This chapter should be cited as follows:
Kennedy R, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.421063

The Continuous Textbook of Women’s Medicine Series – Gynecology Module

Volume 15

Reproductive medicine for the obstetrician and gynecologist

Volume Editors: Professor Luca Gianaroli, S.I.S.Me.R. Reproductive Medicine Institute, Italy; Director of Global Educational Programs, IFFS
Professor Edgar Mocanu, RCSI Associate Professor in Reproductive Medicine and Surgery, Rotunda Hospital, Ireland; President, IFFS
Professor Linda Giudice, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, USA; Immediate Past President, IFFS

Published in association with the
International Federation of
Fertility Societies

Chapter

Infertility – A Modern Disease

First published: November 2024

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ABSTRACT

Infertility is disease almost as old as humanity but distinctly modern in its relevance and management. Infertility is defined as a medical disease leading to failure to conceive over a 12-month period, affects 17.5% of couples of adult age and causes significant disability. Global demographic data indicate steadily declining fertility rates, which alongside increased age of women at first conception and major advances in assisted reproduction technologies are driving demand for infertility services. The epidemiology of infertility is diverse and considered in both anatomical and functional terms. The most common causes of female infertility are tubal due to pelvic inflammatory disease and ovulatory dysfunction due to polycystic ovarian disease, and poor quality semen is a factor in about 50% of cases. Environmental and lifestyle factors have an important role in fertility. There are significant global and in country inequalities in access to infertility care and in most countries the need is not met, including in affluent nations, despite socioeconomic arguments in support of provision. New ways of working, including application of artificial intelligence and remote working promise improved efficiency and improved access to care.

INTRODUCTION

Fertility rates are in decline globally, the trend driven by improved education, life expectancy and improving public and child health. This has led to a premium of reproductive success and increasing prioritization of infertility within reproductive health care services. Furthermore, widening reproductive choices in family building, demographic changes and technological advancements in assisted reproduction technology (ART) have contributed to the rapid expansion of infertility treatment services. Up to 10 million children have been born following assisted conception and in some countries as many as 5% of the population have been conceived following ART. Thus, infertility and its management has become increasingly important in 21st century life. In this chapter we will discuss the fundamentals of infertility and provide context for the following chapters on diagnosis and treatment.

HISTORICAL PERSPECTIVE

Is infertility truly a modern disease? Fertility rights and folklore have existed in many societies for millennia, for example, the ancient Hindus and as written in Egyptian Papyrus in 1500 BC and fertility deities in Babylonia, Persia and Assyria.¹ The idea of reproductive difficulties resulting from a physical process, and therefore susceptible to treatment, were described by Hippocrates and Aristotle in the late centuries BC.^2,3 Throughout the first and most of the second millennium AD infertility and its treatment were based on quackery and mythology, and it was not until the late 18C and early 19C that fundamental anatomical and physiological understanding emerged with the discovery of spermatozoa and ova, and in 1868 Marion Sims described the first case of artificial insemination.⁴

From the late 19th century our knowledge and understanding of reproductive biology increased rapidly, and in 1978 the real game changer and, arguably one of the most significant medical achievements in the 20C occurred resulting in the birth of Louise Brown following in vitro fertilization (IVF).⁵ There have been further landmark developments with intra cytoplasmic sperm injection (ICSI),⁶ embryo and gamete cryopreservation⁷ and pre-implantation genetic diagnosis (PGD).⁸ Each of these technological advances has increased the capabilities of scientists and clinicians to overcome almost all our reproductive challenges and unquestionably define infertility as a modern disease.

DEFINITION

There are two currently used definitions of infertility. The first, developed by the World Health Organization (WHO), defines infertility according to the International Classification of Diseases (ICD) version 11 “An international classification of diseases for the twenty-first century” in section 16, GA31 as a “Disease of the reproductive system defined by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse”.^9,10

The WHO definition distinguishes between male and female while having the same definition for each and provides definitions for primary (no prior clinical pregnancy), secondary (any prior clinical pregnancy) and major categories of infertility due to tubal and uterine causes. Ovarian and hypothalamic-pituitary axis disorders are categorized separately as disorders of the gonadal hormone system and pituitary hormone system, respectively, alongside endocrine, metabolic and nutritional diseases in ICD section 5. Within this section detailed definitions of ovarian dysfunction including anovulation and its causes are provided including, anovulation, polycystic ovary syndrome (PCOS) and diminished ovarian reserve. The ICD classification is a comprehensive disease coding system, its definitions are concise and contemporary, if lacking nuance.

