CARE Fertility Group

Nottingham, United Kingdom

CARE Fertility Group

Nottingham, United Kingdom
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Fishel S.,CARE Fertility Group | Baker D.J.,IHG Pharmaco Ltd | Greer I.A.,University of Manchester
Thrombosis Research | Year: 2017

There is biological plausibility that coagulation activation underlies a proportion of in vitro fertilisation IVF failures and recurrent early clinical pregnancy loss (RPL). However, low-molecular-weight heparin (LMWH) use, based upon previous clinical outcome alone, is not effective in preventing RPL. RPL is heterogeneous in mechanism. Identifying those with an underlying thrombotic mechanism would allow stratification for LMWH treatment. Annexin A5 is an anticoagulant protein expressed on the trophoblast surface. The annexin A5 M2 haplotype (ANXA5 M2) is associated with several placenta mediated pregnancy complications (PMPC) and poor IVF outcome. It is transmitted equally by males and females. A pragmatic observational study of IVF couples screened for M2 carriage and treated with LMWH achieved a 37.9% live birth rate, similar to an unscreened and untreated group with fewer adverse risk factors for conception and a better prognosis from assisted conception. This suggests that LMWH may counteract the adverse effects of M2 carriage. Using this biomarker to stratify IVF and PMPC patients for LMWH treatment merits further evaluation. © 2017 Elsevier Ltd


Fishel S.,CARE Fertility Group | Baker D.,IHG Pharmaco Ltd | Elson J.,CARE Fertility Group | Ragunath M.,CARE Nottingham | And 6 more authors.
EBioMedicine | Year: 2016

BACKGROUND: Pregnancy failure and placenta mediated pregnancy complications affect >25% of pregnancies. Although there is biological plausibility for a procoagulant mechanism underlying some of these events, antithrombotic intervention trials demonstrate limited benefit, possibly through lack of stratification in heterogeneous patient groups. The ANXA5 M2 haplotype is a possible procoagulant biomarker and was tested pragmatically to determine whether this screening and LMWH treatment normalized the outcome for ANXA5 M2 positive couples. This was a pragmatic study that aimed to measure the effectiveness of a testing (for the M2 haplotype) and treatment (LMWH) pathway in routine clinical practice where there is variation between patients. Such a study in couples with fertility problems can inform choices between treatments; it is then the management protocol which is the subject of the investigation, not the individual treatments.METHODS: Couples (N=77) with one or both partners ANXA5 M2 positive demonstrated association of this haplotype with adverse IVF outcome. A pragmatic, multicenter, prospective cohort study of ANXA5 M2 haplotype screening, and LWMH treatment following embryo transfer (ET) in 103 IVF couples positive for ANXA5 M2 was performed. They were compared with a group of 1000 contemporaneous randomly selected unscreened and untreated couples undergoing assisted conception, from which 103 matched control couples were derived. The primary outcome measure was live birth incidence. Secondary outcomes were results following embryo transfer (ET) and live birth outcome by gender and M2 carriage, and allelic dose influence.FINDINGS: The tested and treated cohort of ANXA5 M2 carriers achieved a similar live birth rate (37.9%) per ET cycle compared to both the more fertile comparison group (38.5%), and to the 103 matched controls (33.0%). Significantly more treated male carrier only couples had a live birth versus female M2 only (47.7% vs. 25.0% p=0.045).INTERPRETATION: Pragmatic ANXA5 M5 screening and treatment with LMWH in couples undergoing IVF is associated with similar outcome to couples with more favorable prognostic factors. The difference in live birth outcome for treated male only carrier couples may be consistent with an additional maternal thrombophilic factor that may adversely affect pregnancy, although other mechanisms are possible. This study suggests that LMWH treatment should be started prior to clinical pregnancy. Copyright © 2016 The Ohio State University Wexner Medical Center. Published by Elsevier B.V. All rights reserved.


PubMed | Francis Crick Institute, CARE Fertility Group, University of Cambridge and King's College London
Type: Journal Article | Journal: Nature cell biology | Year: 2016

Remodelling of the human embryo at implantation is indispensable for successful pregnancy. Yet it has remained mysterious because of the experimental hurdles that beset the study of this developmental phase. Here, we establish an invitro system to culture human embryos through implantation stages in the absence of maternal tissues and revealthe key events of early human morphogenesis. These include segregation of the pluripotent embryonic and extra-embryonic lineages, and morphogenetic rearrangements leading to generation of a bilaminar disc, formation of a pro-amniotic cavity within the embryonic lineage, appearance of the prospective yolk sac, and trophoblast differentiation. Using human embryos and human pluripotent stem cells, we show that the reorganization of the embryonic lineage is mediated by cellular polarization leading to cavity formation. Together, our results indicate that the critical remodelling events at this stage of human development are embryo-autonomous, highlighting the remarkable and unanticipated self-organizing properties of human embryos.


