Potential risk factors for caesarean scar pregnancy: a retrospective case-control study.

STUDY QUESTION: What are the important risk factors for having a caesarean scar pregnancy (CSP)? SUMMARY ANSWER: Independent risk factors were smoking in the first trimester, higher parity, and previous caesarean section (CS) before the index caesarean delivery. WHAT IS KNOWN ALREADY: A spectrum of risk factors for CSP has been suggested but not proven: parity, number of previous caesarean section, elective as opposed to emergency CS, IVF-pregnancy, breech presentation, previous gynaecological surgery as well as suture technique. STUDY DESIGN SIZE DURATION: This retrospective case-control study included 31 women with a CSP during the period 2003-2018 treated at a tertiary care centre for gynaecology and reproduction. A control cohort of 8300 women with a history of a CS and a subsequent delivery during the same time period was formed. PARTICIPANTS/MATERIALS SETTING METHODS: Variables describing demography, lifestyle factors, and reproductive and obstetric history were retrieved from medical records and the obstetric hospital database. Logistic regression analyses were applied to identify potential risk factors. MAIN RESULTS AND THE ROLE OF CHANCE: In a multivariable analysis, smoking in first trimester (adjusted odds ratio (OR) 3.03, 95% CI 1.01-9.07), higher parity (adjusted OR 1.30, 95% CI 1.03-1.64) and previous CS in addition to the preceding CS (adjusted OR 3.43, 95% CI 1.35-8.66) were independently predictive of a CSP. An elective CS at the index pregnancy was associated with an increased risk of CSP but did not remain significant in the multivariable analysis. LIMITATIONS REASONS FOR CAUTION: CSP is a very rare phenomenon and several of the risk factor estimates are imprecise. Nevertheless, significant risk factors could be identified. Another limitation is the lack of electronically recorded details on suture techniques. WIDER IMPLICATIONS OF THE FINDINGS: The identified factors, namely higher parity and previous CS before the index caesarean section, are in accordance with previously suggested risk factors. Whether there is a true risk association between elective CS and future CSP needs to be investigated further. Smoking in the first trimester is a new finding, which has a plausible rationale. These factors should be recognised when counselling women after a caesarean delivery, particularly in a subsequent pregnancy with early complications. STUDY FUNDING/COMPETING INTERESTS: This work was supported by a grant from the Swedish state under the agreement between the Swedish government and the county councils the ALF-agreement (ALFGBG-720291). None of the authors has any conflict of interest to declare.

Gonadotrophin stimulation and risk of relapse in breast cancer.

