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Nuffield Department of Women's & Reproductive Health sits within the Medical Sciences Division of the University of Oxford. The department encompasses multi-disciplinary research across four overarching themes; Cancer, Global Health, Maternal & Fetal Health and Reproductive Medicine & Genetics
The use of immunomodulation therapy in women with recurrent implantation failure undergoing assisted conception: A multicentre cohort study
AbstractProblemRecurrent implantation failure (RIF) after multiple embryo transfers remains a vexing problem and immunomodulators have been used with conflicting results. This study aims to assess the effect of immunomodulation therapy on live birth rate (LBR) in women with RIF undergoing assisted reproduction treatment (ART).Method of study designThis is a retrospective cohort study in multicentre network of private assisted conception units in the UK. The study included women who had at least two failed attempts of embryo transfers at CARE fertility network in the period from 1997 to 2018. Women in the treatment group had immunomodulator drugs in the form of corticosteroids, low molecular weight heparin (LMWH), and intravenous intralipid (IVIL) infusions, either separately or in combination, after immunological testing, in addition to standard ART whilst women in the control group had only ART without immunomodulators. The primary outcome was LBR per cycle. Secondary outcomes included the rates of clinical pregnancy (CPR), cumulative live birth (CLBR), and miscarriage.ResultsA total of 27 163 ART cycles fulfilled the inclusion criteria, of which 5083 had immunomodulation treatment in addition to standard ART treatment, and 22 080 had standard ART treatment alone. Women in the treatment group were significantly older (mean age 38.5 vs. 37.1 years, p < .001), and had a higher number of previous failed ART cycles (mean 4.3 vs. 3.8, p < .01). There was a higher LBR in women who received immunomodulation therapy when compared with the control group (20.9% vs. 15.8%, odds ratio [OR] 1.4, 95% confidence interval [CI] 1.29–1.53, p < .001). Multivariate regression analysis showed that immunomodulation treatment was a significant independent predictor of live birth after adjusting for other confounders (adjusted OR [aOR] 1.33, 95% CI 1.15–1.54, p < .001). Survival analysis showed a higher CLBR in the treatment group (adjusted hazard ratio [aHR] 1.78, 95% CI 1.62–1.94, p < .001).Conclusion(s)This study provides evidence of a potential beneficial effect of immunomodulation therapy in women with RIF after immunological testing. There remains a need for high quality, adequately powered multicentre RCTs to robustly address the role of immunomodulation in women with RIF. There is also an urgent need for standardised screening tests for immune disorders that could preclude implantation.
Practical Psychiatric Epidemiology
This long-awaited second edition of Practical Psychiatric Epidemiology covers all of the considerable new developments in psychiatric epidemiology that have occurred since the first edition was published in 2003. It includes new content on key topics such as life course epidemiology, gene–environment interactions, bioethics, patient and public involvement in research, mixed methods research, new statistical methods, case registers, policy, and implementation. Looking to the future of this rapidly evolving scientific discipline and how it will respond to the emerging opportunities and challenges posed by ‘big data’, new technologies, open science, and globalization, this new edition will serve as an invaluable reference for clinicians in practice and in training. It will also be of interest to researchers in mental health and people studying or teaching psychiatric epidemiology at undergraduate or postgraduate level.
Guidelines on Placenta Accreta Spectrum Disorders: A Systematic Review.
