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Study Question: Can the priorities for future research in infertility be identified?Summary Answer: The top 10 research priorities for the four areas of male infertility, female and unexplained infertility, medically assisted reproduction, and ethics, access, and organization of care for people with fertility problems were identified.What Is Known Already: Many fundamental questions regarding the prevention, management, and consequences of infertility remain unanswered. This is a barrier to improving the care received by those people with fertility problems.Study Design, Size, Duration: Potential research questions were collated from an initial international survey, a systematic review of clinical practice guidelines, and Cochrane systematic reviews. A rationalized list of confirmed research uncertainties was prioritized in an interim international survey. Prioritized research uncertainties were discussed during a consensus development meeting. Using a formal consensus development method, the modified nominal group technique, diverse stakeholders identified the top 10 research priorities for each of the categories male infertility, female and unexplained infertility, medically assisted reproduction, and ethics, access, and organization of care.Participants/materials, Setting, Methods: Healthcare professionals, people with fertility problems, and others (healthcare funders, healthcare providers, healthcare regulators, research funding bodies and researchers) were brought together in an open and transparent process using formal consensus methods advocated by the James Lind Alliance.Main Results and the Role Of Chance: The initial survey was completed by 388 participants from 40 countries, and 423 potential research questions were submitted. Fourteen clinical practice guidelines and 162 Cochrane systematic reviews identified a further 236 potential research questions. A rationalized list of 231 confirmed research uncertainties were entered into an interim prioritization survey completed by 317 respondents from 43 countries. The top 10 research priorities for each of the four categories male infertility, female and unexplained infertility (including age-related infertility, ovarian cysts, uterine cavity abnormalities, and tubal factor infertility), medically assisted reproduction (including ovarian stimulation, IUI, and IVF), and ethics, access, and organization of care, were identified during a consensus development meeting involving 41 participants from 11 countries. These research priorities were diverse and seek answers to questions regarding prevention, treatment, and the longer-term impact of infertility. They highlight the importance of pursuing research which has often been overlooked, including addressing the emotional and psychological impact of infertility, improving access to fertility treatment, particularly in lower resource settings, and securing appropriate regulation. Addressing these priorities will require diverse research methodologies, including laboratory-based science, qualitative and quantitative research, and population science.Limitations, Reasons For Caution: We used consensus development methods, which have inherent limitations, including the representativeness of the participant sample, methodological decisions informed by professional judgement, and arbitrary consensus definitions.Wider Implications Of the Findings: We anticipate that identified research priorities, developed to specifically highlight the most pressing clinical needs as perceived by healthcare professionals, people with fertility problems, and others, will help research funding organizations and researchers to develop their future research agenda.Study Funding/ Competing Interest(s): The study was funded by the Auckland Medical Research Foundation, Catalyst Fund, Royal Society of New Zealand, and Maurice and Phyllis Paykel Trust. Geoffrey Adamson reports research sponsorship from Abbott, personal fees from Abbott and LabCorp, a financial interest in Advanced Reproductive Care, committee membership of the FIGO Committee on Reproductive Medicine, International Committee for Monitoring Assisted Reproductive Technologies, International Federation of Fertility Societies, and World Endometriosis Research Foundation, and research sponsorship of the International Committee for Monitoring Assisted Reproductive Technologies from Abbott and Ferring. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and editor for the Cochrane Gynaecology and Fertility Group. Hans Evers reports being the Editor Emeritus of Human Reproduction. Andrew Horne reports research sponsorship from the Chief Scientist's Office, Ferring, Medical Research Council, National Institute for Health Research, and Wellbeing of Women and consultancy fees from Abbvie, Ferring, Nordic Pharma, and Roche Diagnostics. M. Louise Hull reports grants from Merck, grants from Myovant, grants from Bayer, outside the submitted work and ownership in Embrace Fertility, a private fertility company. Neil Johnson reports research sponsorship from Abb-Vie and Myovant Sciences and consultancy fees from Guerbet, Myovant Sciences, Roche Diagnostics, and Vifor Pharma. José Knijnenburg reports research sponsorship from Ferring and Theramex. Richard Legro reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. Ben Mol reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. Ernest Ng reports research sponsorship from Merck. Craig Niederberger reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and retains a financial interest in NexHand. Jane Stewart reports being employed by a National Health Service fertility clinic, consultancy fees from Merck for educational events, sponsorship to attend a fertility conference from Ferring, and being a clinical subeditor of Human Fertility. Annika Strandell reports consultancy fees from Guerbet. Jack Wilkinson reports being a statistical editor for the Cochrane Gynaecology and Fertility Group. Andy Vail reports that he is a Statistical Editor of the Cochrane Gynaecology & Fertility Review Group and of the journal Reproduction. His employing institution has received payment from HFEA for his advice on review of research evidence to inform their 'traffic light' system for infertility treatment 'add-ons'. Lan Vuong reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the present work. All authors have completed the disclosure form.Trial Registration Number: Not applicable. [ABSTRACT FROM AUTHOR]

Study Question: Can consensus definitions for the core outcome set for infertility be identified in order to recommend a standardized approach to reporting?Summary Answer: Consensus definitions for individual core outcomes, contextual statements, and a standardized reporting table have been developed.What Is Known Already: Different definitions exist for individual core outcomes for infertility. This variation increases the opportunities for researchers to engage with selective outcome reporting, which undermines secondary research and compromises clinical practice guideline development.Study Design, Size, Duration: Potential definitions were identified by a systematic review of definition development initiatives and clinical practice guidelines and by reviewing Cochrane Gynaecology and Fertility Group guidelines. These definitions were discussed in a face-to-face consensus development meeting, which agreed consensus definitions. A standardized approach to reporting was also developed as part of the process.Participants/materials, Setting, Methods: Healthcare professionals, researchers, and people with fertility problems were brought together in an open and transparent process using formal consensus development methods.Main Results and the Role Of Chance: Forty-four potential definitions were inventoried across four definition development initiatives, including the Harbin Consensus Conference Workshop Group and International Committee for Monitoring Assisted Reproductive Technologies, 12 clinical practice guidelines, and Cochrane Gynaecology and Fertility Group guidelines. Twenty-seven participants, from 11 countries, contributed to the consensus development meeting. Consensus definitions were successfully developed for all core outcomes. Specific recommendations were made to improve reporting.Limitations, Reasons For Caution: We used consensus development methods, which have inherent limitations. There was limited representation from low- and middle-income countries.Wider Implications Of the Findings: A minimum data set should assist researchers in populating protocols, case report forms, and other data collection tools. The generic reporting table should provide clear guidance to researchers and improve the reporting of their results within journal publications and conference presentations. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials statement, and over 80 specialty journals have committed to implementing this core outcome set.Study Funding/competing Interest(s): This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund, and Maurice and Phyllis Paykel Trust. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility group. Hans Evers reports being the Editor Emeritus of Human Reproduction. Richard Legro reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. Ben Mol reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. Craig Niederberger reports being the Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and a financial interest in NexHand. Ernest Ng reports research sponsorship from Merck. Annika Strandell reports consultancy fees from Guerbet. Jack Wilkinson reports being a statistical editor for the Cochrane Gynaecology and Fertility group. Andy Vail reports that he is a Statistical Editor of the Cochrane Gynaecology & Fertility Review Group and of the journal Reproduction. His employing institution has received payment from HFEA for his advice on review of research evidence to inform their 'traffic light' system for infertility treatment 'add-ons'. Lan Vuong reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the work presented. All authors have completed the disclosure form.Trial Registration Number: Core Outcome Measures in Effectiveness Trials Initiative: 1023. [ABSTRACT FROM AUTHOR]

