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Unexplained infertility is a common diagnosis affecting as many as 50% of couples seeking infertility care. As a diagnosis of exclusion, its treatment remains largely empirical. Historically, a step-wise progression in treatment has been initiated with the least invasive, least expensive option followed by a gradual progression to therapies using assisted reproductive technology. In recent years there have been advocates for more rapid-progression IVF. This guideline from the Canadian Fertility and Andrology Society (CFAS) provides comprehensive, evidence-based recommendations for the treatment of unexplained infertility, including expectant management, laparoscopy, intrauterine insemination (IUI) alone, ovarian stimulation with oral agents or gonadotropins alone, ovarian stimulation + IUI, and IVF. The quality of supporting evidence for each recommendation is evaluated using the framework outlined by the Canadian Task Force on Preventive Health Care. This guideline recognizes that the therapeutic approach should be individualized taking into account patient age and duration of infertility, and emphasizes those strategies that are most likely to result in a healthy live birth., (Copyright © 2019 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Published reports have indicated that rates of preimplantation embryo aneuploidy in a control donor population may vary between IVF centres. This suggests that location-specific conditions, in the clinic, IVF or genetics laboratory, may be influencing the chromosome dynamics or diagnosis. More recent reports suggest that rates of embryo mosaicism, representing mitotic errors, may vary between IVF centres. This would suggest perhaps a laboratory-controlled variable is influencing mitotic cell division during preimplantation embryo development. Various IVF laboratory-controlled factors may be impacting chromosome separation and segregation. Variables including type of culture media, pH, temperature, osmolality and oxygen concentration could all be possible factors influencing embryo aneuploidy. Furthermore, laboratory techniques, method of insemination, laser use or handling of biopsied cells may also influence genetic results. These IVF laboratory variables will be reviewed and literature suggesting a possible link to mitotic aneuploidy/mosaicism discussed., (Copyright © 2019 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Research Question: Assisted reproduction laboratories record instrument performance periodically. No standardized guidelines have been produced for this activity despite mandatory auditing systems in several countries. This study of 36 laboratories in 12 different countries was conducted to assess differences and similarities between quality assurance programmes using an adaptable cloud-based quality-control app for instrument monitoring., Design: A total of 36 deidentified IVF laboratories that subscribed to the same quality-assurance application were studied. Data were evaluated based on instrument types allocated to 10 domains: incubators, gas tanks, warming surfaces, refrigerators and freezers, cryo-storage, environment, water purification, peripheral equipment, checklists and miscellaneous., Results: The incubator domain constituted the greatest proportion of parameters (35%), followed by surface warming instruments at 15%. Most incubator O 2 readings were monitored between 4.5 and 5.5%, and between 5.5 and 6.5% for CO 2 . The altitude of the laboratory was poorly correlated with the CO 2 setting. Incubator display and measured values of gases and temperature by built-in sensors vary considerably compared with third-party sensors. A quality-control diligence score or mean average data points was calculated for each laboratory. This score is independent of number of instruments or laboratory size. Higher scores were associated with laboratories in countries with government regulations and mandatory auditing systems., Conclusions: Major differences exist in instrument monitoring practices among laboratories. Although incubator monitoring is the largest domain, many other sensitive instruments are diligently monitored by most laboratories. International standardization and guidelines are needed., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The impact and management of thin endometrium is a common challenge for patients undergoing assisted reproduction. The objective of this Canadian Fertility and Andrology Society (CFAS) guideline is to provide evidence-based recommendations using the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) framework on the assessment, impact and management of thin endometrium in assisted reproduction. The effect of endometrial thickness on pregnancy and live birth outcomes in ovarian stimulation and IVF (fresh and frozen cycles) is addressed. In addition, recommendations on the use of adjuvants to improve endometrial thickness and pregnancy outcomes are provided., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The Vienna consensus, based on the recommendations of an expert panel, has identified 19 performance indicators for assisted reproductive technology (ART) laboratories. Two levels of reference values are established for these performance indicators: competence and benchmark. For over 10 years, the Spanish embryology association (ASEBIR) has participated in the definition and design of ART performance indicators, seeking to establish specific guidelines for ART laboratories to enhance quality, safety and patient welfare. Four years ago, ASEBIR took part in an initiative by AENOR, the Spanish Association for Standardization and Certification, to develop a national standard in this field (UNE 17900:2013 System of quality management for assisted reproduction laboratories), extending the former requirements, based on ISO 9001, to include performance indicators. Considering the experience acquired, we discuss various aspects of the Vienna consensus and consider certain discrepancies in performance indicators between the consensus and UNE 179007:2013, and analyse the definitions, methodology and reference values used., (Copyright © 2018 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

