Publications by authors named "Mourad W Seif"

22 Publications

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The expression and activity of Toll-like receptors in the preimplantation human embryo suggest a new role for innate immunity.

Hum Reprod 2021 Sep;36(10):2661-2675

Department of Reproductive Medicine, Old St. Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK.

Study Question: Is the innate immunity system active in early human embryo development?

Summary Answer: The pattern recognition receptors and innate immunity Toll-like receptor (TLR) genes are widely expressed in preimplantation human embryos and the pathway appears to be active in response to TLR ligands.

What Is Known Already: Early human embryos are highly sensitive to their local environment, however relatively little is known about how embryos detect and respond to specific environmental cues. While the maternal immune response is known to be key to the establishment of pregnancy at implantation, the ability of human embryos to detect and signal the presence of pathogens is unknown.

Study Design, Size, Duration: Expression of TLR family and related genes in human embryos was assessed by analysis of published transcriptome data (n = 40). Day 5 (D-5) human embryos (n = 25) were cultured in the presence of known TLR ligands and gene expression and cytokine production measured compared to controls.

Participants/materials, Setting, Methods: Human embryos surplus to treatment requirements were donated with informed consent from several ART centres. Embryos were cultured to Day 6 (D-6) in the presence of the TLR3 and TLR5 ligands Poly (I: C) and flagellin, with gene expression measured by quantitative PCR and cytokine release into medium measured using cytometric bead arrays.

Main Results And The Role Of Chance: TLR and related genes, including downstream signalling molecules, were expressed variably at all human embryo developmental stages. Results showed the strongest expression in the blastocyst for TLRs 9 and 5, and throughout development for TLRs 9, 5, 2, 6 and 7. Stimulation of Day 5 blastocysts with TLR3 and TLR5 ligands Poly (I: C) and flagellin produced changes in mRNA expression levels of TLR genes, including the hyaluronan-mediated motility receptor (HMMR), TLR5, TLR7, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and monocyte chemoattractant Protein-1 (MCP-1) (P < 0.05, P < 0.001 compared to unstimulated controls), and release into culture medium of cytokines and chemokines, notably IL8 (P = 0.00005 and 0.01277 for flagellin and Poly (I: C), respectively).

Limitations, Reasons For Caution: This was a descriptive and experimental study which suggests that the TLR system is active in human embryos and capable of function, but does not confirm any particular role. Although we identified embryonic transcripts for a range of TLR genes, the expression patterns were not always consistent across published studies and expression levels of some genes were low, leaving open the possibility that these were expressed from the maternal rather than embryonic genome.

Wider Implications Of The Findings: This is the first report of the expression and activity of a number of components of the innate immunity TLR system in human embryos. Understanding the role of TLRs during preimplantation human development may be important to reveal immunological mechanisms and potential clinical markers of embryo quality and pregnancy initiation during natural conception and in ART.

Study Funding/competing Interest(s): This work was funded by the Ministry of Higher Education, The State of Libya, the UK Medical Research Council, and the NIHR Local Comprehensive Research Network and NIHR Manchester Clinical Research Facility and the European Union's Horizon 2020 Research and Innovation Programmes under the Marie Skłodowska-Curie Grant Agreement No. 812660 (DohART-NET). In accordance with H2020 rules, no new human embryos were sacrificed for research activities performed from the EU funding, which concerned only in silico analyses of recorded time-lapse and transcriptomics datasets. None of the authors has any conflict of interest to declare.

Trial Registration Number: n/a.
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http://dx.doi.org/10.1093/humrep/deab188DOI Listing
September 2021

Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial.

Lancet 2021 06 12;397(10290):2182-2193. Epub 2021 May 12.

MRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, London, UK.

Background: Ovarian cancer continues to have a poor prognosis with the majority of women diagnosed with advanced disease. Therefore, we undertook the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) to determine if population screening can reduce deaths due to the disease. We report on ovarian cancer mortality after long-term follow-up in UKCTOCS.

Methods: In this randomised controlled trial, postmenopausal women aged 50-74 years were recruited from 13 centres in National Health Service trusts in England, Wales, and Northern Ireland. Exclusion criteria were bilateral oophorectomy, previous ovarian or active non-ovarian malignancy, or increased familial ovarian cancer risk. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer generated random numbers to annual multimodal screening (MMS), annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. Follow-up was through national registries. The primary outcome was death due to ovarian or tubal cancer (WHO 2014 criteria) by June 30, 2020. Analyses were by intention to screen, comparing MMS and USS separately with no screening using the versatile test. Investigators and participants were aware of screening type, whereas the outcomes review committee were masked to randomisation group. This study is registered with ISRCTN, 22488978, and ClinicalTrials.gov, NCT00058032.

Findings: Between April 17, 2001, and Sept 29, 2005, of 1 243 282 women invited, 202 638 were recruited and randomly assigned, and 202 562 were included in the analysis: 50 625 (25·0%) in the MMS group, 50 623 (25·0%) in the USS group, and 101 314 (50·0%) in the no screening group. At a median follow-up of 16·3 years (IQR 15·1-17·3), 2055 women were diagnosed with tubal or ovarian cancer: 522 (1·0%) of 50 625 in the MMS group, 517 (1·0%) of 50 623 in the USS group, and 1016 (1·0%) of 101 314 in the no screening group. Compared with no screening, there was a 47·2% (95% CI 19·7 to 81·1) increase in stage I and 24·5% (-41·8 to -2·0) decrease in stage IV disease incidence in the MMS group. Overall the incidence of stage I or II disease was 39·2% (95% CI 16·1 to 66·9) higher in the MMS group than in the no screening group, whereas the incidence of stage III or IV disease was 10·2% (-21·3 to 2·4) lower. 1206 women died of the disease: 296 (0·6%) of 50 625 in the MMS group, 291 (0·6%) of 50 623 in the USS group, and 619 (0·6%) of 101 314 in the no screening group. No significant reduction in ovarian and tubal cancer deaths was observed in the MMS (p=0·58) or USS (p=0·36) groups compared with the no screening group.

