Publications
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Bonnardel F, Haslam SM, Dell A, et al., 2021, Proteome-wide prediction of bacterial carbohydrate-binding proteins as a tool for understanding commensal and pathogen colonisation of the vaginal microbiome, npj Biofilms and Microbiomes, Vol: 7, Pages: 1-10, ISSN: 2055-5008
Bacteria use carbohydrate-binding proteins (CBPs), such as lectins and carbohydrate-binding modules (CBMs), to anchor to specific sugars on host surfaces. CBPs in the gut microbiome are well studied, but their roles in the vagina microbiome and involvement in sexually transmitted infections, cervical cancer and preterm birth are largely unknown. We established a classification system for lectins and designed Hidden Markov Model (HMM) profiles for data mining of bacterial genomes, resulting in identification of >100,000 predicted bacterial lectins available at unilectin.eu/bacteria. Genome screening of 90 isolates from 21 vaginal bacterial species shows that those associated with infection and inflammation produce a larger CBPs repertoire, thus enabling them to potentially bind a wider array of glycans in the vagina. Both the number of predicted bacterial CBPs and their specificities correlated with pathogenicity. This study provides new insights into potential mechanisms of colonisation by commensals and potential pathogens of the reproductive tract that underpin health and disease states.
Mowla S, Bennett P, MacIntyre D, 2021, The vaginal microbiome, NEW GENETIC DIAGNOSTIC TECHNOLOGIES IN REPRODUCTIVE MEDICINE 2E, Editors: Simon, Rubio
There is now substantial evidence implicating the vaginal microbiome in reproductive tract health and disease. As technology has developed, our ability to characterise the composition of the vaginal microbiome has improved providing new insights into how commensal and pathogenic microbes interact with the host to protect against, or potentiate pathology and disease. In this chapter we discuss the current understanding of what shapes the structure of the vaginal microbiome throughout a woman’s life span, how it can be characterised and how specific microbiota-host interactions at the mucosal interface may influence reproductive success or failure.
Ng S, Chen M, Kundu S, et al., 2021, Large-scale characterisation of the pregnancy vaginal microbiome and sialidase activity in a low-risk Chinese population, Publisher: Nature Research
Vaginal microbiota-host interactions are linked to preterm birth (PTB), which continues to be the primary cause of global childhood mortality. Despite the majority of PTB occuring in Asia, studies of the pregnancy vaginal microbiota are largely limited to Northern American and European populations. Here, we characterised the vaginal microbiome of 2689 pregnant Chinese women using metataxonomics and in a subset (n=823), the relationship between vaginal microbiota composition, sialidase activity and leukocyte presence and pregnancy outcomes. Vaginal microbiota were most frequently dominated by Lactobacillus crispatus or L. iners , with the latter associated with vaginal leukocyte presence. Women with high sialidase activity were enriched for bacterial vaginosis-associated genera including Gardnerella, Atopobium and Prevotella . Vaginal microbiota composition, high sialidase activity and/or leukocyte presence was not associated with PTB risk suggesting underlying differences in the vaginal microbiota and/or host immune responses of Chinese women, possibly accounting for low PTB rates in this population. <h4>Importance</h4> Specific vaginal microorganisms or ‘vaginal microbiota’, are associated with preterm birth, which is the primary cause of death in children under 5yrs of age worldwide. Despite most preterm births occuring in Asia, almost all studies of the pregnancy vaginal microbiota have been limited to Northern American and European women. Here, we studied the vaginal microbiota in a large cohort of 2689 pregnant Chinese women and showed that it was most frequently dominated by Lactobacillus crispatus or L. iners . The latter was associated with leukocyte infiltration of vaginal secretions. Women with high activity of the enzyme sialidase, were frequently colonised by species associated with the common condition bacterial vaginosis, including Gardnerella, Atopobium and Prevotella species. Vaginal microbiota, high sialidase activity and/or
Semertzidou A, MacIntyre D, Marchesi J, et al., 2021, The role of genital tract microbiota continuum in endometrial malignancy, Publisher: WILEY, Pages: 115-116, ISSN: 1470-0328
Raglan O, MacIntyre D, Mitra A, et al., 2021, The association between obesity and weight loss after bariatric surgery on the vaginal microbiota, Microbiome, Vol: 9, Pages: 1-17, ISSN: 2049-2618
