Publications by authors named "Phillip Bennett"

131 Publications

Proteome-wide prediction of bacterial carbohydrate-binding proteins as a tool for understanding commensal and pathogen colonisation of the vaginal microbiome.

NPJ Biofilms Microbiomes 2021 06 15;7(1):49. Epub 2021 Jun 15.

University Grenoble Alpes, CNRS, CERMAV, Grenoble, France.

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.
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http://dx.doi.org/10.1038/s41522-021-00220-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206207PMC
June 2021

The association between obesity and weight loss after bariatric surgery on the vaginal microbiota.

Microbiome 2021 05 28;9(1):124. Epub 2021 May 28.

IRDB, Department of Metabolism, Digestion and Reproduction - Surgery and Cancer, Hammersmith Campus, Imperial College London, W12 0NN, London, UK.

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 6 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 weight loss 6-month post-surgery are most likely to have a Lactobacillus-dominant VMB. Video abstract.
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http://dx.doi.org/10.1186/s40168-021-01011-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164250PMC
May 2021

Recurrent miscarriage: evidence to accelerate action.

Lancet 2021 May 27;397(10285):1675-1682. Epub 2021 Apr 27.

Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Warwick, UK; Tommy's National Centre for Miscarriage Research, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK.

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.
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http://dx.doi.org/10.1016/S0140-6736(21)00681-4DOI Listing
May 2021

Sporadic miscarriage: evidence to provide effective care.

Lancet 2021 May 27;397(10285):1668-1674. Epub 2021 Apr 27.

Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Warwick, UK; Tommy's National Centre for Miscarriage Research, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK.

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.
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http://dx.doi.org/10.1016/S0140-6736(21)00683-8DOI Listing
May 2021

Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss.

Lancet 2021 05 27;397(10285):1658-1667. Epub 2021 Apr 27.

Tommy's National Centre for Miscarriage Research, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK.

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 to be available. We recommend that miscarriage data are gathered and reported to facilitate comparison of rates among countries, to accelerate research, and to improve patient care and policy development.
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http://dx.doi.org/10.1016/S0140-6736(21)00682-6DOI Listing
May 2021

Genome-Wide Association Study Identifies Two Novel Loci Associated with Female Stress and Urgency Urinary Incontinence.

J Urol 2021 Apr 27:101097JU0000000000001822. Epub 2021 Apr 27.

Institute for Reproductive and Developmental Biology, Imperial College London, UK.

Purpose: Genome-wide association studies have not identified replicable genetic risk loci for stress or urgency urinary incontinence.

Materials And Methods: We carried out a discovery stage, case control, genome-wide association study in 3 independent discovery cohorts of European women (8,979) for stress incontinence, urgency incontinence, and any incontinence phenotypes. We conducted replication in 6 additional studies of European ancestry (4,069). We collected bladder biopsies from women with incontinence to further investigate bladder expression of implicated genes and pathways (50) and used symptom questionnaires for phenotyping. We conducted meta-analyses using inverse variance fixed effects models in METAL (http://www.sph.umich.edu/csg/abecasis/metal/), and whole transcriptome analyses using Affymetrix® arrays with replication with TaqMan® polymerase chain reaction.

Results: In the discovery stage, we identified 16 single nucleotide polymorphisms genotyped or imputed at 5 loci that reached genome-wide significance (p <5×10). In replication, rs138724718 on chromosome 2 near the macrophage receptor with collagenous structure () gene (replication p=0.003) was associated with stress incontinence. In addition, rs34998271 on chromosome 6 near the endothelin 1 () gene (replication p=0.0008) was associated with urgency incontinence. In combined meta-analyses of discovery and replication cohorts, associations with genome-wide significance for these 2 single nucleotide polymorphisms were confirmed. Transcriptomics analyses showed differential expression of 7 of 19 genes in the endothelin pathway between stress and urgency incontinence (p <0.0001).

Conclusions: We uncovered 2 new risk loci near the genes endothelin 1 (), associated with urgency incontinence, and macrophage receptor with collagenous structure (), associated with stress incontinence. These loci are biologically plausible given their roles in smooth muscle contraction and innate host defense, respectively.
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http://dx.doi.org/10.1097/JU.0000000000001822DOI Listing
April 2021

Genetic variation in cervical preinvasive and invasive disease: a genome-wide association study.