Study Question: Can a core outcome set to standardize outcome selection, collection, and reporting across future infertility research be developed?Summary Answer: A minimum data set, known as a core outcome set, has been developed for randomized controlled trials (RCT) and systematic reviews evaluating potential treatments for infertility.What Is Known Already: Complex issues, including a failure to consider the perspectives of people with fertility problems when selecting outcomes, variations in outcome definitions, and the selective reporting of outcomes on the basis of statistical analysis, make the results of infertility research difficult to interpret.Study Design, Size, Duration: A three-round Delphi survey (372 participants from 41 countries) and consensus development workshop (30 participants from 27 countries).Participants/materials, Setting, Methods: Healthcare professionals, researchers, and people with fertility problems were brought together in an open and transparent process using formal consensus science methods.Main Results and the Role Of Chance: The core outcome set consists of: viable intrauterine pregnancy confirmed by ultrasound (accounting for singleton, twin, and higher multiple pregnancy); pregnancy loss (accounting for ectopic pregnancy, miscarriage, stillbirth, and termination of pregnancy); live birth; gestational age at delivery; birthweight; neonatal mortality; and major congenital anomaly. Time to pregnancy leading to live birth should be reported when applicable.Limitations, Reasons For Caution: We used consensus development methods which have inherent limitations, including the representativeness of the participant sample, Delphi survey attrition, and an arbitrary consensus threshold.Wider Implications Of the Findings: Embedding the core outcome set within RCTs and systematic reviews should ensure the comprehensive selection, collection, and reporting of core outcomes. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement, and over 80 specialty journals, including the Cochrane Gynaecology and Fertility Group, Ferility and Sterility, and Human Reproduction, have committed to implementing this core outcome set.Study Funding/competing Interest(s): This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund, and Maurice and Phyllis Paykel Trust. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility group. Hans Evers reports being the Editor Emeritus of Human Reproduction. José Knijnenburg reports research sponsorship from Ferring and Theramex. Richard Legro reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. Ben Mol reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. Craig Niederberger reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and retains a financial interest in NexHand. Annika Strandell reports consultancy fees from Guerbet. Ernest Ng reports research sponsorship from Merck. Lan Vuong reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the work presented. All authors have completed the disclosure form.Trial Registration Number: Core Outcome Measures in Effectiveness Trials Initiative: 1023. [ABSTRACT FROM AUTHOR]

Objective: To estimate the incidence of caesarean scar pregnancy (CSP) and to describe the management outcomes associated with this condition.Design: A national cohort study using the UK Early Pregnancy Surveillance Service (UKEPSS).Setting: 86 participating Early Pregnancy Units.Population: All women diagnosed in the participating units with CSP between November 2013 and January 2015.Methods: Cohort study of women identified through the UKEPSS monthly mailing system.Main Outcome Measures: Incidence, clinical outcomes and complications.Results: 102 cases of CSP were reported, with an estimated incidence of 1.5 per 10 000 (95% CI 1.1-1.9) maternities. Full outcome data were available for 92 women. Management was expectant in 21/92 (23%), medical in 15/92 (16%) and surgical in 56/92 (61%). The success rates of expectant, medical and surgical management were 43% (9/21), 46% (7/15) and 96% (54/56), respectively. The complication rates were 15/21 (71%) with expectant, 9/15 (60%) with medical and 20/56 (36%) with surgical management. Discharge from care (median number of days) was 82 (range 37-174) with expectant, 21 (range 10-31) with medical and 11 (range 4-49) with surgical management.Conclusions: Surgical management appears to be associated with a high success rate, low complication rate and short post-treatment follow up.Tweetable Abstract: Surgery for CSP appears to be successful, with low complication rates and short post-treatment follow up. [ABSTRACT FROM AUTHOR]

In order to assess whether markers of cell senescence are related to reproductive failure, the expression of telomerase and telomere length in endometrial biopsies from women with and without reproductive failure were assessed. This pilot study included 45 women of whom 10 had idiopathic recurrent loss of empty gestational sacs. 10 had idiopathic recurrent fetal loss (miscarriage following identification of fetal cardiac activity). 10 had recurrent implantation failure and 15 had two or more normal pregnancies (control group). An endometrial sample was collected during the window of implantation from each woman. The mean endometrial telomere length was determined by quantitative polymerase chain reaction. Telomerase expression was evaluated by immunohistochemistry. The endometria of the control group showed virtually no telomerase immunoreactivity during the window of implantation. However, the immunostaining for telomerase was significantly and differentially increased in various endometrial cellular compartments in women with recurrent reproductive failure (P < 0.05). There were no significant differences in mean telomere length between groups. These data provide a novel insight into the biological correlates of clinical types of recurrent reproductive failure and suggest that specific alterations in the regulation of endometrial cell fate are associated with different types of recurrent reproductive failure. [ABSTRACT FROM AUTHOR]

Objective: To assess the maternal response to low molecular weight heparin during pregnancy, by estimation of plasma anti-Xa activity, at three specified gestation points and in the nonpregnant state.Methods: A longitudinal, prospective, observational study was set in a tertiary referral recurrent miscarriage clinic. Twenty-four women, attending consecutively, were invited to participate and gave informed consent. Each woman had a history of recurring pregnancy loss and positive preconception screening for antiphospholipid syndrome. After confirmation of a viable pregnancy all subjects began taking 5000 IU of dalteparin once daily subcutaneously. Serial measurement of plasma anti-Xa activity after administration of dalteparin was performed at three standard gestation points (12, 24, and 36 weeks) and in the nonpregnant state (6 weeks postpartum).Results: Peak anti-Xa levels occurred at 4 hours postbolus in pregnancy, as compared with 2 hours in the nonpregnant state. The mean anti-Xa levels at 12, 24, and 36 weeks' gestation were significantly reduced, at 2 hours postinjection, as compared with the nonpregnant state (P <.001, P <.01, P <.001, respectively). The lowest dose-response curve was at 36 weeks' gestation. A repeated-measures analysis of variance found a significant difference (P <.05) between the 36-week group and the postterm group but not between any of the other groups.Conclusion: During pregnancy, differences in the pharmacokinetics of low molecular weight heparin were observed, with an overall reduction in anti-Xa activity. On the basis of this study it is questionable to extrapolate dosing and lack of dose monitoring, in pregnant women, using data derived from a nonpregnant population. [ABSTRACT FROM AUTHOR]

