Female fertility: hostage to affluence, age and the search for self-fulfilment In modern industrialized societies female fertility is compromised due to a perfect storm of social, economic, educational and political factors that far outweigh any attempt by Governments to encourage women to have more children. In affluent societies, there is no need to have a large family. Infant and childhood mortalities are low and children are not needed in the workforce to facilitate survival of the family unit. As a result of the reduction in family size, women are freed to pursue their educational and professional goals. This ultimately means that childbearing is postponed to the point that fertility goes into age-dependent decline, around the age of 35. Many women in this situation will look to the IVF industry for salvation, however live births decline with age following assisted conception just as they do in natural cycles. Oocyte donation and/or cryopreservation are the only realistic methods to address age-dependent female infertility at the present time, although even these techniques are far from infallible. As societies engage in the long march to affluence, we shall inevitably witness repeated collisions between the tectonic plates of female biology and our prosperity-driven quests for gender equality, longevity and fulfilment. Ultimately fertility is the victim.

The gathering storm – the creation of an Infertility TrapWhile previous publications have looked at individual aspects of the issues shaping our population size, the reality is that many different factors are working together to drive human fertility into a cul-de-sac of its own making. From a social perspective many young people, particularly young, educated women, do not feel that life’s purpose necessarily involves the creation of a family. As fertility rates fall, this lack of interest in procreation will be reinforced by the economic pressures placed on a dwindling workforce to achieve the productivity needed to support the swelling ranks of elderly citizens. We shall not be able to turn to immigration to solve this problem because the fall in fertility rates is global and the barriers to international movement put up by COVID will persist for some time to come. Affluent societies are also characterized by lifestyles, diets and levels of environmental pollution that negatively impact reproductive health. These features, when coupled with the lack of selection pressure on high fertility in modern industrialized societies, and the ability of ART to encourage poor fertility genotypes to remain within the population, will combine to drive fertility down to historically low levels.

Prologue- the pending collapse of human populationsA perfect storm of social, political, environmental and biological factors is conspiring to suppress the fertility of our species. In this book, we shall explore the fundamental nature of human population dynamics and the wide range of factors responsible for the change that is about to come. Societies touched by prosperity’s wand experience many advantages including good health, education, security and longevity. However, these gifts come at a cost. Prosperous societies experience high levels of environmental pollution, psychological stress, obesity, addiction and a focus on individual fulfilment that combine to generate extremely low levels of fertility. As societies accumulate wealth, they sow the seeds of their own demise. In the short term, our ‘superaged’ societies must be supported by a shrinking, overstretched workforce, that have neither the motivational energy nor the biological capacity to procreate. In the long term, the lack of selection pressure on fertility, combined with the exponential growth of the IVF industry, will serve to drive fertility rates down still further. Unless we recognise and respond to the factors suppressing human fertility, we shall not be able to control the predictable population collapse – and escape will be challenging.

How do we escape the trap?Many of the social, biological and environmental mechanisms that are driving down human fertility, are self-reinforcing. They operate to accelerate the rate of fertility loss, not stabilize it. Escape from this downward spiral will involve several initiatives that, working together, may provide a measure of control over the rate and depth of fertility decline. For example, we need a complete overhaul of sex education that recognizes the fragility of human fertility and is not so focused on the prevention of teenage pregnancies. We also need to raise the profile of reproductive toxicology so that we can secure better control over the release of potentially harmful compounds into the biosphere. There is a particular need to control male exposures to oestrogens and to counteract those elements of lifestyle, metabolism and the environment, responsible for creating oxidative stress in both the male and female reproductive tract. Accommodating the ART industry would be easier if we secured a deeper understanding of the causes of human infertility so that ART does not become the default therapy for every couple and, when it is used, that IVF is preferred over ICSI. Finally, we need to engineer new social structures wherein fertility is facilitated and encouraged.

A uterine septum is a congenital abnormality that has been associated with poor reproductive outcome that can be readily corrected by hysteroscopic surgery. For this debate article we argue that all women with a uterine septum should have hysteroscopic septal resection before undergoing any fertility treatment. A uterine septum is a congenital uterine anomaly arising from the failure of canalisation of the uterus during embryological development. Uterine septa are more prevalent in women with a history of pregnancy loss, but not infertility alone, and are associated with an increased risk of first and second trimester miscarriage and preterm birth [1,2]. Diagnosis is straightforward with three-dimensional ultrasound. Adequate assessment of uterine morphology requires concurrent imaging of the external and internal controls of the uterus. Three-dimensional ultrasound facilitates such views and is safer and more acceptable to women than surgical assessment with hysteroscopy and laparoscopy which are required to see the internal and external fundal contours.

