Obstetric Syndrome Research Articles

Serum Neurofilament Light: a Potential Diagnostic and Prognostic Biomarker in Obstetric Posterior Reversible Encephalopathy Syndrome.

Obstetric posterior reversible encephalopathy syndrome (PRES), caused by preeclampsia (PE) or eclampsia, is a clinical imaging syndrome and a critical maternal complication, with vasogenic edema in white matter as a typical imaging characteristic. Serum neurofilament light (NFL) is a marker of neuroaxonal injury. Therefore, we performed this study to explore the diagnostic and prognostic role of NFL in obstetric PRES. We used stored serum samples and clinical data obtained from 2148 PE or eclampsia patients from the Guangzhou Medical Centre for Critical Pregnant Women from January 2015 to January 2020. The serum NFL concentration was measured by Simoa assay. Patients without complete data and MRI examinations were excluded. All patients were grouped into the PRES and non-PRES groups based on the PRES diagnostic criteria. In total, 222 patients met the inclusion criteria and were grouped into the PRES (n = 123) and non-PRES (n = 99) groups. The NFL level was significantly higher in the PRES group than in the non-PRES group (p < 0.0001). The discriminatory accuracy of diagnostic panels (headaches + NFL, NFL) in receiver operating characteristic curve analysis (area under the curve) was 0.9338 and 0.7664. Importantly, the NFL level was significantly correlated with edema severity (Spearman's correlation, p < 0.0001), and a poorer pregnancy outcome was observed in the PRES group. In conclusion, an increased NFL level can add predictive value for diagnosing obstetric PRES, and its level is associated with both clinical severity and pregnancy outcome, suggesting that NFL could serve as a diagnostic and prognostic biomarker for obstetric PRES.

Сравнительный анализ эффективности препаратов экулизумаба в лечении акушерского атипичного гемолитико-уремического синдрома

Obstetric atypical hemolytic-uremic syndrome (aHUS) is an emergency with an unfavorable prognosis. The implementation of the complement-blocking drug Eculizumab into clinical practice significantly improved prognosis of patients with obstetric aHUS. In 2019, the first biosimilar of Eculizumab was developed in Russia by GENERIUM.

Predicting the Development of Great Obstetric Syndromes Based on Multilocus Genetic Analysis: Results of a Retrospective Comparative Cohort Study

Background. Great obstetric syndromes are pathological conditions, related to the level of maternal, perinatal and infant morbidity and mortality. There is a genetic component in the development of pregnancy complications, as evidenced by numerous clinical observations and research results. Purpose to study the frequency characteristics of the occurrence of polymorphic variants of various genes and their combinations in patients who underwent pregnancy complicated by great obstetric syndromes in comparison with women whose pregnancy proceeded without complications and successfully ended with the birth of a live full-term baby. Methods. A retrospective comparative cohort study was conducted. Molecular genetic research was carried out in 391 women: 279 women who underwent one of the verified clinical forms related to great obstetric syndromes (main group), 112 women were included in the control group. 37 polymorphisms in 33 genes were studied (FGB, F2, F5, F7, F13, GPIa, GPIIIa, GPVI, PROC, PAI1, PLAT, MTHFR, MTHFD, MTRR, MTR, SLC19A1, CBS, NOS3, END1, ACE, ADD1, AGT , CYP11B2, GSTM, GSTT, GSTP1, MnSOD, GPX1, IL1, TNF-a, ESR1, ESR2, PGR). Results. The most significant polymorphisms and their combinations were identified. In the main group, the following combinations were more common: ACE Alu I/D ID + AGT А704G GG, AGT А704G GG + MTRR A66G AG, F7 G10976A GG + AGT А704G GG, F7 G10976A GG + F13 G103A GG, F7 G10976A GG + GPIa С807T CC, F7 G10976A GG + MTHFR C677T CC, CYP11B2 G-344A GA + IL1 G+3953A GA, PAI1-657 5G/4G 5G4G + IL1 G+3953A AA, PAI1-657 5G/4G 4G4G + IL1 G+3953A AA, in control group AGT A704G AA + MTRR A66G AG, AGT A704G AG + MTRR A66G AG (the differences are statistically significant). To simplify the practical application of the analysis for genetic polymorphisms, a computer program named GOS RISK was created to assess the risk of pregnancy complications. The sensitivity and specificity were 70.8% and 78.8%, the efficiency of the method 74.8%. Conclusion. Analysis of individual polymorphic variants of genes indicates their role in the discussed pathology. Creation of computer programs based on multilocus genome analysis increases the predictive value of molecular genetic studies.

