Development of a core outcome set (COS) for studies relating to awareness and clinical management of reduced fetal movement: study protocol

From Springer Nature via Jisc Publications RouterHistory: received 2021-03-05, accepted 2021-11-17, registration 2021-11-17, collection 2021-12, pub-electronic 2021-12-09, online 2021-12-09Publication status: PublishedFunder: Tommy's Baby Charity; doi: http://dx.doi.org/10.13039/501100000306; Grant(s): R125598Abstract: Background: Concerns regarding reduced fetal movements (RFM) are reported in 5–15% of pregnancies, and RFM are associated with adverse pregnancy outcomes including fetal growth restriction and stillbirth. Studies have aimed to improve pregnancy outcomes by evaluating interventions to raise awareness of RFM in pregnancy, such as kick counting, evaluating interventions for the clinical management of RFM, or both. However, there is not currently a core outcome set (COS) for studies of RFM. This study aims to create a COS for use in research studies that aim to raise awareness of RFM and/or evaluate interventions for the clinical management of RFM. Methods: A systematic review will be conducted, to identify outcomes used in randomised and non-randomised studies with control groups that aimed to raise awareness of RFM (for example by using mindfulness techniques, fetal movement counting, or other tools such as leaflets or mobile phone applications) and/or that evaluated the clinical management of RFM. An international Delphi consensus will then be used whereby stakeholders will rate the importance of the outcomes identified in the systematic review in (i) awareness and (ii) clinical management studies. The preliminary lists of outcomes will be discussed at a consensus meeting where one final COS for awareness and management, or two discrete COS (one for awareness and one for management), will be agreed upon. Discussion: A well-developed COS will provide researchers with the minimum set of outcomes that should be measured and reported in studies that aim to quantify the effects of interventions

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

The Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia : design, results and future prospects

The impact of many unfavorable childhood traits or diseases, such as low birth weight and mental disorders, is not limited to childhood and adolescence, as they are also associated with poor outcomes in adulthood, such as cardiovascular disease. Insight into the genetic etiology of childhood and adolescent traits and disorders may therefore provide new perspectives, not only on how to improve wellbeing during childhood, but also how to prevent later adverse outcomes. To achieve the sample sizes required for genetic research, the Early Growth Genetics (EGG) and EArly Genetics and Lifecourse Epidemiology (EAGLE) consortia were established. The majority of the participating cohorts are longitudinal population-based samples, but other cohorts with data on early childhood phenotypes are also involved. Cohorts often have a broad focus and collect(ed) data on various somatic and psychiatric traits as well as environmental factors. Genetic variants have been successfully identified for multiple traits, for example, birth weight, atopic dermatitis, childhood BMI, allergic sensitization, and pubertal growth. Furthermore, the results have shown that genetic factors also partly underlie the association with adult traits. As sample sizes are still increasing, it is expected that future analyses will identify additional variants. This, in combination with the development of innovative statistical methods, will provide detailed insight on the mechanisms underlying the transition from childhood to adult disorders. Both consortia welcome new collaborations. Policies and contact details are available from the corresponding authors of this manuscript and/or the consortium websites.Peer reviewe

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

A systematic scoping review to identify the design and assess the performance of devices for antenatal continuous fetal monitoring.

BackgroundAntepartum fetal monitoring aims to assess fetal development and wellbeing throughout pregnancy. Current methods utilised in clinical practice are intermittent and only provide a 'snapshot' of fetal wellbeing, thus key signs of fetal demise could be missed. Continuous fetal monitoring (CFM) offers the potential to alleviate these issues by providing an objective and longitudinal overview of fetal status. Various CFM devices exist within literature; this review planned to provide a systematic overview of these devices, and specifically aimed to map the devices' design, performance and factors which affect this, whilst determining any gaps in development.MethodsA systematic search was conducted using MEDLINE, EMBASE, CINAHL, EMCARE, BNI, Cochrane Library, Web of Science and Pubmed databases. Following the deletion of duplicates, the articles' titles and abstracts were screened and suitable papers underwent a full-text assessment prior to inclusion in the review by two independent assessors.ResultsThe literature searches generated 4,885 hits from which 43 studies were included in the review. Twenty-four different devices were identified utilising four suitable CFM technologies: fetal electrocardiography, fetal phonocardiography, accelerometry and fetal vectorcardiography. The devices adopted various designs and signal processing methods. There was no common means of device performance assessment between different devices, which limited comparison. The device performance of fetal electrocardiography was reduced between 28 to 36 weeks' gestation and during high levels of maternal movement, and increased during night-time rest. Other factors, including maternal body mass index, fetal position, recording location, uterine activity, amniotic fluid index, number of fetuses and smoking status, as well as factors which affected alternative technologies had equivocal effects and require further investigation.ConclusionsA variety of CFM devices have been developed, however no specific approach or design appears to be advantageous due to high levels of inter-device and intra-device variability