This proceedings report presents the outcomes from an international Expert Meeting to establish a consensus on the recommended technical and operational requirements for air quality within modern assisted reproduction technology (ART) laboratories. Topics considered included design and construction of the facility, as well as its heating, ventilation and air conditioning system; control of particulates, micro-organisms (bacteria, fungi and viruses) and volatile organic compounds (VOCs) within critical areas; safe cleaning practices; operational practices to optimize air quality while minimizing physicochemical risks to gametes and embryos (temperature control versus air flow); and appropriate infection-control practices that minimize exposure to VOC. More than 50 consensus points were established under the general headings of assessing site suitability, basic design criteria for new construction, and laboratory commissioning and ongoing VOC management. These consensus points should be considered as aspirational benchmarks for existing ART laboratories, and as guidelines for the construction of new ART laboratories., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Two articles recently published in Reproductive BioMedicine Online described how fertility centres in the USA and Brazil implemented air quality control to newly designed facilities. In both case scenarios, a highly efficient air filtration was achieved by installing a centred system supplying filtered air to the IVF laboratory and other critical areas, combining air particulate and volatile organic compound (VOC) filtration. Evaluating retrospective data of over 3000 cycles from both centres, live birth rates were increased by improvements in air quality and laboratory environment. This commentary discusses some of the key aspects of air contamination in the IVF settings, and highlights the fact that a risk management analysis taking into consideration all variables that play a role in air contamination is paramount for the reduction of the risk of poor IVF outcomes due to improper air quality conditions., (Copyright © 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

The embryologist presides over the fulfillment of a patient's treatment in the laboratory for IVF through use of assisted reproduction techniques, and is in a unique position to impart quality to the process. Although the technical skill of the embryologist is critical, the embryologist's contribution to quality is equally conveyed through a knowledge of reproductive biology, keen observation and judgment, astute decision-making, the 'grit' to work under pressure and time constraints, and a sense of mission in the provision and continual development of a safe and effective laboratory. The embryologist also ensures that the laboratory complies with the regulations of federal, state, local and institutional authorities and the recommendations and guidelines of professional associations. In these roles, the embryologist assumes unique responsibilities counterbalanced by the unique rewards of assisting patients in having a family. This article aspires to illuminate this singular profession for those who may be contemplating a career in embryology and act as a resource for those who seek insight into this amalgam of basic science, technical proficiency, and managerial skill and acumen that characterize the practice of clinical embryology and the myriad of ways that practitioners contribute to the quality of assisted reproduction techniques and patient care., (Copyright © 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

The regulation of assisted reproductive technologies is a contested area. Some jurisdictions, such as the UK and a number of Australian states, have comprehensive regulation of most aspects of assisted reproductive technologies; others, such as the USA, have taken a more piecemeal approach and rely on professional guidelines and the general regulation of medical practice to govern this area. It will be argued that such a laissez-faire approach is inadequate for regulating the complex area of assisted reproductive technologies. Two key examples, reducing multiple births and registers of donors and offspring, will be considered to illustrate the effects of the regulatory structure of assisted reproductive technologies in the USA on practice. It will be concluded that the regulatory structure in the USA fails to provide an adequate mechanism for ensuring the ethical and safe conduct of ART services, and that more comprehensive regulation is required., (Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Since the first birth by IVF was achieved in 1978, the techniques involved in assisted reproductive technology have grown at an enormous rate. However, new technology has rarely been robustly validated before clinical use and developing scientific understanding of the available techniques has done little to alter their use. Furthermore, there are inconsistencies in the available clinical studies and endpoints. The benefits of some technologies already established for routine use are currently dubious and there are clear ethical concerns with providing them to patients when their scientific basis is not clear. As the uptake of assisted reproductive technology increases and newer technologies continue to push the boundaries of science, it is important to consider the clinical benefits and safety of all assisted reproductive technologies. This review will discuss aspects of some of the more recent techniques, including sperm DNA-damage tests, intracytoplasmic morphologically selected sperm injection, amino acid and metabolomics profiling, preimplantation genetic screening and time-lapse imaging, and those that may have substantial impacts on the field of reproductive medicine in the future including artificial gametes, ovarian transplantation and gene therapy., (Copyright © 2012 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

