the onset of preeclampsia and its related complications. This study evaluated the feasibility of the sFlt-1/PlGF biomarker ratio in predicting preeclampsia and adverse pregnancy outcomes using a single cut-off point of >38. This is a prospective cohort study conducted at a single tertiary centre, in an urban setting in Kuala Lumpur, Malaysia, between December 2019 and April 2021. A total of 140 medium to high risk mothers with singleton pregnancies were recruited at ≥20 weeks' gestation. sFlt-1/PlGF ratio was measured and the participant monitored according to a research algorithm until delivery. The primary outcome measure was incidence of preeclampsia and the secondary outcome measure was incidence of other adverse pregnancy outcomes. The overall incidence of preeclampsia was 20.7% (29/140). The mean sFlt-1/PlGF ratio was significantly higher in preeclampsia (73.58 ± 93.49) compared to no preeclampsia (13.41 ± 21.63) (p = 0.002). The risk of preeclampsia (adjusted OR 28.996; 95% CI 7.920-106.164; p<0.001) and low Apgar score (adjusted OR 17.387; 95% CI 3.069-98.517; p = 0.028) were significantly higher among women with sFlt-1/PlGF ratio >38 compared with sFLT-1/PlGF ratio ≤38. The area under the receiver-operator characteristic curve (AUC) for a combined approach (maternal clinical characteristics and biomarker) was 86.9% (p<0.001, 95% CI 78.7-95.0) compared with AUC biomarker alone, which was 74.8% (p<0.001, 95% CI 63.3-86.3) in predicting preeclampsia. The test sensitivity(SEN) was 58.6%, specificity (SPEC) 91%,positive predictive value (PPV) 63% and negative predictive value (NPV) 89.3% for prediction of preeclampsia. For predicting a low Apgar score at 5 minutes, the SEN was 84.6%, SPEC 87.4%, PPV 40.7%, and NPV 98.2%; low birth weight with SEN 52.6%,SPEC 86.0%, PPV 37.0%, NPV 92.0%; premature delivery with SEN 48.5%, SPEC 89.5%, PPV 59.3%, NPV 84.7% and NICU admission with SEN 50.0%, SPEC 85.8%, PPV 37.0% and NPV 91.2%. It is feasible to use single cut-off point of >38 ratio of the biomarkers sFlt-1/PlGF in combination with other parameters (maternal clinical characteristics) in predicting preeclampsia and adverse pregnancy outcomes among medium to high risk mothers without restricting outcome measurement period to 1 and 4 weeks in a single urban tertiary centre in Kuala Lumpur, Malaysia.

CircFN1 upregulation initiated oxidative stress-induced apoptosis and inhibition of proliferation and migration in trophoblasts via circFN1-miR-19a/b-3p-ATF2 ceRNA network

Recently, the etiopathogenesis of preeclampsia (PE) has been developed from the perspective of circular RNA, microRNA and their crosstalk in placental oxidative stress. Real-time quantitative PCR and western blotting detected expression of circular RNA-fibronectin 1 (circFN1; ID hsa_circ_0058152), microRNA (miR)-19a/b-3p and activating transcription factor 2 (ATF2). Receiver operating characteristic (ROC) curve analyzed the predictive value of circFN1. Oxidative stress, apoptosis, proliferation, and migration were measured using superoxide dismutase (SOD) and malonaldehyde (MDA) assay kits, Annexin V/Prodium iodide and western blotting methods, MTS and EdU assays, and scratch wound assay, respectively. Target relationships were retrieved by miRNA target prediction software and confirmed by dual-luciferase reporter assay, RNA immunoprecipitation and RNA pull-down. Expression of circFN1 was upregulated in the serum of PE pregnancies, and the area under the ROC curve of serum circFN1 was 0.7826 (95% confidence interval: 0.6495-0.9157; sensitivity 86.96%; specificity 56%). Functionally, its upregulation decreased SOD activity, cell viability, EdU incorporation, migration rate, and Bcl-2 expression in human trophoblast HTR-8/SV-neo cells, but meanwhile increased MDA level, apoptosis rate, and Bax and cleaved-caspase3 expression. Moreover, its downregulation played the opposite effects in HTR-8/SV-neo cells. Mechanistically, circFN1 functioned as "miRNA sponge" for miR-19a/b-3p and modulated the latter's target gene ATF2. There were feedback effects of miR-19a/b-3p restorations and ATF2 depletion on circFN1 actions in HTR-8/SV-neo cells. Oxidative injury-mediated placental trophoblast dysfunction in PE was through competing endogenous RNA (ceRNA) mechanism of CircFN1-miR-19a/b-3p-ATF2 axes.