SARS-CoV-2: diagnostic and design conundrums in the context of male factor infertility.

The question of whether SARS-CoV-2 (severe acute respiratory syndrome-related coronavirus-2 [SARS-CoV-2], leading to the COVID-19 infection) can be harboured in the testes and/or semen is currently unanswered. It is essential to understand the limitations of both antibody and real-time PCR tests in interpreting SARS-CoV-2 data in relation to analyses of semen and testicular tissue without appropriate controls. This article critically analyses the evidence so far on this, and the possible implications. The limitations of diagnostic tests in both sampling and testing methodologies, their validation and their relevance in interpreting data are also highlighted.

Correlation of IVF outcomes and number of oocytes retrieved: a UK retrospective longitudinal observational study of 172 341 non-donor cycles.

OBJECTIVE: How do numbers of oocytes retrieved per In vitro fertilisation (IVF) cycle impact on the live birth rate (LBR) and multiple gestation pregnancy (MGP) rates? DESIGN: Retrospective observational longitudinal study. SETTING: UK IVF clinics. POPULATION: Non-donor IVF patients. MAIN OUTCOME MEASURES: LBR per IVF cycle and MGP levels against number of oocytes retrieved into subgroups: 0, 1-5, 6-15, 16-25, 26-49 oocytes and 50+ oocytes. Relative risk (RR) and 95% CIs were calculated for each group against the intermediate responder with '6-15 oocytes collected'. RESULTS: From 172 341 attempted fresh oocyte retrieval cycles, the oocyte retrieved was: 0 in 10 148 (5.9%) cycles from 9439 patients; 1-5 oocytes in 42 574 cycles (24.7%); 6-15 oocytes in 91 797 cycles (53.3%); 16-25 oocytes in 23 794 cycles (13.8%); 26-49 oocytes in 3970 cycles (2.3%); ≥50 oocytes in 58 cycles (0.033%). The LBRs for the 1-5, 6-15, 16-25 and 26-49 subgroups of oocytes retrieved were 17.2%, 32.4%, 35.3% and 18.7%, respectively. The RR (95% CI) of live birth in comparison to the intermediate group (6-15) for 1-5, 16-25 and 26-49 groups was 0.53 (0.52 to 0.54), 1.09 (1.07 to 1.11) and 0.58 (0.54 to 0.62), respectively. The corresponding MGP rates and RR were 9.2%, 11.0%, 11.4% and 11.3%, respectively and 0.83 (0.77 to 0.90), 1.04 (0.97 to 1.11) and 1.03 (0.84 to 1.26), respectively. CONCLUSION: There was only limited benefit in LBR beyond the 6-15 oocyte group going to the 16-25 oocytes group, after which there was significant decline in LBR. The MGP risk was lower in 1-5 group.

Global inequality in sub-fertility treatment needs safer, cost effective, evidence-based and economically viable choices for patients and stakeholders.

The global increase in subfertility diagnosis and treatments and the rise of private equity investors concentrating on high profits based on in vitro fertilisation (IVF) treatments raise profound societal and economic questions for stakeholders and patients. The question remains as to whose benefits will ultimately be greater when promoting high margins treatment options resulting from cross-border mergers and acquisitions of IVF clinics.This paper covers wide-ranging issues from the erroneously constructed UK National Institute for Health and Care Excellence's (NICE) guidelines on treatment choices, the cost-effectiveness of treatments, the promotion of IVF, and add-ons where evidence remains minimal, the commercial size of the fertility industry. Investment in improving intrauterine insemination (IUI) success rates has understandably been avoided for its short-term impact on the IVF industry. However, IUI efficiency would cut across many of the global subfertility treatment economic and access problems while allowing stakeholder, feepaying, and patients financial savings will likely allow for more funded IVF cycles in acutely deserving cases. The recommendations will help expand choices for globally economically challenged patients' and services while enhancing an ethical and moral dimension towards fertility treatment choices for patients and stakeholders.

IUI needs fairer appraisal to improve patient and stakeholder choices.

Information supporting IVF at the expense of intrauterine insemination (IUI) has become commonplace, but it lacks critical analyses. Data from poorly practiced IUI, without an equivalent comparison to IVF, has been generalised to recommend a total abandonment of IUI in favour of IVF treatment. Our intention with this paper is to reappraise and balance arguments so that patients and stakeholders can have an unbiased informed choice. We provide information that reveals IUI to predominate over IVF in terms of integrated success, risks and cost to deliver one live birth whilst obviating the maternal and neonatal costs. Exceptional cost savings are demonstrated for IUI over IVF for fee-paying agencies and patients with lowered risks of maternal and neonatal care along with other risks including OHSS, fetal reduction and termination of pregnancies. This analysis supports the view that patients and stakeholders can choose IUI instead of IVF in most instances, except with bilateral tubal blockage and severe male factor infertility. It is apparent that fertility clinics need to re-evaluate and reconsider this field, and IUI can be of benefit to both subfertile patients and the stakeholders.