This proceedings report presents the outcomes from an international workshop designed to establish consensus on: definitions for key performance indicators (KPIs) for oocyte and embryo cryopreservation, using either slow freezing or vitrification; minimum performance level values for each KPI, representing basic competency; and aspirational benchmark values for each KPI, representing best practice goals. This report includes general presentations about current practice and factors for consideration in the development of KPIs. A total of 14 KPIs were recommended and benchmarks for each are presented. No recommendations were made regarding specific cryopreservation techniques or devices, or whether vitrification is 'better' than slow freezing, or vice versa, for any particular stage or application, as this was considered to be outside the scope of this workshop., (Copyright © 2012 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

From an economist's perspective, cross-border reproductive care (CBRC) reflects a global market economy bringing together the needs of patients and skills of doctors at an agreed price. From this perspective CBRC is neither wrong nor right, rather it reflects rational economic behaviour of couples to maximize their wellbeing. The major economic criticism of CBRC relates to the costs and risks of multiple pregnancies, as couples paying out-of-pocket may have more embryos transferred than is desirable to optimize their chances of having a live birth. This criticism is valid, suggesting a need to communicate the hidden costs of failing to adequately fund fertility services. However, under some circumstances health authorities may be willing to bear these additional costs if the savings from not providing fertility services are sufficiently large enough to warrant a no-funding policy. Because infertility is often viewed as a low health priority, the likelihood of CBRC persisting is real, particularly as many health services adjust to the challenges of ageing populations and decreased public financing. To counter funding challenges, there is a need to communicate the medical benefits of assisted reproduction and the economic benefits that these children will offer in an era of austerity and ageing populations., (Copyright © 2011 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Cross-border reproductive care (CBRC) is not a new concept, having been around since the beginning of assisted reproductive technology. Countries having taken the lead in developing new technologies have seen an influx of patients from other countries, because of legal limitations or the unavailability of good-quality care in their home country. This paper describes the experience of the Ghent University Hospital fertility centre with Dutch and French patients and tries to set out standards of care for CBRC patients. Dutch patients usually have longer histories, more complex pathology and are better informed, more outspoken and more financially secure. Thus, the care for these patients is challenging. The standards of care should be the same for local patients and CBRC patients; however, the nature of the complexity of the problems they come with will necessitate more time investment. Experience shows that many patients who have no access to treatment in their own country obtain reasonably good results. Some of them, however, are beyond possible help and these patients need a high standard of psychological care. All should be done to avoid that cross-border patients compromise the local care system. Special arrangements should be taken to manage possible complications following treatment., (Copyright © 2011 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Cross-border reproductive care (CBRC) is a rapidly growing phenomenon of interest to governments and regulators, professionals working within the field of assisted reproductive technologies and men and women seeking to use their services. However, to date, discussions have been dominated by media debates and scholarly commentary, with only partial and fragmentary evidence from empirical research studies. This article identifies the pressing gaps in the literature, elucidates the main theoretical and methodological challenges for investigating CBRC and outlines a future research agenda. Cross-border reproductive care (CBRC) is a rapidly growing phenomenon of interest to governments and regulators, professionals working within the field of assisted reproductive technologies and men and women seeking to use their services. However, to date, discussions have been dominated by media debates and scholarly commentary, with only partial and fragmentary evidence from empirical research studies. This article identifies the pressing gaps in the literature, elucidates the main theoretical and methodological challenges for investigating CBRC and outlines a future research agenda., (Copyright © 2011 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