Uterus transplantation involves a vascularised composite allograft for women with absolute uterine factor infertility, and is considered research. It requires a large medical and surgical multidisciplinary team, requires adequate psychological support and risks premature birth in the offspring. We compare it with the alternative of surrogacy, with the pros and cons regarding the prospective parents and offspring, the parental project collaborators, whether dead or live uterine donor or the gestating surrogate, and society at large. The possible aspects of cross-border reproductive care are also considered before concluding that it is still ‘a step too far’.

Mitochondrial (mt)DNA mutations can cause a broad range of severely debilitating or fatal disorders. There is no cure available and the only available treatments have purely symptomatic effects. Preventing mitochondrial disease transmission is therefore a major priority. Germline nuclear transfer (NT), such as maternal spindle (ST), pronuclear (PNT) or polar body (PBT) transfer, has been proposed as a possible strategy to prevent mother-to-child transmission of mtDNA mutations. This technology involves nuclear genome transfer from an oocyte or zygote carrying mtDNA mutations to an enucleated donor counterpart with healthy mtDNA. In addition, the technology has also been considered as a treatment option for certain infertility indications, such as women experiencing poor embryo development, with the expectation of improving in vitro treatment outcomes. Here, we provide an overview on recent developments in the field of NT, either with the aim to avoid mtDNA diseases or to overcome certain forms of female infertility.

This chapter discusses the epidemiology of infertility and the importance of the initial assessment of the infertile individual. Profound changes in society over the last two decades challenge previously agreed on norms in our understanding of the nature of parenthood and family. Defining infertility in a contemporary context has thus also changed as the profile of those seeking advice has evolved. Nevertheless it remains essential that efficient mechanisms for referral and investigation are established for those involved in the planning of fertility services. These must involve good liaison between primary care providers and medical, nursing and diagnostic laboratory staff in specialist centres. Adherence to agreed on protocols will facilitate appropriate and timely investigation along standardised paths, thereby minimising risk of delay and repetition of tests which those seeking assistance find particularly demoralising. Once a diagnosis is reached it should be possible to offer people with infertility an accurate prognosis and the opportunity to consider the issues relevant to treatment choices for their particular situation.

Endometriosis is a chronic oestrogen-dependent condition that affects 10% of women from puberty to menopause. It is characterised by the presence and proliferation of endometrial-like cells outside the uterine cavity, generally within the pelvis. Endometriosis can present as superficial or deep peritoneal lesions, ovarian endometrioma or deep rectovaginal disease. The two hallmark symptoms of endometriosis are pelvic pain and infertility resulting in poor quality of life. There is no correlation between the extent of the disease and severity of symptoms. The true prevalence of the condition is not known, as it requires a laparoscopy to confirm the diagnosis. It is found in up to 30% of women with infertility and in 45% of those with pelvic pain. While there are several theories of pathogenesis, an interplay of genetic, hormonal, environmental and immunological factors is implicated in the development of endometriosis in susceptible women. Symptoms are managed with a combination of hormonal treatment and laparoscopic ablation or excision of lesions for pain and usually assisted reproduction for infertility. Endometriosis is prone to recurrence after treatment, requiring multiple contacts with healthcare and repeat surgery. Management of endometriosis requires an individualised approach based on the woman’s age, predominant symptoms and priorities, which are subject to change over time.

Psychosocial support in fertility clinics or centres  providing third-party reproduction has changed over time as reproductive techniques have developed; social norms, legal systems and counselling standards have evolved; and access to information expanded with the world wide web. Today patient support and infertility counselling involves supporting and assessing patients, donors, surrogates and their partners, and the parents and children at all stages of family building from initial decision-making about choices to later family life. Infertility counsellors also address support needs of staff providing fertility care. However, not all centres provide this range of services. The present chapter will review essential components of patient support in third-party reproduction provided by clinic staff and infertility counsellors, highlighting key features of good practice according to the Human Fertilisation & Embryology Code of Practice (2019, 9th edition).

While intracytoplasmic sperm injection (ICSI) is the most significant advance in assisted reproductive technology (ART) for the alleviation of male factor subfertility, its use has become increasingly widespread and indiscriminate in ART clinics, extending well beyond the reasons for its necessary application. But ICSI is not “better” than IVF using any established outcome metric. Indeed, available evidence indicates that ICSI yields fewer embryos per treatment cycle, embryos which may have impaired developmental potential compared to IVF-derived embryos. This chapter investigates the basis for the over-use of ICSI, and identifies risks to which couples are exposed by the unjustified use of ICSI: a debate that has been raging for two decades, and is now also extending into considerations of “andrological ignorance”, how ICSI has effectively blocked scientific advances in andrology, and how obligate ICSI has effectively transferred the treatment burden for male factor infertility to the female partner, who is expected to undergo possibly unnecessary controlled ovarian hyperstimulation, oocyte retrieval and embryo transfer procedures.