Objective Measurement of Blood Loss following Vaginal Delivery in a UK Hospital

Background: Postpartum haemorrhage (PPH) is the leading cause of maternal morbidity and mortality worldwide. The reported incidence of PPH varies globally, which is often due to the use of subjective visual estimation of blood loss. The aim of this study was to measure the rate of PPH and severe PPH at a UK hospital using objective measurement of blood loss. Methods: Blood loss after vaginal birth was objectively measured in 2009 women at Birmingham Women’s Hospital, UK using a blood collection drape. Results: The postpartum haemorrhage rate, defined as blood loss of 500 mL or more, was 22.2%. The severe PPH rate, defined as blood loss of 1000 mL or more, was 5.3%. Conclusions: The objective measurement of blood loss following vaginal birth is necessary for the accurate calculation of PPH rates

Vaginal micronised progesterone for the prevention of hypertensive disorders of pregnancy : A systematic review and meta-analysis

ACKNOWLEDGEMENTS The investigators thank all trial authors who provided information about their own studies, including Zarko Alfirevic, Ana Luisa Areia, Camil Castelo-Branco, Ozlem Erdem, Fabio Facchinetti, Luke McLindon, Ben Willem Mol, Kypros Nicolaides and Ariel Weissman.Peer reviewe

Quantitative genome-wide methylation analysis of high-grade non-muscle invasive bladder cancer

High-grade non-muscle invasive bladder cancer (HG-NMIBC) is a clinically unpredictable disease with greater risks of recurrence and progression relative to their low-intermediate-grade counterparts. The molecular events, including those affecting the epigenome, that characterise this disease entity in the context of tumour development, recurrence and progression, are incompletely understood. We therefore interrogated genome-wide DNA methylation using HumanMethylation450 BeadChip-arrays in 21 primary HG-NMIBC tumours relative to normal bladder controls. Using strict inclusion-exclusion criteria we identified 1,057 hypermethylated CpGs within gene promoter-associated CpG islands, representing 256 genes. Bisulphite Pyrosequencing validated the array data and examined 25 array-identified candidate genes in an independent cohort of 30 HG-NMIBC and 18 low-intermediate-grade NMIBC. These analyses revealed significantly higher methylation frequencies in high-grade tumours relative to low-intermediate-grade tumours for the ATP5G2, IRX1 and VAX2 genes (p<0.05), and similarly significant increases in mean levels of methylation in high-grade tumours for the ATP5G2, VAX2, INSRR, PRDM14, VSX1, TFAP2b, PRRX1, and HIST1H4F genes (p<0.05). Although inappropriate promoter methylation was not invariantly associated with reduced transcript expression, a significant association was apparent for the ARHGEF4, PON3, STAT5a, and VAX2 gene transcripts (p<0.05). Herein, we present the first genome-wide DNA methylation analysis in a unique HG-NMIBC cohort, showing extensive and discrete methylation changes relative to normal bladder and low-intermediate-grade tumours. The genes we identified hold significant potential as targets for novel therapeutic intervention either alone, or in combination, with more conventional therapeutic options in the treatment of this clinically unpredictable disease

Cell-free DNA in the investigation of miscarriage

Approximately one in four pregnancies result in pregnancy loss, and ~50% of these miscarriages are caused by chromosomal abnormalities. Genetic investigations are recommended after three consecutive miscarriages on products of conception (POC) tissue. Cell-free DNA (cfDNA) has been utilised for prenatal screening, but very little work has been carried out in nonviable pregnancies. We investigated the use of cfDNA from maternal blood to identify chromosomal abnormalities in miscarriage. One hundred and two blood samples from women experiencing a first trimester miscarriage were collected and stored. The mean gestational age was 7.1 weeks (range: 5–11 weeks). In this research, samples without a genetic test result from POC were not analysed. CfDNA was extracted and analysed using a modified commercial genome-wide non-invasive prenatal test. No results were provided to the patient. In 57 samples, cytogenetic results from POC analysis were available. Chromosomal abnormalities were identified in 47% (27/57) of POC analyses, and cfDNA analysis correctly identified 59% (16/27) of these. In total, 75% (43/57) of results were correctly identified. The average cfDNA fetal fraction was 6% (2–19%). In conclusion, cfDNA can be used to detect chromosomal abnormalities in miscarriages where the ‘fetal fraction’ is high enough; however, more studies are required to identify variables that can affect the overall results