STUDY QUESTION: Is gonadotrophin stimulation as part of IVF associated with an increased risk of relapse in breast cancer? SUMMARY ANSWER: Controlled ovarian stimulation (COS) in connection with IVF in women with previous breast cancer was not associated with an increased risk of breast cancer relapse. WHAT IS KNOWN ALREADY: Breast cancer is the most common malignancy among women worldwide and the leading cause of cancer death among females. The use of COS with gonadotrophins with subsequent cryopreservation of oocytes or embryos in order to enhance the chances of pregnancy after cancer treatment is the current most established fertility preservation method for women with breast cancer. To date, there are only a few small retrospective hospital-based controlled studies evaluating the risk of breast cancer relapse in patients undergoing fertility preservation with or without COS, showing no evident risk of relapse in breast cancer after the use of gonadotoxic agents. STUDY DESIGN SIZE DURATION: This was a retrospective, population-based cohort study comprising 5857 women with previous breast cancer of whom 337 were exposed to COS. Exposure (COS) and outcomes (relapse and death) were identified for all patients from 2005 to 2014 by assessing the National Quality Register for Assisted Reproduction, the Swedish Medical Birth Register, the National Patient Register, the Swedish Prescribed Drug Register, the Swedish Cause of Death Register, the National Breast Cancer Register and the Swedish Cancer Register. Matching according to set criteria was possible for 334 women, who constituted the control group. A total of 274 women had undergone IVF after completing breast cancer treatment and 63 women had undergone COS for fertility preservation at the time of breast cancer diagnosis. PARTICIPANTS/MATERIALS SETTING METHODS: Women aged 20-44 years previously diagnosed with breast cancer and exposed to COS were matched for age at breast cancer diagnosis ±5 years, tumour size and lymph node involvement with a non-exposed control group, including women with known T- and N-stages. In a subsequent analysis, the matched cohort was assessed by also including women with unknown T- and N-stages. A secondary analysis comprised the entire non-matched cohort, including all women with known T- and N-stages. Also here, a subsequent analysis included women with missing data for T- and N-stages. The risk of relapse in breast cancer was estimated as crude hazard ratios (HRs) and 95% CI using Cox proportional hazards models in the primary and secondary analyses where T- and N-stages were known: otherwise the risks of relapse were only given descriptively. MAIN RESULTS AND THE ROLE OF CHANCE: In the primary matched analysis, relapse occurred in 20 of 126 women exposed to COS (15.9%) compared with 39 of 126 (31.0%) in the control cohort (HR = 0.70; 95% CI 0.39-1.45; P = 0.22). In the subsequent analysis, also including women with unknown T- and N-stages, relapse occurred in 27 of 337 (8.0%) women having undergone COS compared with 71/334 (21.3%) among the non-exposed. In the secondary adjusted analysis, relapse occurred in 20 of 126 (15.9%) exposed women and in 918 of 3729 (24.6%) non-exposed women (HR = 0.81; 95% CI 0.49-1.33; P = 0.70). In the subsequent analysis, including unknown T- and N-stages, relapse occurred in 27 of 337 (8.0%) women in the exposed group and 1176 of 5520 (21.3%) in the non-exposed cohort. LIMITATIONS REASONS FOR CAUTION: A substantial degree of missing data on important prognostic variables was a limitation, particularly when analysing the total cohort. Furthermore, data on confounding factors, such as BMI, were not completely covered. Another limitation was that a pre-specified variable for relapse was not in use for the majority of the National Breast Cancer Register. Furthermore, the follow-up time from available register data (2005-2014) is rather short. Finally, we cannot be sure whether the prognostic information from receptor status, showing a lower incidence in the exposed group, is representative. Information on T- and N-stages was missing in more than half of the patients. WIDER IMPLICATIONS OF THE FINDINGS: In this large, retrospective, matched cohort study, we found no increased risk of relapse in breast cancer among women who had been exposed to gonadotrophins as part of IVF. This is reassuring but might be confounded by the selection of a group of women with a more favourable prognosis than those not undergoing IVF. The present study strengthens previous findings by being large, national and register based. Its results are applicable to women undergoing fertility preservation as well as to those undergoing regular IVF treatment. STUDY FUNDING/COMPETING INTERESTS: Supported in part by grants from the Swedish state under the agreement between the Swedish government and the county councils the ALF-agreement (ALFGBG-720291), The Assar Gabrielsson Fund (FB 15-20), The Breast Cancer Fund and the Swedish Association of Local authorities and Regions, SKR. There are no conflicts of interest to declare. TRIAL REGISTRATION: N/A.

Top 10 priorities for future infertility research: an international consensus development study.

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.

Developing a core outcome set for future infertility research: an international consensus development study.

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.

Standardizing definitions and reporting guidelines for the infertility core outcome set: an international consensus development study.

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.

Standardizing definitions and reporting guidelines for the infertility core outcome set: an international consensus development study† ‡.

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.

Top 10 priorities for future infertility research: an international consensus development study† ‡.

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.

Developing a core outcome set for future infertility research: an international consensus development study† ‡.

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.

Age-related natural fertility outcomes in women over 35 years: a systematic review and individual participant data meta-analysis.