The second definition is included in a “consensus and evidence based driven” set of 283 terminologies used in infertility care developed by a group of content experts led by The International Committee for Monitoring Assisted Reproductive Technologies (ICMART). They were refined by a variety of stakeholders including professional representative organizations, scientific societies and service user groups. From this work infertility is defined as “A disease characterized by the failure to establish a clinical pregnancy after twelve months of regular, unprotected sexual intercourse or due to an impairment of a person's capacity to reproduce either as an individual or with his/her partner. Fertility interventions may be initiated in less than one year based on medical, sexual and reproductive history, age, physical findings and diagnostic testing. Infertility is a disease, which generates disability as an impairment of function”.¹¹

Both these definitions have the same basis; both describing a disease characterized by a time period (12 months), during which “regular” sexual intercourse takes place. The second definition adds nuance inasmuch as it establishes infertility as a disability causing impairment of function (ability to bear a child), allows for an individual (without partner) to be infertile and sets the definition in the context of management strategy, i.e. timing of intervention.

The simple take home message is that 12 monthly attempts at achieving a pregnancy either by regular sexual intercourse or artificial insemination constitute an indication for diagnostic tests and, if appropriate, treatment. This 12-month threshold must also be seen in the context of the clinical history and age of the female. Thus, if the female is known to have, for example, severe endometriosis or the male partner cryptorchism or the female is 40 years old at first presentation, then the time period may be modified. Notwithstanding the variances, both definitions provide a pragmatic guide for clinical practice and a sound basis for harmonization of epidemiological data collection.

POPULATION DEMOGRAPHIC CHANGES

Fertility rates have halved globally since 1950 and are predicted to decrease till the end of this century at which time they converge towards replacement level (2.1), or lower, in all regions except Sub-Saharan Africa (Figure 1).¹² These trends result in two distinct demographic impacts. In low- and some middle-income countries with high young age dependency ratios (ADRs) and low old ADRs from which an economic population dividend results, that is more economically productive younger people supporting proportionately fewer older dependents. For high-income countries the reverse is true resulting in an aging and dependent society.

Maternal age at first childbirth has increased in the last 50 years in the Organization for Economically Developed Countries (OECD) (Figure 2).¹³ This is explained by several possible factors: rising female education and employment, delayed entry into the labor market, housing problems, and variable welfare support. Economic trends also play a part, with a demonstrable relationship between economic downturns, resulting financial insecurity and reproductive intentions.^14,15 Delayed child bearing leads to increased age-related infertility and higher incidence in obstetric and perinatal complications, often underestimated.^16,17 Changing patterns of global migration are also impacting on fertility in unpredictable ways with both increased fertility rates in newly arrived migrants compared to native women and delayed childbearing¹⁸ compounded by inequity in access to fertility care and poorer perinatal outcomes.

The overarching demographic impacts on infertility and reproductive health services, including infertility and ART, are declining fertility rates and increased age at first conception. The impact of these changes varies globally, with different time courses but are being affected unpredictably by economics, conflict, and climate change.

GLOBAL BURDEN OF DISEASE

Determination of true prevalence has been challenging due to differences in methodology, measured outcome, definition, and reporting bias. Rustein and Shah¹⁹ reported data from 47 demographic and health surveys in developing countries and concluded that 186 million women of child bearing age were affected by primary and secondary infertility. In another review of 28 population surveys²⁰ estimates for both current and lifetime infertility were obtained. The authors focussed on current infertility as being more relevant and concluded that 72 million were affected globally and estimated the prevalence of current infertility ranged from 3.5% to 16.7% with a median of 9%. They further concluded that the clinically relevant range was 5% to 15% with no difference between developed and developing countries.