Background: Obesity and vaginal microbiome (VMB) dysbiosis are each risk factors for adverse reproductive and oncological health outcomes in women. Here we investigated the relationship between obesity, vaginal bacterial composition, local inflammation and bariatric surgery.Methods: Vaginal bacterial composition assessed by high-throughput sequencing of bacterial 16S rRNA genes and local cytokine levels measured using a multiplexed Magnetic Luminex Screening Assay were compared between 67 obese and 42 non-obese women. We further assessed temporal changes in the microbiota and cytokines in a subset of 27 women who underwent bariatric surgery. Results: The bacterial component of the vaginal microbiota in obese women was characterised by a lower prevalence of a Lactobacillus-dominant VMB and higher prevalence of a high diversity (Lactobacillus spp., and Gardnerella- spp. depleted) VMB, compared with non-obese subjects (p<0.001). Obese women had higher relative abundance of Dialister species (p<0.001), Anaerococcus vaginalis (p=0.021) and Prevotella timonensis (p=0.020) and decreased relative abundance of Lactobacillus crispatus (p=0.014). Local vaginal IL-1β, IL-4, IL-6, IL-8, IFNγ, MIP-1α, and TNFα levels were all higher among obese women, however only IL-1β and IL-8 correlated with VMB species diversity. In a subset of obese women undergoing bariatric surgery, there were no significant overall differences in VMB following surgery, however 75% of these women remained obese at six months. Prior to surgery there was no relationship between body mass index (BMI) and VMB structure, however post-surgery women with a Lactobacillus-dominant VMB had a significantly lower BMI than those with a high diversity VMB.Conclusions: Obese women have a significantly different vaginal microbiota composition with increased levels of local inflammation compared to non-obese women. Bariatric surgery does not change the VMB, however, those with the greatest
Coomarasamy A, Gallos ID, Papadopoulou A, et al., 2021, Sporadic miscarriage: evidence to provide effective care, The Lancet, Vol: 397, Pages: 1668-1674, ISSN: 0140-6736
The physical and psychological effect of miscarriage is commonly underappreciated. The journey from diagnosis of miscarriage, through clinical management, to supportive aftercare can be challenging for women, their partners, and caregivers. Diagnostic challenges can lead to delayed or ineffective care and increased anxiety. Inaccurate diagnosis of a miscarriage can result in the unintended termination of a wanted pregnancy. Uncertainty about the therapeutic effects of interventions can lead to suboptimal care, with variations across facilities and countries. For this Series paper, we have developed recommendations for practice from a literature review, appraisal of guidelines, and expert group discussions. The recommendations are grouped into three categories: (1) diagnosis of miscarriage, (2) prevention of miscarriage in women with early pregnancy bleeding, and (3) management of miscarriage. We recommend that every country reports annual aggregate miscarriage data, similarly to the reporting of stillbirth. Early pregnancy services need to focus on providing an effective ultrasound service, as it is central to the diagnosis of miscarriage, and be able to provide expectant management of miscarriage, medical management with mifepristone and misoprostol, and surgical management with manual vacuum aspiration. Women with the dual risk factors of early pregnancy bleeding and a history of previous miscarriage can be recommended vaginal micronised progesterone to improve the prospects of livebirth. We urge health-care funders and providers to invest in early pregnancy care, with specific focus on training for clinical nurse specialists and doctors to provide comprehensive miscarriage care within the setting of dedicated early pregnancy units.
Quenby S, Gallos I, Dhillon-Smith R, et al., 2021, Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss, The Lancet, Vol: 397, Pages: 1658-1667, ISSN: 0140-6736
Miscarriage is generally defined as the loss of a pregnancy before viability. An estimated 23 million miscarriages occur every year worldwide, translating to 44 pregnancy losses each minute. The pooled risk of miscarriage is 15·3% (95% CI 12·5–18·7%) of all recognised pregnancies. The population prevalence of women who have had one miscarriage is 10·8% (10·3–11·4%), two miscarriages is 1·9% (1·8–2·1%), and three or more miscarriages is 0·7% (0·5–0·8%). Risk factors for miscarriage include very young or older female age (younger than 20 years and older than 35 years), older male age (older than 40 years), very low or very high body-mass index, Black ethnicity, previous miscarriages, smoking, alcohol, stress, working night shifts, air pollution, and exposure to pesticides. The consequences of miscarriage are both physical, such as bleeding or infection, and psychological. Psychological consequences include increases in the risk of