Interpretation: The reduction in stage III or IV disease incidence in the MMS group was not sufficient to translate into lives saved, illustrating the importance of specifying cancer mortality as the primary outcome in screening trials. Given that screening did not significantly reduce ovarian and tubal cancer deaths, general population screening cannot be recommended.

Funding: National Institute for Health Research, Cancer Research UK, and The Eve Appeal.
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http://dx.doi.org/10.1016/S0140-6736(21)00731-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192829PMC
June 2021

Assisted hatching on assisted conception (in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI)).

Cochrane Database Syst Rev 2021 03 17;3:CD001894. Epub 2021 Mar 17.

Reproductive Medicine, St Mary's Hospital, Manchester, UK.

Background: Failure of implantation and conception may result from inability of the blastocyst to escape from its outer coat, which is known as the zona pellucida. Artificial disruption of this coat is known as assisted hatching and has been proposed as a method for improving the success of assisted conception by facilitating embryo implantation.

Objectives: To determine effects of assisted hatching (AH) of embryos derived from assisted conception on live birth and multiple pregnancy rates.  SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register (until May 2020), the Cochrane Central Register of Controlled Trials (CENTRAL; until May 2020), in the Cochrane Library; MEDLINE (1966 to May 2020); and Embase (1980 to May 2020). We also searched trial registers for ongoing and registered trials (http://www.clinicaltrials.gov - a service of the US National Institutes of Health; http://www.who.int/trialsearch/Default.aspx - The World Health Organization International Trials Registry Platform search portal) (May 2020).

Selection Criteria: Two review authors identified and independently screened trials. We included randomised controlled trials (RCTs) of AH (mechanical, chemical, or laser disruption of the zona pellucida before embryo replacement) versus no AH that reported live birth or clinical pregnancy data.

Data Collection And Analysis: We used standard methodological procedures recommended by Cochrane. Two review authors independently performed quality assessments and data extraction.

Main Results: We included 39 RCTs (7249 women). All reported clinical pregnancy data, including 2486 clinical pregnancies. Only 14 studies reported live birth data, with 834 live birth events. The quality of evidence ranged from very low to low. The main limitations were serious risk of bias associated with poor reporting of study methods, inconsistency, imprecision, and publication bias. Five trials are currently ongoing. We are uncertain whether assisted hatching improved live birth rates compared to no assisted hatching (odds ratio (OR) 1.09, 95% confidence interval (CI) 0.92 to 1.29; 14 RCTs, N = 2849; I² = 20%; low-quality evidence). This analysis suggests that if the live birth rate in women not using assisted hatching is about 28%, the rate in those using assisted hatching will be between 27% and 34%. Analysis of multiple pregnancy rates per woman showed that in women who were randomised to AH compared with women randomised to no AH, there may have been a slight increase in multiple pregnancy rates (OR 1.38, 95% CI 1.13 to 1.68; 18 RCTs, N = 4308; I² = 48%; low-quality evidence). This suggests that if the multiple pregnancy rate in women not using assisted hatching is about 9%, the rate in those using assisted hatching will be between 10% and 14%. When all of the included studies (39) are pooled, the clinical pregnancy rate in women who underwent AH may improve slightly in comparison to no AH (OR 1.20, 95% CI 1.09 to 1.33; 39 RCTs, N = 7249; I² = 55%; low-quality evidence). However, when a random-effects model is used due to high heterogeneity, there may be little to no difference in clinical pregnancy rate (P = 0.04). All 14 RCTs that reported live birth rates also reported clinical pregnancy rates, and analysis of these studies illustrates that AH may make little to no difference in clinical pregnancy rates when compared to no AH (OR 1.07, 95% CI 0.92 to 1.25; 14 RCTs, N = 2848; I² = 45%). We are uncertain about whether AH affects miscarriage rates due to the quality of the evidence (OR 1.13, 95% CI 0.82 to 1.56; 17 RCTs, N = 2810; I² = 0%; very low-quality evidence).

Authors' Conclusions: This update suggests that we are uncertain of the effects of assisted hatching (AH) on live birth rates. AH may lead to increased risk of multiple pregnancy. The risks of complications associated with multiple pregnancy may be increased without evidence to demonstrate an increase in live birth rate, warranting careful consideration of the routine use of AH for couples undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). AH may offer a slightly increased chance of achieving a clinical pregnancy, but data quality was of low grade. We are uncertain about whether AH influences miscarriage rates.
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http://dx.doi.org/10.1002/14651858.CD001894.pub6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094760PMC
March 2021

Lynch syndrome for the gynaecologist.

Obstet Gynaecol 2021 Jan 18;23(1):9-20. Epub 2021 Jan 18.

Professor of Gynaecology Oncology and Honorary Consultant Gynaecological Oncologist Division of Cancer Sciences Faculty of Biology, Medicine and Health University of Manchester St Mary's Hospital Manchester UK.

Key Content: Lynch syndrome is an autosomal dominant condition closely associated with colorectal, endometrial and ovarian cancer.Women with Lynch syndrome are at increased risk of both endometrial and ovarian cancer and should be offered personalised counselling regarding family planning, red flag symptoms and risk-reducing strategies.Surveillance for gynaecological cancer in women with Lynch syndrome remains controversial; more robust data are needed to determine its effectiveness.Universal testing for Lynch syndrome in endometrial cancer is being adopted by centres across Europe and is now recommended by the National Institute for Health and Care Excellence; thus, gynaecologists must become familiar with testing strategies and their results.Testing strategies involve risk stratification of cancers based on phenotypical features and definitive germline testing.

Learning Objectives: To define the pathogenesis of Lynch syndrome and its associated gynaecological cancers.To understand the testing strategies for Lynch syndrome in women with gynaecological cancer.To learn how best to counsel women with Lynch syndrome regarding gynaecological cancer and risk-reducing strategies to enable informed decision-making.

