COVID-19 and hemolysis,elevated liver enzymes and thrombocytopenia syndrome in pregnant women - association or causation?

Pregnant women are among the high-risk population for severe coronavirus disease 2019 (COVID-19) with unfavorable peripartum outcomes and increased incidence of preterm births. Hemolysis, the elevation of liver enzymes, and low platelet count (HELLP) syndrome and severe preeclampsia are among the leading causes of maternal mortality. Evidence supports a higher odd of pre-eclampsia in women with COVID-19, given overlapping pathophysiology. Involvement of angiotensin-converting enzyme 2 receptors by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for the entry to the host cells and its downregulation cause dysregulation of the renin-angiotensin-aldosterone system. The overexpression of Angiotensin II mediated via p38 Mitogen-Activated Protein Kinase pathways can cause vasoconstriction and uninhibited platelet aggregation, which may be another common link between COVID-19 and HELLP syndrome. On PubMed search from January 1, 2020, to July 30, 2022, we found 18 studies on of SARS-COV-2 infection with HELLP Syndrome. Most of these studies are case reports or series, did not perform histopathology analysis of the placenta, or measured biomarkers linked to pre-eclampsia/HELLP syndrome. Hence, the relationship between SARS-CoV-2 infection and HELLP syndrome is inconclusive in these studies. We intend to perform a mini-review of the published literature on HELLP syndrome and COVID-19 to test the hypothesis on association vs causation, and gaps in the current evidence and propose an area of future research.     

A Randomised,Double-Blinded,Placebo-Controlled Study of the Phosphodiesterase Type 5 Inhibitor Sildenafil for the Treatment of Preeclampsia

Objective:?To determine if the phosphodiesterase type 5 inhibitor sildenafil prolongs pregnancy in women with preeclampsia.?Methods:?Women with preeclampsia at gestational ages 24–34 weeks were recruited from nine hospitals in the UK, and randomly assigned to sildenafil citrate or placebo. Medication was increased every 3 days from 20 mg three times daily (tid), to 40 mg, and 80 mg tid. The primary endpoint was prolongation of pregnancy from randomisation to delivery (days). Secondary endpoints were markers of maternal disease and cord pH at delivery and infant weight. Details of all adverse events were also collected. Plasma samples were taken to establish pharmacokinetic information. Data analysed on a modified intention to treat analysis. The study had a power of >95% to detect a difference of 5 days.?Results:?Of 35 women, 17 were allocated to sildenafil and 18 to placebo. There was no difference in time from randomisation to delivery in the two treatment groups, with a median time of 4 days (range 1–15) in the sildenafil group and 4.5 days (range 1–30) in the placebo group. Sildenafil achieved maximum drug concentrations of 48 ng/ml, 88 ng/ml, and 271 ng/ml after 3 days of 20 mg, 40 mg and 80 mg tid, respectively.?Conclusion:?We have safely conducted a clinical trial of a drug not routinely used during pregnancy. Sildenafil in the escalating dose regimen 20–80 mg tid was well tolerated, with no increase in maternal or fetal morbidity or mortality but did not prolong pregnancy duration in women with preeclampsia. (ClinicalTrials.gov number, NCT 00141310).     

SLC41A1 is the only magnesium responsive gene significantly overexpressed in placentas of preeclamptic women

Objective: To examine expression profile of magnesium responsive genes (MRGs) in placentas of normoevolutive and preeclamptic women. Methods: The expression profiles of MRGs were determined in placentas of normoevolutive (N?=?26) and preeclamptic (N?=?25) women by RT-qPCR. Results: Among all tested MRGs (9) only SLC41A1 (encoding for Na⁺/Mg²⁺ exchanger) was significantly overexpressed in ～54.2% of preeclamptic (n?=?24) and in ～9.5% of normoevolutive (n?=?21) specimens. On average, SLC41A1 was overexpressed sixfold in the preeclamptic group. Presence of SLC41A1 in placentas was confirmed by Western blot analysis. Conclusion. SLC41A1 is significantly overexpressed in nearly 55% of preeclamptic placentas. This may indicate a direct contribution of changed Mg homeostasis in the development of preeclampsia.     