Antiphospholipid antibodies (aPL) are associated with an increased risk of thrombosis and recurrent miscarriage. We assessed levels of coagulation activation markers and aPL during normal pregnancy and in women with the antiphospholipid syndrome (aPS). Fluctuations in aPL levels were observed in all patients with aPS. No particular pattern of antibody positivity, or fluctuation in aPL level, was associated with poor pregnancy outcome. A significant increase was observed in levels of factor XIIa (FXIIa; P < 0.001), factor VIIa (FVIIa, P < 0.001), thrombin antithrombin complexes (TAT; P < 0.001), prothrombin fragment F1.2 (F1.2; P < 0.001) and D-dimer (DD; P < 0.05) during normal pregnancy. Factor VIIa, TAT, F1.2 and DD increased significantly before 20 weeks gestation, while a statistically significant increase in FXIIa levels was first detected between weeks 20 and 30 of gestation. In pregnant women with aPS, increases in FXIIa were similar to those in normal pregnancy, but increased FVIIa levels were not observed until after 30 weeks gestation. Similar to normal pregnancy, increased levels of TAT and F1.2 were detected in aPS pregnancies before 20 weeks gestation, but increased DD were not observed until after week 20. Surprisingly, women with aPS receiving low molecular weight heparin prophylaxis had significantly higher (P = 0.02) levels of TAT (median 8.6; interquartile range (IQR) 6.5-20.8) between weeks 20 and 30 of gestation compared to the normal pregnant population (median 5.9; IQR 4.7-7.9), thus indicating increased thrombin generation in women with aPS in mid-pregnancy. [ABSTRACT FROM AUTHOR]