anxiety, depression, post-traumatic stress disorder, and suicide. Miscarriage, and especially recurrent miscarriage, is also a sentinel risk marker for obstetric complications, including preterm birth, fetal growth restriction, placental abruption, and stillbirth in future pregnancies, and a predictor of longer-term health problems, such as cardiovascular disease and venous thromboembolism. The costs of miscarriage affect individuals, health-care systems, and society. The short-term national economic cost of miscarriage is estimated to be £471 million per year in the UK. As recurrent miscarriage is a sentinel marker for various obstetric risks in future pregnancies, women should receive care in preconception and obstetric clinics specialising in patients at high risk. As psychological morbidity is common after pregnancy loss, effective screening instruments and treatment options for mental health consequences of miscarriage need
Coomarasamy A, Dhillon-Smith RK, Papadopoulou A, et al., 2021, Recurrent miscarriage: evidence to accelerate action, The Lancet, Vol: 397, Pages: 1675-1682, ISSN: 0140-6736
Women who have had repeated miscarriages often have uncertainties about the cause, the likelihood of recurrence, the investigations they need, and the treatments that might help. Health-care policy makers and providers have uncertainties about the optimal ways to organise and provide care. For this Series paper, we have developed recommendations for practice from literature reviews, appraisal of guidelines, and a UK-wide consensus conference that was held in December, 2019. Caregivers should individualise care according to the clinical needs and preferences of women and their partners. We define a minimum set of investigations and treatments to be offered to couples who have had recurrent miscarriages, and urge health-care policy makers and providers to make them universally available. The essential investigations include measurements of lupus anticoagulant, anticardiolipin antibodies, thyroid function, and a transvaginal pelvic ultrasound scan. The key treatments to consider are first trimester progesterone administration, levothyroxine in women with subclinical hypothyroidism, and the combination of aspirin and heparin in women with antiphospholipid antibodies. Appropriate screening and care for mental health issues and future obstetric risks, particularly preterm birth, fetal growth restriction, and stillbirth, will need to be incorporated into the care pathway for couples with a history of recurrent miscarriage. We suggest health-care services structure care using a graded model in which women are offered online health-care advice and support, care in a nurse or midwifery-led clinic, and care in a medical consultant-led clinic, according to clinical needs.
Cartwright J, Frankin L, Tikkinen K, et al., 2021, Genome wide association study identifies two novel loci associated with female stress and urgency urinary incontinence, The Journal of Urology, ISSN: 0022-5347
Background:Genome-wide association studies (GWAS) have not identified replicable genetic risk loci for stress or urgency urinary incontinence.Methods:We carried out a discovery stage case control GWAS in three independent discovery cohorts of European women (n=8,979) for stress incontinence, urgency incontinence, and any incontinence phenotypes. We conducted replication in six additional studies of European ancestry (n=4,069). We collected bladder biopsies from women with incontinence to further investigate bladder expression of implicated genes and pathways (n=50) and used symptom questionnaires for phenotyping. We conducted meta-analyses using inverse variance fixed effects models in METAL, and whole transcriptome analyses using Affymetrix arrays, with replication with TaqMan PCR.Results:In the discovery stage we identified 16 single nucleotide polymorphisms (SNPs) genotyped or imputed at five loci that reached genome-wide significance (p<5x10-8). In replication, rs138724718 on chromosome 2, near the macrophage receptor with collagenous structure (MARCO) gene (replication p=0.003) associated with stress incontinence. In addition, rs34998271 on chromosome 6 near the Endothelin 1 (EDN1) gene (replication p=0.0008) associated with urgency incontinence. In combined meta-analyses of discovery and replication cohorts, associations with genome-wide significance for these two SNPs were confirmed. Transcriptomics analyses showed differential expression of 7 of 19 genes in the endothelin pathway between stress and urgency incontinence (p<0.0001).Conclusion:We uncovered two new risk loci near the genes Endothelin 1 (EDN1), associated with urgency incontinence and Macrophage Receptor with Collagenous Structure (MARCO), associated with stress incontinence. These loci are biologically plausible given their roles in smooth muscle contraction and innate host defense respectively.