Availability of COLLECT,a database for pregnancy and placental research studies worldwide

Cost and availability of a database often impede research while the lack of compatibility inhibits collaboration by making merging of databases difficult or impossible. The Global Pregnancy Collaboration (CoLab) has promoted harmonization of studies and standardized data collection to facilitate pregnancy and placental research. Its online database, COLLECT, allows collection of minimal and optimal clinical datasets to accompany basic and applied science studies and provides a placental sample inventory system. COLLECT is available free of charge in LMIC and for $100 per month in HIC. Data is the property of the investigator but with permission can be combined into larger studies across centers and countries.     

Key players of the necroptosis pathway RIPK1 and SIRT2 are altered in placenta from preeclampsia and fetal growth restriction

IntroductionPreeclampsia (PE) and fetal growth restriction (FGR) are among the leading causes of perinatal morbidity and mortality. Placental insufficiency is central to these conditions. The mechanisms underlying placental insufficiency are poorly understood. Apoptosis has long been considered the only form of regulated cell death, recent research has identified an alternate process of programmed cell death known as necroptosis [1]. Necroptosis is distinct from apoptosis, relying on the deacetylase sirtuin-2 [2], receptor interacting kinases RIPK1 and 3, and the pseudokinase MLKL [3]. We aimed to determine whether these key necroptosis effector molecules were present in human placenta and whether they are differentially expressed in severe preterm (PT) PE and FGR.MethodsPT placentas from severe early onset (<34 weeks) PE (n = 30), FGR (n = 12) and control (18) pregnancies were collected. SIRT2 and RIPK1 localization and quantitation was determined by immunohistochemistry and western blot. Immunocytochemistry was used to detect SIRT2 and RIPK1 in trophoblastic debris from first trimester, term control and PE pregnancies. Expression of SIRT2, RIPK1, RIPK3 and MLKL was examined by qPCR.ResultsSIRT2 and RIPK1 were localized to the syncytiotrophoblast, villous leukocytes and vasculature in all PT placentas. A significant reduction in SIRT2 protein expression in both PE and FGR placentas was identified. RIPK1 mRNA expression was significantly increased in PE placentas. Immunofluorescence identified both SIRT2 and RIPK1 in the cytotrophoblast cytoplasm.DiscussionWe have identified the presence of activators of necroptosis in human placenta. Interestingly, there is differential expression in major pregnancy complications. We conclude necroptosis may contribute to placental pathophysiology that underlies serious pregnancy complications.     

Hypoproteinemia in the second trimester among patients with preeclampsia prior to the onset of clinical symptoms

Objective: To find a risk factor for “uncomplicated” preeclampsia (PE) comparing blood biochemical parameters between women with uncomplicated PE and healthy pregnant women in each trimester of pregnancy. Methods: A retrospective study was performed on 83 cases of uncomplicated PE, selected from 434 patients with PE, disregarding subjects with other complications relevant to hypertension during pregnancy. The study was limited to women with PE occurring in the third trimester, and records of blood biochemical parameters were evaluated. Controls were recruited from 108 healthy volunteers with normal singleton pregnancies. Results: A significant decrease in total protein was observed in the uncomplicated PE group in the second trimester prior to the onset of clinical symptoms. Conclusion: Hypoproteinemia during pregnancy may be a risk factor for this pathophysiology, and the maintenance of sufficient protein in early pregnancy could contribute to prophylaxis for women with uncomplicated PE.     

子痫前期并可逆性后部白质脑病综合征分析

目的:探讨子痫前期并可逆性后部白质脑病综合征(reversible posterior leukoencephalopathy syndrome,RPLS)的临床表现、影像学特点,以便早诊断、早治疗,获得良好的预后。方法:回顾性分析57例病例报道及同仁医院发生的1例子痫前期并可逆性后部白质脑病综合征。结果:产前46例,产后9例,3例发生时间不详。58例均有高血压、蛋白尿伴头痛、视物不清、进而皮质盲。58例中30人行头颅CT检查,2l例未发现异常,7例表现为局灶性低密度改变,以双侧枕部多见,2例表现为病灶广泛、弥漫性水肿。19例行头颅MRI,5例未发现异常,12例提示后部脑白质血管源性水肿。积极治疗、及时终止妊娠视力完全恢复47例,2例视力未恢复,8例未报结局,1例入院后未及时终止妊娠19 h死于脑出血。结论:高血压、蛋白尿伴头痛、皮质盲是子痫前期伴RPLS常见的临床表现,其特点是可逆性大脑皮质性视觉障碍,MRI是诊断的首选方法;早期诊断,及时终止妊娠,合理治疗,预后良好。