A Systematic Review of the Safety of Blocking the IL-1 System in Human Pregnancy

Blockade of the interleukin-1 (IL-1) pathway has been used therapeutically in several inflammatory diseases including arthritis and cryopyrin-associated periodic syndrome (CAPS). These conditions frequently affect women of childbearing age and continued usage of IL-1 specific treatments throughout pregnancy has been reported. IL-1 is involved in pregnancy complications and its blockade could have therapeutic potential. We systematically reviewed all reported cases of IL-1 blockade in human pregnancy to assess safety and perinatal outcomes. We searched several databases to find reports of specific blockade of the IL-1 pathway at any stage of pregnancy, excluding broad spectrum or non-specific anti-inflammatory intervention. Our literature search generated 2439 references of which 22 studies included, following extensive review. From these, 88 different pregnancies were assessed. Most (64.8%) resulted in healthy term deliveries without any obstetrical/neonatal complications. Including pregnancy exposed to Anakinra or Canakinumab, 12 (15.0%) resulted in preterm birth and one stillbirth occurred. Regarding neonatal complications, 2 cases of renal agenesis (2.5%) were observed, and 6 infants were diagnosed with CAPS (7.5%). In conclusion, this systematic review describes that IL-1 blockade during pregnancy is not associated with increased adverse perinatal outcomes, considering that treated women all presented an inflammatory disease associated with elevated risk of pregnancy complications

Umbilical cord characteristics and their association with adverse pregnancy outcomes: A systematic review and meta-analysis.

ObjectiveCurrent data on the role of the umbilical cord in pregnancy complications are conflicting; estimates of the proportion of stillbirths due to cord problems range from 3.4 to 26.7%. A systematic review and meta-analysis were undertaken to determine which umbilical cord abnormalities are associated with stillbirth and related adverse pregnancy outcomes.MethodsMEDLINE, EMBASE, CINAHL and Google Scholar were searched from 1960 to present day. Reference lists of included studies and grey literature were also searched. Cohort, cross-sectional, or case-control studies of singleton pregnancies after 20 weeks' gestation that reported the frequency of umbilical cord characteristics or cord abnormalities and their relationship to stillbirth or other adverse outcomes were included. Quality of included studies was assessed using NIH quality assessment tools. Analyses were performed in STATA.ResultsThis review included 145 studies. Nuchal cords were present in 22% of births (95% CI 19, 25); multiple loops of cord were present in 4% (95% CI 3, 5) and true knots of the cord in 1% (95% CI 0, 1) of births. There was no evidence for an association between stillbirth and any nuchal cord (OR 1.11, 95% CI 0.62, 1.98). Comparing multiple loops of nuchal cord to single loops or no loop gave an OR of 2.36 (95% CI 0.99, 5.62). We were not able to look at the effect of tight or loose nuchal loops. The likelihood of stillbirth was significantly higher with a true cord knot (OR 4.65, 95% CI 2.09, 10.37).ConclusionsTrue umbilical cord knots are associated with increased risk of stillbirth; the incidence of stillbirth is higher with multiple nuchal loops compared to single nuchal cords. No studies reported the combined effects of multiple umbilical cord abnormalities. Our analyses suggest specific avenues for future research

Decreased fetal movements : Report from the International Stillbirth Alliance conference workshop.

Maternal reports of decreased fetal movement (DFM) are a common reason to present to maternity care and are associated with stillbirth and other adverse outcomes. Promoting awareness of fetal movements and prompt assessment of DFM has been recommended to reduce stillbirths. However, evidence to guide clinical management of such presentations is limited. Educational approaches to increasing awareness of fetal movements in pregnant women and maternity care providers with the aim of reducing stillbirths have recently been evaluated in a several large clinical trials internationally. The International Stillbirth Alliance Virtual Conference in Sydney 2021 provided an opportunity for international experts in fetal movements to share reports on the findings of fetal movement awareness trials, consider evidence for biological mechanisms linking DFM and fetal death, appraise approaches to clinical assessment of DFM, and highlight research priorities in this area. Following this workshop summaries of the sessions prepared by the authors provide an overview of understandings of fetal movements in maternity care at the current time and highlights future directions in fetal movement research