Killer-cell immunoglobulin-like receptor/human leukocyte antigen-C combination and 'great obstetrical syndromes' (Review).

Recurrent pregnancy loss (RPL), pre-eclampsia (PE), fetal growth restriction (FGR), and preterm delivery are examples of ‘great obstetrical syndromes’ (GOS). Placental dysfunction is the most common pathogenesis of GOS. In human pregnancies, the effects of uterine natural killer cells involve angiogenesis, promoting the remodeling of uterine spiral artery, and improving the invasion of trophoblast cells. The uNK cells supply killer immunoglobulin-like receptors (KIRs), which come into contact with human leukocyte antigen-C (HLA-C) ligands expressed by extravillous trophoblast cells (EVTs). Numerous studies have investigated the association between GOS and KIR/HLA-C combination. However, the outcomes have not been conclusive. The present review aimed to reveal the association between GOS and KIR/HLA-C combination to screen out high-risk pregnancies, strengthen the treatment of pregnancy complications, and reduce the frequency of adverse maternal and fetal outcomes. It has been reported that a female with a KIR AA genotype and a neonate with a paternal HLA-C2 molecule is more prone to develop GOS and have a small fetus since less cytokines were secreted by uNK cells. Conversely, the combination of KIR BB haplotype (including the activating KIR2DS1) and HLA-C2 can induce the production of cytokines and increase trophoblast invasion, leading to the birth of a large fetus. KIR/HLA-C combinations may be applicable in selecting third-party gametes or surrogates. Detection of maternal KIR genes and HLA-C molecules from the couple could serve as useful markers for predicting and diagnosing GOS.

“The First Thousand Days” Define a Fetal/Neonatal Neurology Program

Gene–environment interactions begin at conception to influence maternal/placental/fetal triads, neonates, and children with short- and long-term effects on brain development. Life-long developmental neuroplasticity more likely results during critical/sensitive periods of brain maturation over these first 1,000 days. A fetal/neonatal program (FNNP) applying this perspective better identifies trimester-specific mechanisms affecting the maternal/placental/fetal (MPF) triad, expressed as brain malformations and destructive lesions. Maladaptive MPF triad interactions impair progenitor neuronal/glial populations within transient embryonic/fetal brain structures by processes such as maternal immune activation. Destructive fetal brain lesions later in pregnancy result from ischemic placental syndromes associated with the great obstetrical syndromes. Trimester-specific MPF triad diseases may negatively impact labor and delivery outcomes. Neonatal neurocritical care addresses the symptomatic minority who express the great neonatal neurological syndromes: encephalopathy, seizures, stroke, and encephalopathy of prematurity. The asymptomatic majority present with neurologic disorders before 2 years of age without prior detection. The developmental principle of ontogenetic adaptation helps guide the diagnostic process during the first 1,000 days to identify more phenotypes using systems-biology analyses. This strategy will foster innovative interdisciplinary diagnostic/therapeutic pathways, educational curricula, and research agenda among multiple FNNP. Effective early-life diagnostic/therapeutic programs will help reduce neurologic disease burden across the lifespan and successive generations.

New obstetric systemic inflammatory response syndrome criteria for early identification of high-risk of sepsis in obstetric patients.