This paper reports the proceedings of an international consensus meeting on oocyte and embryo morphology assessment. Following background presentations about current practice, the expert panel developed a set of consensus points to define the minimum criteria for oocyte and embryo morphology assessment. It is expected that the definition of common terminology and standardization of laboratory practice related to embryo morphology assessment will result in more effective comparisons of treatment outcomes. This document is intended to be referenced as a global consensus to allow standardized reporting of the minimum dataset required for the accurate description of embryo development. This paper reports the proceedings and outcomes of an international consensus meeting on human oocyte and embryo morphology assessment. An expert panel developed a series of consensus points to define the minimum criteria for such assessments. The definition of common terminology, and standardization of laboratory practices related to these morphological assessments, will permit more effective comparisons of treatment outcomes around the world. This report is intended to be referenced as a global consensus to allow standardized reporting of the minimum descriptive criteria required for routine clinical evaluations of human embryo development in vitro., (Copyright © 2011 Elsevier Limited and ALPHA Scientists in Reproductive Medicine and the European Society of Human Reproduction and Embryology. Published by Elsevier Ltd.. All rights reserved.)

Routine morphological scoring systems in assisted reproduction treatment are based on parameters that presumably correlate with the biological quality of gametes and embryos, including chromosome abnormalities. Maternal age is a key factor predicting pregnancy and live birth, and it is therefore of considerable interest to identify age-related indicators of oocyte and embryo quality in assisted reproduction treatment. The purpose of this study was to examine whether routine morphological scoring systems reflect age-related impact on oocyte and embryo quality among 4587 couples undergoing their first assisted reproduction treatment. This study assessed over 43,000 oocytes, 25,000 embryos and 7900 transferred embryos and analysed the associations among the following parameters: number of oocytes retrieved, oocyte quality, including maturity, fertilization rates, embryo quality, based on morphological features, and treatment outcome. Advanced chronological age was found to be associated with fewer oocytes retrieved, fewer embryos available for cryopreservation, as well as lower pregnancy, implantation, live birth rates and a higher miscarriage rate. No age-related correlation was found between fertilization rates, oocyte or embryo quality. Routinely-used morphological scoring systems, such as assessment of blastomere count, shape and fragmentation, fail to reflect age-related impact on oocyte and embryo quality., (2010 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

In their quest for a child, infertile couples embark on a journey that is full of expectations and hopes. Over recent years, treatment procedures for assisted conception have become safer and more efficient. However, couples undergoing treatment can still experience some degree of emotional stress due to disappointment if pregnancy is not achieved, or if treatment cycles may have to be cancelled due to a low- or hyper-response. Strategies aimed at minimizing the variability of ovarian response or overall treatment outcome can be expected to significantly reduce this emotional stress. New developments have led to the production of follitropin alfa filled by mass. This is a highly consistent FSH preparation improving the consistency of ovarian response and reducing the risk of cycle cancellation. The impact of this new FSH preparation for assisted reproduction treatments is discussed in this review.

The European Union's Tissues and Cell Directive and the US regulations for tissue banks, both produced in 2004, recognize the need to revise current tissue-processing activities and address related risks of infection. The principle behind these regulations and the Australian and New Zealand, Reproductive Technology Accreditation Committee (RTAC) Code of Practice, produced in 2005, are all similar with an underlying quality management theme. Each of these documents is based on the premise to safeguard public health in the prevention of transmission of infectious diseases via transplanted tissues and cells.

Assisted conception is among many tissue-processing disciplines encompassed by new European legislation on the quality and safety of tissues and cells used therapeutically. These directives have highlighted interdisciplinary differences in some current practices, such as variations in laboratory air quality. This commentary discusses the likely requirements of the EU directives for air quality in tissue-processing laboratories. It also draws attention to the concept of validation. Validation becomes essential to justify all processes, and would be an essential tool to support any deviations from normal 'Good Manufacturing Practices', such as adopting a lesser grade of laboratory air quality.

The European Union's Tissues and Cells Directive (2004) establishes an extensive framework of standards for all tissue banks throughout the EU. This article considers how the requirements of the Directive might be expected to achieve the stated goals of promoting the safety of assisted conception treatments and/or facilitating the achievement of higher success rates. While there will certainly be some significant costs to implementing these systems, there are substantial benefits and returns, for example, quality improvement and risk minimization. However, there are grave problems with the feasibility, effectiveness, and probable adverse impacts of applying arbitrary clean room air quality standards to assisted conception facilities, especially IVF laboratories. This is likely to have negligible impact on the already low risks of both culture contamination and operator infection, but would severely compromise the ability to maintain gametes and embryos under optimum environmental conditions. Proper consideration must therefore be given to the particular circumstances that affect reproductive tissues (indeed, the same is true for all areas of tissue banking), to ensure that the final technical regulations are founded upon realistic expectations based on objective evidence from process-based systems. The creation of the highest quality embryos, and healthy children, must always remain the primary focus of assisted conception treatment.