Bowden S, Bodinier B, Kalliala I, et al., 2021, Genetic variation in cervical preinvasive and invasive disease: a genome-wide association study, The Lancet Oncology, Vol: 22, Pages: 548-557, ISSN: 1213-9432
Background: Most uterine cervical high-risk HPV infections (hrHPV) are transient, with only a small 3fraction developing into cervical cancer. Family aggregation studies and heritability estimates suggest 4a significant inherited genetic component. Candidate gene studies and previous genome-wide 5association studies (GWAS) report associations between the human leukocyte antigen (HLA) region 6and cervical cancer. 78Methods: Adopting a genome-wide approach, we compared the genetic variation in women with 9invasive cervical cancer (ICC) and cervical intra-epithelial neoplasia (CIN) grade 3, to that in healthy 10controls using the largest reported cohort of unrelated European individuals (N=150,314)to date. We 11sought for replication in a second large independent dataset (N=128,123). We further performed a two-12sample Mendelian Randomisation approach to explore the role of risk factors in the genetic risk of 13cervical cancer.1415Findings: In our analysis (N=4,769 CIN3 and ICC cases; N=145,545 controls), of the (N=9,600,464) 16assayed and imputed SNPs, six independent variants were found associated with CIN3and ICC. These 17included novel loci rs10175462(PAX8; OR=0.87(95%CI=0.84-0.91); P=1.07x10-9) and rs27069 18(CLPTM1L;OR=0.88(95%CI=0.84-0.92); P=2.51x10-9), and previously reported signals at rs9272050 19(HLA-DQA1;OR=1.27(95%CI=1.21-1.32); P=2.51x10-28), rs6938453 (MICA;OR=0.7920(95%CI=0.75-0.83); P=1.97x10-17), rs55986091 (HLA-DQB1;OR=0.66(95%CI=0.60-0.72); 21P=6.42x10-22) and rs9266183 (HLA-B;OR=0.73(95%CI=0.64-0.83); P=1.53x10-6). Mendelian 22randomisation further supported the complementary role of smoking, age at first pregnancy, and number 23of sexual partners in the risk of developing cervical cancer.2425Interpretation: Our results provide substantial new evidence for genetic susceptibility to cervical cancer, 26including PAX8, CLPTM1LandHLA genes, suggesting disruption in apoptotic and immun
Semertzidou A, Macintyre D, Marchesi J, et al., 2021, THE ROLE OF GENITAL TRACT MICROBIOTA CONTINUUM IN ENDOMETRIAL MALIGNANCY, Publisher: BMJ PUBLISHING GROUP, Pages: A135-A135, ISSN: 1048-891X
Norman JE, Norrie J, MacLennan G, et al., 2021, Evaluation of the Arabin cervical pessary for prevention of preterm birth in women with a twin pregnancy and short cervix (STOPPIT-2): An open-label randomised trial and updated meta-analysis, PLOS MEDICINE, Vol: 18, ISSN: 1549-1277
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Short C-E, Brown R, Quinlan R, et al., 2021, Lactobacillus-depleted vaginal microbiota in pregnant women living with HIV-1 infection are associated with increased local inflammation and preterm birth, Frontiers in Cellular and Infection Microbiology, Vol: 10, ISSN: 2235-2988
Background: Pregnant women living with HIV-1 infection (PWLWH) have an elevated risk of preterm birth (PTB) of unknown aetiology, which remains after successful suppression of HIV. Women at high risk for HIV have a common bacterial profile which has been associated with poor birth outcomes. We set out to explore factors associated with gestational age at delivery of PWLWH in a UK population.Methods: Prospective study of PWLWH (n = 53) in whom the vaginal microbiota and cervicovaginal cytokine milieu were assessed using metataxonomics and multiplexed immunoassays, respectively. Cross-sectional characterisation of vaginal microbiota in PWLWH were compared with 22 HIV uninfected pregnant women (HUPW) at a similar second trimester timepoint. Within PWLWH the relationships between bacterial composition, inflammatory response, and gestational age at delivery were explored.Findings: There was a high rate of PTB among PWLWH (12%). In the second trimester the vaginal microbiota was more diverse in PWLWH than in HUPW (Inverse Simpson Index, p = 0.0004 and Species Observed, p = 0.009). PWLWH had a lower prevalence of L. crispatus dominant vaginal microbiota group (VMB I, 15 vs 54%) than HUPW and higher prevalence of L. iners dominant (VMB III, 36 vs 9% and VMB IIIB, 15 vs 5%) and mixed anaerobes (VMB IV, 21 vs 0%). Across the second and third trimesters in PWLWH, VMB III/IIIB and IV were associated with PTB and with increased local inflammation [cervicovaginal fluid (CVF) cytokine concentrations in upper quartile]. High bacterial diversity and anaerobic bacterial abundance were also associated with CVF pro-inflammatory cytokines, most notably IL-1β.Interpretation: There is an association between local inflammation, vaginal dysbiosis and PTB in PWLWH. Understanding the potential of antiretroviral therapies to influence this cascade will be important to improve birth outcomes in this population.
MacIntyre DA, Bennett PR, 2021, Microbial signatures of preterm birth, The Human Microbiome in Early Life: Implications to Health and Disease, Pages: 55-79, ISBN: 9780128180983
Preterm birth remains the primary cause of death in children under the age of 5 years worldwide. A causal relationship between infection and preterm birth has long been recognized. However, recent applications of molecular-based profiling techniques have provided new insights into the relationship between specific bacterial compositions of the lower reproductive tract and subsequent preterm birth risk. In this chapter, we investigate evidence for “microbial signatures” of preterm birth and examine mechanisms by which shifts in microbiome composition could contribute to an infectious etiology of preterm birth. Despite high levels of heterogeneity between studies, vaginal depletion of Lactobacillus spp. and high-diversity communities enriched for potentially pathogenic bacteria are frequently associated with preterm birth, whereas Lactobacillus spp. dominant communities appear to confer protection against preterm birth, particularly when dominated by Lactobacillus crispatus. Strategies focused toward promoting optimal microbial signatures during pregnancy may help reduce rates of preterm birth and improve maternal and neonatal outcomes.