Kirkegaard K.,Aarhus University Hospital | Kirkegaard K.,University of Aarhus | Campbell A.,CARE Fertility Group | Agerholm I.,Braedstrup Hospital | And 6 more authors.
Reproductive BioMedicine Online | Year: 2014

The goal of embryo selection models is to select embryos with the highest reproductive potential, whilst minimizing the rejection of viable embryos. Ultimately, any embryo selection model must be tested on clinical outcome. We therefore retrospectively tested a published blastocyst prediction model on a large combined set of transferred embryos with known clinical outcome. The model was somewhat effective in that we found a relative increase of 30% for implantation in the model-selected group of embryos. There was, however, a concomitant large rejection of embryos from our test cohort, which actually resulted in pregnancy. This hypothetical experiment highlights the limitations of predicting blastulation only. Crucially, it illustrates that both sensitivity and specificity are important parameters when developing embryo selection models for prospective clinical use. © 2014 Reproductive Healthcare Ltd. © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.


Kwak-Kim J.,Rosalind Franklin University of Medicine and Science | Han A.R.,Rosalind Franklin University of Medicine and Science | Gilman-Sachs A.,Rosalind Franklin University of Medicine and Science | Fishel S.,CARE Fertility Group | And 2 more authors.
American Journal of Reproductive Immunology | Year: 2013

Problem: Reproductive immunology has evolved from basic research studies to clinical applications. In this study, we aim to investigate the actual application of reproductive immunology concepts and findings in clinical reproductive medicine such as recurrent pregnancy losses (RPL), repeated implantation failures (RIF), and failed in vitro fertilization (IVF) cycles. Method of Study: A web-based survey was performed on IVF-Worldwide.com. Collected data were analyzed by the computerized software. Results: A significant proportion of physicians recommend thrombophilia workups (86%), parental genetic study (79%), and immunologic evaluations (69%) to IVF candidates who have a history of RPL or chemical pregnancy losses. IVF physicians consider an immunologic workup when patients have two (30%) or three (21%) failed IVF cycles. Assays for anticardiolipin antibody, lupus anticoagulant, thyroid peroxidase antibody, and antinuclear antibody are the four most commonly ordered immunologic tests for RPL (88, 84, 50, 47% each) and RIF (68, 63, 38, 38% each). Cellular immune evaluations, such as NK assay, human leukocyte antigen study, Th1/Th2 study or immunophenotype assay, are less commonly ordered. Conclusions: Reproductive immunology principles have been applied to the clinical management of RPL, RIF, and failed IVF cycles, and a significant proportion of IVF physicians acknowledge the importance of immunologic alterations with reproductive outcomes. © 2012 John Wiley & Sons A/S.


PubMed | Ciconia Aarhus Privathospital, Klinikk Hausken, Maigaard Fertility Clinic, Aarhus University Hospital and 3 more.
Type: Journal Article | Journal: Reproductive biomedicine online | Year: 2014

The goal of embryo selection models is to select embryos with the highest reproductive potential, whilst minimizing the rejection of viable embryos. Ultimately, any embryo selection model must be tested on clinical outcome. We therefore retrospectively tested a published blastocyst prediction model on a large combined set of transferred embryos with known clinical outcome. The model was somewhat effective in that we found a relative increase of 30% for implantation in the model-selected group of embryos. There was, however, a concomitant large rejection of embryos from our test cohort, which actually resulted in pregnancy. This hypothetical experiment highlights the limitations of predicting blastulation only. Crucially, it illustrates that both sensitivity and specificity are important parameters when developing embryo selection models for prospective clinical use.


Ciray H.N.,University of Leeds | Campbell A.,CARE Fertility Group | Agerholm I.E.,Hospitalsenheden Horsens | Aguilar J.,University of Vigo | And 3 more authors.
Human Reproduction | Year: 2014

STUDY QUESTION Can the approach to, and terminology for, time-lapse monitoring of preimplantation embryo development be uniformly defined in order to improve the utilization and impact of this novel technology? SUMMARY ANSWER The adoption of the proposed guidelines for defining annotation practice and universal nomenclature would help unify time-lapse monitoring practice, allow validation of published embryo selection algorithms and facilitate progress in this field. WHAT IS KNOWN ALREADY An increasing quantity of publications and communications relating to time-lapse imaging of in vitro embryo development have demonstrated the added clinical value of morphokinetic data for embryo selection. Several articles have identified similar embryo selection or de-selection variables but have termed them differently. An evidence-based consensus document exists for static embryo grading and selection but, to date, no such reference document is available for time-lapse methodology or dynamic embryo grading and selection. STUDY DESIGN, SIZE AND DURATION A series of meetings were held between September 2011 and May 2014 involving time-lapse users from seven different European centres. The group reached consensus on commonly identified and novel time-lapse variables. PARTICIPANTS/MATERIALS, SETTING, METHODS Definitions, calculated variables and additional annotations for the dynamic monitoring of human preimplantation development were all documented. MAIN RESULTS AND THE ROLE OF CHANCE Guidelines are proposed for a standard methodology and terminology for the of use time-lapse monitoring of preimplantation embryo development. LIMITATIONS, REASONS FOR CAUTION The time-lapse variables considered by this group may not be exhaustive. This is a relatively new clinical technology and it is likely that new variables will be introduced in time, requiring revised guidelines. A different group of users from those participating in this process may have yielded subtly different terms or definitions for some of the morphokinetic variables discussed. Due to the technical processes involved in time-lapse monitoring, and acquisition of images at varied intervals through limited focal planes, this technology does not currently allow continuous monitoring such that the entire process of preimplantation embryo development may be visualized. WIDER IMPLICATIONS This is the first time that a group of experienced time-lapse users has systematically evaluated current evidence and theoretical aspects of morphokinetic monitoring to propose guidelines for a standard methodology and terminology of its use and study, and its clinical application in IVF. The adoption of a more uniform approach to the terminology and definitions of morphokinetic variables within this developing field of clinical embryology would allow practitioners to benefit from improved interpretation of data and the sharing of best practice and experience, which could impact positively and more swiftly on patient treatment outcome. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.