Lancet Oncol 2021 04;22(4):548-557

Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK; Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK; West London Gynaecological Cancer Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK. Electronic address:

Background: Most uterine cervical high-risk human papillomavirus (HPV) infections are transient, with only a small fraction developing into cervical cancer. Family aggregation studies and heritability estimates suggest a significant inherited genetic component. Candidate gene studies and previous genome-wide association studies (GWASs) report associations between the HLA region and cervical cancer. Adopting a genome-wide approach, we aimed to compare genetic variation in women with invasive cervical cancer and cervical intraepithelial neoplasia (CIN) grade 3 with that in healthy controls.

Methods: We did a GWAS in a cohort of unrelated European individuals using data from UK Biobank, a population-based cohort including 273 377 women aged 40-69 years at recruitment between March 13, 2006, and Oct 1, 2010. We used an additive univariate logistic regression model to analyse genetic variants associated with invasive cervical cancer or CIN3. We sought replication of candidate associations in FinnGen, a large independent dataset of 128 123 individuals. We also did a two-sample mendelian randomisation approach to explore the role of risk factors in the genetic risk of cervical cancer.

Findings: We included 4769 CIN3 and invasive cervical cancer case samples and 145 545 control samples in the GWAS. Of 9 600 464 assayed and imputed single-nucleotide polymorphisms (SNPs), six independent variants were associated with CIN3 and invasive cervical cancer. These included novel loci rs10175462 (PAX8; odds ratio [OR] 0·87, 95% CI 0·84-0·91; p=1·07 × 10) and rs27069 (CLPTM1L; 0·88, 0·84-0·92; p=2·51 × 10), and previously reported signals at rs9272050 (HLA-DQA1; 1·27, 1·21-1·32; p=2·51 × 10), rs6938453 (MICA; 0·79, 0·75-0·83; p=1·97 × 10), rs55986091 (HLA-DQB1; 0·66, 0·60-0·72; p=6·42 × 10), and rs9266183 (HLA-B; 0·73, 0·64-0·83; p=1·53 × 10). Three SNPs were replicated in the independent Finnish dataset of 1648 invasive cervical cancer cases: PAX8 (rs10175462; p=0·015), CLPTM1L (rs27069; p=2·54 × 10), and HLA-DQA1 (rs9272050; p=7·90 × 10). Mendelian randomisation further supported the complementary role of smoking (OR 2·46, 95% CI 1·64-3·69), older age at first pregnancy (0·80, 0·68-0·95), and number of sexual partners (1·95, 1·44-2·63) in the risk of developing cervical cancer.

Interpretation: Our results provide new evidence for the genetic susceptibility to cervical cancer, specifically the PAX8, CLPTM1L, and HLA genes, suggesting disruption in apoptotic and immune function pathways. Future studies integrating host and viral, genetic, and epigenetic variation, could further elucidate complex host-viral interactions.

Funding: NIHR Imperial BRC Wellcome 4i Clinician Scientist Training Programme.
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http://dx.doi.org/10.1016/S1470-2045(21)00028-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8008734PMC
April 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 Med 2021 03 29;18(3):e1003506. Epub 2021 Mar 29.

Multiple Births Foundation, London, United Kingdom.

Background: Preterm-labour-associated preterm birth is a common cause of perinatal mortality and morbidity in twin pregnancy. We aimed to test the hypothesis that the Arabin pessary would reduce preterm-labour-associated preterm birth by 40% or greater in women with a twin pregnancy and a short cervix.

Methods And Findings: We conducted an open-label randomised controlled trial in 57 hospital antenatal clinics in the UK and Europe. From 1 April 2015 to 14 February 2019, 2,228 women with a twin pregnancy underwent cervical length screening between 18 weeks 0 days and 20 weeks 6 days of gestation. In total, 503 women with cervical length ≤ 35 mm were randomly assigned to pessary in addition to standard care (n = 250, mean age 32.4 years, mean cervical length 29 mm, with pessary inserted in 230 women [92.0%]) or standard care alone (n = 253, mean age 32.7 years, mean cervical length 30 mm). The pessary was inserted before 21 completed weeks of gestation and removed at between 35 and 36 weeks or before birth if earlier. The primary obstetric outcome, spontaneous onset of labour and birth before 34 weeks 0 days of gestation, was present in 46/250 (18.4%) in the pessary group compared to 52/253 (20.6%) following standard care alone (adjusted odds ratio [aOR] 0.87 [95% CI 0.55-1.38], p = 0.54). The primary neonatal outcome-a composite of any of stillbirth, neonatal death, periventricular leukomalacia, early respiratory morbidity, intraventricular haemorrhage, necrotising enterocolitis, or proven sepsis, from birth to 28 days after the expected date of delivery-was present in 67/500 infants (13.4%) in the pessary group compared to 76/506 (15.0%) following standard care alone (aOR 0.86 [95% CI 0.54-1.36], p = 0.50). The positive and negative likelihood ratios of a short cervix (≤35 mm) to predict preterm birth before 34 weeks were 2.14 and 0.83, respectively. A meta-analysis of data from existing publications (4 studies, 313 women) and from STOPPIT-2 indicated that a cervical pessary does not reduce preterm birth before 34 weeks in women with a short cervix (risk ratio 0.74 [95% CI 0.50-1.11], p = 0.15). No women died in either arm of the study; 4.4% of babies in the Arabin pessary group and 5.5% of babies in the standard treatment group died in utero or in the neonatal period (p = 0.53). Study limitations include lack of power to exclude a smaller than 40% reduction in preterm labour associated preterm birth, and to be conclusive about subgroup analyses.