Zarasvand S, Bayar E, Adan M, et al., 2020, Rapid quality improvement in a preterm birth clinic care pathway during the COVID-19 pandemic, BMJ Open Quality, Vol: 9, Pages: 1-9, ISSN: 2399-6641
Background Preterm birth (PTB) occurs in 8% of births in the UK. At Imperial College Healthcare NHS Trust, our PTB prevention clinic manages the care of approximately 1000 women/year. Women referred to the clinic are seen from 12 weeks of pregnancy with subsequent appointments every 2–4 weeks to measure cervical length (CL) using transvaginal ultrasound (TVUS). Women with a history of cervical weakness or short cervix on TVUS are offered a cervical cerclage.Local problem During the COVID-19 outbreak, pregnant women were strongly advised to avoid social mixing and public transport. The National Health Service had to rapidly adopt remote consultation and redesign clinical pathways in order to reduce transmission, exposure and spread among women at high risk of PTB.Methods We focused on Specific, Measurable, Achievable, Realistic and Timebound aims and used a driver diagram to visualise our changes. We used a series of Plan Do Study Act cycles to evaluate and adapt change ideas through the UK’s national lockdown during the COVID-19 pandemic between 23 March and 29 May 2020.Results We reduced the number of face-to-face appointments by 54%. This was achieved by increasing remote telephone consultations from 0% to 64%, and by reducing the intensity of surveillance. The rate of regional anaesthetic was increased from 53% to 95% for cerclage placement in order to minimise the number of aerosol-generating procedures. Patient and staff satisfaction responses to these changes were used to tailor practices. No women tested positive for COVID-19 during the study period.Conclusions By using quality improvement methodology, we were able to safely and rapidly implement a new care pathway for women at high risk of PTB which was acceptable to patients and staff, and effective in reducing exposure of COVID-19.
Kim SH, MacIntyre D, Binkhamis R, et al., 2020, Maternal plasma miRNAs as potential biomarkers for detecting risk of small-for-gestational-age births, EBioMedicine, Vol: 62, ISSN: 2352-3964
BackgroundSmall-for-gestational-age fetuses (SGA) (birthweight <10th centile) are at high risk for stillbirth or long-term adverse outcomes. Here, we investigate the ability of circulating maternal plasma miRNAs to determine the risk of SGA births.MethodsMaternal plasma samples from 29 women of whom 16 subsequently delivered normally grown babies and 13 delivered SGA (birthweight <5th centile) were selected from a total of 511 women recruited to form a discovery cohort in which expression data for a total of 800 miRNAs was determined using the Nanostring nCounter miRNA assay. Validation by RT-qPCR was performed in an independent cohort.FindingsPartial least-squares discriminant analysis (PLS-DA) of the Nanostring nCounter miRNA assay initially identified seven miRNAs at 12–14+6 weeks gestation, which discriminated between SGA cases and controls. Four of these were technically validated by RT-qPCR. Differential expression of two miRNA markers; hsa-miR-374a-5p (p = 0•0176) and hsa-let-7d-5p (p = 0•0036), were validated in an independent population of 95 women (SGA n = 12, Control n = 83). In the validation cohort, which was enriched for SGA cases, the ROC AUCs were 0•71 for hsa-miR-374a-5p, and 0•74 for hsa-let-7d-5p, and 0•77 for the two combined.InterpretationWhilst larger population-wide studies are required to validate their performance, these findings highlight the potential of circulating miRNAs to act as biomarkers for early prediction of SGA births.
Coomarasamy A, Devall AJ, Brosens JJ, et al., 2020, Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence, Obstetrical and Gynecological Survey, Vol: 75, Pages: 743-744, ISSN: 0029-7828
Historically, a lack of methodologically strong and generalizable studies has limited policy makers from recommending the use of progesterone supplementation to improve outcomes in women at high risk of miscarriage. The PROMISE and PRISM trials were carried out to rectify this and generate robust evidence on the role of progesterone supplementation to prevent miscarriage.