STUDY QUESTION: What is the rate of natural conception leading to ongoing pregnancy or livebirth over 6-12 months for infertile women of age ≥35 years? SUMMARY ANSWER: Natural conception rates were still clinically relevant in women aged 35 years and above and were significantly higher in women with unexplained infertility compared to those with other diagnoses. WHAT IS KNOWN ALREADY: In recent years, increasing numbers of women have attempted to conceive at a later age, resulting in a commensurate increase in the need for ART. However, there is a lack of data on natural fertility outcomes (i.e. no interventions) in women with increasing age. STUDY DESIGN, SIZE, DURATION: A systematic review with individual participant data (IPD) meta-analysis was carried out. PubMed, MEDLINE, EMBASE, the Cochrane Library, clinicaltrials.gov were searched until 1 July 2018 including search terms 'fertility service', 'waiting list', 'treatment-independent' and 'spontaneous conception'. Language restrictions were not imposed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Inclusion criteria were studies (at least partly) reporting on infertile couples with female partner of age ≥35 years who attended fertility services, underwent fertility workup (e.g. history, semen analysis, tubal status and ovulation status) and were exposed to natural conception (e.g. independent of treatment such as IVF, ovulation induction and tubal surgery). Studies that exclusively studied only one infertility diagnosis, without including other women presenting to infertility services for other causes of infertility, were excluded. For studies that met the inclusion criteria, study authors were contacted to provide IPD, after which fertility outcomes for women of age ≥35 years were retrieved. Time to pregnancy or livebirth and the effect of increasing age on fertility outcomes after adjustment for other prognostic factors were analysed. Quality of studies was graded with the Newcastle-Ottawa Scale (non-randomised controlled trials (RCTs)) or the Cochrane Risk of Bias tool (for RCTs). MAIN RESULTS AND THE ROLE OF CHANCE: We included nine studies (seven cohort studies and two RCTs) (n = 4379 women of at least age 35 years), with the observed composite primary outcome of ongoing pregnancy or livebirth occurring in 429 women (9.8%) over a median follow-up of 5 months (25th to 75th percentile: 2.5-8.5 months). Studies were of moderate to high quality. The probability of natural conception significantly decreased with any diagnosis of infertility, when compared with unexplained infertility. We found non-linear effects of female age and duration of infertility on ongoing pregnancy and tabulated the predicted probabilities for unexplained infertile women aged 35-42 years with either primary or secondary infertility and with a duration of infertility from 1 to 6 years. For a 35-year-old woman with 2 years of primary unexplained infertility, the predicted probability of natural conception leading to ongoing pregnancy or livebirth was 0.15 (95% CI 0.11-0.19) after 6 months and 0.24 (95% CI 0.17-0.30) after 12 months. For a 42-year-old woman, this decreased to 0.08 (95% CI 0.04-0.11) after 6 months and 0.13 (95% CI 0.07-0.18) after 12 months. LIMITATIONS, REASONS FOR CAUTION: In the studies selected, there were different study designs, recruitment strategies in different centres, protocols and countries and different methods of assessment of infertility. Data were limited for women above the age of 40 years. WIDER IMPLICATIONS OF THE FINDINGS: Women attending fertility services should be encouraged to pursue natural conception while waiting for treatment to commence and after treatment if it is unsuccessful. Our results may aid in counselling women, and, in particular, for those with unexplained infertility. STUDY FUNDING/COMPETING INTEREST(S): S.J.C. received funding from the University of Adelaide Summer Research Scholarship. B.W.M. is supported by a NHMRC Investigator grant (GNT1176437), B.W.M. reports consultancy for ObsEva, Merck, Merck KGaA, iGenomix and Guerbet. B.W.M. reports research support by Merck and Guerbet. PROSPERO REGISTRATION NUMBER: CRD42018096552.

No increased risk of relapse of breast cancer for women who give birth after assisted conception.