A systematic review undertaken in 2010²¹ obtained data from 277 demographic and reproductive health surveys and compared prevalence in 2010 to data from 1990. The authors estimated a global burden of 48.5 million affected by infertility. They found the prevalence of primary infertility varied from 1.5% (1.2%, 1.8%) in the Latin America/Caribbean region, to 2.6% in North Africa/Middle East. They also found marked differences in the prevalence of secondary infertility with 7.2% (5.0%, 10.2%) in high-income states compared to 18.0% (13.8%, 24.1%) in the Central/Eastern Europe and Central Asia region. Surprisingly they found a decrease in secondary infertility in Sub Saharan Africa 11.6% (10.6%, 12.6%) compared to 13.5% (12.5%, 14.5%) in 1990, which they attributed to falling fertility rates although improvements in safe abortion are also likely to impact infertility in this region.²²

Most recently, the WHO have undertaken a systematic prevalence study of 133 studies conducted between 1990 and 2021. They found an overall lifetime prevalence of 17.5% and periodic (current) prevalence of 12.6%. They found significant variation in regional periodic prevalence rates ranging from 10.1 to 18.1 shown in Table 1.²³

From the available evidence we can conclude the overall burden of infertility disease, defined as the inability to conceive within 12 months is substantial. At least 10% of women experience infertility in any given period. Furthermore, infertility is a global disease and conforms to no geographic or socioeconomic barriers, yet, as we shall discuss below, due to access and economic reasons, disproportionately impacts low- and middle-income countries. This, coupled with the stated WHO Sustainable Development Goals 3 and 5,²⁴ supports policy makers to include infertility care in their health plans. The imprecision of estimates in the prevalence studies conducted to date does not invalidate this proposal but necessitates healthcare agencies, professional organizations and healthcare professionals to agree methodologies for accurately measuring infertility prevalence and diagnostic groupings within.

EPIDEMIOLOGY OF INFERTILITY

There are a number of studies that have reported on global epidemiology of infertility but data on geographical variation in the causes of infertility is sparse. A large systematic review of national health surveys reported primary and secondary infertility prevalence in 2010 of 1.9% and 10.5%, respectively, with a non-significant decrease in primary infertility from 2.0% in 1990. They also reported an overall non-significant increase in secondary infertility up from 10.2% in 1990 and in all regions except Sub Saharan Africa, which reported a decrease from 13.5% to 11.6% (p = 0.99).²¹ In the same study regional variations in primary infertility were found: 1.5% (95% CI: 1.2%, 1.8%) in Latin America/Caribbean, to 2.6% (95% CI: 2.1%, 3.1%) in the North Africa/Middle East. They also found greater variations in secondary infertility (Figure 3): 7.2% (95% CI: 5.0%, 10.2%) in the high-income region to 18.0% (95% CI: 13.8%, 24.1%) in the Central/Eastern Europe and Central Asia region.²¹

The WHO undertook the most recent global infertility prevalence study and found pooled lifetime prevalence of primary infertility to be 9.6% (95% CI: 6.3, 14.3, n = 12) and secondary infertility 6.5% (95% CI: 3.9, 10.7, n = 10). They found no significant differences between regions and surprisingly no difference between high- and low-income countries, in part attributed to significant heterogeneity between studies.²³

Infertility is the consequence of an underlying disease process in at least 80% of cases, the remainder being “unexplained”. The causes are well understood and are cataloged by the WHO International Classification of Diseases (ICD).¹⁰ They fall within four broad groups of tubal, ovulatory dysfunction, uterine, and male factor. There are several common diseases associated with infertility whose mechanism of action may fall into one of these:

• Polycystic ovarian syndrome is an endocrinological and metabolic condition with a genetic basis linking multiple phenotypes.^25,26 It is the commonest cause of ovulatory dysfunction. Additionally, it is associated with obesity, which itself impacts on reproductive success. Globally there are phenotypic variations but there appears to be no epidemiological bias.²⁷
• Fibroids are common, benign, smooth muscle tumors of the uterus affecting women in their reproductive years. They are associated with infertility mainly due to a mechanical effect on the uterine cavity or through distortion of the utero-tubal junction. They are more than twice as common in African, African American and Caribbean women and planning of fertility services in countries affected necessitate consideration of fibroid management.²⁸
• Endometriosis is a common systemic condition of uncertain cause affecting up to 10% of women and is associated with infertility in up to 30% of cases^29,30,31 and there appears to be no geographical or demographic predisposition. Endometriosis has variable pathology and the mechanism for its impact on infertility is dependent to a large extent on the degree of severity. Its presence in a woman who has infertility adds the complication of managing both conditions.
• Sexually transmitted diseases (STIs) are a cause of infertility in both men and women.^32,33 Chlamydia and gonorrhea are most commonly associated and are endemic globally but with significant regional variances. Their importance lies in their causal relationship with tubal infertility (females) and vas obstruction (males), early diagnosis and treatment may minimize the impact on fertility and that they are preventable through effective public health measures. Prevalence rates are highest in Central and South America, Asia and Sub-Saharan Africa with a slight downward trend in the last two decades.^34,35

A WHO sponsored systematic review set out to characterize the global epidemiology of gonorrhea infection in infertile populations and found a prevalence of 2.2% (95% CI 1.3% to 3.2%), compared to 0.8%³² in the general population. They also found marked regional differences with the highest rate in the African infertile population: 5.0% (95% CI 1.9% to 9.3%), which was twice the rate of any other region and compared to 1% (95% CI 0.0% to 3.4%) in the European region. Furthermore, they discovered a higher rate in women with tubal infertility 3.6% (95% CI 0.9% to 7.7%) compared to 2.6% (95% CI 1.1% to 4.5%) for general/unspecified infertility, 1.4% (95% CI 0.2% to 3.3%) for male factor infertility and 0.06% (95% CI 0.0% to 0.8%) in women with ovarian and non-tubal infertility.³⁶

Male infertility is a contributory factor in up 50% of couples with childlessness.³⁷ has multiple possible causes and, as reported here, is affected by STIs, environmental and lifestyle factors. Declines in semen quality in Western men have been reported although not in non-Western populations. In a systematic review, significant declines in sperm count (52.4%) and total sperm count (59.3%) between 1973 and 2011 were found in studies from North America, Europe and Australia and New Zealand.³⁸

Complete absence of sperm (Azoospermia) results in unambiguous infertility. Obstructive azoospermia maybe be rarely genetic (cystic fibrosis) or more commonly iatrogenic or the result of STI and, importantly, is treatable. Non-obstructive azoospermia may result from abnormalities in the hypothalamic-pituitary-gonadal axis, which are also potentially treatable. Mumps which can result in orchitis in up one third of cases with possible testicular atrophy and azoospermia, is preventable through childhood vaccination programmes. However anti-vax campaigns, parental vaccine hesitancy and lack of effective public health measures have led to a recent increase in outbreaks in many countries.^39,40 Other than mumps, a number of viral infections including ZIKH and HIV are also implicated in reducing male fertility.⁴¹ Abuse of anabolic steroids is widespread, multinational and have profound adverse effects including on male reproduction, which are potentially treatable.^42,43,44,45 Varicocele is reported in 15.7% of healthy males⁴⁶ and is associated with impaired semen quality.⁴⁷ However, treatment in controversial especially in clinically asymptomatic male partners of infertile couples with normal semen parameters.^48,49 Most commonly however male infertility is related to reduced quality or quantity of sperm without obvious cause.

Other factors that affect the epidemiology of infertility are environmental, lifestyle, and age of the female at presentation.