Ethical Issues: Offering gynaecological surveillance despite a lack of robust evidence for its clinical effectiveness may falsely reassure women and delay risk-reducing hysterectomy.Genetic testing may yield variants of unknown significance with ill-defined clinical implications, which can lead to confusion and anxiety.Genetic testing has implications not only for the individual, but also for the whole family, so expert counselling is crucial.
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http://dx.doi.org/10.1111/tog.12706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898635PMC
January 2021

Tumor Suppression in Asymptomatic Postmenopausal Endometrial Polyps.

Anticancer Res 2020 Feb;40(2):789-794

Department of Obstetrics and Gynecology, University of Manchester and St. Mary's Hospital, Manchester, U.K.

Background/aim: To investigate tumor suppression as an indicator of malignization potential within endometrial polyps in asymptomatic postmenopausal women.

Materials And Methods: Immunohistochemical studies of the phosphatase and tensin homolog (PTEN) were performed. Cases included 52 benign postmenopausal polyps, 19 endometrioid carcinomas with coexisting benign polyps, and 12 polyps with foci of carcinoma. Controls included 31 atrophic endometria and 32 benign premenopausal polyps. PTEN was scored by quantitative methods according to staining intensity.

Results: The mean epithelial and stromal PTEN H-score in postmenopausal benign endometrial polyps (193.8 and 123.2, respectively) was significantly higher than that in the atrophic endometrium (135.5 and 90.2, p=0.008), and premenopausal benign endometrial polyps (100.7 and 198.7, p<0.001). Significant difference between postmenopausal endometrial polyps and endometrial carcinoma was noticed in the epithelial compartment (193.8 vs. 65.7, respectively, p<0.001).

Conclusion: Asymptomatic benign postmenopausal polyps have a distinctively high tumor suppression compared with endometrial cancer, suggesting low malignization potential.
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http://dx.doi.org/10.21873/anticanres.14010DOI Listing
February 2020

Proliferation in Postmenopausal Endometrial Polyps-A Potential for Malignant Transformation.

Medicina (Kaunas) 2019 Aug 28;55(9). Epub 2019 Aug 28.

Department of Obstetrics and Gynaecology, University of Manchester and St. Mary's Hospital, Manchester M13 9WL, UK.

Endometrial polyps in asymptomatic postmenopausal women are often incidentally found, yet only 1.51% of them are malignant. Their potential for malignant transformation has not been adequately addressed. The aim of this study was to investigate the proliferation within endometrial polyps as one of the indicators of their malignization potential in asymptomatic postmenopausal women. Immunohistochemical studies of Ki-67 were performed. Cases included 52 benign postmenopausal polyps, 19 endometrioid carcinoma with coexisting benign polyps, 12 polyps with foci of carcinoma and 4 cases of polyps, which later developed carcinoma. The control group included 31 atrophic endometria and 32 benign premenopausal polyps. Ki-67 was scored in either 10 or 20 "hot spot" fields, as percentage of positively stained cells. Results: The median epithelial Ki-67 score in postmenopausal benign polyps (4.7%) was significantly higher than in atrophic endometria (2.41%, < 0.0001) and significantly lower than in premenopausal benign polyps (11.4%, = 0.003) and endometrial cancer (8.3%, < 0.0001). Where endometrial polyps were found in association with endometrial carcinoma, Ki-67 was significantly higher in cancer ( < 0.0001). No significant difference was found between Ki-67 scores of cancer focus and of the polyps tissue itself, respectively 2.8% and 4.55%, = 0.37. Ki-67 expression, where polyps were resected and women later developed cancer, was not significantly different ( = 0.199). Conclusion: Polyps from asymptomatic postmenopausal women showed significantly more proliferation in both epithelial and stromal components than inactive atrophic endometria but less than premenopausal benign polyps and/or endometrial cancer. Benign postmenopausal endometrial polyps exhibit low proliferative activity, suggesting low malignant potential and may not require resection in asymptomatic women.
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http://dx.doi.org/10.3390/medicina55090543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780687PMC
August 2019

The Manchester International Consensus Group recommendations for the management of gynecological cancers in Lynch syndrome.

Genet Med 2019 10 28;21(10):2390-2400. Epub 2019 Mar 28.

Prevention Early Detection Theme, NIHR Biomedical Research Centre, The Christie NHS Foundation Trust, Manchester, UK.

Purpose: There are no internationally agreed upon clinical guidelines as to which women with gynecological cancer would benefit from Lynch syndrome screening or how best to manage the risk of gynecological cancer in women with Lynch syndrome. The Manchester International Consensus Group was convened in April 2017 to address this unmet need. The aim of the Group was to develop clear and comprehensive clinical guidance regarding the management of the gynecological sequelae of Lynch syndrome based on existing evidence and expert opinion from medical professionals and patients.

Methods: Stakeholders from Europe and North America worked together over a two-day workshop to achieve consensus on best practice.

Results: Guidance was developed in four key areas: (1) whether women with gynecological cancer should be screened for Lynch syndrome and (2) how this should be done, (3) whether there was a role for gynecological surveillance in women at risk of Lynch syndrome, and (4) what preventive measures should be recommended for women with Lynch syndrome to reduce their risk of gynecological cancer.

Conclusion: This document provides comprehensive clinical guidance that can be referenced by both patients and clinicians so that women with Lynch syndrome can expect and receive appropriate standards of care.
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http://dx.doi.org/10.1038/s41436-019-0489-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774998PMC
October 2019

The cost-effectiveness of screening for ovarian cancer: results from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

Br J Cancer 2017 Aug 25;117(5):619-627. Epub 2017 Jul 25.

Department of Women's Cancer, Institute for Women's Health, University College London, London W1T 7DN, UK.

Background: To assess the within-trial cost-effectiveness of an NHS ovarian cancer screening (OCS) programme using data from UKCTOCS and extrapolate results based on average life expectancy.