We aimed to establish new cut-off values for SIRS (Systemic Inflammatory Response Syndrome) variables in the obstetric population. A prospective cohort study in pregnant and postpartum women admitted with systemic infections between December 2017 and January 2019. Patients were divided into three cohorts: Group A, patients with infection but without severe maternal outcomes (SMO); Group B, patients with infection and SMO or admission to the intensive care unit (ICU); and Group C, a control group. Outcome measures were ICU admission and SMO. The relationship between SIRS criteria and SMO was expressed as the area under the receiver operating characteristics curve (AUROC), selecting the best cut-off for each SIRS criterion. A total of 541 obstetric patients were enrolled, including 341 with infections and 200 enrolled as the reference group (Group C). The patients with infections included 313 (91.7%) in Group A and 28 (8.2%) in Group B. There were significant differences for all SIRS variables in Group B, compared with Groups A and C, but there were no significant differences between Groups A and C. The best cut-off values were the following: temperature 38.2°C, OR 4.1 (1.8-9.0); heart rate 120bpm, OR 2.9 (1.2-7.4); respiratory rate 22bpm, OR 4.1 (1.6-10.1); and leukocyte count 16,100 per mcl, OR 3.5 (1.6-7.6). The cut-off values for SIRS variables did not differ between healthy and infected obstetric patients. However, a higher cut-off may help predict the population with a higher risk of severe maternal outcomes.

ULTRASOUND MEASUREMENT OF TRANSCEREBELLAR DIAMETER (TCD)/ABDOMINAL CIRCUMFERENCE (AC) RATIO IN NORMAL AND GROWTH RESTRICTED FETUSES ABOVE TWENTY WEEKS OF GESTATION

Background: Intrauterine growth retardation (IUGR) is an obstetrical syndrome that is generally associated with increased mortality and morbidity. In IUGR, maternal placental blood flow is extremely compromised and that worsen the inter-villous circulation leading to an end-stage fetal distress. Objective: To compare TCD/AC ratio in both normal and growth restricted fetuses in second and third trimesters and to find if there is any correlation between TCD/AC ratio and EFW. Patients and methods: The study was conducted on 100 singleton pregnant women at EL-Sayed Galal University Hospital and Damanhour Teaching Hospital in the period between March 2019 till May 2020 and the patients were divided into two main equal groups. Group I included pregnant females with normally growing fetuses and Group II included pregnant females with growth restricted fetuses above 20 weeks of gestation. Results: This study demonstrated the usefulness of the single cut-off value (13.75%) of the TCD/AC ratio which may contribute to the early identification of SGA infants. The problem lied in identifying the process at the onset or before the IUGR has become severe. Usually the first parameter to decrease is the fetal AC due to depletion of hepatic glycogen and subcutaneous fat stores. The TCD/AC ratio, which utilized a single cut-off value (13.75%) independent of GA, improved diagnostic sensitivity and specificity in these cases. The possible contribution of the TCD/AC ratio in identifying the fetal growth failure itself, which was more important than predicting weight at birth to be further evaluated. There was no correlation between TCD/AC ratio and EFW and no statistical significant correlation between TCD/AC ratio and UA Doppler. Conclusion: In IUGR fetuses, the fetal TCD was less affected than fetal head circumference (HC) suggesting preferential preservation of cerebellar growth relative to other cranial structures. The TCD/AC ratio was helpful in recognizing abnormal fetal growth even when the GA was uncertain since this ratio was gestational age-independent.

Women and babies are dying from inertia: a collaborative framework for obstetrical drug development is urgently needed

Obstetrical complications, often referred to as the "great obstetrical syndromes," are among the most common global causes of mortality and morbidity in young women and their infants. However, treatments for these syndromes are underdeveloped compared with other fields of medicine and are urgently needed. This current paucity of treatments for obstetrical complications is a reflection of the challenges of drug development in pregnancy. The appetite of pharmaceutical companies to invest in research for obstetrical syndromes is generally reduced by concerns for maternal, fetal, and infant safety, poor definition, and high-risk regulatory paths toward product approval. Notably, drug candidates require large investments for development with an unguaranteed return on investment. Furthermore, the discovery of promising drug candidates is hampered by a poor understanding of the pathophysiology of obstetrical syndromes and their uniqueness to human pregnancies. This limits translational extrapolation and de-risking strategies in preclinical studies, as available for other medical areas, compounded with limited fetal safety monitoring to capture early prenatal adverse reactions. In addition, the ethical review committees are reluctant to approve the inclusion of pregnant women in trials, and in the absence of regulatory guidance in obstetrics, clinical development programs are subject to unpredictable regulatory paths. To develop effective and safe drugs for pregnancy complications, substantial commitment, and investment in research for innovative therapies are needed in parallel with the creation of an enabling ethical, legislative, and guidance framework. Solutions are proposed to enable stakeholders to work with a common set of expectations to facilitate progress in this medical discipline. Addressing this significant unmet need to advance maternal and possibly perinatal health requires the involvement of all stakeholders and specifically patients, couples, and clinicians facing pregnancy complications in the dearth of appropriate therapies. This paper focused on the key pharmaceutical research and development challenges to achieve effective and safe treatments for obstetrical syndromes.