• Environmental toxicants adversely affect reproduction in both males⁵⁰ and females.⁵¹ Exposure to a range of chemicals and pollutants has been associated with adverse reproductive outcomes^52,53 and the impact disproportionately affects the socioeconomically deprived due to educational, financial, and housing constraints.
• Weight obesity has long been associated with delays in conception^54,55 likely through disturbance in ovulation⁵⁶ and life style modification improves fertility in this group.⁵⁷ In contrast a study of East African women showed that women who were malnourished (AOR = 1.74; 95%CI: 1.54–1.98) were significantly associated with secondary infertility.⁵⁸
• Smoking in both men and women is a well-known contributor to reduced reproductive potential⁵⁹ although for women who are light smokers the impact is less clear.⁶⁰ The use of E-cigarettes poses less risk than conventional smoking, however the use of vaping devices has become widespread in adolescent. In the UK there has been a reported increased use of vaping devices in 11–17 year olds from 15.7% in 2022 to 20.5% in 2023⁶¹ and concerns have been raised about a range of toxicants vaping devices produce, especially heavy metals, and their potential impact on fertility.⁶²
• Age-related infertility has become a prominent factor in the four decades, is most marked in high-income countries and presents a complex clinical challenge.⁶³ This changing epidemiology has complex origins, including reproductive autonomy, personal choice, professional opportunity, and economic. Secondary amenorrhoea with elevated gonadotrophins occurring under the age of 40 (premature ovarian failure) and between 41 and 44 years (early menopause) affects 1–2% and 5% of women in the general population, respectively.^64,65,66,67 Decision making for treatment in this group needs to take account of the lower fecundity and typically longer duration of pregnancy seeking. Moreover, if the infertility work-up is unremarkable, duration of pregnancy seeking should be extended up to more than 2 years prior to making a diagnosis of unexplained infertility regardless of age.⁶⁸

Knowledge of the epidemiology of infertility provides clinicians with a template for investigation and how its emphasis may be modified by geography. It also throws up so-called “red flags” in the clinical history, meaning features that indicate a high likelihood of abnormal pathology requiring further assessment and specialist referral. These include in the women pelvic pain, infrequent or abnormal periods, pelvic surgery; in the man cryptorchidism and in either partner STIs.

ACCESS TO CARE

Access to Sexual and Reproductive Health Rights (SRHRs) form part of Goal 5 of the United Nations 2030 Sustainable Development Agenda.²⁴ Explicit therein is the right to decide whether and when to have children, the means to do so and thus receive infertility care.⁶⁹ Aside this basic human right there are other drivers affecting demand for access to infertility care including falling fertility rates, therapeutic opportunity, economic security, globalization and reproductive autonomy.⁷⁰ SRHRs are also impacted globally by disparate development of appropriate healthcare facilities, gender violence, forced migration, environmental disasters and conflict.^71,72,73

Utilization rates of healthcare treatments are regarded as an indicator of access to care.⁷⁴ Assisted reproduction technology (ART) treatment, meaning in vitro fertilization (IVF) and related procedures, is the only globally measured activity of infertility management and its utilization is recommended as a surrogate for access to infertility care.⁷⁵ It has been estimated that ART need is approximately satisfied by 1500 cycles of ART per million population per year.⁷⁶ Data from the European IVF monitoring consortium,⁷⁷ International Committee for Monitoring ART (ICMART),⁷⁸ Latin American ART registry⁷⁹ and the African registry – ANARA⁸⁰ show that despite increasing ART cycle numbers there is marked variation in expansion globally with many countries, especially in Latin America and Africa, well below estimated need (Figure 4). The International Federation of Fertility Societies (IFFS) survey of global policy and practice in ART in their 2022 report demonstrate the growth in clinics providing IVF/ART, rising from 3524 in 2010 to 6977 in 2022 with the largest expansions taking place in China, India, Malaysia, Mexico, Nigeria, Peru, Russia and South Africa. In contrast, of 78 countries for which there was comparative data, 47.4% (37) reported no change or a decrease in the number of clinics in 2022 compared to 2019.⁸¹

Even in high-income countries substantial differences in ART cycles per million population exist (Figure 5) and unmet need exists.^83,84 In the US both racial and economic inequalities in access to ART have been reported with lower utilization in African American, Asian and Hispanic women⁸⁵ and delay in referral for infertility treatment.^86,87,88,89 Indeed poorer ART outcomes have also been reported in Black, Asian and Hispanic women compared to white women.^80,90,91