Conclusions: These results led us to reject our hypothesis that the Arabin pessary would reduce the risk of the primary outcome by 40%. Smaller treatment effects cannot be ruled out.

Trial Registration: ISRCTN Registry ISRCTN 02235181. ClinicalTrials.gov NCT02235181.
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http://dx.doi.org/10.1371/journal.pmed.1003506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041194PMC
March 2021

-Depleted Vaginal Microbiota in Pregnant Women Living With HIV-1 Infection Are Associated With Increased Local Inflammation and Preterm Birth.

Front Cell Infect Microbiol 2020 11;10:596917. Epub 2021 Feb 11.

Department of Metabolism, Digestion, and Reproduction, March of Dimes Prematurity Research Centre, Division of the Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London, United Kingdom.

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 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 dominant vaginal microbiota group (VMB I, 15 vs 54%) than HUPW and higher prevalence of 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.
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http://dx.doi.org/10.3389/fcimb.2020.596917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905210PMC
June 2021

Rapid quality improvement in a preterm birth clinic care pathway during the COVID-19 pandemic.

BMJ Open Qual 2020 12;9(4)

Imperial College Healthcare NHS Trust, London, UK

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.
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http://dx.doi.org/10.1136/bmjoq-2020-001049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771216PMC
December 2020

Maternal plasma miRNAs as potential biomarkers for detecting risk of small-for-gestational-age births.

EBioMedicine 2020 Dec 28;62:103145. Epub 2020 Nov 28.

Parturition Group, Department of Metabolism, Digestion and Reproduction, Imperial College London, Institute of Reproductive and Developmental Biology, Du Cane Road, London W12 0NN, United Kingdom; March of Dimes European Preterm Birth Research Centre, Imperial College London, United Kingdom; Queen Charlotte's and Chelsea Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom; Academic Department of Obstetrics and Gynaecology, Chelsea and Westminster Hospital, London, United Kingdom. Electronic address:

Background: Small-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.

Methods: Maternal 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.

Findings: Partial least-squares discriminant analysis (PLS-DA) of the Nanostring nCounter miRNA assay initially identified seven miRNAs at 12-14 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.

Interpretation: Whilst 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.

Funding: This work was supported by Genesis Research Trust, March of Dimes, and the National Institute for Health Research Biomedical Research Centre (NIHR BRC) based at Imperial Healthcare NHS Trust and Imperial College London.
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http://dx.doi.org/10.1016/j.ebiom.2020.103145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708817PMC
December 2020

Vaginal Microbiome in Preterm Rupture of Membranes.

Obstet Gynecol Clin North Am 2020 Dec;47(4):503-521

Institute for Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London W12 0NN, UK; March of Dimes European Prematurity Research Centre, Imperial College London W12 0NN, UK. Electronic address:

There is an association between vaginal microbiota dysbiosis and preterm premature rupture of membranes (PPROM). In PPROM, reduced Lactobacillus spp abundance is linked to the emergence of high-risk vaginal microbiota, close to the time of membrane rupture. Although PPROM itself can change vaginal microbial composition, antibiotic therapy profoundly effects community structure. Erythromycin may have a beneficial effect in women deplete in Lactobacillus spp but damages a healthy microbiome by targeting Lactobacillus spp. Increased rates of chorioamnionitis and early-onset neonatal sepsis are associated with vaginal microbiota dysbiosis close to the time of delivery.
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http://dx.doi.org/10.1016/j.ogc.2020.08.001DOI Listing
December 2020

Differential Response of Gestational Tissues to TLR3 Viral Priming Prior to Exposure to Bacterial TLR2 and TLR2/6 Agonists.