STUDY QUESTION: Is childbirth after IVF associated with a risk of relapse in breast cancer? SUMMARY ANSWER: Women who had been diagnosed with breast cancer and completed treatment had no increased risk of relapse if they gave birth after conceiving with IVF. WHAT IS KNOWN ALREADY: Pregnancy and childbirth have not been shown to increase the risk of relapse in breast cancer. Ovarian stimulation during IVF increases the oestrogen levels and could theoretically increase the risk of relapse in breast cancer. STUDY DESIGN SIZE DURATION: This is a retrospective register study, using national Swedish register data from the National Patient Register, the Medical Birth Register, the Swedish National Cancer Register, the National Breast Cancer Register, the National Quality Registry of Assisted Reproduction (Q-IVF), the National IVF Dataset, the Swedish Prescribed Drug Register and the Cause of Death Register. All women diagnosed with breast cancer who were between 20 and 44 years of age during the years 1982 to 2014 and identified in the cancer registries were assessed. PARTICIPANTS/MATERIALS SETTING METHODS: Women, previously diagnosed with breast cancer, who had given birth after IVF (29 after completed breast cancer treatment and 8 after fertility preservation) were compared with a matched control group who had given birth after spontaneous conception. Matching was done in a ratio 1:4, based on T-stage (size of the tumour) and year of diagnosis +/-5 years. MAIN RESULTS AND THE ROLE OF CHANCE: We found 26 114 women that had been diagnosed with breast cancer when 20-44 years old and of those 860 had subsequently given birth, 823 after spontaneous and 37 after IVF conception. Follow-up time was similar between the groups, ranging from 2.6 to 24.0 years, with a mean follow-up time of 10.3 (SD 4.2) years in the IVF group and 10.7 (SD 4.4) years in the control group. There were no relapses (0/37) in the IVF group. The relapse rate for the matched controls was 36/148 (24.8%). Ten women who suffered relapse died due to breast cancer. LIMITATIONS REASONS FOR CAUTION: This is reassuring data; however, the result is based on a few cases. The poor coverage of important prognostic variables in the register resulted in uncertain comparability of the groups. The main limitation in this study is the extent of missing data on tumour-related variables, due to poor coverage from the early years of the National Breast Cancer Register. It is possible that the women accepted for IVF had a less aggressive breast cancer and were generally healthier than women delivering after conceiving spontaneously and therefore had a lower risk of relapse. Other limitations are the lack of information on the anticancer therapies used and type of disease relapse, plus the older of the two IVF registers did not hold information on unsuccessful IVF cycles, leaving only cycles leading to birth, to be analysed. WIDER IMPLICATIONS OF THE FINDINGS: We found no indication that women who had been diagnosed with breast cancer had an increased risk of relapse if they gave birth after conceiving with IVF. Based on our findings, there is no evidence to advise against IVF treatment in this group of women. More detailed registry data would be valuable for future studies, enabling proper matching of tumour characteristics between groups. STUDY FUNDING/COMPETING INTERESTS: The study was financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-720291), The Assar Gabrielsson Fund (FB 15-20), The Breast Cancer Fund and the Swedish Association of Local Authorities and Regions, SKL. There are no conflicts of interest to declare.

A protocol developing, disseminating and implementing a core outcome set for infertility.

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.

Efficacy of salpingectomy at hysterectomy to reduce the risk of epithelial ovarian cancer: a systematic review.

BACKGROUND: It has been argued that salpingectomy would reduce the risk of epithelial ovarian cancer (EOC), based on the theory of the tube being the site of origin. OBJECTIVES: To conduct a systematic review of 'salpingectomy' associated with ovarian cancer risk and 'salpingectomy with concomitant hysterectomy' on outcomes of complications including endocrine function. SEARCH STRATEGY: A comprehensive search was conducted in PubMed, Embase, and the Cochrane library. SELECTION CRITERIA: Original studies and systematic reviews were eligible. DATA COLLECTION AND ANALYSIS: Each article was quality assessed. Data were extracted and, when possible, pooled in meta-analyses. The certainty of evidence across studies was evaluated using GRADE. MAIN RESULTS: Of 844 articles found, 11 were included. No study evaluated risk reduction for EOC after salpingectomy in conjunction with hysterectomy. Two retrospective studies reported a reduced ovarian cancer risk after indicated salpingectomy, compared with no surgery: adjusted hazard ratio 0.65 (95% confidence interval, 95% CI 0.52-0.81) and adjusted odds ratio 0.58 (95% CI 0.36-0.95). Complications did not differ between groups with or without salpingectomy, but were non-systematically reported. Ovarian endocrine function, measured with surrogate outcomes, did not differ at short-term follow-up in randomised or observational studies. The certainty of evidence was very low or low for all outcomes. CONCLUSIONS: There is currently insufficient evidence to state that opportunistic salpingectomy reduces the risk of EOC. The impact on long-term endocrine function is unknown. The heterogeneity in results and identified knowledge gaps stress the need for a prospective trial. TWEETABLE ABSTRACT: Insufficient evidence for prophylactic removal of the fallopian tubes for risk reduction of ovarian cancer.