Observational retrospective study of UK national success, risks and costs for 319,105 IVF/ICSI and 30,669 IUI treatment cycles.

OBJECTIVE: To compare success rates, associated risks and cost-effectiveness between intrauterine insemination (IUI) and in vitro fertilisation (IVF). DESIGN: Retrospective observational study. SETTING: The UK from 2012 to 2016. PARTICIPANTS: Data from Human Fertilisation and Embryology Authority's freedom of information request for 2012-2016 for IVF/ICSI (intracytoplasmic sperm injection)and IUI as practiced in 319 105 IVF/ICSI and 30 669 IUI cycles. Direct-cost calculations for maternal and neonatal expenditure per live birth (LB) was constructed using the cost of multiple birth model, with inflation-adjusted Bank of England index-linked data. A second direct-cost analysis evaluating the incremental cost-effective ratio (ICER) was modelled using the 2016 national mean (baseline) IVF and IUI success rates. OUTCOME MEASURES: LB, risks from IVF and IUI, and costs to gain 1 LB. RESULTS: This largest comprehensive analysis integrating success, risks and costs at a national level shows IUI is safer and more cost-effective than IVF treatment.IVF LB/cycle success was significantly better than IUI at 26.96% versus 11.49% (p<0.001) but the IUI success is much closer to IVF at 2.35:1, than previously considered. IVF remains a significant source of multiple gestation pregnancy (MGP) compared with IUI (RR (Relative Risk): 1.45 (1.31 to 1.60), p<0.001) as was the rate of twins (RR: 1.58, p<0.001).In 2016, IVF maternal and neonatal cost was £115 082 017 compared with £2 940 196 for IUI and this MGP-related perinatal cost is absorbed by the National Health Services. At baseline tariffs and success rates IUI was £42 558 cheaper than IVF to deliver 1LB with enhanced benefits with small improvements in IUI. Reliable levels of IVF-related MGP, OHSS (ovarian hyperstimulation syndrome), fetal reductions and terminations are revealed. CONCLUSION: IUI success rates are much closer to IVF than previously reported, more cost-effective in delivering 1 LB, and associated with lower risk of complications for maternal and neonatal complications. It is prudent to offer IUI before IVF nationally.

Growing body of evidence supports intrauterine insemination as first line treatment and rejects unfounded concerns about its efficacy, risks and cost effectiveness.

IUI has been practiced for five decades but only three unconvincing trials attempted to demonstrate the superiority of IUI over sexual intercourse (SI). In the absence of evidence of its effectiveness, the National Institute for Clinical Excellence (NICE) recommended IVF over IUI after 2 years of unprotected SI. High-quality recent data in well-constructed studies suggest that biases against IUI procedures and in favour of IVF are invalid. It is unethical to continue to misinform patients and stakeholders. The well-constructed randomised controlled trials (RCT) show IUI procedure to be efficient, with minimal risk, and above all improved cost-effectiveness when compared to IVF for live birth. IUI as first-line treatment should be offered to most patients, while funding agencies and stakeholders need to be urgently informed of the cost-benefit in offering IUI. Fertility clinics, IVF interest groups, and regulatory bodies should amend their patient information and guidance to state that IUI should be the first line treatment and that IVF should be offered only when essential. Reappraising and promoting IUI based on evidence enhances patient autonomy, choices, and trust, while allowing the fertility industry to operate within an ethical and acceptable framework not seen as exploitative toward vulnerable patients.

Pandora's box: ethics of PGD for inherited risk of late-onset disorders.

Until recently, the primary use of preimplantation genetic diagnosis (PGD) has been the selection of embryos to avoid lethal or debilitating gene mutations or abnormal chromosome complement. PGD can be used to reduce the risk of transferring to the uterus an embryo with Down syndrome, and parents who are carriers of severe genetic diseases may choose to avoid having children with these debilitating genetic conditions. The use of PGD is now being extended to include gene mutations that increase the risk of late-onset disorders such as breast and ovarian cancer. This paper argues for caution in advocating reproductive methods that are costly, have a limited chance of success, and for which the long-term outcome is unknown. Counselling should allow women a true choice of declining the option of PGD without recrimination, feelings of guilt or social pressure. There is concern that the Human Fertilisation and Embryology Authority has approved extension of PGD to late-onset multifactorial diseases without clear guidelines for its use. Guidelines for embryo selection should be revised to deal with potential conflict between reproductive success and genetic screening for disorders that do not profoundly affect the embryo or the children.