IMPORTANCE: Placenta accreta spectrum (PAS) is a complex, life-threatening condition that demands a multidisciplinary approach involving obstetrics, maternal-fetal medicine, and various surgical and medical specialties. Effective management relies on multispecialty collaboration and consensus, supported by standardized protocols, to optimize outcomes, guide informed clinical decisions, and mitigate the risks associated with PAS. OBJECTIVE: To examine clinical practice guidelines for PAS inclusive of high-income countries and low- to middle-income countries (LMICs) identifying areas of consensus and gaps in guidance. EVIDENCE REVIEW: A comprehensive search of PubMed, GIN Library, and ECRI Guidelines Trust identified all PAS-related clinical practice guidelines published from January 1, 2014, to January 31, 2024. Additional searches included professional societies' designated websites and cited references. Two independent reviewers screened the guidelines, resolving conflicts through cross-referencing. Initially, 2 independent reviewers provided structured review and feedback to refine, correct, or highlight areas of consensus, disagreement, or insufficient evidence. Any instances of nonagreement were adjudicated by majority panel agreement, arising from a panel of 15 to 18 experts, all authors of PAS guidelines. Agreement scores for each recommendation area (eg, epidemiology, diagnosis, and antenatal management) were categorized as high agreement (≥75%), poor consensus (<50% or ≥30% insufficient evidence), and high levels of insufficient evidence (≥50% of recommendations with insufficient evidence) based on a priori score criteria. FINDINGS: A total of 14 guidelines from 18 articles from national and international societies were included. High agreement was noted in areas such as specialized expertise (100%), antenatal management (88.9%), diagnosis (76.9%), and epidemiology (75.0%). Poor consensus characterized cesarean hysterectomy management (38.5% insufficient evidence and 23.0% disagreement), conservative techniques (33.3% insufficient evidence and 11.1% disagreement), and fertility counseling (30.0% insufficient evidence and 10.0% disagreement). Despite the high risk of anemia, consensus was lacking on iron supplementation strategies. Recommendations for thromboembolism prevention varied, with some guidelines favoring pharmacologic interventions and others advocating for nonpharmacologic measures. Hemorrhage management and postnatal management recommendations, including iron supplementation and thromboembolism prevention, were characterized by high levels of insufficient evidence (55.6% and 57.1%, respectively). Only 1 article (5.6%) specifically addressed LMICs, highlighting substantial underrepresentation. CONCLUSIONS AND RELEVANCE: This systematic review of PAS guidelines identified significant discrepancies and insufficient evidence in key aspects of care. The findings underscore the urgent need for further research and quality measures to enhance standardized approaches and improve patient outcomes. The limited availability of recommendations applicable to LMICs highlights the critical need for tailored guidance that accounts for resource constraints and clinical access challenges unique to these settings.
Plasma protein biomarkers of Plasmodium falciparum infection in pregnant women: a high-throughput proteomics study.
INTRODUCTION: Pregnant women in sub-Saharan Africa face heightened susceptibility to Plasmodium falciparum malaria, with placental sequestration driving adverse outcomes. The infection may lead to pregnancy-associated malaria (PAM) because of the sequestration of Plasmodium falciparum-infected erythrocytes in the placental intervillous space. Although there are several tools for diagnosing malaria infection during pregnancy, including blood smear microscopic examination, rapid diagnostic tests, and PCR, there are no tools for detecting placental infection and, by extension, any dysfunction associated with PAM. Thus, PAM, specifically placental infection, can only be confirmed via postnatal placental histopathology. Therefore, there is an urgent need for specific plasma biomarkers of PAM. METHODS: Here, we used the high throughput proximity extension assay to screen plasma from malaria-exposed pregnant women for differentially expressed proteins that may serve as candidate biomarkers of Plasmodium falciparum infection during pregnancy, with future potential to inform diagnosis of PAM or adverse malaria outcomes. Such biomarkers may also elucidate the pathophysiology of PAM. RESULTS: Using proximity extension assay (PEA), we identified elevated IgG Fc receptor IIb (FCGR2B) and heme oxygenase-1 (HO-1) in malaria-positive pregnancies, while neurturin (NRTN) and IL-20 were downregulated. DISCUSSION: IL-20 emerged as a top candidate biomarker, warranting validation in large cohorts with placental histopathology.
The effects of lacosamide, pregabalin, and tapentadol on peripheral nerve excitability: A randomized, double-blind, placebo-controlled, crossover, multi-center trial in healthy subjects.
BACKGROUND: Chronic pain is a leading cause of disability globally, with limited treatment options and frequent adverse effects. The IMI-PainCare-BioPain project aimed to enhance analgesic drug development by standardizing biomarkers. This study, IMI2-PainCare-BioPain-RCT1, evaluated the effects of lacosamide, pregabalin, and tapentadol on peripheral nerve excitability in healthy subjects through a randomized, double-blind, placebo-controlled crossover trial. METHODS: The study included 43 healthy participants aged 18-45 years. Participants underwent four treatment periods where they received single doses of lacosamide (200 mg), pregabalin (150 mg), tapentadol (100 mg), or placebo. High-frequency stimulation was applied to induce hyperalgesia. The two primary endpoints were changes in Strength Duration Time Constant (SDTC) in large sensory and motor fibers between lacosamide and placebo periods at the first post-dose timepoint compared to baseline (60 min). Other predefined endpoints included recovery cycle, threshold electrotonus (TEd), and S2 accommodation as well as effects of pregabalin and tapentadol. RESULTS: Lacosamide statistically significantly reduced SDTC in large sensory fibers (mean reduction 0.04 (95% CI 0.01-0.08), p = 0.012) and in motor fibers (mean reduction 0.04 (95% CI 0.00-0.07), p = 0.039) but had no effect on small sensory fibers at the first timepoint compared to placebo. There were no effects of pregabalin and tapentadol on SDTC. Of other predefined endpoints, lacosamide produced statistically significant changes in subexcitability, S2 accommodation TEd(peak), and TEd40(Accom) in large sensory fibers. No statistically significant changes were observed in refractoriness, relative refractory period, or accommodation half-time at the first timepoint compared to placebo. CONCLUSIONS: This study demonstrates that nerve excitability testing can detect pharmacodynamic effects on large myelinated fibers in healthy subjects. Lacosamide statistically significantly reduced peripheral nerve excitability, particularly in large sensory fibers.