Classification of pregnancies of unknown location according to four different hCG-based protocols.

STUDY QUESTION: How do four protocols based on serial human chorionic gonadotropin (hCG) measurements perform when classifying pregnancies of unknown location (PULs) as low or high risk of being an ectopic pregnancy (EP)? SUMMARY ANSWER: The use of cut-offs in hCG level changes published by NICE, and a logistic regression model, M4, correctly classify more PULs as high risk, compared with two other protocols. WHAT IS KNOWN ALREADY: A logistic regression model, M4, based on the mean of two consecutive hCG values and the hCG ratio (hCG 48 h/hCG 0 h) that classify PULs into low- and high-risk groups for triage purposes, identifies more EPs than a protocol using the cut-offs between a 13% decline and a 66% rise in hCG levels over 48 h. STUDY DESIGN, SIZE, DURATION: A retrospective comparative study of four different hCG-based protocols classifying PULs as low or high risk of being an EP was performed at a gynaecological emergency unit over 3 years. PARTICIPANTS/MATERIALS, SETTING, METHOD: We identified 915 women with a PUL. Initial transvaginal ultrasonography (TVS) findings categorised 187 of the PULs as probable intrauterine pregnancies (IUPs) and 16 as probable EPs. The rate of change in hCG levels over 48 h was calculated for each patient and subjected to three different hCG threshold intervals and a logistic regression model for outcome prediction. Each PUL was subsequently dichotomised to either low-risk (i.e. failed PUL/IUP) or high-risk (i.e. EP) classification, which allowed us to compare the diagnostic performance. In 'Protocol A', a PUL was classified as low risk if >13% hCG level decline or >66% hCG level rise was achieved; otherwise, the PUL was classified as high risk of being an EP. 'Protocol B' classified a PUL as low or high risk using cut-offs of 35-50% declining hCG levels and of 53% rising hCG levels. Similarly, 'Protocol C' used hCG level cut-offs published by NICE, 50% for declining hCG levels and 63% for rising hCG levels. Finally, if a logistic regression model 'Protocol M4' calculated a ≥5% risk of the PUL being an EP, it was classified as high risk, and otherwise the PUL was classified as low risk. When the time interval between two hCG measurements failed to meet an exact 48 h, extrapolation and interpolation of hCG values was made, using log linear transformation. MAIN RESULTS AND THE ROLE OF CHANCE: Protocols A, B, C and M4 classified 73, 66, 55 and 56% of PULs as low risk. The sensitivity for protocols A, B, C and M4 was 68% (95% confidence interval (CI) 61-75%), 81% (74-86%), 87% (82-92%) and 88% (83-93%), respectively. The specificity was 82% (80-85%), 77% (74-80%), 66% (62-69%) and 67% (63-70%) for protocols A, B, C and M4, respectively. All comparisons of sensitivity and specificity between the protocols were statistically significant except for protocol C versus protocol M4. In protocol C, 87% (66-97%) of misclassified EPs had rising hCG levels, compared with 19% (6-41%) for protocol M4 (P < 0.01). In a secondary analysis excluding probable IUPs and probable EPs, the results for 712 PULs were analysed. The sensitivity subsequently remained stable for all protocols. Protocol M4 reached a 78% (74-81%) specificity, which was significantly higher than 70% (66-74%) for protocol C (P = 0.01) and protocol M4 classified 63% of PULs as low risk compared with 58% for protocol C. LIMITATIONS, REASONS FOR CAUTION: The retrospective design of the study is a limitation. The results are derived from a population where laparoscopy played an important role in PUL management and diagnosis of EPs, although it did reflect real clinical practice. Although we tried to adhere to definitions of PUL and final outcomes as in previous studies and a recent consensus statement, potential differences in this regard must be acknowledged. Where the time interval between two serial hCG measurements deviated from 48 h we estimated 48 h hCG values. WIDER IMPLICATIONS OF THE FINDINGS: A logistic regression model, M4, classifies more PULs correctly as low risk in a selected PUL population without probable IUPs and EPs and identifies as many EPs, in comparison with the cut-offs available in the NICE guideline. This advantage for model M4 may result in a reduction of unnecessary follow-up visits, when fewer low-risk PULs are misclassified as high risk. These findings, however, ought to be clarified in a randomised controlled trial. STUDY FUNDING/COMPETING INTERESTS: The study was supported by LUA/ALF grant No. 70940. There are no competing interests.