Front Immunol 2020 25;11:1899. Epub 2020 Aug 25.

Imperial College Parturition Research Group, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom.

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 models of ascending and haematogenous infection. 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. 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 mRNA expression of TLR3 and TLR2 but not TLR6. This study provides human evidence that viral infection may increase the susceptibility of women to bacterial-induced sPTB. Improved understanding of interactions between viral and bacterial components of the maternal microbiome and host immune response may offer new therapeutic options, such as antivirals for the prevention of PTB.
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http://dx.doi.org/10.3389/fimmu.2020.01899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477080PMC
April 2021

Laser-assisted rapid evaporative ionisation mass spectrometry (LA-REIMS) as a metabolomics platform in cervical cancer screening.

EBioMedicine 2020 Oct 25;60:103017. Epub 2020 Sep 25.

Department of Metabolism, Digestion and Reproduction & Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, 665 Sir Alexander Fleming Building, South Kensington Campus, London W12 0NN, United Kingdom; Imperial College Healthcare NHS Trust, London, United Kingdom. Electronic address:

Background: The 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.

Methods: In 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.

Findings: In 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.

Interpretation: This 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.

Funding: Work was funded by the MRC Imperial Confidence in Concept Scheme, Imperial College Healthcare Charity, British Society for Colposcopy and Cervical Pathology, National Research Development and Innovation Office of Hungary, Waters corporation and NIHR BRC.
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http://dx.doi.org/10.1016/j.ebiom.2020.103017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522750PMC
October 2020

The pregnancy microbiome and preterm birth.

Semin Immunopathol 2020 08 14;42(4):487-499. Epub 2020 Aug 14.

Imperial College Parturition Research Group, Institute for Reproductive and Developmental Biology, Imperial College London, Du Cane Road, London, W12 0HS, UK.

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.
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http://dx.doi.org/10.1007/s00281-020-00817-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508933PMC
August 2020

The vaginal microbiota associates with the regression of untreated cervical intraepithelial neoplasia 2 lesions.

Nat Commun 2020 04 24;11(1):1999. Epub 2020 Apr 24.

Institute for Reproductive and Developmental Biology, Imperial College, Hammersmith Hospital Campus, London, W12 0NN, UK.

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.
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http://dx.doi.org/10.1038/s41467-020-15856-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181700PMC
April 2020

The intelligent knife (iKnife) and its intraoperative diagnostic advantage for the treatment of cervical disease.

Proc Natl Acad Sci U S A 2020 03 16;117(13):7338-7346. Epub 2020 Mar 16.

Department of Gut, Metabolism and Reproduction, Institute of Reproductive and Developmental Biology, Faculty of Medicine, Imperial College London, London SW7 2DD, United Kingdom;

Clearance of surgical margins in cervical cancer prevents the need for adjuvant chemoradiation and allows fertility preservation. In this study, we determined the capacity of the rapid evaporative ionization mass spectrometry (REIMS), also known as intelligent knife (iKnife), to discriminate between healthy, preinvasive, and invasive cervical tissue. Cervical tissue samples were collected from women with healthy, human papilloma virus (HPV) ± cervical intraepithelial neoplasia (CIN), or cervical cancer. A handheld diathermy device generated surgical aerosol, which was transferred into a mass spectrometer for subsequent chemical analysis. Combination of principal component and linear discriminant analysis and least absolute shrinkage and selection operator was employed to study the spectral differences between groups. Significance of discriminatory features was tested using univariate statistics and tandem MS performed to elucidate the structure of the significant peaks allowing separation of the two classes. We analyzed 87 samples (normal = 16, HPV ± CIN = 50, cancer = 21 patients). The iKnife discriminated with 100% accuracy normal (100%) vs. HPV ± CIN (100%) vs. cancer (100%) when compared to histology as the gold standard. When comparing normal vs. cancer samples, the accuracy was 100% with a sensitivity of 100% (95% CI 83.9 to 100) and specificity 100% (79.4 to 100). Univariate analysis revealed significant MS peaks in the cancer-to-normal separation belonging to various classes of complex lipids. The iKnife discriminates healthy from premalignant and invasive cervical lesions with high accuracy and can improve oncological outcomes and fertility preservation of women treated surgically for cervical cancer. Larger in vivo research cohorts are required to validate these findings.
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http://dx.doi.org/10.1073/pnas.1916960117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132269PMC
March 2020

Peri-implantation urinary hormone monitoring distinguishes between types of first-trimester spontaneous pregnancy loss.