Bennett PR, Brown RG, MacIntyre DA, 2020, Vaginal microbiome in preterm rupture of membranes, Obstetrics and Gynecology Clinics of North America, Vol: 47, Pages: 503-521, ISSN: 0889-8545
MacIntyre D, Bennett P, 2020, Chapter 3 - Microbial signatures of preterm birth, The Human Microbiome in Early Life Implications to Health and Disease, Publisher: Academic Press, ISBN: 9780128180976
Preterm birth remains the primary cause of death in children under the age of 5 years worldwide. A causal relationship between infection and preterm birth has long been recognized. However, recent applications of molecular-based profiling techniques have provided new insights into the relationship between specific bacterial compositions of the lower reproductive tract and subsequent preterm birth risk. In this chapter, we investigate evidence for “microbial signatures” of preterm birth and examine mechanisms by which shifts in microbiome composition could contribute to an infectious etiology of preterm birth. Despite high levels of heterogeneity between studies, vaginal depletion of Lactobacillus spp. and high-diversity communities enriched for potentially pathogenic bacteria are frequently associated with preterm birth, whereas Lactobacillus spp. dominant communities appear to confer protection against preterm birth, particularly when dominated by Lactobacillus crispatus. Strategies focused toward promoting optimal microbial signatures during pregnancy may help reduce rates of preterm birth and improve maternal and neonatal outcomes.
Paraskevaidi M, Cameron SJS, Whelan E, et al., 2020, Laser-assisted rapid evaporative ionisation mass spectrometry (LA-REIMS) as a metabolomics platform in cervical cancer screening, EBioMedicine, Vol: 60, ISSN: 2352-3964
BackgroundThe introduction of high-risk human papillomavirus (hrHPV) testing as part of primary cervical screening is anticipated to improve sensitivity, but also the number of women who will screen positive. Reflex cytology is the preferred triage test in most settings but has limitations including moderate diagnostic accuracy, lack of automation, inter-observer variability and the need for clinician-collected sample. Novel, objective and cost-effective approaches are needed.MethodsIn this study, we assessed the potential use of an automated metabolomic robotic platform, employing the principle of laser-assisted Rapid Evaporative Ionisation Mass Spectrometry (LA-REIMS) in cervical cancer screening.FindingsIn a population of 130 women, LA-REIMS achieved 94% sensitivity and 83% specificity (AUC: 91.6%) in distinguishing women testing positive (n = 65) or negative (n = 65) for hrHPV. We performed further analysis according to disease severity with LA-REIMS achieving sensitivity and specificity of 91% and 73% respectively (AUC: 86.7%) in discriminating normal from high-grade pre-invasive disease.InterpretationThis automated high-throughput technology holds promise as a low-cost and rapid test for cervical cancer screening and triage. The use of platforms like LA-REIMS has the potential to further improve the accuracy and efficiency of the current national screening programme.
Foo L, Johnson S, Marriott L, et al., 2020, Peri-implantation urinary hormone monitoring distinguishes between types of first-trimester spontaneous pregnancy loss, Paediatric and Perinatal Epidemiology, Vol: 34, Pages: 495-503, ISSN: 0269-5022
BackgroundLutenising hormone (LH) and human chorionic gonadotropin (hCG) hormone are useful biochemical markers to indicate ovulation and embryonic implantation, respectively. We explored “point‐of‐care” LH and hCG testing using a digital home‐testing device in a cohort trying to conceive.ObjectiveTo determine conception and spontaneous pregnancy loss rates, and to assess whether trends in LH‐hCG interval which are known to be associated with pregnancy viability could be identified with point‐of‐care testing.MethodsWe recruited healthy women aged 18‐44 planning a pregnancy. Participants used a home monitor to track LH and hCG levels for 12 menstrual cycles or until pregnancy was conceived. Pregnancy outcomes (viable, clinical miscarriage, or biochemical pregnancy loss) were recorded. Monitor data were analysed by a statistician blinded to pregnancy outcome.ResultsFrom 387 recruits, there were 290 pregnancies with known outcomes within study timeline. Adequate monitor data for analysis were available for 150 conceptive cycles. Overall spontaneous first‐trimester pregnancy loss rate was 30% with clinically recognised miscarriage rate of 17%. The difference to LH‐hCG interval median had wider spread for biochemical losses (0.5‐8.5 days) compared with clinical miscarriage (0‐5 days) and viable pregnancies (0‐6 days). Fixed effect hCG profile change distinguished between pregnancy outcomes from as early as day‐2 post‐hCG rise from baseline.ConclusionThe risk of first‐trimester spontaneous pregnancy loss in our prospective cohort is comparable to studies utilising daily urinary hCG collection and laboratory assays. A wider LH‐hCG interval range is associated with biochemical pregnancy loss and may relate to late or early implantation. Although early hCG changes discriminate between pregnancies that will miscarry from viable pregnancies, this point‐of‐care testing model is not sufficiently developed to be predictive.