Psychological Interventions for Poor Oral Health: A Systematic Review.

The aim of this systematic review and meta-analysis was to study the effectiveness of psychological interventions in adults and adolescents with poor oral health. The review follows the PRISMA guidelines for systematic reviews. The PICO format (population, intervention, comparison, and outcome) was used to define eligible studies. The populations were adults or adolescents (≥13 y of age and independent of others) with poor oral health (defined as dental caries, periodontal disease, and/or peri-implantitis). The interventions were psychological and/or behavioral models and theories, in comparison with traditional oral health education/information. The primary outcomes were dental caries, periodontitis, gingivitis, and peri-implantitis. Secondary outcomes were dental plaque, oral health-related behavior, health-related quality of life, health beliefs and attitudes, self-perceived oral health, and complications/risks. The systematic literature search identified 846 articles in December 2013 and 378 articles in July 2015. In total, 11 articles on 9 randomized controlled trials were found to meet the inclusion criteria. These reported on adults with periodontal disease, and several used motivational interviewing (MI) as their mode of intervention. The CONSORT guidelines and the GRADE approach were used for study appraisal and rating of evidence. The meta-analysis showed no statistically significant differences in gingivitis or plaque presence. In addition, a meta-analysis on MI compared with education/information found no statistically significant differences in gingivitis presence. Only 1 meta-analysis-on psychological interventions versus education/information regarding the plaque index-showed a small but statistically significant difference. There were also statistically significant differences reported in favor of psychological interventions in oral health behavior and self-efficacy in toothbrushing. However, the clinical relevance of these differences is difficult to estimate. The certainty of evidence was low. Future research needs to address several methodological issues and not only study adults with periodontal disease but also adolescents and patients with dental caries and peri-implantitis.

Cost-effectiveness of salpingotomy and salpingectomy in women with tubal pregnancy (a randomized controlled trial).