Paediatr Perinat Epidemiol 2020 09 13;34(5):495-503. Epub 2020 Feb 13.

Institute for Reproductive and Developmental Biology, Imperial College, London, UK.

Background: Lutenising 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.

Objective: To 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.

Methods: We 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.

Results: From 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.

Conclusions: The 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.
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http://dx.doi.org/10.1111/ppe.12613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496486PMC
September 2020

Correction: Oligonucleotide-templated lateral flow assays for amplification-free sensing of circulating microRNAs.

Chem Commun (Camb) 2019 11 24;55(89):13470. Epub 2019 Oct 24.

Department of Bioengineering, Imperial College London, South Kensington Campus, London SW7 2AZ, UK. and March of Dimes European Preterm Birth Research Centre, Imperial College London, London, UK.

Correction for 'Oligonucleotide-templated lateral flow assays for amplification-free sensing of circulating microRNAs' by Suraj Pavagada et al., Chem. Commun., 2019, 55, 12451-12454.
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http://dx.doi.org/10.1039/c9cc90472gDOI Listing
November 2019

MAVRIC: a multicenter randomized controlled trial of transabdominal vs transvaginal cervical cerclage.

Am J Obstet Gynecol 2020 03 1;222(3):261.e1-261.e9. Epub 2019 Oct 1.

Department of Women and Children's Health, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.

Background: Vaginal cerclage (a suture around the cervix) commonly is placed in women with recurrent pregnancy loss. These women may experience late miscarriage or extreme preterm delivery, despite being treated with cerclage. Transabdominal cerclage has been advocated after failed cerclage, although its efficacy is unproved by randomized controlled trial.

Objective: The objective of this study was to compare transabdominal cerclage or high vaginal cerclage with low vaginal cerclage in women with a history of failed cerclage. Our primary outcome was delivery at <32 completed weeks of pregnancy.

Study Design: This was a multicenter randomized controlled trial. Women were assigned randomly (1:1:1) to receive transabdominal cerclage, high vaginal cerclage, or low vaginal cerclage either before conception or at <14 weeks of gestation.

Results: The data for 111 of 139 women who were recruited and who conceived were analyzed: 39 had transabdominal cerclage; 39 had high vaginal cerclage, and 33 had low vaginal cerclage. Rates of preterm birth at <32 weeks of gestation were significantly lower in women who received transabdominal cerclage compared with low vaginal cerclage (8% [3/39] vs 33% [11/33]; relative risk, 0.23; 95% confidence interval, 0.07-0.76; P=.0157). The number needed to treat to prevent 1 preterm birth was 3.9 (95% confidence interval, 2.32-12.1). There was no difference in preterm birth rates between high and low vaginal cerclage (38% [15/39] vs 33% [11/33]; relative risk, 1.15; 95% confidence interval, 0.62-2.16; P=.81). No neonatal deaths occurred. In an exploratory analysis, women with transabdominal cerclage had fewer fetal losses compared with low vaginal cerclage (3% [1/39] vs 21% [7/33]; relative risk, 0.12; 95% confidence interval, 0.016-0.93; P=.02). The number needed to treat to prevent 1 fetal loss was 5.3 (95% confidence interval, 2.9-26).

Conclusion: Transabdominal cerclage is the treatment of choice for women with failed vaginal cerclage. It is superior to low vaginal cerclage in the reduction of risk of early preterm birth and fetal loss in women with previous failed vaginal cerclage. High vaginal cerclage does not confer this benefit. The numbers needed to treat are sufficiently low to justify transabdominal surgery and cesarean delivery required in this select cohort.
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http://dx.doi.org/10.1016/j.ajog.2019.09.040DOI Listing
March 2020

Oligonucleotide-templated lateral flow assays for amplification-free sensing of circulating microRNAs.

Chem Commun (Camb) 2019 Oct;55(83):12451-12454

Department of Bioengineering, Imperial College London, South Kensington Campus, London SW7 2AZ, UK. and March of Dimes European Preterm Birth Research Centre, Imperial College London, London, UK.