Epidemiology of Pregnancy Complications Through the Lens of Immunological Memory.

In the fifteen minutes it takes to read this short commentary, more than 400 babies will have been born too early, another 300 expecting mothers will develop preeclampsia, and 75 unborn third trimester fetuses will have died in utero (stillbirth). Given the lack of meaningful progress in understanding the physiological changes that occur to allow a healthy, full term pregnancy, it is perhaps not surprising that effective therapies against these great obstetrical syndromes that include prematurity, preeclampsia, and stillbirth remain elusive. Meanwhile, pregnancy complications remain the leading cause of infant and childhood mortality under age five. Does it have to be this way? What more can we collectively, as a biomedical community, or individually, as clinicians who care for women and newborn babies at high risk for pregnancy complications, do to protect individuals in these extremely vulnerable developmental windows? The problem of pregnancy complications and neonatal mortality is extraordinarily complex, with multiple unique, but complementary perspectives from scientific, epidemiological and public health viewpoints. Herein, we discuss the epidemiology of pregnancy complications, focusing on how the outcome of prior pregnancy impacts the risk of complication in the next pregnancy — and how the fundamental immunological principle of memory may promote this adaptive response.

A Decrease in the Increased Marker of Tissue Hypoxia Pco2&gt; (Av-Gap) in Microcirculatory-Mitochondrial Distress Syndrome in Critical Obstetrics is Achieved by Complex Methods of Recruiting Microcircula

Considering maternal mortality in state-of-the-art clinics and sophisticated methods of treatment and diagnosis, the human factor of the doctor and the available methods of treatment and diagnosis remained a priority in reducing and even eliminating obstetric mortality. The of success since the last century as in this century of which we described in this work, as in many other previously published works, and represented at international congresses in the Republic of Moldova, Romania, Spain, the Netherlands, Russia and others, where decrease in the increased marker of tissue hypoxia pCO2&gt; (AV-gap) in microcirculatory-mitochondrial distress syndrome in critical obstetrics is achieved by complex methods of recruiting microcirculatory-mitochondrial distress syndrome, contributed to the absence of maternal mortality over 40 years of work in critical obstetrics is presented as a brilliant proof of an affordable model in any medical institution that finds itself next to a dying woman in labor.

Peculiarities of micronutrient metabolism in obese pregnant women (literature review)

Here we summarize uptodate data on the influence of the most significant micro, macroelements, and vitamins, such as magnesium, vitamin D, iron, and folic acid, on the course of pregnancy and childbirth in obese women. The paper considers both domestic and foreign recommendations for correcting nutritional deficiencies to prevent the development of complications from the pregravid stage to the end of lactation. Nowadays, the deficiency of micro-, macroelements and vitamins is an extremely urgent problem, especially in a group of special risk, i.e. overweight and obese women, whose number is steadily growing simultaneously with an increase of the number of pregnant women of 35+ years of age. It is important to consider a woman's body mass index to prescribe the minimum effective dose of the necessary drugs. Timely preventive personalized correction of the micronutrient state can reduce the risks of such major obstetric syndromes as preeclampsia, premature birth, fetal growth retardation, miscarriage, and placental dysfunction.