Methods: Within-trial economic evaluation of no screening (C) vs either (1) an annual OCS programme using transvaginal ultrasound (USS) or (2) an annual ovarian cancer multimodal screening programme with serum CA125 interpreted using a risk algorithm (ROCA) and transvaginal ultrasound as a second-line test (MMS), plus comparison of lifetime extrapolation of the no screening arm and the MMS programme using both a predictive and a Markov model.

Results: Using a CA125-ROCA cost of £20, the within-trial results show USS to be strictly dominated by MMS, with the MMS vs C comparison returning an incremental cost-effectiveness ratio (ICER) of £91 452 per life year gained (LYG). If the CA125-ROCA unit cost is reduced to £15, the ICER becomes £77 818 per LYG. Predictive extrapolation over the expected lifetime of the UKCTOCS women returns an ICER of £30 033 per LYG, while Markov modelling produces an ICER of £46 922 per QALY.

Conclusion: Analysis suggests that, after accounting for the lead time required to establish full mortality benefits, a national OCS programme based on the MMS strategy quickly approaches the current NICE thresholds for cost-effectiveness when extrapolated out to lifetime as compared with the within-trial ICER estimates. Whether MMS could be recommended on economic grounds would depend on the confirmation and size of the mortality benefit at the end of an ongoing follow-up of the UKCTOCS cohort.
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http://dx.doi.org/10.1038/bjc.2017.222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572177PMC
August 2017

Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial.

Lancet 2016 Mar 17;387(10022):945-956. Epub 2015 Dec 17.

Department of Gynaecological Oncology, St Bartholomew's Hospital, London, UK.

Background: Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years. We designed this trial to establish the effect of early detection by screening on ovarian cancer mortality.

Methods: In this randomised controlled trial, we recruited postmenopausal women aged 50-74 years from 13 centres in National Health Service Trusts in England, Wales, and Northern Ireland. Exclusion criteria were previous bilateral oophorectomy or ovarian malignancy, increased risk of familial ovarian cancer, and active non-ovarian malignancy. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer-generated random numbers to annual multimodal screening (MMS) with serum CA125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. The primary outcome was death due to ovarian cancer by Dec 31, 2014, comparing MMS and USS separately with no screening, ascertained by an outcomes committee masked to randomisation group. All analyses were by modified intention to screen, excluding the small number of women we discovered after randomisation to have a bilateral oophorectomy, have ovarian cancer, or had exited the registry before recruitment. Investigators and participants were aware of screening type. This trial is registered with ClinicalTrials.gov, number NCT00058032.

Findings: Between June 1, 2001, and Oct 21, 2005, we randomly allocated 202,638 women: 50,640 (25·0%) to MMS, 50,639 (25·0%) to USS, and 101,359 (50·0%) to no screening. 202,546 (>99·9%) women were eligible for analysis: 50,624 (>99·9%) women in the MMS group, 50,623 (>99·9%) in the USS group, and 101,299 (>99·9%) in the no screening group. Screening ended on Dec 31, 2011, and included 345,570 MMS and 327,775 USS annual screening episodes. At a median follow-up of 11·1 years (IQR 10·0-12·0), we diagnosed ovarian cancer in 1282 (0·6%) women: 338 (0·7%) in the MMS group, 314 (0·6%) in the USS group, and 630 (0·6%) in the no screening group. Of these women, 148 (0·29%) women in the MMS group, 154 (0·30%) in the USS group, and 347 (0·34%) in the no screening group had died of ovarian cancer. The primary analysis using a Cox proportional hazards model gave a mortality reduction over years 0-14 of 15% (95% CI -3 to 30; p=0·10) with MMS and 11% (-7 to 27; p=0·21) with USS. The Royston-Parmar flexible parametric model showed that in the MMS group, this mortality effect was made up of 8% (-20 to 31) in years 0-7 and 23% (1-46) in years 7-14, and in the USS group, of 2% (-27 to 26) in years 0-7 and 21% (-2 to 42) in years 7-14. A prespecified analysis of death from ovarian cancer of MMS versus no screening with exclusion of prevalent cases showed significantly different death rates (p=0·021), with an overall average mortality reduction of 20% (-2 to 40) and a reduction of 8% (-27 to 43) in years 0-7 and 28% (-3 to 49) in years 7-14 in favour of MMS.

Interpretation: Although the mortality reduction was not significant in the primary analysis, we noted a significant mortality reduction with MMS when prevalent cases were excluded. We noted encouraging evidence of a mortality reduction in years 7-14, but further follow-up is needed before firm conclusions can be reached on the efficacy and cost-effectiveness of ovarian cancer screening.

Funding: Medical Research Council, Cancer Research UK, Department of Health, The Eve Appeal.
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http://dx.doi.org/10.1016/S0140-6736(15)01224-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779792PMC
March 2016

Risk Algorithm Using Serial Biomarker Measurements Doubles the Number of Screen-Detected Cancers Compared With a Single-Threshold Rule in the United Kingdom Collaborative Trial of Ovarian Cancer Screening.

J Clin Oncol 2015 Jun 11;33(18):2062-71. Epub 2015 May 11.