A recent study from Mexico found that women who spoke an indigenous language or received education in a rural setting were significantly less likely to access infertility care.⁹² Living in a rural setting per se has also been shown to disadvantage couples seeking ART treatment.⁹³ A national cohort study in Denmark found that though there was equal access to ART in the publicly funded healthcare system, inequality in access was found to first treatment according to socioeconomic, educational and employment indicators.⁹⁴

In some societies, especially for women, infertility can lead to social isolation and economic deprivation, disproportionately affecting women in low- and middle-income countries.^95,96 This fact coupled with poor access to technological solutions may lead women to seek intracontinental or transcontinental solutions.^97,98,99,100 Even in some affluent countries cross-border treatment is being driven by cost, limited access, especially to donor gametes and regulatory constraints.^{101,102,103,104}

It is clear from the available data access to basic ART is variable and, in many parts of the globe, insufficient to meet need. Furthermore, where technology has been implemented, its cost may be prohibitive to many and access constrained by regulation. The maintenance and development of national and global registries and surveys such as those undertaken by EIM, ICMART and IFFS are critical to evidence the case for need and clinicians have a vital role in supporting the collection and submission of data to these enquiries.

SOCIOECONOMIC COSTS AND BENEFIT

The most recent global assessment of healthcare funding was undertaken through the Global Burden of Disease project in 2017–2018. It predicted future healthcare funding will grow at a slower pace than the two decades to 2016 with persistent disparities in per-capita health spending between countries. It also predicted out-of-pocket (OOP) spending to remain substantial, outside of high-income countries, with many low-income countries expected to remain dependent on development assistance.¹⁰⁵ Of note, this study was published immediately before the Covid-19 pandemic and war in Ukraine, global events which will downgrade spending predictions.

This pessimistic outlook is likely to have a greater impact on access to infertility and ART treatment and accentuate the pre-existing disparities highlighted in many studies.^78,106 A recent review of ART funding in European countries showed significant variation in either insurance or public funding with qualifiers typically based on female age and fecundity compounding this.¹⁰⁷

In Africa and parts of Asia the lack of public funding and social consequences of infertility lead to desperate couples incurring catastrophic expenditure for ART treatment, defined as >/=40% of annual non-food expenditure.¹⁰⁸ A systematic review of ART costs in 17 countries found that more than half had direct costs for one ART cycle higher than the average annual per capita GDP (Figure 6).¹⁰⁹ A similar survey of advanced economies found ART costs as a proportion of annual disposable income ranged from 50% in the US to 12% in Japan.¹¹⁰ Out-of-pocket expenses drive patient choices when public funding is not available, even in affluent states.^101,111 When public services are available, patients from lower socioeconomic groups may be disadvantaged by longer waits and lower success rates.¹¹² In a recent review of infertility services in low- and middle-income countries (LMICs) the lack of economic solutions to infertility treatment was highlighted.¹¹³ Furthermore, public funding policies leading to significant out-of-pocket expenses may influence clinical decision making, for example, in respect of the number of embryos to replace during ART, with consequently high rates of multiple pregnancies, increasing maternal and perinatal risk and cost.^114,115

The call for increased public funding of infertility services takes its place alongside many other demands on limited public funds. Commissioner attitudes to provision of infertility services have shifted positively but not far enough to meet need. A recent survey in the US showed there is still widespread perception infertility is not a disease¹¹⁶ despite statements to the contrary by the WHO.^{10,23,117,118} In contrast, a large multinational survey including over 7000 respondents found that 75.5% thought infertility to be a medical condition and the majority of respondents supported access to treatment.¹¹⁹ Furthermore, a large European survey of over 6000 public respondents found a similarly favorable attitude to state funding of ART services.¹²⁰

More work is needed to influence policy makers and commissioners of healthcare in favor of the infertile, drawing upon contemporary epidemiological, economic and social arguments.^{121,122,123,124} When added to the sharp global fall in fertility rates these will strengthen the case for inclusion of infertility services in population strategies.¹²⁵ However, there is concern that conventional methodology used by policy makers to assess the societal cost benefit/utility that informs decisions on healthcare resource allocation, namely quality adjusted life years (QUALYs), do not adequately represent the benefit of infertility treatment.^126,127,128 In this regard, clinicians and scientists also have an important role in directing research and service improvement programmes toward the development of more cost-effective and economic ways of delivering infertility care.¹¹⁴