Background: Infertility affects 48.5 million couples worldwide with a prevalence estimated at 3.5-16.7% in low- and middle-income countries (LMIC), and as high as 30-40% in Sub-Saharan Africa. ART services are not accessible to the majority of these infertile couples due to the high cost of treatments in addition to cultural, religious and legal barriers. Infertility and childlessness, particularly in LMIC, have devastating consequences, which has resulted in considerable interest in developing affordable IVF procedures. However, there is a paucity of evidence on the safety, efficiency and ability to replicate techniques under different field conditions, and how to integrate more affordable ART options into existing infrastructures., Objective and Rationale: This review was performed to investigate the current availability of IVF in LMIC and which other ART options are under development. This work will unfold the landscape of available and potential ART services in LMIC and is a key element in positioning infertility more broadly in the Global Public Health Agenda., Search Methods: A systematic literature search was performed of articles and gray literature on IVF and other ART options in LMIC published between January 2010 and January 2020. We selected studies on IVF and other ART treatments for infertile couples of reproductive age (18-44 years) from LMIC. The review was limited to articles published after 2010, based on the recent evolution in the field of ART practices in LMIC over the last decade. Citations from high-income countries, including data prior to 2010 and focusing on specialized ART procedures, were excluded. The literature search included PubMed, Popline, CINHAL, EMBASE and Global Index Medicus. No restrictions were applied with regard to study design or language. Two reviewers independently screened the titles and abstracts, and extracted data. A search for gray literature was performed using the 'Google' search engine and specific databases (worldcat.org, greylit.org). In addition, the reference lists of included studies were assessed., Outcomes: The search of the electronic databases yielded 3769 citations. After review of the titles and abstracts, 283 studies were included. The full texts were reviewed and a further 199 articles were excluded. The gray literature search yielded 586 citations, most of which were excluded after screening the title, and the remaining documents were excluded after full-text assessment due to duplicate entries, not from LMIC, not relevant or no access to the full document. Eighty-four citations were included as part of the review and separated into regions. The majority of the studies were observational and qualitative studies. In general, ART services are available and described in several LMIC, ranging from advanced techniques in China to basic introduction of IVF in some African countries. Efforts to provide affordable ART treatments are described in feasibility studies and efficacy studies; however, most citations were of low to very low quality. We found no studies from LMIC reporting the implementation of low-cost ART that is effective, accessible and affordable to most of those in need of the services., Wider Implications: The World Health Organization is in a unique position to provide much needed guidance for infertility management in LMIC. This review provides insight into the landscape of ART in LMIC in various regions worldwide, which will guide efforts to improve the availability, quality, accessibility and acceptability of biomedical infertility care, including ART in these countries., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Study Question: Can a core outcome set to standardize outcome selection, collection and reporting across future infertility research be developed?, Summary Answer: A minimum data set, known as a core outcome set, has been developed for randomized controlled trials (RCTs) and systematic reviews evaluating potential treatments for infertility., What Is Known Already: Complex issues, including a failure to consider the perspectives of people with fertility problems when selecting outcomes, variations in outcome definitions and the selective reporting of outcomes on the basis of statistical analysis, make the results of infertility research difficult to interpret., Study Design, Size, Duration: A three-round Delphi survey (372 participants from 41 countries) and consensus development workshop (30 participants from 27 countries)., Participants/materials, Setting, Methods: Healthcare professionals, researchers and people with fertility problems were brought together in an open and transparent process using formal consensus science methods., Main Results and the Role of Chance: The core outcome set consists of: viable intrauterine pregnancy confirmed by ultrasound (accounting for singleton, twin and higher multiple pregnancy); pregnancy loss (accounting for ectopic pregnancy, miscarriage, stillbirth and termination of pregnancy); live birth; gestational age at delivery; birthweight; neonatal mortality; and major congenital anomaly. Time to pregnancy leading to live birth should be reported when applicable., Limitations, Reasons for Caution: We used consensus development methods which have inherent limitations, including the representativeness of the participant sample, Delphi survey attrition and an arbitrary consensus threshold., Wider Implications of the Findings: Embedding the core outcome set within RCTs and systematic reviews should ensure the comprehensive selection, collection and reporting of core outcomes. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement, and over 80 specialty journals, including the Cochrane Gynaecology and Fertility Group, Fertility and Sterility and Human Reproduction, have committed to implementing this core outcome set., Study Funding/competing Interest(s): This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund and Maurice and Phyllis Paykel Trust. The funder had no role in the design and conduct of the study, the collection, management, analysis or interpretation of data, or manuscript preparation. B.W.J.M. is supported by a National Health and Medical Research Council Practitioner Fellowship (GNT1082548). S.B. was supported by University of Auckland Foundation Seelye Travelling Fellowship. S.B. reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. J.M.L.K. reports research sponsorship from Ferring and Theramex. R.S.L. reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.J.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. C.N. reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and retains a financial interest in NexHand. A.S. reports consultancy fees from Guerbet. E.H.Y.N. reports research sponsorship from Merck. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the work presented. All authors have completed the disclosure form., Trial Registration Number: Core Outcome Measures in Effectiveness Trials Initiative: 1023., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Study Question: Can the priorities for future research in infertility be identified?, Summary Answer: The top 10 research priorities for the four areas of male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care for people with fertility problems were identified., What Is Known Already: Many fundamental questions regarding the prevention, management and consequences of infertility remain unanswered. This is a barrier to improving the care received by those people with fertility problems., Study Design, Size, Duration: Potential research questions were collated from an initial international survey, a systematic review of clinical practice guidelines and Cochrane systematic reviews. A rationalized list of confirmed research uncertainties was prioritized in an interim international survey. Prioritized research uncertainties were discussed during a consensus development meeting. Using a formal consensus development method, the modified nominal group technique, diverse stakeholders identified the top 10 research priorities for each of the categories male infertility, female and unexplained infertility, medically assisted reproduction and ethics, access and organization of care., Participants/materials, Setting, Methods: Healthcare professionals, people with fertility problems and others (healthcare funders, healthcare providers, healthcare regulators, research funding bodies and researchers) were brought together in an open and transparent process using formal consensus methods advocated by the James Lind Alliance., Main Results and the Role of Chance: The initial survey was completed by 388 participants from 40 countries, and 423 potential research questions were submitted. Fourteen clinical practice guidelines and 162 Cochrane systematic reviews identified a further 236 potential research questions. A rationalized list of 231 confirmed research uncertainties was entered into an interim prioritization survey completed by 317 respondents from 43 countries. The top 10 research priorities for each of the four categories male infertility, female and unexplained infertility (including age-related infertility, ovarian cysts, uterine cavity abnormalities and tubal factor infertility), medically assisted reproduction (including ovarian stimulation, IUI and IVF) and ethics, access and organization of care were identified during a consensus development meeting involving 41 participants from 11 countries. These research priorities were diverse and seek answers to questions regarding prevention, treatment and the longer-term impact of infertility. They highlight the importance of pursuing research which has often been overlooked, including addressing the emotional and psychological impact of infertility, improving access to fertility treatment, particularly in lower resource settings and securing appropriate regulation. Addressing these priorities will require diverse research methodologies, including laboratory-based science, qualitative and quantitative research and population science., Limitations, Reasons for Caution: We used consensus development methods, which have inherent limitations, including the representativeness of the participant sample, methodological decisions informed by professional judgment and arbitrary consensus definitions., Wider Implications of the Findings: We anticipate that identified research priorities, developed to specifically highlight the most pressing clinical needs as perceived by healthcare professionals, people with fertility problems and others, will help research funding organizations and researchers to develop their future research agenda., Study Funding/competing Interest(s): The study was funded by the Auckland Medical Research Foundation, Catalyst Fund, Royal Society of New Zealand and Maurice and Phyllis Paykel Trust. G.D.A. reports research sponsorship from Abbott, personal fees from Abbott and LabCorp, a financial interest in Advanced Reproductive Care, committee membership of the FIGO Committee on Reproductive Medicine, International Committee for Monitoring Assisted Reproductive Technologies, International Federation of Fertility Societies and World Endometriosis Research Foundation, and research sponsorship of the International Committee for Monitoring Assisted Reproductive Technologies from Abbott and Ferring. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and editor for the Cochrane Gynaecology and Fertility Group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. A.W.H. reports research sponsorship from the Chief Scientist's Office, Ferring, Medical Research Council, National Institute for Health Research and Wellbeing of Women and consultancy fees from AbbVie, Ferring, Nordic Pharma and Roche Diagnostics. M.L.H. reports grants from Merck, grants from Myovant, grants from Bayer, outside the submitted work and ownership in Embrace Fertility, a private fertility company. N.P.J. reports research sponsorship from AbbVie and Myovant Sciences and consultancy fees from Guerbet, Myovant Sciences, Roche Diagnostics and Vifor Pharma. J.M.L.K. reports research sponsorship from Ferring and Theramex. R.S.L. reports consultancy fees from AbbVie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. E.H.Y.N. reports research sponsorship from Merck. C.N. reports being the Co Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring and retains a financial interest in NexHand. J.S. reports being employed by a National Health Service fertility clinic, consultancy fees from Merck for educational events, sponsorship to attend a fertility conference from Ferring and being a clinical subeditor of Human Fertility. A.S. reports consultancy fees from Guerbet. J.W. reports being a statistical editor for the Cochrane Gynaecology and Fertility Group. A.V. reports that he is a Statistical Editor of the Cochrane Gynaecology & Fertility Review Group and the journal Reproduction. His employing institution has received payment from Human Fertilisation and Embryology Authority for his advice on review of research evidence to inform their 'traffic light' system for infertility treatment 'add-ons'. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the present work. All authors have completed the disclosure form., Trial Registration Number: N/A., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Study Question: Can consensus definitions for the core outcome set for infertility be identified in order to recommend a standardized approach to reporting?, Summary Answer: Consensus definitions for individual core outcomes, contextual statements and a standardized reporting table have been developed., What Is Known Already: Different definitions exist for individual core outcomes for infertility. This variation increases the opportunities for researchers to engage with selective outcome reporting, which undermines secondary research and compromises clinical practice guideline development., Study Design, Size, Duration: Potential definitions were identified by a systematic review of definition development initiatives and clinical practice guidelines and by reviewing Cochrane Gynaecology and Fertility Group guidelines. These definitions were discussed in a face-to-face consensus development meeting, which agreed consensus definitions. A standardized approach to reporting was also developed as part of the process., Participants/materials, Setting, Methods: Healthcare professionals, researchers and people with fertility problems were brought together in an open and transparent process using formal consensus development methods., Main Results and the Role of Chance: Forty-four potential definitions were inventoried across four definition development initiatives, including the Harbin Consensus Conference Workshop Group and International Committee for Monitoring Assisted Reproductive Technologies, 12 clinical practice guidelines and Cochrane Gynaecology and Fertility Group guidelines. Twenty-seven participants, from 11 countries, contributed to the consensus development meeting. Consensus definitions were successfully developed for all core outcomes. Specific recommendations were made to improve reporting., Limitations, Reasons for Caution: We used consensus development methods, which have inherent limitations. There was limited representation from low- and middle-income countries., Wider Implications of the Findings: A minimum data set should assist researchers in populating protocols, case report forms and other data collection tools. The generic reporting table should provide clear guidance to researchers and improve the reporting of their results within journal publications and conference presentations. Research funding bodies, the Standard Protocol Items: Recommendations for Interventional Trials statement, and over 80 specialty journals have committed to implementing this core outcome set., Study Funding/competing Interest(s): This research was funded by the Catalyst Fund, Royal Society of New Zealand, Auckland Medical Research Fund and Maurice and Phyllis Paykel Trust. Siladitya Bhattacharya reports being the Editor-in-Chief of Human Reproduction Open and an editor of the Cochrane Gynaecology and Fertility Group. J.L.H.E. reports being the Editor Emeritus of Human Reproduction. R.S.L. reports consultancy fees from Abbvie, Bayer, Ferring, Fractyl, Insud Pharma and Kindex and research sponsorship from Guerbet and Hass Avocado Board. B.W.M. reports consultancy fees from Guerbet, iGenomix, Merck, Merck KGaA and ObsEva. C.N. reports being the Editor-in-Chief of Fertility and Sterility and Section Editor of the Journal of Urology, research sponsorship from Ferring, and a financial interest in NexHand. E.H.Y.N. reports research sponsorship from Merck. A.S. reports consultancy fees from Guerbet. J.W. reports being a statistical editor for the Cochrane Gynaecology and Fertility Group. A.V. reports that he is a Statistical Editor of the Cochrane Gynaecology & Fertility Review Group and of the journal Reproduction. His employing institution has received payment from Human Fertilisation and Embryology Authority for his advice on review of research evidence to inform their 'traffic light' system for infertility treatment 'add-ons'. N.L.V. reports consultancy and conference fees from Ferring, Merck and Merck Sharp and Dohme. The remaining authors declare no competing interests in relation to the work presented. All authors have completed the disclosure form., Trial Registration Number: Core Outcome Measures in Effectiveness Trials Initiative: 1023., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Study Questions: We aim to produce, disseminate and implement a core outcome set for future infertility research., What Is Known Already: Randomized controlled trials (RCTs) evaluating infertility treatments have reported many different outcomes, which are often defined and measured in different ways. Such variation contributes to an inability to compare, contrast and combine results of individual RCTs. The development of a core outcome set will ensure outcomes important to key stakeholders are consistently collected and reported across future infertility research., Study Design Size Duration: This is a consensus study using the modified Delphi method. All stakeholders, including healthcare professionals, allied healthcare professionals, researchers and people with lived experience of infertility will be invited to participate., Participants/materials Setting Methods: An international steering group, including people with lived experience of infertility, healthcare professionals, allied healthcare professionals and researchers, has been formed to guide the development of this core outcome set. Potential core outcomes have been identified through a comprehensive literature review of RCTs evaluating treatments for infertility and will be entered into a modified Delphi method. Participants will be asked to score potential core outcomes on a nine-point Likert scale anchored between one (not important) and nine (critical). Repeated reflection and rescoring should promote convergence towards consensus 'core' outcomes. We will establish standardized definitions and recommend high-quality measurement instruments for individual core outcomes., Study Funding/competing Interests: This project is funded by the Royal Society of New Zealand Catalyst Fund (3712235). BWM reports consultancy fees from Guerbet, Merck, and ObsEva. R.S.L. reports consultancy fees from Abbvie, Bayer, Fractyl and Ogeda and research sponsorship from Ferring. S.B. is the Editor-in-Chief of Human Reproduction Open. The remaining authors declare no competing interests.