Herein we demonstrate the first example of oligonucleotide-templated reaction (OTR) performed on paper, using lateral flow to capture and concentrate specific nucleic acid biomarkers on a test line. Quantitative analysis, using a low-cost benchtop fluorescence reader showed very high specificity down to the single nucleotide level and proved sensitive enough for amplification-free, on-chip, detection of endogenous concentrations of miR-150-5p, a recently identified predictive blood biomarker for preterm birth.
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http://dx.doi.org/10.1039/c9cc05607fDOI Listing
October 2019

High rates of maternal depression amongst Syrian refugees in Lebanon - a pilot study.

Sci Rep 2019 08 14;9(1):11849. Epub 2019 Aug 14.

University of Edinburgh, Centre for Cardiovascular Science, Queen's Medical Research Centre, 47 Little France Crescent, Edinburgh, Scotland, EH16 4TJ, UK.

This pilot study compares symptoms of depression and risk factors amongst Syrian refugees and low-income Lebanese mothers accessing a primary care centre in Beirut between January and June 2018. Women who gave birth in the previous two years or who were currently pregnant were included in the study. Depressive symptoms were assessed using the Arabic Edinburgh Postnatal Depression Scale (EPDS). Correlations between EPDS score and sociodemographic and mental health variables were analysed using Pearson's coefficient and ANOVA. 35 Syrian and 25 Lebanese women were recruited, 15 of whom were pregnant. EPDS scores were high in the whole group (mean 16.12 (SD 7.72), n = 60). Scores were higher amongst Syrian refugees than Lebanese mothers (17.77, SD 7.66 vs, 13.80, SD 7.34, p < 0.05). Illegal residence (p < 0.001), domestic violence (p < 0.05) and a history of mental illness (p < 0.01) were associated with higher scores. This pilot study demonstrates high rates of symptoms of depression amongst mothers in this population. Symptoms were particularly prevalent amongst Syrian refugees; three-quarters were 'probably depressed' and would warrant psychiatric assessment. This highlights the importance of improved mental healthcare for refugee mothers, the importance of addressing the social determinants of maternal mental health and further research into the effects of depression on these women and their children.
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http://dx.doi.org/10.1038/s41598-019-48247-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694169PMC
August 2019

Reducing the impact of preterm birth: Preterm birth commissioning in the United Kingdom.

Eur J Obstet Gynecol Reprod Biol X 2019 Jul 21;3:100018. Epub 2019 Apr 21.

Department of Women and Children's Health, School of Life Courses Sciences, King's College London, St Thomas' Hospital, London, SE1 7EH, United Kingdom.

Reducing preterm birth is a priority for Maternity and Children's services. In the recent UK Department of Health publication 'Safer Maternity Care' the Secretary of State for Health aimed to achieve the national maternity safety ambition by pledging to reduce the rate of preterm birth from 8% to 6%. It was proposed that specialist preterm birth services should be established in the UK in order to achieve this aim. In response the Preterm Clinical Network has written Commissioning Guidance aimed to establish best practice pathways and agreed models of care to reduce variation nationally. They have been developed by clinical experts in the field, from within the UK, to provide recommendations for commissioning groups and to recommend pathways to organisations with the aim of reducing the incidence of preterm birth. Three key areas of care provision are focused on: prediction, prevention and preparation of women at high risk of PTB. This Expert Opinion, will summarise the Commissioning Guidance.
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http://dx.doi.org/10.1016/j.eurox.2019.100018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687377PMC
July 2019

Discovery of a CD10-negative B-progenitor in human fetal life identifies unique ontogeny-related developmental programs.

Blood 2019 09 5;134(13):1059-1071. Epub 2019 Aug 5.

Department of Paediatrics and.

Human lymphopoiesis is a dynamic lifelong process that starts in utero 6 weeks postconception. Although fetal B-lymphopoiesis remains poorly defined, it is key to understanding leukemia initiation in early life. Here, we provide a comprehensive analysis of the human fetal B-cell developmental hierarchy. We report the presence in fetal tissues of 2 distinct CD19 B-progenitors, an adult-type CD10+ve ProB-progenitor and a new CD10-ve PreProB-progenitor, and describe their molecular and functional characteristics. PreProB-progenitors and ProB-progenitors appear early in the first trimester in embryonic liver, followed by a sustained second wave of B-progenitor development in fetal bone marrow (BM), where together they form >40% of the total hematopoietic stem cell/progenitor pool. Almost one-third of fetal B-progenitors are CD10-ve PreProB-progenitors, whereas, by contrast, PreProB-progenitors are almost undetectable (0.53% ± 0.24%) in adult BM. Single-cell transcriptomics and functional assays place fetal PreProB-progenitors upstream of ProB-progenitors, identifying them as the first B-lymphoid-restricted progenitor in human fetal life. Although fetal BM PreProB-progenitors and ProB-progenitors both give rise solely to B-lineage cells, they are transcriptionally distinct. As with their fetal counterparts, adult BM PreProB-progenitors give rise only to B-lineage cells in vitro and express the expected B-lineage gene expression program. However, fetal PreProB-progenitors display a distinct, ontogeny-related gene expression pattern that is not seen in adult PreProB-progenitors, and they share transcriptomic signatures with CD10-ve B-progenitor infant acute lymphoblastic leukemia blast cells. These data identify PreProB-progenitors as the earliest B-lymphoid-restricted progenitor in human fetal life and suggest that this fetal-restricted committed B-progenitor might provide a permissive cellular context for prenatal B-progenitor leukemia initiation.
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http://dx.doi.org/10.1182/blood.2019001289DOI Listing
September 2019