NEW WAYS OF WORKING, FEMTECH AND ARTIFICIAL INTELLIGENCE

The Covid-19 pandemic and resulting restrictions caused a major disturbance to healthcare systems globally. The impact on access to sexual and reproductive healthcare was marked, many assisted conception services were shut down temporarily and infertile couples suffered significant psychological stress.¹²⁹ Traditional care delivery models were disrupted but also allowed the piloting of novel solutions and pivoting to new ways of working at an unprecedented pace and scale.¹³⁰ The rapid introduction of remote working to overcome enforced lockdowns have paradoxically unlocked restriction to access in health service delivery. Patient satisfaction with video consultations has been reported to be high and is not a barrier toward a paradigm shift away from traditional in-person clinic visits.¹³¹ It has the potential for improved efficiency and reduced waits,¹³² can interface with remote physical assessment technologies and transcend geographical and socioeconomical boundaries whilst still preserving the doctor–patient relationship.¹³³ The place for telehealth is still to be determined in future service delivery¹³⁴ but the potential patient benefits should not be lost by a return to pre-pandemic working.^135,136,137

The disruptive influences of the pandemic came at the time of the emergence of so-called “Femtech”,^138,139 that is the increasing number of apps and high-tech services specifically addressing women’s needs, including digital-driven fertility and menstruation tracking, at-home endocrine testing, and mobile health applications that enable patients to self-manage their reproductive care.¹⁴⁰ The use of digital applications to support access to reproductive healthcare is advocated by the WHO¹⁴¹ but ethical and security challenges need to be addressed. A recent review of apps found that many of the most popular women’s health apps on the market have poor data privacy, sharing, and security standards.¹⁴²

Artificial intelligence (AI) and its application to assisted conception laboratory processes and clinical decision-making tools has developed coincidentally with Femtech and the new world post Covid. The use of big data and machine learning coupled with genomics has increased the horizon of personalized care and use of precision medicine in many areas of infertility practice, including prediction algorithms for natural conception, ovarian stimulation dose scheduling and embryo selection in ART.¹⁴³ If AI is to deliver its full potential, its outcome must be measured through improved outcomes and access to care through reduced cost.¹⁴⁴

Taken together, judicious use of Femtech with security protections, AI and selected use of remote working is already transforming the landscape of reproductive healthcare. The clinical and scientific community working in partnership with service users and other stakeholders must ensure the risks and benefits are rigorously evaluated if they are to be adopted with confidence and bring real improvements in patient care.

CONCLUSIONS

Infertility is a common disease affecting up to 17.5% of adults through their reproductive years according to recent estimates. It causes significant disability in both men and women with potentially serious consequences for physical and mental health. Infertility occurs equally in all ethnicities and socioeconomic groups but disproportionately affects the poorest and those with limited access to healthcare. The burden of this disease in the 21st century is in the context of sharp global declines in fertility rates and major technological advances in its treatment.

Infertility arises from a range of endocrinological, genetic, gynecological, developmental and microbiological causes but simplistically is due to functional disturbances of ovulation, semen quality, transport of the sperm to the site of the egg. The single most common cause of female infertility is polycystic ovarian disease leading to ovulatory dysfunction and abnormal sperm quality or quantity is a factor in up to 50 percent of couples with infertility. Prevention of infertility includes mitigating the risks of STIs, other causes of pelvic infection such as unsafe abortion, modification of lifestyle choices and environmental factors known to impact fertility.

We are now able to treat successfully the vast majority of those suffering from infertility but access to care is variable, insufficient to meet need in most countries and incurs significant out-of-pocket expenses for the majority of those affected globally. Practitioners can influence health policy makers through their understanding of infertility, its causes, implications and treatment but also by using knowledge from this and other texts to choose cost-effective options for their patients and supporting research where this knowledge does not exist. Infertility is not a modern disease but its epidemiology, challenges and solutions are most definitely 21st century.

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