Pregnancy complications in G20210A mutation carriers associated with high prothrombin activity

ObjectiveTo study the association between high activity of Factor II (prothrombin) in blood plasma with G20210A mutation and the development of great obstetrical syndromes.Material and methodsA prospective clinical cohort study was conducted on 290 pregnant women (average age 31.7 ± 4.7 years old). The main group was made up of 140 G20210A patients, while the control group comprised 150 women with the wild G20210G type. The aim was to evaluate the activity of Factor II in the venous blood plasma during the stages of pregnancy with regard to trophoblast invasion waves. As per results, association analysis of Factor II activity value and gestational complications was carried out.ResultsIn the control group, the median (Me) of Factor II activity ranged from 108% (preconception period) to 144% (pregnancy) [95% CI 130–150]. In patients with the GA type, the value was significantly higher in related periods, ranging from 149 to 181% [95% CI 142–195], p < 0.0001. With Factor II activity ranging from 148.5 to 180.6%, pregnancies in the main group had no complications. Higher levels of Factor II activity were associated with the development of early and/or severe preeclampsia (PE) and fetal growth retardation (FGR).ConclusionThe data obtained regarding Factor II activity in blood plasma, juxtaposed with the development of great obstetrical syndromes, allow to assume that manifestation of G20210A in early and/or severe PE and FGR is associated with this coagulation factor’s level of activity. Threshold value of the Factor II activity with G20210A mutation, allowing to predict the development of PE, comprised 171.0% at the preconception stage (AUC – 0.86; p < 0.0001) and within 7–8 weeks of gestation it was 181.3% (AUC – 0.84; p < 0.0001).

Clinical characteristics and prognosis of patients with isolated thrombotic vs. obstetric antiphospholipid syndrome: a prospective cohort study

BackgroundSeveral studies suggested that thrombotic and obstetric antiphospholipid syndromes could be independent identities, but few have systematically compared their clinical characteristics and prognosis.ObjectiveThe objective of this study is to identify key differences between thrombotic APS (tAPS) and obstetric APS (oAPS).MethodsThis single-center, prospective study included consecutive patients with primary antiphospholipid syndrome (APS) receiving treatment at the Peking Union Medical College Hospital during a period from 2013 to 2020.ResultsScreening of the database yielded a total of 244 women with positive antiphospholipid antibody (aPL). Among the 105 women with primary APS, 39 (37.14%) had isolated tAPS (ItAPS), 44 (41.90%) had isolated oAPS (IoAPS), and 9 (8.57%) had both tAPS and tAPS+oAPS. In comparison to those with IoAPS, patients with ItAPS had older age (41.92 ± 11.97 vs. 33.16 ± 4.22 years, P < 0.01), higher rate of cardiovascular risk (at least one positive of coronary heart disease, hypertension, obesity, diabetes, and hyperlipidemia) (41.03% vs. 6.82%, P < 0.01), and higher frequency of thrombocytopenia (43.59% vs. 20.45%, P < 0.05). Antibody profiles were generally similar among the groups, but isolated anti-β2GPI positivity was more common in patients with IoAPS (52.27% vs. 17.94% for ItAPS, P = 0.01). Triple aPL positivity was more common in patients with both tAPS and oAPS (66.67% vs. 46.15% for ItAPS vs. 25% for IoAPS, P = 0.022). Blood homocysteine was higher in patients with ItAPS (11.20 vs. 9.90 μmol/L for IoAPS, P < 0.05), but there were no differences in inflammatory markers or complements. Recurrence rate of thrombosis was higher in patients with ItAPS (33.33% vs. 2.27% for IoAPS, P ≤ 0.001) with a mean follow-up of 61 months.ConclusionDespite generally similar antibody and biochemical profiles, patients with ItAPS had much higher risk of recurrent thrombosis than IoAPS, supporting distinct mechanisms of pathogenesis.

MiRNAs and Their Gene Targets-A Clue to Differentiate Pregnancies with Small for Gestational Age Newborns, Intrauterine Growth Restriction, and Preeclampsia.