What is the recommended diagnostic work-up of female genital anomalies according to the European Society of Human Reproduction and Embryology (ESHRE)/European Society for Gynaecological Endoscopy (ESGE) system? The ESHRE/ESGE consensus for the diagnosis of female genital anomalies is presented. Accurate diagnosis of congenital anomalies still remains a clinical challenge due to the drawbacks of the previous classification systems and the non-systematic use of diagnostic methods with varying accuracy, with some of them quite inaccurate. Currently, a wide range of non-invasive diagnostic procedures are available, enriching the opportunity to accurately detect the anatomical status of the female genital tract, as well as a new objective and comprehensive classification system with well-described classes and sub-classes. The ESHRE/ESGE Congenital Uterine Anomalies (CONUTA) Working Group established an initiative with the goal of developing a consensus for the diagnosis of female genital anomalies. The CONUTA working group and imaging experts in the field have been appointed to run the project. The consensus is developed based on (1) evaluation of the currently available diagnostic methods and, more specifically, of their characteristics with the use of the experts panel consensus method and of their diagnostic accuracy performing a systematic review of evidence and (2) consensus for (a) the definition of where and how to measure uterine wall thickness and (b) the recommendations for the diagnostic work-up of female genital anomalies, based on the results of the previous evaluation procedure, with the use of the experts panel consensus method. Uterine wall thickness is defined as the distance between interostial line and external uterine profile at the midcoronal plane of the uterus; alternatively, if a coronal plane is not available, the mean anterior and posterior uterine wall thickness at the longitudinal plane could be used. Gynaecological examination and two-dimensional ultrasound (2D US) are recommended for the evaluation of asymptomatic women. Three-dimensional ultrasound (3D US) is recommended for the diagnosis of female genital anomalies in "symptomatic" patients belonging to high-risk groups for the presence of a female genital anomaly and in any asymptomatic woman suspected to have an anomaly from routine avaluation. Magnetic resonance imaging (MRI) and endoscopic evaluation are recommended for the sub-group of patients with suspected complex anomalies or in diagnostic dilemmas. Adolescents with symptoms suggestive for the presence of a female genital anomaly should be thoroughly evaluated with 2D US, 3D US, MRI and endoscopy. The various diagnostic methods should be used in a proper way and evaluated by experts to avoid mis-, over- and underdiagnosis. The role of a combined ultrasound examination and outpatient hysteroscopy should be prospectively evaluated. It is a challenge for further research, based on diagnosis, to objectively evaluate the clinical consequences related to various degrees of uterine deformity.

Rationale: Pseudomonas aeruginosa infection is a significant cause of morbidity and mortality in patients with cystic fibrosis and is associated with a high economic burden. A recently published comparator trial demonstrated that outcomes in patients with cystic fibrosis with chronic P. aeruginosa infections switched from tobramycin solution for inhalation to aztreonam lysine for inhalation were better than those of patients who continued on tobramycin., Objectives: To compare overall costs of treatment of chronic inhaled tobramycin and aztreonam lysine in patient with cystic fibrosis who have chronic Pseudomonas infection, taking differences in outcomes into account., Methods: A cost-effectiveness analysis with a 3-year time horizon was performed to simulate the economic consequences of either treatment from the perspective of a third party payer in the United States. We extrapolated results from the comparator trial and used data regarding clinical outcomes, quality of life, and costs from published literature and proprietary databases. A Markov structure was used to consider transitions between health states, defined principally by levels of percent predicted of FEV1. Extensive scenario and probabilistic sensitivity analyses were performed., Measurements and Main Results: Use of aztreonam lysine for inhalation was associated with an average cost saving of $41,947 per patient over 3 years, as well as greater quality-adjusted life-years and total life-years. Scenario analyses demonstrated that these findings were robust to changes in key assumptions., Conclusions: It appears, with high likelihood, that the use of aztreonam solution for inhalation is associated with cost savings, an increase in quality-adjusted life-years, and improved clinical outcomes among patients with extensive prior use of tobramycin solution for inhalation who are naive to inhaled aztreonam lysine.