Bayar E, Bennett PR, Chan D, et al., 2020, The pregnancy microbiome and preterm birth, Springer Seminars in Immunopathology, Vol: 42, Pages: 487-499, ISSN: 1863-2297
Preterm birth is a global health concern and continues to contribute to substantial neonatal morbidity and mortality despite advances in obstetric and neonatal care. The underlying aetiology is multi-factorial and remains incompletely understood. In this review, the complex interplay between the vaginal microbiome in pregnancy and its association with preterm birth is discussed in depth. Advances in the study of bacteriology and an improved understanding of the human microbiome have seen an improved awareness of the vaginal microbiota in both health and in disease.
Tzafetas M, Mitra A, Paraskevaidi M, et al., 2020, The intelligent knife (iKnife) and its intraoperative diagnostic advantage for the treatment of cervical disease (vol 117, pg 7338, 2020), PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 117, Pages: 18892-18892, ISSN: 0027-8424
Coomarasamy A, Devall AJ, Brosens JJ, et al., 2020, Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence, American Journal of Obstetrics and Gynecology, Vol: 223, Pages: 167-176, ISSN: 0002-9378
Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone supplementation may reduce the risk of miscarriage in women with recurrent or threatened miscarriage. Cochrane Reviews summarized the evidence and found that the trials were small with substantial methodologic weaknesses. Since then, the effects of first-trimester use of vaginal micronized progesterone have been evaluated in 2 large, high-quality, multicenter placebo-controlled trials, one targeting women with unexplained recurrent miscarriages (the PROMISE [PROgesterone in recurrent MIScarriagE] trial) and the other targeting women with early pregnancy bleeding (the PRISM [PRogesterone In Spontaneous Miscarriage] trial). The PROMISE trial studied 836 women from 45 hospitals in the United Kingdom and the Netherlands and found a 3% greater live birth rate with progesterone but with substantial statistical uncertainty. The PRISM trial studied 4153 women from 48 hospitals in the United Kingdom and found a 3% greater live birth rate with progesterone, but with a P value of .08. A key finding, first observed in the PROMISE trial, and then replicated in the PRISM trial, was that treatment with vaginal micronized progesterone 400 mg twice daily was associated with increasing live birth rates according to the number of previous miscarriages. Prespecified PRISM trial subgroup analysis in women with the dual risk factors of previous miscarriage(s) and current pregnancy bleeding fulfilled all 11 conditions for credible subgroup analysis. For the subgroup of women with a history of 1 or more miscarriage(s) and current pregnancy bleeding, the live birth rate was 75% (689/914) with progesterone vs 70% (619/886) with placebo (rate difference 5%; risk ratio, 1.09, 95% confidence interval, 1.03-1.15; P=.003). The benefit was greater for the subgroup of women with 3 or more previous miscarriages and current pregnancy bleeding; live birth rate was 72% (98/137) with progest
Rasheed ZBM, Lee YS, Kim SH, et al., 2020, Differential response of gestational tissues to TLR3 viral priming prior to exposure to bacterial TLR2 and TLR2/6 agonists, Frontiers in Immunology, Vol: 11, Pages: 1-27, ISSN: 1664-3224
Background: Infection/inflammation is an important causal factor in spontaneous preterm birth (sPTB). Most mechanistic studies have concentrated on the role of bacteria, with limited focus on the role of viruses in sPTB. Murine studies support a potential multi-pathogen aetiology in which a double or sequential hit of both viral and bacterial pathogens leads to a higher risk preterm labour. This study aimed to determine the effect of viral priming on bacterial induced inflammation in human in vitro models of ascending and haematogenous infection.Methods: Vaginal epithelial cells, and primary amnion epithelial cells and myocytes were used to represent cell targets of ascending infection while interactions between peripheral blood mononuclear cells (PBMCs) and placental explants were used to model systemic infection. To model the effect of viral priming upon the subsequent response to bacterial stimuli, each cell type was stimulated first with a TLR3 viral agonist, and then with either a TLR2 or TLR2/6 agonist, and responses compared to those of each agonist alone. Immunoblotting was used to detect cellular NF-κB, AP-1, and IRF-3 activation. Cellular TLR3, TLR2, and TLR6 mRNA was quantified by RT-qPCR. Immunoassays were used to measure supernatant cytokine, chemokine and PGE2 concentrations.Results: TLR3 (“viral”) priming prior to TLR2/6 agonist (“bacterial”) exposure augmented the pro-inflammatory, pro-labour response in VECs, AECs, myocytes and PBMCs when compared to the effects of agonists alone. In contrast, enhanced anti-inflammatory cytokine production (IL-10) was observed in placental explants. Culturing placental explants in conditioned media derived from PBMCs primed with a TLR3 agonist enhanced TLR2/6 agonist stimulated production of IL-6 and IL-8, suggesting a differential response by the placenta to systemic inflammation compared to direct infection as a result of haematogenous spread. TLR3 agonism generally caused increased m
Shennan A, Chandiramani M, Bennett P, et al., 2020, MAVRIC: A Multicenter Randomized Controlled Trial of Transabdominal vs Transvaginal Cervical Cerclage, Obstetrical and Gynecological Survey, Vol: 75, Pages: 392-394, ISSN: 0029-7828
Womenwho experience multiple late miscarriages or spontaneous pretermbirths may be candidates for vaginal cerclage. In women with a history of pregnancy loss with vaginal cerclage, observational studies have suggested that transabdominal cerclage (TAC) may be beneficial over high vaginal cerclage (HVC) and low vaginal cerclage (LVC). However, TAC has not been evaluated in a randomized clinical trial. The aim of this study was to determine if TAC or HVC would result in lower rates of late miscarriage or preterm births compared with LVC in women with a history of pregnancy loss. The Multicentre Abdominal vs Vaginal Randomized Intervention of Cerclage trial was a multicenter randomized clinical trial involving 9 hospitals across the United Kingdom. Women were recruited between January 2008 and September 2014. Eligibility for the study included a history of spontaneous late miscarriage or preterm birth between 14 and 28 weeks of pregnancy with a previous failed cerclage. Women requiring rescue cerclage procedures were excluded.