STUDY QUESTION: Is salpingotomy cost effective compared with salpingectomy in women with tubal pregnancy and a healthy contralateral tube? SUMMARY ANSWER: Salpingotomy is not cost effective over salpingectomy as a surgical procedure for tubal pregnancy, as its costs are higher without a better ongoing pregnancy rate while risks of persistent trophoblast are higher. WHAT IS KNOWN ALREADY: Women with a tubal pregnancy treated by salpingotomy or salpingectomy in the presence of a healthy contralateral tube have comparable ongoing pregnancy rates by natural conception. Salpingotomy bears the risk of persistent trophoblast necessitating additional medical or surgical treatment. Repeat ectopic pregnancy occurs slightly more often after salpingotomy compared with salpingectomy. Both consequences imply potentially higher costs after salpingotomy. STUDY DESIGN, SIZE, DURATION: We performed an economic evaluation of salpingotomy compared with salpingectomy in an international multicentre randomized controlled trial in women with a tubal pregnancy and a healthy contralateral tube. Between 24 September 2004 and 29 November 2011, women were allocated to salpingotomy (n = 215) or salpingectomy (n = 231). Fertility follow-up was done up to 36 months post-operatively. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: We performed a cost-effectiveness analysis from a hospital perspective. We compared the direct medical costs of salpingotomy and salpingectomy until an ongoing pregnancy occurred by natural conception within a time horizon of 36 months. Direct medical costs included the surgical treatment of the initial tubal pregnancy, readmissions including reinterventions, treatment for persistent trophoblast and interventions for repeat ectopic pregnancy. The analysis was performed according to the intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: Mean direct medical costs per woman in the salpingotomy group and in the salpingectomy group were €3319 versus €2958, respectively, with a mean difference of €361 (95% confidence interval €217 to €515). Salpingotomy resulted in a marginally higher ongoing pregnancy rate by natural conception compared with salpingectomy leading to an incremental cost-effectiveness ratio €40 982 (95% confidence interval -€130 319 to €145 491) per ongoing pregnancy. Since salpingotomy resulted in more additional treatments for persistent trophoblast and interventions for repeat ectopic pregnancy, the incremental cost-effectiveness ratio was not informative. LIMITATIONS, REASONS FOR CAUTION: Costs of any subsequent IVF cycles were not included in this analysis. The analysis was limited to the perspective of the hospital. WIDER IMPLICATIONS OF THE FINDINGS: However, a small treatment benefit of salpingotomy might be enough to cover the costs of subsequent IVF. This uncertainty should be incorporated in shared decision-making. Whether salpingotomy should be offered depends on society's willingness to pay for an additional child. STUDY FUNDING/COMPETING INTERESTS: Netherlands Organisation for Health Research and Development, Region Västra Götaland Health & Medical Care Committee. TRIAL REGISTRATION NUMBER: ISRCTN37002267.

Are patient characteristics associated with the accuracy of hysterosalpingography in diagnosing tubal pathology? An individual patient data meta-analysis.

BACKGROUND: Conventional meta-analysis has estimated the sensitivity and specificity of hysterosalpingography (HSG) to be 65% and 83%. The impact of patient characteristics on the accuracy of HSG is unknown. The aim of this study was to assess by individual patient data meta-analysis whether the accuracy of HSG is associated with different patient characteristics. METHODS: We approached authors of primary studies reporting on the accuracy of HSG using findings at laparoscopy as the reference. We assessed whether patient characteristics such as female age, duration of subfertility and a clinical history without risk factors for tubal pathology were associated with the accuracy of HSG, using a random intercept logistic regression model. RESULTS: We acquired data of seven primary studies containing data of 4521 women. Pooled sensitivity and specificity of HSG were 53% and 87% for any tubal pathology and 46% and 95% for bilateral tubal pathology. In women without risk factors, the sensitivity of HSG was 38% for any tubal pathology, compared with 61% in women with risk factors (P = 0.005). For bilateral tubal pathology, these rates were 13% versus 47% (P = 0.01). For bilateral tubal pathology, the sensitivity of HSG decreased with age [factor 0.93 per year (P = 0.05)]. The specificity of HSG was very stable across all subgroups. CONCLUSIONS: The accuracy of HSG in detecting tubal pathology was similar in all subgroups, except for women without risk factors in whom sensitivity was lower, possibly due to false-positive results at laparoscopy. HSG is a useful tubal patency screening test for all infertile couples.

Influence of HyCoSy on spontaneous pregnancy: a randomized controlled trial.

BACKGROUND: The aim of the study was to test whether the use of sonography contrast could enhance the chance of spontaneous clinical pregnancy in women undergoing subfertility investigation. METHODS: Couples with at least 1 year of infertility who were scheduled for a consultation including a hysterosalpingo contrast sonography (HyCoSy) were invited to participate in the study. We compared flushing with water-soluble contrast medium (WSCM) versus no flushing. Randomization sequence was computer generated, stratified for age and group allocation was concealed. Primary outcome was clinical pregnancy defined as a sonographically visible fetal sac, detected within 6 months from randomization. Secondary outcomes were spontaneous miscarriage and birth. Exclusion criteria were female age >or=40 years, severe male infertility, previously known severe tubal infertility and suspected anovulation. RESULTS: The mean age of the study population (n = 334) was 31.9 years. Duration of infertility was 2.1 years. The clinical pregnancy rate was 29.2% in the HyCoSy group and 26.5% in the non-flushing group, the difference being 2.7% (95% confidence interval -6.9 to 12.3%, P = 0.63). CONCLUSION: The clinical impression of an enhanced pregnancy rate after performing HyCoSy could not be confirmed. Tubal investigation with sonography using water-soluble contrast has a function as a diagnostic procedure but not in terms of increasing pregnancy rates in subfertile patients. TRIAL REGISTRATION NUMBER: ISRCTN20715945.