Usha Menon, Andy Ryan, Jatinderpal Kalsi, Aleksandra Gentry-Maharaj, Mariam Habib, Sophia Apostolidou, Matthew Burnell, Susan Davies, Richard Gunu, Martin Widschwendter, Elizabeth Benjamin, Mahesh Parmar, and Ian Jacobs, University College London; Anne Dawnay and Tim Mould, University College London Hospital; Naveena Singh, Barts and the London School of Medicine and Dentistry; David Oram and Karina Reynolds, St Bartholomew's Hospital; Alistair McGuire, London School of Economics; Stuart Campbell, Create Health Clinic; Aarti Sharma, University Hospital of Wales; Nazar N. Amso, Cardiff University, Cardiff; Keith Godfrey, Queen Elizabeth Hospital, Gateshead; Alberto Lopes, Royal Cornwall Hospital, Truro; Jonathan Herod, Liverpool Women's Hospital, Liverpool; Karin Williamson, Nottingham City Hospital, Nottingham; Mourad W. Seif, St Mary's Hospital, Manchester; Howard Jenkins and Ian Scott, Royal Derby Hospital, Derby; Robert Woolas, Queen Alexandra Hospital, Portsmouth; John B. Murdoch, St Michael's Hospital, Bristol; Stephen Dobbs, Belfast City Hospital, Belfast; Simon Leeson, Llandudno Hospital, Ysbyty Gwynedd; Derek Cruickshank, James Cook University Hospital, Middlesbrough; Lesley Fallowfield, University of Sussex, Falmer, United Kingdom; Steven J. Skates, Massachusetts General Hospital and Harvard Medical School, Boston, MA; and Ian Jacobs, UNSW Australia, Sydney, NSW, Australia.

Purpose: Cancer screening strategies have commonly adopted single-biomarker thresholds to identify abnormality. We investigated the impact of serial biomarker change interpreted through a risk algorithm on cancer detection rates.

Patients And Methods: In the United Kingdom Collaborative Trial of Ovarian Cancer Screening, 46,237 women, age 50 years or older underwent incidence screening by using the multimodal strategy (MMS) in which annual serum cancer antigen 125 (CA-125) was interpreted with the risk of ovarian cancer algorithm (ROCA). Women were triaged by the ROCA: normal risk, returned to annual screening; intermediate risk, repeat CA-125; and elevated risk, repeat CA-125 and transvaginal ultrasound. Women with persistently increased risk were clinically evaluated. All participants were followed through national cancer and/or death registries. Performance characteristics of a single-threshold rule and the ROCA were compared by using receiver operating characteristic curves.

Results: After 296,911 women-years of annual incidence screening, 640 women underwent surgery. Of those, 133 had primary invasive epithelial ovarian or tubal cancers (iEOCs). In all, 22 interval iEOCs occurred within 1 year of screening, of which one was detected by ROCA but was managed conservatively after clinical assessment. The sensitivity and specificity of MMS for detection of iEOCs were 85.8% (95% CI, 79.3% to 90.9%) and 99.8% (95% CI, 99.8% to 99.8%), respectively, with 4.8 surgeries per iEOC. ROCA alone detected 87.1% (135 of 155) of the iEOCs. Using fixed CA-125 cutoffs at the last annual screen of more than 35, more than 30, and more than 22 U/mL would have identified 41.3% (64 of 155), 48.4% (75 of 155), and 66.5% (103 of 155), respectively. The area under the curve for ROCA (0.915) was significantly (P = .0027) higher than that for a single-threshold rule (0.869).

Conclusion: Screening by using ROCA doubled the number of screen-detected iEOCs compared with a fixed cutoff. In the context of cancer screening, reliance on predefined single-threshold rules may result in biomarkers of value being discarded.
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http://dx.doi.org/10.1200/JCO.2014.59.4945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463475PMC
June 2015

Obesity and menstrual disorders.

Best Pract Res Clin Obstet Gynaecol 2015 May 1;29(4):516-27. Epub 2014 Nov 1.

St. Mary's Hospital, Manchester, CMFT, Manchester, UK; University of Manchester, Manchester, UK. Electronic address:

Obese women often present with oligomenorrhoea, amenorrhoea or irregular periods. The association between obesity and heavy menstrual bleeding is not well documented and data on its prevalence are limited. While the investigation protocols should be the same as for women of normal weight, particular focus is required to rule out endometrial hyperplasia in obese women. The treatment modalities of menstrual disorders for obese women will be, in principle, similar to those of normal weight. However, therapeutic outcomes in terms of effectiveness and adverse outcomes need special consideration when dealing with women with a high body mass index (BMI). Here, different treatment strategies are reviewed paying particular attention to the effect of weight on their efficacy and the challenges of providing each treatment option. This chapter aims to review the current literature and address areas where further evidence is needed, which will subsequently influence clinical practice.
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http://dx.doi.org/10.1016/j.bpobgyn.2014.10.010DOI Listing
May 2015

Monochorionic diamniotic twin cervical ectopic pregnancy following assisted conception: a case report.

J Reprod Med 2013 Sep-Oct;58(9-10):445-7

Department of Obstetrics and Gynecology, St. Mary's Hospital, Oxford Road, Manchester, UK.

Background: Ectopic pregnancy is a leading cause of maternal mortality. Its incidence has progressively increased in recent years. Assisted conception techniques are associated with a significantly higher rate of ectopic pregnancies. Cervical ectopic pregnancies are very rare, accounting for < 1% of all ectopic pregnancies.

Case: A 41-year-old, Caucasian woman presented for routine transvaginal scan at 6 weeks' gestation following a single embryo transfer as part of in vitro fertilization (IVF) follow-up. This revealed a monochorionic diamniotic twin pregnancy within the cervix. Serum beta-hCG concentration was 18,470 IU/L, and she reported only a mild brown-stained vaginal discharge. She was counseled regarding the risks of this pregnancy and was managed medically, receiving oral mifepristone and systemic methotrexate. She was subsequently monitored with serial serum beta-hCG measurements and transvaginal ultrasonography. After 6 weeks, due to the slow serum beta-hCG decline and lack of spontaneous menstruation, she was counseled regarding the potential risks of the persistent pregnancy and underwent suction evacuation.

Conclusion: This case is an example of a complication of LVF. To the best of our knowledge and following a search of the Medline database, this is the only case of monochorionic twin pregnancy located within the cervical canal.
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October 2013

Impact on mortality and cancer incidence rates of using random invitation from population registers for recruitment to trials.

Trials 2011 Mar 1;12:61. Epub 2011 Mar 1.

