Inhorn & Patrizio Infertility Around the Globe: A Comprehensive Overview

Infertility Around the Globe: New Thinking on Gender, Reproductive Technologies, and Global Movements in the 21st Century

Introduction

Infertility remains a prevalent global condition in the second decade of the new millennium.
Estimated to affect 8-12% of reproductive-aged couples worldwide, with 9% as the probable global average.
Rates can reach >30% in some regions like South Asia, sub-Saharan Africa, the Middle East and North Africa, Central and Eastern Europe and Central Asia
IVF, initially for blocked fallopian tubes, is over 35 years old (first baby in 1978).
It remains absent, inaccessible, or unaffordable for most infertile couples.
Lack of IVF access has inspired clinician-led efforts to bring 'low-cost IVF' (LCIVF) to resource-poor settings.
Without LCIVF, couples face catastrophic expenditures or cross-border reproductive care (CBRC).
The article explores five key questions:
1. Why is infertility an ongoing global reproductive health problem, especially for women in low-resource settings?
2. What are the gender effects of infertility, and are they changing?
3. What do we know about the globalization of IVF services, including their mal-distribution and inaccessibility?
4. How are new clinician-led initiatives attempting to improve access to IVF in resource-poor settings, particularly through LCIVF?
5. What can be done to prevent infertility from obstructing the desire for children?
The article aims to answer these questions and suggest three future directions for infertility and IVF activism.

Methods

An exhaustive literature review was conducted using MEDLINE, Google Scholar, and the Yale University Library's search function.
Identified 103 peer-reviewed journal articles and 37 monographs, chapters, and reports from 2000-2014.
Areas of focus include infertility demography, ART in low-resource settings, gender and infertility in low-resource settings, and the rise of LCIVF initiatives.
International Federation of Fertility Societies (IFFSs) Surveillance reports were helpful in identifying global trends in the ART sector between 2005 and 2010.
Ten world reports on ART availability, efficacy, and safety between 1995 and 2004 were consulted, including five by the International Committee for Monitoring Assisted Reproductive Technology (ICMART).
ICMART collaborated with the World Health Organization (WHO) to publish an extensive glossary of ART terminology and estimate levels of international CBRC.
A series of articles published by Willem Ombelet and other scholars on the growing LCIVF movement were also invaluable.