Despite the differences in the clinical manifestations of major obstetric syndromes, such as preeclampsia (PE) and intrauterine growth restriction (IUGR), their pathogenesis is based on the dysregulation of proliferation, differentiation, and invasion of cytotrophoblast cells that occur in the developing placenta, decidual endometrium, and myometrial parts of the spiral arteries. To understand the similarities and differences in the molecular mechanisms of PE and IUGR, samples of the placental bed and placental tissue were analyzed using protein mass spectrometry and the deep sequencing of small RNAs, followed by validation of the data obtained by quantitative RT-PCR in real time. A comparison of the transcriptome and proteomic profiles in the samples made it possible to conclude that the main changes in the molecular profile in IUGR occur in the placental bed, in contrast to PE, in which the majority of molecular changes occurs in the placenta. In placental bed samples, significant changes in the ratio of miRNA and its potential target gene expression levels were revealed, which were unique for IUGR (miR-30c-5p/VIM, miR-28-3p/VIM, miR-1-3p/ANXA2, miR-30c-5p/FBN1; miR-15b-5p/MYL6), unique for PE (miR-185-3p/FLNA), common for IUGR and PE (miR-30c-5p/YWHAZ and miR-654-3p/FGA), but all associated with abnormality in the hemostatic and vascular systems as well as with an inflammatory process at the fetal‒maternal interface.

Clinical and pathogenetic variants of fetal growth restriction with different periods of manifestation

The article presents data on the clinical and pathogenetic variants of fetal growth restriction (FGR). FGR is one of the typical clinical manifestations of large obstetric syndromes, is associated with a high perinatal morbidity and has a significant impact on the quality and duration of human life. The emphasis is made on the differences in pathogenesis, the features of prediction, diagnosis, obstetric management and the assessment of perinatal outcomes in the early and late phenotype of the FGR. The review includes materials from domestic and foreign scientific literature that found in eLibrary and PubMed on this topic and published for the last 10 years. This article discusses the role of the formation of the embryo(feto)placental system under the influence of existing periconceptional risk factors in the implementation of various phenotypes of FGR. An analysis of the literature shows that the fetal growth potential, which genetically and epigenetically determined, changes during pregnancydepending on maternal, placental and fetal factors, which ultimately determine the final weight-growth parameters of the newborn. The issues of informativeness of clinical, laboratory and instrumental predictors, diagnostic criteria, the choice of rational obstetric management in case of FGR of various periods of manifestation are discussed in this article. Convincing data on the perinatal and long-term consequences of intrauterine growth restriction are presented. The pathogenetic variant of FGR determines the features of the functioning of the immune system, has a significant impact on the programming of metabolic and endocrine processes, the formation of fetal brain structures. Identification of pregnant women at risk for the development of FGR of various periods of manifestation, timely diagnosis, selection of the timing and method of delivery should correspond to the main directions of the "4P-model" of modern medicine and represent an integral predictive, preventive and personalized system of examination and observation based on evidence-based medicine data and the requirements of practical obstetrics and perinatology.

Cellular immune responses in the pathophysiology of preeclampsia.

Preeclampsia, defined as new-onset hypertension accompanied by proteinuria occurring at 20weeks of gestation or later, is a leading cause of perinatal morbidity and mortality worldwide. The pathophysiology of this major multi-systemic syndrome includes defective deep placentation, oxidative stress, endothelial dysfunction, the presence of an anti-angiogenic state, and intravascular inflammation, among others. In this review, we provide a comprehensive overview of the cellular immune responses involved in the pathogenesis of preeclampsia. Specifically, we summarize the role of innate and adaptive immune cells in the maternal circulation, reproductive tissues, and at the maternal-fetal interface of women affected by this pregnancy complication. The major cellular subsets involved in the pathogenesis of preeclampsia are regulatory T cells, effector T cells, NK cells, monocytes, macrophages, and neutrophils. We also summarize the literature on those immune cells that have been less characterized in this clinical condition, such as γδ T cells, invariant natural killer T cells, dendritic cells, mast cells, and B cells. Moreover, we discuss in vivo studies utilizing a variety of animal models of preeclampsia to further support the role of immune cells in this disease. Finally, we highlight the existing gaps in knowledge of the immunobiology of preeclampsia that require further investigation. The goal of this review is to promote translational research leading to clinically relevant strategies that can improve adverse perinatal outcomes resulting from the obstetrical syndrome of preeclampsia.