This paper summarizes the 2005 report of the Parliamentary Standing Committee on Science and Technology, which considered the 1990 Human Fertilisation and Embryology (HFE) Act and the Human Fertilisation and Embryology Authority (HFEA) in the light of new developments in IVF and embryo research. It considers the report's recommendations as to future legislation concerning the legal status of the embryo, and regarding which forms of embryos should be used for reproductive purposes. It discusses the suggestion that the current obligation to consider the welfare of the child is unhelpful and that the case has not been made against using preimplantation genetic diagnosis (PGD) for sex selection. It examines the report's recommendations concerning reform of the HFEA in the areas of its composition, inspection and licensing processes, and the suggestion that it make data on the uptake and success of IVF more readily available and encourage research into its social impact. It considers issues such as whether the HFEA has exceeded its remit and the need to compare international regulatory models and IVF practice. It explores the conflict the inquiry saw between the HFEA's role as regulator and policy maker, the recommendation that it merge its policy function with the Human Genetics Commission, and that a greater role be allotted to Parliament to consider the ethical dimension of new developments, while clinical decisions and technical standards are devolved to patients and practitioners.

In this commentary it is argued that David Mortimer's contention (Mortimer, 2005) that 'there are grave problems with the feasibility, effectiveness and likely adverse impact of applying clean room and air quality standards to assisted conception facilities, especially IVF laboratories', as envisaged in the European Union's Tissues and Cells Directive (2004), is fully justified. As he says, 'effective regulations need to recognize what is impossible, what is possible and what is realistic'. The Directive, while necessary in principle, does not take into account the fact that what may appear to be ideal from a narrow technical point of view may, in fact, in a larger context, defeat its purpose by actually being harmful.

Unlike most medical laboratories that play a diagnostic role, laboratories for assisted reproductive technologies, ART laboratories, are involved in the treatment of infertile couples. Handling human gametes and producing human embryos in order to achieve much-sought pregnancies form the key tasks of an ART laboratory. The impact of the activities and the possible risks makes it necessary to ensure the safety and reproducibility of all methods. To achieve and maintain the highest level of patient care and the highest success rates, a quality management system should be implemented. Several guidelines, compiled by professional associations of ART experts, official international standards and quality management models have been developed and issued and can be applied. Irrespective of the choice, establishing a quality management system in an ART laboratory leads to a huge amount of additional work and requires a lot of investment in all kind of areas. However, due to the increased standardization and efficiency of all procedures as well as the improved transparency and traceability of all actions performed, the quality of service provided by the laboratory will improve substantially and the effort will be worthwhile.

In assisted reproductive technology, three main areas are relevant from a health policy perspective: first, the technical excellence of the services rendered; second, a licensing and monitoring system to control all practitioners and the premises in which they work; and third, legislation to avoid abuse, prevent possible damage to the mother and the child and outlaw techniques unacceptable in a given cultural setting, including mechanisms to ensure the adherence by all to ethical and deontological principles. No one refuses the need to ensure that services offering assisted reproductive technologies adhere to technical excellence and everyone agrees that technical guidelines should exist and should be thoroughly enforced. When it comes to legislating about assisted reproductive techniques and, more specifically, to ruling in favour of limiting the use of existing technology to certain groups and not to others, or to ban altogether individual methods, views are sometimes totally divergent. In countries where legislation is fairly liberal, usually both physicians and the public view legislation with favour; conversely, where a number of restrictions exist, many complain that legislation impairs their ability to offer proper services. The solution seems to be a simple, well-defined, legislative act setting clear principles and providing for the creation of an Authority capable of resolving the myriad of individual problems that invariably arise from applying assisted reproductive techniques. Homo sum et nihil humanum a me alienum puto I am a human being and therefore cannot consider alien to me anything that helps another human being.