Maternal vaccination against COVID-19 and neonatal outcomes during Omicron: INTERCOVID-2022 study.
BACKGROUND: In early 2023, when Omicron was the variant of concern, we showed that vaccinating pregnant women decreased the risk for severe COVID-19-related complications and maternal morbidity and mortality. OBJECTIVE: This study aimed to analyze the impact of COVID-19 during pregnancy on newborns and the effects of maternal COVID-19 vaccination on neonatal outcomes when Omicron was the variant of concern. STUDY DESIGN: INTERCOVID-2022 was a large, prospective, observational study, conducted in 40 hospitals across 18 countries, from November 27, 2021 (the day after the World Health Organization declared Omicron the variant of concern) to June 30, 2022, to assess the effect of COVID-19 in pregnancy on maternal and neonatal outcomes and to assess vaccine effectiveness. Women diagnosed with laboratory-confirmed COVID-19 during pregnancy were compared with 2 nondiagnosed, unmatched women recruited concomitantly and consecutively during pregnancy or at delivery. Mother-newborn dyads were followed until hospital discharge. The primary outcomes were a neonatal positive test for COVID-19, severe neonatal morbidity index, severe perinatal morbidity and mortality index, preterm birth, neonatal death, referral to neonatal intensive care unit, and diseases during the neonatal period. Vaccine effectiveness was estimated with adjustment for maternal risk profile. RESULTS: We enrolled 4707 neonates born to 1577 (33.5%) mothers diagnosed with COVID-19 and 3130 (66.5%) nondiagnosed mothers. Among the diagnosed mothers, 642 (40.7%) were not vaccinated, 147 (9.3%) were partially vaccinated, 551 (34.9%) were completely vaccinated, and 237 (15.0%) also had a booster vaccine. Neonates of booster-vaccinated mothers had less than half (relative risk, 0.46; 95% confidence interval, 0.23-0.91) the risk of being diagnosed with COVID-19 when compared with those of unvaccinated mothers; they also had the lowest rates of preterm birth, medically indicated preterm birth, respiratory distress syndrome, and number of days in the neonatal intensive care unit. Newborns of unvaccinated mothers had double the risk for neonatal death (relative risk, 2.06; 95% confidence interval, 1.06-4.00) when compared with those of nondiagnosed mothers. Vaccination was not associated with any congenital malformations. Although all vaccines provided protection against neonatal test positivity, newborns of booster-vaccinated mothers had the highest vaccine effectiveness (64%; 95% confidence interval, 10%-86%). Vaccine effectiveness was not as high for messenger RNA vaccines only. Vaccine effectiveness against moderate or severe neonatal outcomes was much lower, namely 13% in the booster-vaccinated group (all vaccines) and 25% and 28% in the completely and booster-vaccinated groups, respectively (messenger RNA vaccines only). Vaccines were fairly effective in protecting neonates when given to pregnant women ≤100 days (14 weeks) before birth; thereafter, the risk increased and was much higher after 200 days (29 weeks). Finally, none of the neonatal practices studied, including skin-to-skin contact and direct breastfeeding, increased the risk for infecting newborns. CONCLUSION: When Omicron was the variant of concern, newborns of unvaccinated mothers had an increased risk for neonatal death. Neonates of vaccinated mothers had a decreased risk for preterm birth and adverse neonatal outcomes. Because the protective effect of COVID-19 vaccination decreases with time, to ensure that newborns are maximally protected against COVID-19, mothers should receive a vaccine or booster dose no more than 14 weeks before the expected date of delivery.
Pre-operative GnRH agonist use and surgical outcomes in rectovaginal/colorectal endometriosis: an international multicentre prospective cohort study.