PubMed | CARE Nottingham, IHG Pharmaco Ltd, CARE Sheffield, Beacon CARE Fertility and 4 more.
Type: | Journal: EBioMedicine | Year: 2016

Pregnancy failure and placenta mediated pregnancy complications affect >25% of pregnancies. Although there is biological plausibility for a procoagulant mechanism underlying some of these events, antithrombotic intervention trials demonstrate limited benefit, possibly through lack of stratification in heterogeneous patient groups. The ANXA5 M2 haplotype is a possible procoagulant biomarker and was tested pragmatically to determine whether this screening and LMWH treatment normalized the outcome for ANXA5 M2 positive couples. This was a pragmatic study that aimed to measure the effectiveness of a testing (for the M2 haplotype) and treatment (LMWH) pathway in routine clinical practice where there is variation between patients. Such a study in couples with fertility problems can inform choices between treatments; it is then the management protocol which is the subject of the investigation, not the individual treatments.Couples (N=77) with one or both partners ANXA5 M2 positive demonstrated association of this haplotype with adverse IVF outcome. A pragmatic, multicenter, prospective cohort study of ANXA5 M2 haplotype screening, and LWMH treatment following embryo transfer (ET) in 103 IVF couples positive for ANXA5 M2 was performed. They were compared with a group of 1000 contemporaneous randomly selected unscreened and untreated couples undergoing assisted conception, from which 103 matched control couples were derived. The primary outcome measure was live birth incidence. Secondary outcomes were results following embryo transfer (ET) and live birth outcome by gender and M2 carriage, and allelic dose influence.The tested and treated cohort of ANXA5 M2 carriers achieved a similar live birth rate (37.9%) per ET cycle compared to both the more fertile comparison group (38.5%), and to the 103 matched controls (33.0%). Significantly more treated male carrier only couples had a live birth versus female M2 only (47.7% vs. 25.0% p=0.045).Pragmatic ANXA5 M5 screening and treatment with LMWH in couples undergoing IVF is associated with similar outcome to couples with more favorable prognostic factors. The difference in live birth outcome for treated male only carrier couples may be consistent with an additional maternal thrombophilic factor that may adversely affect pregnancy, although other mechanisms are possible. This study suggests that LMWH treatment should be started prior to clinical pregnancy.


Campbell A.,CARE Fertility Group | Fishel S.,CARE Fertility Group | Laegdsmand M.,Unisense FertiliTech
Reproductive BioMedicine Online | Year: 2014

In a previous paper, we had reported use of time-lapse monitoring to develop an aneuploidy risk classification model after identifying significant periblastulation delays in aneuploid embryos compared with euploid embryos. The model was validated subsequently in a second paper by retrospective assessment of transferred blastocysts that had also undergone time-lapse monitoring in which clinical pregnancy or live birth outcomes were established. A significant difference was seen for both outcome measures between embryos classified as low and medium risk by the model. Here we respond to the commentary entitled 'A cautionary note against embryo aneuploidy risk assessment using time-lapse imaging', which presented a case for our conclusions being unsound on the basis that maternal age, rather than aneuploidy, might be the cause of the developmental delays observed. We demonstrate that this is not the case and strengthen the argument that ploidy is a key factor influencing morphokinetics of blastulation. We also describe why the arguments made in the commentary based on comparisons between static standard observations and timings of the preimplantation embryo compared with those obtained from dynamic or time-lapse methodologies are inexact. © 2013, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.


Fishel S.,CARE Fertility Group
Reproductive BioMedicine Online | Year: 2013

The wholesale introduction of any new procedure to medical practice requires an acceptance based on evidence-based medicine, which is primarily acquired using prospective randomized controlled trials. However, for self-funded treatments, as are the majority of IVF cycles, this has always been very difficult to achieve. Generally, new technologies are introduced and adopted by patients who have failed in previous attempts at IVF. Urging patients to enter into a prospective randomized controlled trial is problematic, especially when they are self-funding; eagerness to conceive when time is against them, and/or having undergone previously failed treatment attempts, convince most patients to fund the new technology/opportunity rather than risk falling into the control arm and repeating their previous failure(s). The UK is uniquely placed to advance IVF medicine by helping practitioners and patients gain access to vital trials through the National Health Service. © 2013, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

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