Kyriacou C, Kim SH, Bobdiwala S, et al., 2020, The assessment of microRNA expression in pregnancies classified as a pregnancy of unknown location, Publisher: WILEY, Pages: E63-E63, ISSN: 1470-0328
Devall AJ, Gallos ID, Khalaf Y, et al., 2020, Re: Effect of progestogen for women with threatened miscarriage: a systematic review and meta-analysis, BJOG: an International Journal of Obstetrics and Gynaecology, Vol: 127, Pages: 1303-1304, ISSN: 1470-0328
Mitra A, MacIntyre D, Ntritsos G, et al., 2020, The vaginal microbiota associates with the regression of untreated cervical intraepithelial neoplasia 2 lesions, Nature Communications, Vol: 11, Pages: 1-13, ISSN: 2041-1723
Emerging evidence suggests associations between the vaginal microbiota (VMB) composition, human papillomavirus (HPV) infection, and cervical intraepithelial neoplasia (CIN); however, causal inference remains uncertain. Here, we use bacterial DNA sequencing from serially collected vaginal samples from a cohort of 87 adolescent and young women aged 16–26 years with histologically confirmed, untreated CIN2 lesions to determine whether VMB composition affects rates of regression over 24 months. We show that women with a Lactobacillus-dominant microbiome at baseline are more likely to have regressive disease at 12 months. Lactobacillus spp. depletion and presence of specific anaerobic taxa including Megasphaera, Prevotella timonensis and Gardnerella vaginalis are associated with CIN2 persistence and slower regression. These findings suggest that VMB composition may be a future useful biomarker in predicting disease outcome and tailoring surveillance, whilst it may offer rational targets for the development of new prevention and treatment strategies.
Al-Memar M, Vaulet T, Fourie H, et al., 2020, Intrauterine haematomas in the first trimester and pregnancy complications, Ultrasound in Obstetrics and Gynecology, Vol: 55, Pages: 536-545, ISSN: 0960-7692
OBJECTIVES: The role of intrauterine haematoma on pregnancy outcomes remains uncertain. Some studies report an association with miscarriage, whilst others refute this. The impact on long-term outcomes is not known. We aimed to assess if intrauterine haematomas detected using ultrasonography in the first trimester are associated with adverse pregnancy outcomes. METHODS: A prospective observational cohort study at Queen Charlotte's & Chelsea Hospital, London, was conducted between March 2014 and March 2016. Participants with intrauterine pregnancies were recruited and underwent serial ultrasound scans in the first trimester. Clinical symptoms, including pelvic pain and vaginal bleeding were recorded using validated symptom scores at each visit. The presence, location and size of any intrauterine haematoma seen on ultrasonography was noted. Pregnancy outcomes were obtained from hospital records. RESULTS: Of 1003 recruited participants, 268 had an intrauterine haematoma (27%). The presence of intrauterine haematoma in the first trimester was associated with preterm birth (OR 1.94; 95% CI 1.07-3.53). No association was found with miscarriage (OR 0.916; 95% CI 0.571-1.471). This was irrespective of the absolute size of the haematoma or the presence or absence of vaginal bleeding and pelvic pain. A retroplacental haematoma was associated with an increase in overall antenatal complications (P = 0.0395). CONCLUSIONS: Our data demonstrates no association between the presence of intrauterine haematoma in the first trimester and first trimester miscarriage. However, a relationship with preterm birth independent of the presence of symptoms of pain and bleeding is evident. These women should be counseled about their increased risk of preterm birth and possibly be offered increased surveillance during their pregnancies. This article is protected by copyright. All rights reserved.
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