The presentation and outcomes of Hermansky-Pudlak syndrome in obstetrics and gynecological settings: A systematic review.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal-recessive disorder with clinical manifestations of bleeding diathesis, multi-organ disease and variable oculocutaneous albinism (OCA). In women, it can cause life-threatening obstetric and gynecological (OB/GYN) bleeding. To summarize OB/GYN presentations, outcomes, and management strategies in women with HPS. Main databases (MEDLINE, EMBASE, Cochrane, PubMed, Web of Science Core Collection and Google Scholar) were searched from inception until June 30, 2020. Case reports/series of women with confirmed HPS. A systematic review using PRISMA guidelines. Methodological quality assessment performed using adapted Newcastle Ottawa scale. A total 29 pregnancies in 15 women and 2 gynecological patients were identified. Heavy menstrual bleeding (HMB), the most common bleeding symptom, was reported in 8/15 (53%) of women. HMB and post-partum hemorrhage (PPH) led to diagnosis of HPS in 5/17 (29%) women. Primary PPH was reported in 12/27 (44%) of viable pregnancies; half were major PPH. In 17 pregnancies with known HPS diagnosis, 9 had hemostatic cover with desmopressin and 8 with platelet transfusion. Major PPH occurred in 3/9 (33%) pregnancies covered with desmopressin compared with none in the platelet group. Diagnosis of HPS should be considered in women with OCA presenting with HMB or PPH. Hemostatic management options include desmopressin and platelet transfusion. Management should be multidisciplinary with close collaboration between OB/GYN and hematology teams.

Circular RNA Sequencing of Maternal Platelets: A Novel Tool for the Identification of Pregnancy-Specific Biomarkers.

In the first trimester of pregnancy, the maternal platelet is directly involved in a positive feedback mechanism that facilitates invasion of the extravillous trophoblast into the maternal spiral arteries. Dysfunctional trophoblast invasion with defective deep placentation is primordial in the etiology of the "great obstetrical syndromes." In this proof-of-concept study, using transcriptome analysis of circular RNA (circRNA) following RNA sequencing of maternal platelets, we tested whether pregnancy-specific circRNA markers could be identified in the first trimester of normal pregnancies. Differential transcript expression analysis of circRNAs, as predicted by Accurate CircRNA Finder Suite, CircRNA Identifier (version 2), and Known and Novel Isoform Explorer, was done using thromboSeq.R with variation of multiple settings. Test performance was checked for (a) de novo circRNA identification using the novel platelet-specific Plt-circR4 as a positive control, (b) complete segregation of groups (pregnant vs nonpregnant) after heat map-dendrogram clustering, (c) identification of pregnancy-specific circRNA markers at a false discovery rate (FDR) <0.05, and (d) confirmation of differentially expressed circRNA markers with an FDR <0.05 by an independent method, reverse transcription-quantitative PCR. Of the differentially expressed circRNAs with P values <0.05, 41 circRNAs were upregulated (logFC >2), and 52 circRNAs were downregulated (logFC less than -2) in first-trimester platelet RNA. Of these, nuclear receptor-interacting protein 1 circRNA covering exons 2 and 3 of the 5'-untranslated region was pregnancy specific with upregulation in first-trimester maternal platelets compared to nonpregnant controls. CircRNA sequencing of first-trimester maternal platelets permits the identification of novel pregnancy-specific RNA biomarkers. Future use could include the assessment of maternal and fetal well-being.

Clinical Manifestations of Rift Valley Fever in Humans: Systematic Review and Meta-Analysis