Specialist training in reproductive medicine within Europe continues to evolve. Recent revisions, updates, and initiatives have helped to refine the core educational needs for the specialist trainee., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Pregnancy loss prior to viability is common and research in the field is extensive. Unfortunately, terminology in the literature is inconsistent. The lack of consensus regarding nomenclature and classification of pregnancy loss prior to viability makes it difficult to compare study results from different centres. In our opinion, terminology and definitions should be based on clinical findings, and when possible, transvaginal ultrasound. With this Early Pregnancy Consensus Statement, it is our goal to provide clear and consistent terminology for pregnancy loss prior to viability., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Chronic pain (CP) poses a diverse and substantial burden for employees, employers, and society. The deleterious consequences of CP in the workplace are frequently underestimated., Objective: To estimate the burden of CP in the European workplace., Methods: A systematic review following PRISMA statement guidelines was conducted to identify studies reporting work-related outcomes for people with CP. EMBASE, MEDLINE, EconLit, and Cochrane Library databases were searched up to 18th August 2010., Results: We identified 91 observational studies. Few were specifically designed to investigate the association between CP, productivity, and employment. The focus for this review was studies clearly reporting outcomes relating to the burden of CP on employment status (n = 37), sickness absence (absenteeism, n = 47), and loss of productivity because of reduced ability at work (presenteeism, n = 8)., Conclusion: The body of evidence identified from the systematic review indicates that CP has a substantial negative impact on work-related outcomes, supporting the importance of interventions to reduce the burden of CP. Well-designed prospective studies specifically assessing the direct consequences of CP on employment are needed to confirm these findings., (© 2012 Abacus International. Pain Practice © 2012 World Institute of Pain.)

Purpose of Review: Acquired and inherited thrombophilia is an important research avenue in the recurrent miscarriage field. The optimum treatment for patients with recurrent miscarriage and a confirmed thrombophilia remains a contentious issue. We aim to appraise and explore the latest research in the field of thrombophilia and recurrent miscarriage in this review., Recent Findings: Antiphospholipid syndrome (APS) is the only proven thrombophilia that is associated with adverse pregnancy outcomes. Research involving inherited thrombophilia and recurrent miscarriage is limited to small observational studies with small and heterogeneous populations. Aspirin and heparin therapy are frequently prescribed for APS, yet there is no robust evidence for the most efficacious regime. The combination of inherited hypercoagulability and environmental factors in association with recurrent miscarriage has recently been explored as an aid to identify high-risk individuals., Summary: The cause of recurrent miscarriage is multifactorial and appropriate treatment continues to be a challenge. Laboratory tests need to be standardized and well designed multicentre research trials are essential to expand on the current knowledge base with the aim to produce strong evidence-based medicine.

Background:  Although women with antiphospholipid antibodies (APLAs) are at increased risk of recurrent miscarriage, the outcome of a subsequent pregnancy is not clearly elucidated., Objectives: To assess the pregnancy outcome of a subsequent pregnancy in women with APLAs and compare this outcome with women with unexplained recurrent miscarriage., Methods:  We performed a cohort study among all women who attended the Miscarriage Clinic at Liverpool Women's Hospital between 1987 and 2006 after being referred due to recurrent miscarriage (≥2 consecutive pregnancy losses). All women underwent a standardized investigation sequence. Women with other reasons for recurrent miscarriage were excluded., Results:  A total of 693 women fulfilled the selection criteria, of whom 176 (25%) had APLAs. One hundred and twenty-two (69%) women with APLAs had a subsequent live birth compared with 324 (63%) women with unexplained recurrent miscarriage (OR 1.3, 95% CI 0.9-1.9). No differences were found for birth weight, gestational age, and intra-uterine growth restriction. When treatment was analyzed, 53/67 (79%) of women with APLAs who had received aspirin and heparin during their pregnancy had a live birth, compared with 64/104 (62%) of women with APLAs who received aspirin only (adjusted OR 2.7, 95% CI 1.3-5.8). In unexplained recurrent miscarriage, stratification for treatment showed no differences in outcome., Conclusion: The prognosis of a subsequent pregnancy in women with APLAs is good. Although this was not a randomized clinical trial, combined treatment of aspirin and heparin seemed associated with a better outcome in women with APLAs, but not in women with unexplained recurrent miscarriage., (© 2010 International Society on Thrombosis and Haemostasis.)

BACKGROUND The aim was to evaluate the impact of early pregnancy events and complications as predictors of adverse obstetric outcome. METHODS We conducted a literature review on the impact of first trimester complications in previous and index pregnancies using Medline and Cochrane databases covering the period 1980-2008. RESULTS Clinically relevant associations of adverse outcome in the subsequent pregnancy with an odds ratio (OR) > 2.0 after complications in a previous pregnancy are the risk of perinatal death after a single previous miscarriage, the risk of very preterm delivery (VPTD) after two or more miscarriages, the risk of placenta praevia, premature preterm rupture of membranes, VPTD and low birthweight (LBW) after recurrent miscarriage and the risk of VPTD after two or more termination of pregnancy. Clinically relevant associations of adverse obstetric outcome in the ongoing pregnancy with an OR > 2.0 after complications in the index pregnancy are the risk of LBW and very low birthweight (VLBW) after a threatened miscarriage, the risk of pregnancy-induced hypertension, pre-eclampsia, placental abruption, preterm delivery (PTD), small for gestational age and low 5-min Apgar score after detection of an intrauterine haematoma, the risk of VPTD and intrauterine growth restriction after a crown-rump length discrepancy, the risk of VPTD, LBW and VLBW after a vanishing twin phenomenon and the risk of PTD, LBW and low 5-min Apgar score in a pregnancy complicated by severe hyperemesis gravidarum. CONCLUSIONS Data from our literature review indicate, by finding significant associations, that specific early pregnancy events and complications are predictors for subsequent adverse obstetric and perinatal outcome. Though, some of these associations are based on limited or small uncontrolled studies. Larger population-based controlled studies are needed to confirm these findings. Nevertheless, identification of these risks will improve obstetric care.

Background: Recurrent miscarriage (RM) has been associated with the thrombophilia, activated protein C resistance (APCR). The factor V Leiden mutation located on the B domain of the factor V gene, causes 95% of APCR and since the B domain is pivotal to APCR, it seemed plausible that other mutations or polymorphisms affecting this active domain may instigate acquired APCR. The objective of this study was to determine whether other polymorphisms exist on the parts of the gene encoding the B domain of the factor V in women with acquired APCR and RM., Methods: There were 51 women with RM and acquired APCR, 24 parous women (with no history of miscarriage and at least one normal full-term delivery) and 15 women with a history of idiopathic RM, who formed the study and two control groups, respectively. Six exons of the B domain of the factor V gene were intensely analysed using polymerase chain reactions, single-strand conformation polymorphism, genetic sequencing and restriction enzyme digestion analysis to identify single-nucleotide polymorphisms (SNPs)., Results: A significantly increased frequency of some SNPs on the factor V gene were observed in the women with acquired APCR and RM when compared with the control groups., Conclusions: The presence of some of these SNPs may predispose these women to acquired APCR and RM.