Economic evaluation of infertility treatment for tubal disease.

PURPOSE: The number of published studies comparing cost-effectiveness of tubal surgery and IVF treatment is limited, in part because of the difficulties of conducting randomized trials, given that IVF is now a clinically accepted treatment and the decision to offer surgery or IVF is often dictated by the severity of the tubal disease and by the availability of the methods. The aim of this study was to compare the costs of our policy of offering tubal surgery to patients with mild or moderate tubal disease with the cost of offering IVF to these and severe tubal disease. METHODS: In this retrospective cohort study patients with tubal pathology as the sole reason for their infertility were included: 61 patients in the tubal surgery group and 464 patients in the IVF group. The delivery rates and costs per delivery were compared. RESULTS: Delivery rates were 28% in the tubal surgery group within 2 years of follow-up and 52% in the IVF group that involved up to three cycles of treatment. This economic evaluation demonstrated only small differences in the average cost when considering the cost per delivery. CONCLUSIONS: With a policy involving strict selection of patients, tubal surgery will continue to have a role in the treatment of infertility.

Hydrosalpinx and IVF outcome: cumulative results after salpingectomy in a randomized controlled trial.

BACKGROUND: A randomized controlled trial of salpingectomy prior to IVF in patients with hydrosalpinges has been conducted in Scandinavia. The results from the first transfer cycle have been published and clearly demonstrated an improved pregnancy outcome after salpingectomy had been performed in patients with hydrosalpinges large enough to be visible on ultrasound. The present article is aimed at analysing the effect of salpingectomy on cumulative birth rate, including all individual transfer cycles. METHODS AND RESULTS: A total of 186 women underwent 452 cycles. Among the 77 women randomized to no surgical intervention, 24 underwent salpingectomy after one or two failed cycles. Cumulative results were analysed by Cox regression, taking into account the number of cycles per patient and the presence of a salpingectomy after a previous transfer. Salpingectomy implied a significant increase in birth rate (hazard ratio 2.1, 95% CI 1.6-3.6, P = 0.014). Within the subgroup of patients with ultrasound-visible hydrosalpinges, the birth rate was even higher (hazard ratio 3.8, 95% CI 1.5-9.2, P = 0.004). Implantation rate was significantly higher in patients who had undergone salpingectomy (27.2% versus 20.2, P = 0.03) and, in the subgroup of patients with ultrasound-visible hydrosalpinges, the difference was even larger (30.3% versus 17.1%, P = 0.003). CONCLUSIONS: The results of the cumulative cycles strengthen the recommendation for a laparoscopic salpingectomy prior to IVF in patients with ultrasound-visible hydrosalpinges.

Prophylactic salpingectomy does not impair the ovarian response in IVF treatment.

To examine the effect of prophylactic salpingectomy in patients with hydrosalpinges on the ovarian response to stimulation prior to IVF, 26 patients were included in a study in which they acted as their own controls. They were all part of a randomized controlled study, in which they had been randomized to no surgical intervention prior to IVF. After one or two failed cycles, they underwent laparoscopic uni- or bilateral salpingectomy of their diseased tubes. The cycles before and after surgery were compared and the ovarian response was assessed as the dose and duration of gonadotrophins and the number of retrieved and fertilized oocytes. There were no significant differences in any of the measured outcomes. The increasing age between cycles did not influence the ovarian response, assessed by a comparison with two matched control groups from the same original study; 46 patients salpingectomized before IVF and 25 patients without surgery. It is concluded that removal of hydrosalpinx as a prophylactic laparoscopic procedure does not compromise ovarian function.