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

Background: Participants in trials evaluating preventive interventions such as screening are on average healthier than the general population. To decrease this 'healthy volunteer effect' (HVE) women were randomly invited from population registers to participate in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) and not allowed to self refer. This report assesses the extent of the HVE still prevalent in UKCTOCS and considers how certain shortfalls in mortality and incidence can be related to differences in socioeconomic status.

Methods: Between 2001 and 2005, 202 638 postmenopausal women joined the trial out of 1 243 312 women randomly invited from local health authority registers. The cohort was flagged for deaths and cancer registrations and mean follow up at censoring was 5.55 years for mortality, and 2.58 years for cancer incidence. Overall and cause-specific Standardised Mortality Ratios (SMRs) and Standardised Incidence Ratios (SIRs) were calculated based on national mortality (2005) and cancer incidence (2006) statistics. The Index of Multiple Deprivation (IMD 2007) was used to assess the link between socioeconomic status and mortality/cancer incidence, and differences between the invited and recruited populations.

Results: The SMR for all trial participants was 37%. By subgroup, the SMRs were higher for: younger age groups, extremes of BMI distribution and with each increasing year in trial. There was a clear trend between lower socioeconomic status and increased mortality but less pronounced with incidence. While the invited population had higher mean IMD scores (more deprived) than the national average, those who joined the trial were less deprived.

Conclusions: Recruitment to screening trials through invitation from population registers does not prevent a pronounced HVE on mortality. The impact on cancer incidence is much smaller. Similar shortfalls can be expected in other screening RCTs and it maybe prudent to use the various mortality and incidence rates presented as guides for calculating event rates and power in RCTs involving women.
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http://dx.doi.org/10.1186/1745-6215-12-61DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058013PMC
March 2011

Sensitivity of transvaginal ultrasound screening for endometrial cancer in postmenopausal women: a case-control study within the UKCTOCS cohort.

Lancet Oncol 2011 Jan 10;12(1):38-48. Epub 2010 Dec 10.

Gynaecological Oncology, UCL EGA Institute for Women's Health, London, UK.

Background: The increase in the worldwide incidence of endometrial cancer relates to rising obesity, falling fertility, and the ageing of the population. Transvaginal ultrasound (TVS) is a possible screening test, but there have been no large-scale studies. We report the performance of TVS screening in a large cohort.

Methods: We did a nested case-control study of postmenopausal women who underwent TVS in the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) following recruitment between April 17, 2001, and Sept 29, 2005. Endometrial thickness and endometrial abnormalities were recorded, and follow-up, through national registries and a postal questionnaire, documented the diagnosis of endometrial cancer. Our primary outcome measure was endometrial cancer and atypical endometrial hyperplasia (AEH). Performance characteristics of endometrial thickness and abnormalities for detection of endometrial cancer within 1 year of TVS were calculated. Epidemiological variables were used to develop a logistic regression model and assess a screening strategy for women at higher risk. Our study is registered with ClinicalTrials.gov, number NCT00058032, and with the International Standard Randomised Controlled Trial register, number ISRCTN22488978.

Findings: 48,230 women underwent TVS in the UKCTOCS prevalence screen. 9078 women were ineligible because they had undergone a hysterectomy and 2271 because their endometrial thickness had not been recorded; however, 157 of these women had an endometrial abnormality on TVS and were included in the analysis. Median follow-up was 5·11 years (IQR 4·05-5·95). 136 women with endometrial cancer or AEH within 1 year of TVS were included in our primary analysis. The optimum endometrial thickness cutoff for endometrial cancer or AEH was 5·15 mm, with sensitivity of 80·5% (95% CI 72·7-86·8) and specificity of 86·2% (85·8-86·6). Sensitivity and specificity at a 5 mm or greater cutoff were 80·5% (72·7-86·8) and 85·7% (85·4-86·2); for women with a 5 mm or greater cutoff plus endometrial abnormalities, the sensitivity and specificity were 85·3% (78·2-90·8) and 80·4% (80·0-80·8), respectively. For a cutoff of 10 mm or greater, sensitivity and specificity were 54·1% (45·3-62·8) and 97·2% (97·0-97·4). When our analysis was restricted to the 96 women with endometrial cancer or AEH who reported no symptoms of postmenopausal bleeding at the UKCTOCS scan before diagnosis and had an endometrial thickness measurement available, a cutoff of 5 mm achieved a sensitivity of 77·1% (67·8-84·3) and specificity of 85·8% (85·7-85·9). The logistic regression model identified 25% of the population as at high risk and 39·5% of endometrial cancer or AEH cases were identified within this high risk group. In this high-risk population, a cutoff at 6·75 mm achieved sensitivity of 84·3% (71·4-93·0) and specificity of 89·9% (89·3-90·5).

Interpretation: Our findings show that TVS screening for endometrial cancer has good sensitivity in postmenopausal women. The burden of diagnostic procedures and false-positive results can be reduced by limiting screening to a higher-risk group. The role of population screening for endometrial cancer remains uncertain, but our findings are of immediate value in the management of increased endometrial thickness in postmenopausal women undergoing pelvic scans for reasons other than vaginal bleeding.
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http://dx.doi.org/10.1016/S1470-2045(10)70268-0DOI Listing
January 2011

Global perspective of legal abortion - Trends analysis and accessibility.

Best Pract Res Clin Obstet Gynaecol 2010 Aug 11;24(4):457-66. Epub 2010 May 11.

Department of Obstetrics & Gynaecology, Maternal and Fetal Health Research Centre, University of Manchester, St Mary's Hospital, United Kingdom.