This study investigated the hypothesis that different types of recurrent miscarriage history are associated with different markers of endometrial receptivity. A secondary objective was to compare the distribution in endometrial epithelium of a group of cell surface components with roles in cell adhesion. Of 54 women who had an implantation window endometrial biopsy, 17 had idiopathic recurrent fetal loss, 17 had idiopathic recurrent loss of empty gestation sacs, 10 had recurrent implantation failure and 10 had two or more normal pregnancies. Immunohistochemistry and HSCORE was used with frozen sections for integrins (alpha1beta1, alpha4beta1, alpha(v)beta3), and MUC1 (BC2) and paraffin sections for osteopontin and MUC1 (BC3). Epithelial beta1 integrins were located primarily in the basolateral membrane compartment. Consistently greater expression of alpha4beta1, alpha1beta1 and alpha(v)beta3 was seen in the luminal epithelium and greater expression of alpha4beta1 and alpha1beta1 in the glandular epithelium of women with recurrent fetal loss when compared with those with recurrent loss of empty gestation sacs. There were no significant differences in the expression of osteopontin or MUC1 between groups. Different endometrial integrin distribution was found in women suffering different types of recurrent pregnancy loss. It is postulated that impairment of the implantation barrier contributes to recurrent fetal loss.

Quantitative proteome analyses of meristematic and nonmeristematic tissues from Medicago truncatula primary and lateral roots and meristem tissues from plants treated with acetohydroxyacid synthase-inhibiting herbicides were made. The accumulation of 81 protein spots changed in meristematic and nonmeristematic tissues and 51 protein spots showed significant changes in accumulation in herbicide-treated meristems. Identified proteins indicate two trends, (i) increased accumulation of cell division and redox-mediating proteins in meristems compared to nonmeristematic tissues and (ii) increased accumulation of pathogenesis-related and decreased accumulation of metabolic proteins in herbicide-treated roots.

Uterine natural killer (uNK) cells are the most abundant leukocytes in preimplantation endometrium and early pregnancy decidua. Maternal uNK cells are adjacent to, and have the ability to interact directly with, fetal trophoblasts. uNK cells can secrete an array of cytokines that are important in angiogenesis and thus placental development and the establishment of pregnancy. Increased numbers of uNK cells have been associated with reproductive failure. The number of preimplantation uNK cells has been reduced with prednisolone. However, despite these exciting advances in understanding of the uNK cells, considerably more work needs to be done to establish a specific role for uNK cells and to use uNK cells as a test of malfunctioning endometrium and the basis for future treatment for reproductive failure.

Objective: To test the hypothesis that high numbers of uterine natural killer (uNK) cells in the endometrium of women with recurrent miscarriage (RM) could be reduced with prednisolone., Design: A before and after study., Setting: A tertiary referral teaching hospital., Patient(s): Eighty-five women with idiopathic RM recruited from all over the UK and 18 women attending for sterilization (controls)., Intervention(s): An endometrial sample was taken on day 21 +/- 2 of the menstrual cycle. Immunohistochemistry was used to identify uNK (CD56+, CD16-, CD3-). Twenty-nine women with RM and >5% uNK agreed to take 20 mg oral prednisolone daily from day 1 to 21 of their menstrual cycle, when a second biopsy was obtained and analyzed., Main Outcome Measure(s): The percentage of stromal cells that were uNK. The normal range was defined using control samples as <5%., Result(s): Women with RM had significantly more uNK than the controls (P=.008). Prednisolone treatment significantly reduced the number of CD56 cells in the endometrium, from a median of 14% (before) to 9% (after) (P=.0004)., Conclusion(s): We have demonstrated that high numbers of uNK in preimplantation endometrium of women with recurrent miscarriage can be reduced with administration of prednisolone.

Background: Recurrent miscarriage has been associated with antiphospholipid syndrome (APS) and other prothombotic conditions. We tested the hypothesis that women diagnosed as having APS as an aetiological factor for their miscarriages were at higher risk of thrombosis than those with idiopathic recurrent miscarriage., Methods: A retrospective case-control study was performed using validated questionnaires. A total of 141 women with recurrent miscarriage and APS alone were matched with 141 women with idiopathic recurrent miscarriage for age, number and type of pregnancy loss and number of years of follow-up. A subgroup of eight women included those who initially presented with recurrent miscarriage, thrombosis and APS., Results: The mean length of follow-up was 7.3 years and response rate 74%. The incidence of thrombosis was similar in the recurrent miscarriage and APS women (6/1000 women-years) and in the idiopathic recurrent miscarriage women (2/1000 women-years) (P = 0.18). All eight women who presented with recurrent miscarriage, APS and thrombosis reported further thrombotic events., Conclusions: Both idiopathic and APS-associated recurrent miscarriage were associated with a similar long-term risk of thrombosis.

Background: The aim of this study was to assess the effect of long-term low molecular weight heparin (LMWH) on bone mineral density (BMD) during pregnancy., Methods: Fifty-five patients with recurrent miscarriage and known thrombophilia (antiphospholipid syndrome) were followed through pregnancy in an ethically approved prospective observational study. All women had dual energy X-ray absorptiometry (DEXA) scans at the lumbar spine (L1-L4) performed within 6 months prior to conception and in the immediate post-natal period, within 6 weeks of delivery. LMWH (5000 U/day) plus low-dose aspirin was commenced after a positive urine pregnancy test and continued throughout pregnancy and after delivery until 6 weeks post-partum. A group of 20 volunteers with recurrent miscarriage, not requiring any treatment intervention, acted as controls and were monitored in an identical fashion., Results: Characteristics were not significantly different between treated patients and controls. Both groups showed a similar loss in lumbar spine (L1-L4) BMD by the end of the pregnancy [LMWH 4.17% or 0.045 g/cm(3), 95% confidence interval (CI) 0.036-0.062 versus control 3.56% or 0.043 g/cm(3), 95% CI 0.027-0.059]. However, the difference in bone loss between the groups was not statistically significant (0.002 g/cm(3), CI -0.0124 to 0.00865; P = 0.88). No patient suffered vertebral fracture., Conclusions: Bone loss associated with the use of long-term LMWH is not significantly different from physiological losses during pregnancy.

No cause can be found in 50% of patients with recurrent miscarriage. Recent research has shown that high levels of natural killer (NK) cells within the endometrium may be associated with idiopathic recurrent miscarriage. This case report describes a patient in whom an excessive number of uterine NK cells were found. She received preconceptual prednisolone and delivered a live baby. This is a novel observation of untested significance.

Activated protein C resistance is a thrombophilia with an established role in producing thrombosis which more recently has been implicated in the pathogenesis of pregnancy loss. This review will analyse recent literature to evaluate this association and address the gestation and type of pregnancy loss.

Recent data on recurrent miscarriage (RM) is discussed in the framework of the selection failure hypothesis which states, 'Recurrent miscarriage is the result of failure of the prevention of 'poor quality' embryos implanting, allowing embryos that are destined to fail to implant and present clinically as recurrent miscarriage. Thus, recurrent miscarriage is a failure of nature's quality control.' The assumption that RM results from the maternal rejection of normal fetuses is challenged and evidence reviewed regarding the contribution of abnormal embryos and endometrial receptivity. Further research is needed to understand the mechanisms of maternal tract-embryo interaction and move towards improved management of recurrent pregnancy loss.