BACKGROUND: Rectovaginal/colorectal endometriosis is severe form of endometriosis requiring complex surgery, where pre-operative gonadotrophin releasing hormone agonists (GnRHa) are used to improve the surgical outcomes but the evidence supporting this is limited. OBJECTIVES: To evaluate the association between pre-operative use of GnRHa and perioperative and postoperative complications in patients undergoing surgery for rectovaginal or colorectal endometriosis. METHODS: We analysed prospectively collected data from British Society for Gynaecological Endoscopy-accredited endometriosis centres between 2009 and 2021. Multivariable logistic regression analysis was performed to model the odds of each complication by pre-operative GnRHa use, controlling for patient age, body mass index, smoking status, whether a hysterectomy was performed, history of previous endometriosis surgery and surgical complexity. MAIN OUTCOME MEASURES: The association of GnRHa use with perioperative and postoperative complications. RESULTS: We included 9,433 patients aged 18-55 years from 101 specialist endometriosis centres from six countries including UK, USA, Sri Lanka, Saudi Arabia, Turkey and Iran. Patients receiving pre-operative GnRHa were associated with higher rate of perioperative complications [odds ratio (OR): 1.31, 95% confidence interval (CI): 1.08-1.59, P=0.007], late complications (OR: 1.477, 95% CI: 1.15-1.9, P=0.002) and pelvic haematoma (OR: 2.251, 95% CI: 1.41-3.64, P<0.001). After controlling for confounding factors, GnRHa use remained significantly associated with colostomy (aOR: 4.05: 95% CI: 1.51-12.7, P=<0.001] pelvic haematoma (aOR: 3.08, 95% CI: 1.72-5.75, P<0.001) and abscess (aOR: 2.25, 95% CI: 1.10-4.79, P=0.029). Health related quality of life (HR-QOL) improved in the Pre-GnRHa group at 12 months and 24 months (mean difference 2.09/100, 95% CI, 0.27-3.92, P=0.025) and (mean difference 2.85/100, 95% CI 0.55-5.16, P=0.015). CONCLUSIONS: Pre-operative use of GnRHa has been associated with a higher incidence of perioperative and late complications, including significantly increased odds of colostomy, pelvic hematoma and abcess formation. There is need of careful patient counselling and further prospective research to clarify the pre-operative use of GnRHa in rectovaginal/colorectal endometriosis. WHAT IS NEW?: There is need of caution use of pre-operative GnRHa in deep rectovaginal/colorectal endometriosis surgery due to increased association of the risks of complications such as colostomy, pelvic haematoma and abcess. Despite long-term improvement in HR-QOL, there is need for careful patient selection and counselling.
European guidelines for hypertension in 2024: a comparison of key recommendations for clinical practice.
Hypertension is the most prevalent modifiable risk factor for cardiovascular disease and for cardiovascular and all-cause mortality globally. Suboptimal control of elevated blood pressure places a substantial burden on health-care systems worldwide. Several factors contribute to this suboptimal control, such as limited awareness of hypertension, lack of appropriate diagnosis and poor control of blood pressure among those with a diagnosis. These factors can be due to patient non-adherence to treatment, inertia among health-care professionals and low uptake and implementation of clinical guideline recommendations. From 2003 to 2018, the European Society of Hypertension and the European Society of Cardiology jointly published four sets of guidelines on hypertension. However, the two societies released separate guidelines on hypertension in 2023 and 2024, respectively. These two sets of European guidelines agree on most recommendations, but some differences have been identified. In this Expert Recommendation, we highlight the key consensus recommendations from the two guidelines; compare differing approaches to the definition, classification, diagnosis and treatment of hypertension; and aim to help health-care professionals in their decision-making to improve the management of hypertension and to reduce the burden of hypertension-associated outcomes and premature deaths.
A systems-based approach to uterine fibroids identifies differential splicing associated with abnormal uterine bleeding.
BACKGROUND: Uterine fibroids (UFs), benign tumours prevalent in up to 80% of women of reproductive age, are associated with significant morbidity, including abnormal uterine bleeding, pain and infertility. Despite identification of key genomic alterations in MED12 and HMGA2, the pathogenic mechanisms underlying UFs and heavy menstrual bleeding (HMB) remain poorly understood. METHODS: To correlate systematically genetic, transcriptional and proteomic phenotypes, we conducted an integrative multi-omic approach utilising targeted DNA sequencing, RNA sequencing and proteomic methodologies, encompassing fibroid, myometrium, and endometrium tissues from 91 patients. RESULTS: In addition to confirming the presence of MED12 mutations, we identify variants in AHR and COL4A6. Multi-omic analysis of endometrium identifies latent factors that correlate with HMB and fibroid presence with driver mutations of MED12, AHR, and COL4A6, which are associated with pathways involved in angiogenesis, extracellular matrix organisation and RNA splicing. We propose a model, supported by in vivo evidence, where altered signalling of MED12-mutated fibroids influences RNA transcript isoform expression in endometrium, potentially leading to abnormal uterine bleeding. CONCLUSIONS: This study presents a comprehensive integrative approach, revealing that genetic alterations in UF may influence endometrial function via signalling impacts on the RNA splicing mechanism. Our findings advance the understanding of complex molecular pathways in UF pathogenesis and UF-associated endometrial dysfunction, offering insights for targeted therapeutic development.