There are significant variations in the legalisation, restrictions and legal abortion rates worldwide. This undoubtedly influences the provision and accessibility to abortion services. Although there have been changes to the laws in several countries over the last decade, this has not yet been translated into practice in the provision of safe abortion in these countries. In countries where abortions are permitted without restriction; the majority of abortions are carried out by trained practitioners in approved facilities. In contrast, in countries where restrictions are imposed, the majority of abortions performed are considered to be unsafe and therefore associated with significant morbidity and mortality. This article discusses the most recent data available regarding worldwide legal abortion rates, trends over the last ten years and issues related to specific regions which may influence the provision of safe abortion services in the future.
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http://dx.doi.org/10.1016/j.bpobgyn.2010.04.002DOI Listing
August 2010

Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and stage distribution of detected cancers: results of the prevalence screen of the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

Lancet Oncol 2009 Apr 11;10(4):327-40. Epub 2009 Mar 11.

Gynaecological Oncology, University College London Elizabeth Garrett Anderson Institute for Women's Health, London, UK.

Background: Ovarian cancer has a high case-fatality ratio, with most women not diagnosed until the disease is in its advanced stages. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a randomised controlled trial designed to assess the effect of screening on mortality. This report summarises the outcome of the prevalence (initial) screen in UKCTOCS.

Methods: Between 2001 and 2005, a total of 202 638 post-menopausal women aged 50-74 years were randomly assigned to no treatment (control; n=101 359); annual CA125 screening (interpreted using a risk of ovarian cancer algorithm) with transvaginal ultrasound scan as a second-line test (multimodal screening [MMS]; n=50 640); or annual screening with transvaginal ultrasound (USS; n=50 639) alone in a 2:1:1 ratio using a computer-generated random number algorithm. All women provided a blood sample at recruitment. Women randomised to the MMS group had their blood tested for CA125 and those randomised to the USS group were sent an appointment to attend for a transvaginal scan. Women with abnormal screens had repeat tests. Women with persistent abnormality on repeat screens underwent clinical evaluation and, where appropriate, surgery. This trial is registered as ISRCTN22488978 and with ClinicalTrials.gov, number NCT00058032.

Findings: In the prevalence screen, 50 078 (98.9%) women underwent MMS, and 48 230 (95.2%) underwent USS. The main reasons for withdrawal were death (two MMS, 28 USS), non-ovarian cancer or other disease (none MMS, 66 USS), removal of ovaries (five MMS, 29 USS), relocation (none MMS, 39 USS), failure to attend three appointments for the screen (72 MMS, 757 USS), and participant changing their mind (483 MMS, 1490 USS). Overall, 4355 of 50 078 (8.7%) women in the MMS group and 5779 of 48 230 (12.0%) women in the USS group required a repeat test, and 167 (0.3%) women in the MMS group and 1894 (3.9%) women in the USS group required clinical evaluation. 97 of 50 078 (0.2%) women from the MMS group and 845 of 48 230 (1.8%) from the USS group underwent surgery. 42 (MMS) and 45 (USS) primary ovarian and tubal cancers were detected, including 28 borderline tumours (eight MMS, 20 USS). 28 (16 MMS, 12 USS) of 58 (48.3%; 95% CI 35.0-61.8) of the invasive cancers were stage I/II, with no difference (p=0.396) in stage distribution between the groups. A further 13 (five MMS, eight USS) women developed primary ovarian cancer during the year after the screen. The sensitivity, specificity, and positive-predictive values for all primary ovarian and tubal cancers were 89.4%, 99.8%, and 43.3% for MMS, and 84.9%, 98.2%, and 5.3% for USS, respectively. For primary invasive epithelial ovarian and tubal cancers, the sensitivity, specificity, and positive-predictive values were 89.5%, 99.8%, and 35.1% for MMS, and 75.0%, 98.2%, and 2.8% for USS, respectively. There was a significant difference in specificity (p<0.0001) but not sensitivity between the two screening groups for both primary ovarian and tubal cancers as well as primary epithelial invasive ovarian and tubal cancers.

Interpretation: The sensitivity of the MMS and USS screening strategies is encouraging. Specificity was higher in the MMS than in the USS group, resulting in lower rates of repeat testing and surgery. This in part reflects the high prevalence of benign adnexal abnormalities and the more frequent detection of borderline tumours in the USS group. The prevalence screen has established that the screening strategies are feasible. The results of ongoing screening are awaited so that the effect of screening on mortality can be determined.
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http://dx.doi.org/10.1016/S1470-2045(09)70026-9DOI Listing
April 2009

Postpartum bone status in teenage mothers assessed using peripheral quantitative computed tomography.

J Clin Densitom 2009 Apr-Jun;12(2):219-23. Epub 2009 Feb 25.

Clinical Radiology, Imaging Sciences Research Group, University of Manchester, St Mary's Hospital, Oxford Road, Manchester M13 9PT, UK.

Teenage pregnancy occurs during a time when the maternal skeleton may still be accruing mineral. We hypothesized that teenage mothers would have reduced amounts of bone mineral and altered bone geometry compared with controls. This cross-sectional, observational compared teenage mothers (n=18) to age- and ethnicity-matched controls (n=52). The main outcomes were peripheral quantitative computed tomography and dual-energy X-ray absorptiometry to measure bone geometry, bone mineral density (BMD) at radius, lumbar spine and hip, and whole body bone mineral content (WBBMC). In teenage mothers, cortical BMD was reduced at the radial diaphysis (mean difference: -1.3%; p=0.03). Size-adjusted WBBMC was reduced (mean difference: -4.0%; p=0.004) and was lower for a given amount of lean mass (mean difference: -5.8%; p=0.02). No other significant differences between groups were found. The recruitment and retention of participants to this study were extremely difficult and disappointing. Teenage mothers had lower BMD at cortical sites compared with age-matched controls. These data suggest that pregnancy might have a detrimental effect on teenage mothers' future skeletal health. The results of this study require confirmation and provide pilot data for further investigations.
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http://dx.doi.org/10.1016/j.jocd.2009.01.001DOI Listing
July 2009

Proximal tubal disease: the place for tubal cannulation.

Reprod Biomed Online 2007 Oct;15(4):383-8

Academic Unit of Obstetrics and Gynaecology and Reproductive Health, St Mary's Hospital, Manchester, UK.