Erratum to "Proportion of cervical excision for cervical intraepithelial neoplasia as a predictor of pregnancy outcomes"[Int J Gynecol Obstet 128(2015) 141-147].

Int J Gynaecol Obstet 2019 Sep 19;146(3):392. Epub 2019 Jul 19.

Department of Obstetrics and Gynecology-Gynecological Oncology, University Hospital of Ioannina, Ioannina, Greece.

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http://dx.doi.org/10.1002/ijgo.12905DOI Listing
September 2019

Cervical length and quantitative fetal fibronectin in the prediction of spontaneous preterm birth in asymptomatic women with congenital uterine anomaly.

Am J Obstet Gynecol 2019 10 24;221(4):341.e1-341.e9. Epub 2019 May 24.

UCL EGA Institute for Women's Health, University College London, London, UK.

Background: Congenital uterine anomalies are associated with late miscarriage and spontaneous preterm birth.

Objective: Our aim was 1) to determine the rate of spontaneous preterm birth in each type of congenital uterine anomaly, and 2) to assess the performance of quantitative fetal fibronectin and cervical length measurement by transvaginal ultrasound in asymptomatic women with congenital uterine anomalies for the prediction of spontaneous preterm birth at <34 and <37 weeks of gestation.

Materials And Methods: This was a retrospective cohort of women with congenital uterine anomalies asymptomatic for spontaneous preterm birth, from 4 tertiary referral centers in the United Kingdom (2001-2016). Congenital uterine anomalies were categorized into fusion (unicornuate, didelphic, and bicornuate uteri) or resorption defects (septate, with or without resection, and arcuate uteri), based on prepregnancy diagnosis. All women underwent serial transvaginal ultrasound cervical length assessment in the second trimester (16 to 24 weeks' gestation); a subgroup underwent quantitative fetal fibronectin testing from 18 weeks' gestation. We investigated the relationship between congenital uterine anomalies and predictive test performance for spontaneous preterm birth at <34 and <37 weeks' gestation.

Results: A total of 319 women were identified as having congenital uterine anomalies in our high-risk population. Of the women, 7% (23/319) delivered spontaneously at <34 weeks' gestation and 18% (56/319) at <37 weeks' gestation. Rates of spontaneous preterm birth by type were as follows: 26% (7/27) for unicornuate, 21% (7/34) for didelphic, 16% (31/189) for bicornuate, 13% (7/56) for septate, and 31% (4/13) for arcuate. In all, 80% (45/56) of women who had spontaneous preterm birth at <37 weeks did not develop a short cervical length (<25 mm) during the surveillance period (16-24 weeks). The diagnostic accuracy of short cervical length had a low sensitivity (20.3) for predicting spontaneous preterm birth at <34 weeks. Cervical length had an area under the receiver operating curve of 0.56 (95% confidence interval, 0.48-0.64) and 0.59 (95% confidence interval, 0.55-0.64) for prediction of spontaneous preterm birth at <34 and <37 weeks, respectively. The area under the curve for cervical length to predict spontaneous preterm birth at <34 weeks was 0.48 for fusion defects (95% confidence interval, 0.39-0.57) but 0.78 (95% confidence interval, 0.66-0.91) for women with resorption defects. Overall quantitative fetal fibronectin had an area under the curve of 0.63 (95% confidence interval, 0.49-0.77) and 0.58 (95% confidence interval, 0.49- 0.68) for prediction of spontaneous preterm birth at <34 and <37 weeks, respectively. The area under the curve for prediction of spontaneous preterm birth at <37 weeks with quantitative fetal fibronectin for fusion defects was 0.52 (95% confidence interval, 0.41-0.63) but 0.79 (95% confidence interval, 0.63-0.95) for women with resorption defects. Results were similar when women with intervention were excluded.