Miscarriage syndrome : linking early pregnancy loss to obstetric and age-related disorders

Upon embryo implantation, the uterine mucosa - the endometrium - transforms into a robust decidual matrix that accommodates the fetal placenta throughout pregnancy. This transition is driven by the differentiation of endometrial fibroblasts into specialised decidual cells. A synchronised influx of circulating natural killer (NK) cells and bone marrow-derived mesenchymal stem/progenitor cells (BM-MSC) is pivotal for decidual homeostasis and expansion in early pregnancy. We hypothesise that pathological signals interfering with the recruitment or activity of extrauterine cells at the maternal-fetal interface link miscarriage to subsequent adverse pregnancy outcomes, including further pregnancy losses and preterm labour. NK cells and BM-MSC are key homeostatic regulators in multiple tissues, pointing towards a shared aetiology between recurrent miscarriage and age-related disorders, including cardiometabolic disease. We propose the term ‘miscarriage syndrome’ to capture the health risks associated with miscarriage and discuss how this paradigm can inform clinical practice and accelerate the development of preventative strategies

Quantitative assessment of pregnancy outcome following recurrent miscarriage clinic care : a prospective cohort study

Objectives: To measure pregnancy outcome following attendance at a recurrent miscarriage service and identify factors that influence outcome. Design: Prospective, observational electronic cohort study. Setting: Participants attending a specialist recurrent miscarriage clinic, with a history of two or more pregnancy losses. 857 new patients attended over a 30-month period and were invited to participate. Participant data were recorded on a bespoke study database, ‘Tommy’s Net’. Participants: 777 women consented to participate (90.7% of new patients). 639 (82%) women continued within the cohort, and 138 were lost to follow-up. Mean age of active participants was 34 years for women and 37 years for partners, with a mean of 3.5 (1–19) previous pregnancy losses. Rates of obesity (maternal: 23.8%, paternal: 22.4%), smoking (maternal:7.4%, paternal: 19.4%) and alcohol consumption (maternal: 50%, paternal: 79.2%) were high and 55% of participants were not taking folic acid. Outcome measures: Biannual collection of pregnancy outcomes, either through prompted self-reporting, or existing hospital systems. Results: 639 (82%) women were followed up. 404 (83.4%) reported conception and 106 (16.6%) reported no pregnancy, at least 6 months following registration. Of those that conceived, 72.8% (294/404) had a viable pregnancy. Maternal smoking and body mass index (BMI) over 30 were significantly higher in those who did not conceive (p=0.001) Conclusions: Tommy’s Net provides a secure electronic repository on data for couples with recurrent pregnancy loss and associated outcomes. The study identified that subfertility, as well as repeated miscarriage, maternal BMI and smoking status, contributed to failure to achieve live birth. Study findings may enable comparison of clinic outcomes and inform the development of a personalised holistic care package

Genome-wide characterization of mitochondrial DNA methylation in human brain

BackgroundThere is growing interest in the role of DNA methylation in regulating the transcription of mitochondrial genes, particularly in brain disorders characterized by mitochondrial dysfunction. Here, we present a novel approach to interrogate the mitochondrial DNA methylome at single base resolution using targeted bisulfite sequencing. We applied this method to investigate mitochondrial DNA methylation patterns in post-mortem superior temporal gyrus and cerebellum brain tissue from seven human donors.ResultsWe show that mitochondrial DNA methylation patterns are relatively low but conserved, with peaks in DNA methylation at several sites, such as within the D-LOOP and the genes MT-ND2, MT-ATP6, MT-ND4, MT-ND5 and MT-ND6, predominantly in a non-CpG context. The elevated DNA methylation we observe in the D-LOOP we validate using pyrosequencing. We identify loci that show differential DNA methylation patterns associated with age, sex and brain region. Finally, we replicate previously reported differentially methylated regions between brain regions from a methylated DNA immunoprecipitation sequencing study.ConclusionsWe have annotated patterns of DNA methylation at single base resolution across the mitochondrial genome in human brain samples. Looking to the future this approach could be utilized to investigate the role of mitochondrial epigenetic mechanisms in disorders that display mitochondrial dysfunction