A New Dawn for Intrauterine Insemination: Efficient and Prudent Practice will Benefit Patients, the Fertility Industry and the Healthcare Bodies.

This review addresses the misplaced facts about the IUI procedure within a lucrative fertility industry. Evidence suggests IUI must be a first-line treatment option for most couples except in cases of bilateral tubal blockage and severe oligozoospermia. We introduce the concept of using 'consecutive ejaculation' in men with subfertility and one which can radically alter the male infertility definition, thereby providing a new approach to examining and managing male factor infertility. The review also explores various aspects affecting the IUI procedure, its determinants of success, risks and areas for future improvements. Areas such as choice of patients, clinical management of patients, the type of stimulation regime, timing and the management of sperm usage have significant bearing to whether IUI will succeed. The paper asserts that IUI should be the first choice of fertility treatment.

Factors Leading to Pregnancies in Stimulated Intrauterine Insemination Cycles and the Use of Consecutive Ejaculations Within a Small Clinic Environment.

INTRODUCTION: Understanding and improving IUI pregnancy rates has enormous global appeal and application. This pilot study goes one step further by utilising consecutive ejaculates from men with oligozoospermia and comparing with normozoospermic male group. MATERIALS AND METHODS: A retrospective analysis was performed on 117 IUI-stimulated treatment cycles in a small fertility clinic in North Middlesex University Hospitals Trust, UK, within a NHS setting. Risks of OHSS and multiple births are carefully controlled. RESULTS: In our cohort, several factors are associated with positive IUI pregnancies and these were: age of the woman, inseminating with ≥5 total progressive motile sperm; having ≥50 % Grade A sperm progression and having ≥1 follicle achieved with a realistic hMG dosage, hCG trigger and IUI of 29.7 h (2.5-38.4 h), with an endometrial thickness of 10.7 mm (6.6-13.4 mm). Bifollicular presence in at least half the cases along with hMG protocols added usefully to the pregnancy outcomes. CONCLUSIONS: The pregnancy rates per cycle were 19 and 23 % in the consecutive ejaculates and non-consecutive ejaculate groups, respectively, P = 0.59. For the whole cohort, the pregnancy rate was 20.51 % per cycle and 33.8 % per women. This approach if validated with large RCT will have universally beneficial effects.

Cancer patients, gametes, gonadal tissue, and the UK legal status.

With advances in reproductive technologies, there are new opportunities for preservation of fertility potential for cancer patients receiving damaging treatment regimens. These include cryopreservation of gonadal tissue and maturing germ cells. These developments were not envisaged in the UK Human Fertilisation and Embryology Act 1990. Complex legal interpretations have followed in deciding which techniques come under statutory remit of the Human Fertilisation and Embryology Act 1990, and whether a licence is necessary to conduct such activities. The decisions have depended on the legal definition of the gamete and the fact that substituted consent within the Act 1990 is specifically disallowed. In our analyses we believe several areas require further explanation or improvement: the definition relating to the oocyte, its applicability to ovarian tissue, a pre-Tanner stage 2 patient whose immature spermatozoa may satisfy the definition of gamete, and the legal mechanism of substituting consent which may allow the unregulated use of frozen gonadal tissue or germ cells for procreation in future years. In a recent development it appears that gonadal tissue may come under a 'tissue specific body' and not the Human Fertilisation and Embryology Authority. It makes sense from the standpoint of patient welfare and the limited public and clinical resources, to place under one regulatory body all biological material where the ultimate aim is human procreation.

Definitions of human fertilization and preimplantation growth revisited.

Assisted reproductive techniques and the science of embryology have advanced rapidly over the last decades. The fact that social and moral objectives vary from country to country has resulted in differences not only in legislation, but also in the definition of embryological terms. Among the latest additions to the field has been nuclear transfer technology, which has led to concerns about the possibilities of human cloning. These facts call for a review of gametogenesis and early embryogenesis. The aim of the present paper is to initiate a discussion on terminology with a view to reaching a consensus. As a starting point definitions are proposed for the most important terms.

Cytogenetic and Y chromosome microdeletion screening of a random group of infertile males.

OBJECTIVE: To assess whether to perform routine cytogenetic and Y chromosome microdeletion screening on all infertile male patients. DESIGN: A cytogenetic and Y microdeletion study of a random group of infertile men. SETTING: University department. PATIENT(S): In total, 40 patients had azoospermia (21 nonidiopathic), 27 had severe oligozoospermia/oligoasthenozoospermia (

Parliamentary proposals for liberal approaches to assisted conception.

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.