Tubal disease is the cause of subfertility in approximately 30% of women, and 10-25% of these are due to proximal tubal obstruction. False-positive diagnosis of proximal tubal obstruction can be as high as 50%. A decrease in expertise in tubal microsurgery has resulted largely from the use of IVF as the treatment option for most causes of infertility and more specifically for tubal factor infertility. Selective salpingography and tubal cannulation have a unique role in the management of tubal infertility and should be offered to selected candidates prior to IVF. Tubal cannulation can be used effectively to restore patency in a proportion of cases of proximal tubal obstruction thus avoiding the need for expensive assisted reproductive techniques. This review examines the evidence supporting the effectiveness of tubal cannulation and aims to enhance awareness of the procedure as an option for the management of female subfertility secondary to isolated proximal tubal obstruction.
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http://dx.doi.org/10.1016/s1472-6483(10)60362-8DOI Listing
October 2007

Premature ovarian failure.

Curr Opin Obstet Gynecol 2006 Aug;18(4):418-26

Academic Unit of Obs & Gynae, University of Manchester, St Mary's Hospital, Manchester, UK.

Purpose Of Review: To summarize current knowledge about premature ovarian failure (POF) with an emphasis on recent developments regarding its management.

Recent Findings: The incidence of POF is increasing largely due to improved survival rates of cancer patients treated with radiation and chemotherapy. Delayed diagnosis and management of POF leads to suboptimal outcomes. Anticipation and early detection of this condition in high-risk women by means of ovarian function testing, followed by early institution of appropriate management could improve outcomes. Choice of strategies should vary depending on the age of onset, associated symptoms and fertility aspirations of the individual, and should change with the patient's advancing age.

Summary: Early assessment of the individual's risk of developing POF, development of a strategic management plan, and timely commencement of infertility and hormone deficiency treatment, together with counselling in an integrated management plan should improve both the short and long-term health of those with POF.
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http://dx.doi.org/10.1097/01.gco.0000233937.36554.d3DOI Listing
August 2006

Managing disorders of ovulation: a model for evidence-based practice.

Authors:
Mourad W Seif

Curr Opin Obstet Gynecol 2005 Aug;17(4):403-4

Academic Unit of Obstetrics, Gynaecology and Reproductive Health, Division of Human Development, St Mary's Hospital, Manchester, UK.

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http://dx.doi.org/10.1097/01.gco.0000175359.27717.5dDOI Listing
August 2005

Characterizing the endometrium in unexplained and tubal factor infertility: a multiparametric investigation.

Fertil Steril 2004 Nov;82(5):1379-89

Department of Obstetrics and Gynecology, St. Mary's Hospital, Manchester, United Kingdom.

Objective: To characterize endometrial development in unexplained and tubal factor infertility.

Design: Prospective study of 20 women with unexplained infertility, 22 with tubal factor infertility, and 21 fertile controls in the midproliferative, periovulatory, and midluteal phases of the menstrual cycle.

Setting: Reproductive Medicine Department of St. Mary's Hospital, Manchester, United Kingdom.

Patient(s): Women awaiting assisted conception.

Investigation(s): Serum hormone assays, transvaginal ultrasound, Doppler, and midluteal endometrial biopsies.

Main Outcome Measure(s): Serum levels of E2, P, and LH, endometrial ultrasound morphometry, uterine and subendometrial artery Doppler, and endometrial histology and biochemistry.

Result(s): Women with unexplained infertility demonstrated significantly reduced uterine artery flow velocity in all phases, significantly elevated uterine and subendometrial artery impedance in the periovulatory and midluteal phases, and significantly reduced endometrial texture in the midproliferative phase. Women with tubal factor infertility demonstrated significantly reduced uterine artery flow velocity, without a concomitant increase in impedance, and significantly greater expression of endometrial glandular and luminal keratan sulphate.

Conclusion(s): Unexplained infertility is associated with a profound impairment of endometrial perfusion that might be amenable to treatment by perfusion enhancers. Tubal factor infertility is associated with endometrial developmental defects that might be corrected by salpingectomy. Endometrial ultrasound and Doppler studies are likely to become a vital tool in the investigation of infertility.
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http://dx.doi.org/10.1016/j.fertnstert.2004.04.046DOI Listing
November 2004

The impact of assisted hatching on live birth rates and outcomes of assisted conception: a systematic review.

Hum Reprod 2003 Sep;18(9):1828-35

Academic Unit of Obstetrics, Gynaecology and Reproductive Healthcare, St Mary's Hospital, Manchester, UK.

Background: During the past decade in the UK, only one in six cycles of assisted conception has resulted successfully in a live birth. Assisted hatching (AH) has been proposed to improve outcome. This systematic review of randomized controlled trials addresses primary outcomes of live birth, clinical pregnancy and embryo implantation.

Methods: Trials on post-fertilization disruption of the zona pellucida were identified from the Cochrane Controlled Trials Register, MEDLINE, EMBASE and published bibliographies. Outcomes were analysed using random effects meta-analysis, sensitivity analysis, sub-grouping and meta-regression.

Results: Of 23 included trials recruiting 2572 women, only six reported live birth data. AH had no significant effect on live birth (OR 1.21, 95% CI 0.82-1.78). There was a significant benefit of AH on clinical pregnancy (OR 1.63, 95% CI 1.27-2.09), especially in the sub-group of women with previous failure of assisted conception (OR 2.33, 95% CI 1.63-3.34). Meta-regression suggested that AH might be more useful in older women. Implantation data were not considered valid for statistical analysis. The methodological quality of included trials was sub-optimal.

Conclusions: AH probably enhances clinical pregnancy, especially in women with previous failure of assisted conception treatment and in older women; however, trials were of poor quality and so may be biased. Better quality trials reporting live birth are required to confirm any positive effects on the 'take-home-baby rate'.
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http://dx.doi.org/10.1093/humrep/deg334DOI Listing
September 2003
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