Background: In recurrent pregnancy loss, there is much debate about cause and association, as exact pathophysiological mechanisms have not been elucidated. The aim of this study was to assess whether recurrent pregnancy loss (RPL) patterns differ according to causal/associated conditions, suggesting differing disease processes., Methods: Following investigation, 427 women with RPL were classified into the following 'diagnostic' groups: idiopathic, oligomenorrhoea, antiphospholipid syndrome (APS) and 'possible' APS. A total of 323 subsequently conceived, and underwent serial ultrasonography in early pregnancy; of these, 87 (26.9%) miscarried, and the types of pregnancy loss for the four diagnostic groups were allocated to either embryo loss (fetal heart never seen) and fetal loss (fetal heart seen prior to pregnancy loss)., Results: Overall, there were 75 embryonic losses and 12 fetal losses. The fetal loss rates in each group were similar: idiopathic 5.1%, oligomenorrhoea 3.4%, 'possible' APS 4.9% and APS 4.8%., Conclusions: Serial ultrasound helps to discriminate type of pregnancy loss and demonstrates that embryo loss is more common than fetal loss. More importantly, pregnancy loss patterns do not seem to differ between diagnostic groups in a treated population. The fetal loss rate in each of the diagnostic groups is similar to that in other reported populations.

Objective: To determine the incidence of positive pregnancy test on the day of laparoscopic sterilisation., Design: Prospective longitudinal observational study., Setting: Gynaecology unit in a UK teaching hospital., Sample: Between 1 January 1997 and 31 December 1998, eight hundred and two consecutive women were admitted for laparoscopic sterilisation after assessment in the gynaecology clinic. On the day of planned surgery, all women had a pregnancy test performed on a urine sample taken that morning following overnight fasting, immediately prior to operation., Main Outcome Measures: A positive pregnancy test on the day of planned surgery., Results: Of 802 women tested, 21 (2.6%) were pregnant. A careful medical history taken before surgery revealed evidence of amenorrhoea and menstrual irregularity in 17 of the pregnant women. Of the 21 pregnant women, 11 underwent termination of pregnancy, six continued the pregnancy, four had a miscarriage and one had an ectopic pregnancy., Conclusion: The routine practice of pregnancy testing on the day of laparoscopic sterilisation introduced in our hospital should continue to be part of a thorough clinical assessment before surgery. This may help to reduce the considerable level of existing litigation in a high risk area of gynaecological practice.

Vaginal hysterectomy is associated with significant risk of vaginal vault haematoma (40%) and febrile morbidity (30%). Numerous interventions have been used to try and avoid these complications but very few have been shown to be effective.

The effects of pregnancy on bone turnover and the potential risk of developing an osteoporotic fracture in pregnancy are controversial. Utilizing biochemical markers of bone formation and resorption and dual-energy X-ray absorptiometry (DEXA), bone turnover before, during, and after pregnancy was studied in detail. Ten women (mean age 30 years; range 23-40) were recruited. Prepregnancy data were obtained and then a review was performed at 2-week intervals , once pregnancy was confirmed, until 14 weeks of gestation and thereafter monthly until term. Bone mineral density (BMD) was estimated by DEXA scanning of hip, spine, and forearm preconception and postpartum. In addition, BMD of the forearm at 14 weeks and 28 weeks gestation was obtained. All pregnancies had a successful outcome. Urinary free pyridinium cross-links, free pyridinoline (fPyr) and free deoxypyridinoline (fDPyr), were normal prepregnancy (mean [+/-SD]) 14.6 nmol/mmol (1.8) and 5.0 nmol/mmol (1.0) creat, respectively. By 14 weeks, they had increased to 20.8 nmol/mmol (4.3) and 6.1 nmol mmol (1.4) (both p < 0.02) and by 28 weeks to 26.3 nmol/mmol (5.6) and 7.4 nmol/mmol (1.6) (both p < 0.01). The ratio of fPyr to fDPyr remained constant. A similar significant increase was observed in N-telopeptide (NTx). Bone formation was assessed by measurement of carboxyterminal propeptide of type 1 collagen (P1CP) and bone-specific alkaline phosphatase (BSAP). Neither were altered significantly before 28 weeks, but subsequently mean P1CP increased from 110 microg/liter (23) to 235 microg/liter (84) at 38 weeks and mean BSAP increased from 11.1 U/liter (5.0) to 28.6 U/liter (11.1) (p < 0.01 for both variables). Lumbar spine (L1-L4) BMD decreased from a prepregnancy mean of 1.075 g/cm (0.115) to 1.054 g/cm2 (0.150) postpartum (p < 0.05). Total hip BMD decreased from a prepregnancy mean of 0.976 g/cm2 (0.089) to 0.941 g/cm2 (0.097) (p < 0.05). Forearm BMD at midradius, one-third distal and ultradistal decreased but did not reach statistical significance. As assessed by these bone markers, in the first 2 trimesters of pregnancy, bone remodeling is uncoupled with a marked increase in bone resorption. A corresponding increase in formation markers is not observed until the third trimester. Spinal BMD exhibits a significant decrease from prepregnancy to the immediate postpartum period with a mean reduction in BMD of 3.5 % in 9 months.

Recurrent miscarriage is a difficult clinical problem occurring in approximately 1-2% of fertile women. Following investigation, most cases fail to reveal an identifiable cause and are therefore classified as idiopathic. The aim of this study was to identify important gestational milestones for pregnancy success prediction in women following idiopathic recurrent miscarriage. A total of 325 consecutive patients with idiopathic recurrent miscarriage was involved in a prospective longitudinal observational study. Patients were identified from a miscarriage database of 716 patients. Preconceptual presentation and investigation excluded patients from the study sample with known associations of recurrent pregnancy loss, such as antiphosholipid syndrome, oligomenorrhoea, mid-trimester loss and other rare causes, e.g. abnormal parental karyotype. Following early presentation in a subsequent pregnancy, all patients followed a standard clinic protocol including fetal viability ultrasonography on a fortnightly basis throughout the first trimester. Kaplan-Meier curves were constructed for pregnancy outcome. Out of 325 idiopathic cases, 70% (n = 226) conceived, with a 75% success rate. Of 55 miscarriages, longitudinal assessment showed that six losses occurred following detection of fetal cardiac activity (3%). Data from this large study group have enabled accurate prediction of future pregnancy success and have established important gestational milestones for women with idiopathic recurrent miscarriage.

Variations in blood concentrations of antiphospholipid antibodies (APA) were investigated through the course of pregnancy in women who had a history of recurrent pregnancy loss, and were related to changes in pregnancy outcome. Serial measurements of APA were made in 16 women with antiphospholipid syndrome (APS) and 16 with negative APA tests pre-pregnancy. There was considerable intraindividual variation in test results through pregnancy. There was a significantly higher ratio of dilute Russell's viper venom time and IgG ACA titre in the first trimester compared with results pre-pregnancy in women with APS. Furthermore, transiently positive APA results were noted in the control group during pregnancy and some women with antiphospholipid syndrome tested negative for APA in mid- and late pregnancy. We have demonstrated clinically important variations in the results of tests for APA during pregnancy in women with APS.