Background: Rift Valley fever (RVF) is an emerging, neglected, mosquito-borne viral haemorrhagic zoonosis associated with severe morbidity, mortality and expanding geographical scope. Human symptoms have poor specificity and case definitions vary. We determined the clinical manifestations of RVF in humans. Methods: In this systematic review and meta-analysis we searched Medline, Embase, Global Health, and Web of Science databases from indexing inception to 15th October 2019. Studies published in English, reporting frequency of symptoms in humans, and laboratory confirmed RVF were included. Animals studies, those among asymptomatic volunteers and single case reports for which a proportion could not be estimated were excluded. Quality assessment was done, data extracted, and pooled frequency estimates calculated using random effects meta-analysis. Results: Of the 3765 articles retrieved, 32 were included in the systematic review and meta-analysis. Nine RVF clinical syndromes were reported including general febrile, gastrointestinal, hepatic, renal, neurological, haemorrhagic, obstetric, visual, and cardio-pulmonary syndromes. The most common clinical manifestations included fever (81%; 95% Confidence Interval (CI) 69-91), nausea (38%; 12-67), jaundice (26%; 16-36), renal failure (41%; 23-59), encephalitis (21%; 11-33), haemorrhagic disease (26%; 17-36), miscarriage (54%), partial blindness (24%; 7-45), and cough (4%; 0-17), respectively. Death occurred in 21% (95% CI 14-29) of cases. Interpretation: This study delineates the complex symptomatology of human RVF disease into syndromes. This approach is likely to improve case definitions and detection rates, impact outbreaks control, increase public awareness about RVF, and subsequently inform ‘one-health’ policies. Study protocol registration number: CRD42019128928. Funding: (UK Department of Health and Social care) The work was conducted at the MRC/UVRI and LSHTM Uganda Research Unit which is jointly funded by the UK Medical Research Council (MRC) and the UK Department for International Development (DFID) under the MRC/DFID Concordant agreement and is also part of the EDCTP2 programme supported by the European Union. This project was funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC) and the Medical Research Council (MRC)/Department of Health, through the UK Vaccines Network which is a Government Funding Stream (Grant no: 16/107/02). SL was supported by the PANDORA-ID-NET Consortium (EDCTP Reg/Grant RIA2016E-1609) funded by the European and Developing Countries Clinical Trials Partnership (EDCTP2) programme under the Horizon 2020, the European Union’s Framework Programme for Research and Innovation. GMW is supported by an Oak foundation fellowship and a Wellcome Trust grant (grant number 203077_Z_16_Z). Declaration of Interests: All authors declare no potential conflicts of interest.

Disorders of placental villous maturation are present in one-third of cases with spontaneous preterm labor.

Spontaneous preterm labor is an obstetrical syndrome accounting for approximately 65-70% of preterm births, the latter being the most frequent cause of neonatal death and the second most frequent cause of death in children less than five years of age worldwide. The purpose of this study was to determine and compare to uncomplicated pregnancies (1) the frequency of placental disorders of villous maturation in spontaneous preterm labor; (2) the frequency of other placental morphologic characteristics associated with the preterm labor syndrome; and (3) the distribution of these lesions according to gestational age at delivery and their severity. A case-control study of singleton pregnant women was conducted that included (1) uncomplicated pregnancies (controls, n=944) and (2) pregnancies with spontaneous preterm labor (cases, n=438). All placentas underwent histopathologic examination. Patients with chronic maternal diseases (e.g., chronic hypertension, diabetes mellitus, renal disease, thyroid disease, asthma, autoimmune disease, and coagulopathies), fetal malformations, chromosomal abnormalities, multifetal gestation, preeclampsia, eclampsia, preterm prelabor rupture of the fetal membranes, gestational hypertension, gestational diabetes mellitus, and HELLP (hemolysis, elevated liver enzymes and low platelet count) syndrome were excluded from the study. Compared to the controls, the most prevalent placental lesions among the cases were the disorders of villous maturation (31.8% [106/333] including delayed villous maturation 18.6% [62/333] vs. 1.4% [6/442], q<0.0001, prevalence ratio 13.7; and accelerated villous maturation 13.2% [44/333] vs. 0% [0/442], q<0.001). Other lesions in decreasing order of prevalence included hypercapillarized villi (15.6% [68/435] vs. 3.5% [33/938], q<0.001, prevalence ratio 4.4); nucleated red blood cells (1.1% [5/437] vs. 0% [0/938], q<0.01); chronic inflammatory lesions (47.9% [210/438] vs. 29.9% [282/944], q<0.0001, prevalence ratio 1.6); fetal inflammatory response (30.1% [132/438] vs. 23.2% [219/944], q<0.05, prevalence ratio 1.3); maternal inflammatory response (45.5% [195/438] vs. 36.1% [341/944], q<0.01, prevalence ratio 1.2); and maternal vascular malperfusion (44.5% [195/438] vs. 35.7% [337/944], q<0.01, prevalence ratio 1.2). Accelerated villous maturation did not show gestational age-dependent association with any other placental lesion while delayed villous maturation showed a gestational age-dependent association with acute placental inflammation (q-value=0.005). Disorders of villous maturation are present in nearly one-third of the cases of spontaneous preterm labor.