Conclusion: The commonly used markers cervical length and quantitative fetal fibronectin have utility in prediction of spontaneous preterm birth in resorption congenital uterine defects but not in fusion defects. This is contrary to findings in other high-risk populations. These findings need to be accounted for when planning antenatal care, and have potential implications for predictive tests used in spontaneous preterm birth surveillance and intervention.
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http://dx.doi.org/10.1016/j.ajog.2019.05.032DOI Listing
October 2019

First Trimester Circulating MicroRNA Biomarkers Predictive of Subsequent Preterm Delivery and Cervical Shortening.

Sci Rep 2019 04 10;9(1):5861. Epub 2019 Apr 10.

Parturition Research Group, Institute of Reproductive and Developmental Biology, Imperial College London, Du Cane Road, London, W12 0NN, UK.

Preterm birth (PTB) is the leading cause of infant death and disability worldwide. The onset of preterm uterine contractions is preceded by asymptomatic cervical remodelling and ripening, which can be seen on trans-vaginal ultrasound as cervical shortening. This study aimed to identify plasma miRNA biomarkers that predict preterm birth and/or cervical shortening. We collected serial plasma samples from pregnant women prospectively from 12 to 22 weeks gestation. The nCounter miRNA assay was used to identify differentially expressed miRNAs associated with spontaneous PTB and/or cervical shortening (n = 16 term no short, n = 13 preterm, n = 24 short). Predictive values of the miRNA biomarkers were confirmed in an independent validation cohort consisting of 96 women who delivered at term, 14 preterm and 21 early cervical shortening at <20 weeks gestation. Nine miRNAs (hsa-let-7a-5p, hsa-miR-374a-5p, hsa-miR-15b-5p, hsa-miR-19b-3p, hsa-miR-23a-3p, hsa-miR-93-5p, hsa-miR-150-5p, hsa-miR-185-5p and hsa-miR-191-5p) were differentially expressed (P < 0.001) in women subsequently experiencing PTB or cervical shortening. Hsa-miR-150-5p had the strongest ability to predict PTB (AUC = 0.8725) and cervical shortening (AUC = 0.8514). Plasma miRNAs in the first trimester can predict PTB and cervical shortening in women at risk of preterm delivery. This is a key period in pregnancy when early identification of PTB risk allows time to deliver outcome-modifying interventions.
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http://dx.doi.org/10.1038/s41598-019-42166-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458157PMC
April 2019

Oxytocin Receptor Antagonists, Atosiban and Nolasiban, Inhibit Prostaglandin F-induced Contractions and Inflammatory Responses in Human Myometrium.

Sci Rep 2019 04 8;9(1):5792. Epub 2019 Apr 8.

Imperial College London, Parturition Research Group, IRDB, Du Cane Road, London, W12 0NN, UK.

Oxytocin receptor antagonists (OTR-A) have been developed as tocolytics for the management of preterm labour due to the significant role of oxytocin (OT) in the onset of both term and preterm labour. Similar to OT, prostaglandins (PGs) play key roles in myometrial contractility and cervical ripening. Inhibition of PG synthesis/activity is used to delay preterm birth. Thus, targeting the PG pathway in combination with an OTR-A may be an effective strategy for delaying preterm delivery. In this study, we examined the effects of atosiban and nolasiban on PGF-induced contractions and pro-inflammatory responses in human pregnant myometrium. Both OTR-As, atosiban and nolasiban, inhibited PGF-induced contractions in a dose-dependent manner (p < 0.001 and p < 0.01, respectively). These inhibitory effects involved the suppression of PGF-mediated increase in intracellular calcium levels. In addition, the OTR-As significantly suppressed PGF-induced activation of pro-inflammatory pathways such as NF-κB and mitogen activated protein kinases (MAPKs), and the subsequent expression of contraction-associated-protein, COX-2. We have demonstrated that atosiban and nolasiban not only inhibit contractions elicited by OT, but also inhibit contractions and inflammation induced by PGF. This suggests a possible crosstalk between OTR and PG receptor signalling and highlights the importance of understanding G protein-coupled receptor interactions/crosstalk in the development of future tocolytics.
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http://dx.doi.org/10.1038/s41598-019-42181-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6453954PMC
April 2019
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