Infertility Demography

Infertility, or the inability to conceive, remains a problem of global proportions.
Six demographic realities regarding infertility remain salient:
1. Millions of people around the globe suffer from infertility.
  - Difficult to estimate the precise numbers.
  - There are differing definitions of infertility (e.g. 1, 2, or 5 years of trying).
  - There is a complete absence of information on the numbers of infertile men.
  - Three global infertility prevalence surveys published in the new millennium (2004, 2007 and 2012) with differing results (48.5–186 million).
2. Women in many low-resource settings continue to suffer from high rates of secondary infertility.
  - Secondary infertility (the inability to conceive following a prior pregnancy) is the most common form of female infertility.
  - Several regions of high prevalence (sub-Saharan Africa, South Asia, East Asia and the Pacific, Central and Eastern Europe, Central Asia).
  - Rates are declining in sub-Saharan Africa.
  - Rates remain high in Central and Eastern Europe and Central Asia due to unsafe abortion.
3. Africa continues to suffer from inordinately high rates of infertility.
  - There is an ongoing ‘infertility belt’ of primary and secondary infertility across central Africa.
  - There are high rates of untreated or poorly managed RTIs, including STIs.
  - Most cases of infectious infertility are preventable, representing a regional tragedy.
4. High rates of infertility coexist with high rates of fertility in Africa—a demographic paradox known as ‘barrenness amid plenty’.
  - Africa has the world’s highest total fertility rates, even in the midst of high rates of infertility and HIV infection.
  - Adolescent fertility levels are particularly high.
  - Contraceptive prevalence rates remain low, including among women who want to delay or stop childbearing.
  - Desire for children remains strong.
  - Infertility is a form of agony, especially for women, who face suffering and rejection.
  - Infertile women are at increased risk of HIV infection.
  - Infertility represents ‘social death’, and HIV represents physical death for many women.
5. Lack of infertility prevention and treatment services is often justified as a form of population control, particularly in high-fertility settings such as sub-Saharan Africa.
  - Infertility is deemed a low-priority issue in the context of scarce health care resources.
  - Infertility may be justified as a natural solution to achieving the ‘demographic dividend’ (accelerated economic growth from declining fertility and smaller dependent populations).
  - A tacit eugenic view exists that infertile people in developing countries are unworthy of treatment.
  - Overcoming infertility contradicts Western interests in population control.
  - With the exception of the WHO, few international organizations have prioritized or funded infertility efforts.
  - UN’s ‘ICPD Beyond 2014’ does not include infertility care in its Programme of Action on sexual and reproductive health services.
6. Those parts of the world with the highest rates of infertility are least likely to offer reliable diagnosis and treatment, including IVF services.
  - Poor access to IVF is a form of global reproductive health disparity.
  - Parts of the world with the greatest unmet need for IVF have the least access to this technology.
  - IVF is designed to overcome blocked fallopian tubes, the major form of female infertility in developing countries.
  - Developing countries have a huge unmet need for IVF.
  - Sub-Saharan Africa has been bypassed in the new millennial race to IVF.
In 2002, more than 186 million women in developing countries (except China) were infertile due to primary or secondary infertility.
In 2007, an estimated $72.4$ million women were currently infertile, with $40.5$ million (56%) seeking medical care.
In 2010, $48.5$ million couples were affected by infertility.
If the time frame is reduced from 5 to 2 years, the total number of infertile couples increases 2.5-fold to 121 million.
Infertility rates do not appear to have increased significantly over the past two decades, partly because global fertility rates have dropped.
Secondary infertility is the most common form of female infertility, often due to reproductive tract infections (RTIs) damaging fallopian tubes.
In 14 of 23 sub-Saharan African countries surveyed in 2002, the percentage of women with secondary infertility was >25%; in Zimbabwe, it was 62%.
Rates of primary and secondary infertility are decreasing in Africa, likely due to reductions in unsafe abortions and sexually transmitted infections (STIs).
However, sub-Saharan Africa still remains a global ‘hot spot’ of secondary infertility, affecting >10% of reproductive-aged women overall.
In Central and Eastern Europe and Central Asia, rates of secondary infertility range between 16 and 25%, likely due to high rates of unsafe abortions.
Africa’s ‘infertility belt’ includes countries like Angola, Cameroon, Central African Republic, Equatorial Guinea, Gabon, Liberia, Mozambique, and Sierra Leone.
High rates of African infertility are largely due to the sequelae of poorly managed or untreated RTIs; 85% of infertile women in sub-Saharan have a diagnosis of infertility attributable to an infection, compared with 33% of women worldwide.
Approximately 70% of pelvic infections are due to STIs, while the rest are due to pregnancy-related sepsis
STIs, primarily gonorrhea and chlamydia, can also lead to male infertility, due to obstructions along the seminal tract.
Almost half of men in sub-Saharan Africa have a medical history of STIs, a rate that is two to four times higher than the rest of the world.
High rates of infertility coexist with high rates of fertility in Africa, a demographic paradox known as ‘barrenness amid plenty’.
Sub-Saharan Africa has the world’s highest total fertility rates, even with high rates of infertility and HIV infections.
Contraceptive prevalence use rates remain low in sub-Saharan Africa; nearly one-quarter (24%) of women wanting to delay or stop childbearing were not using a family planning method (2000-2008).
Adolescent fertility levels were particularly high in the WHO African Region, at 118 births per 1000 women aged 15 –19 years, or about 2.5 times the global average.
Infertile women in sub-Saharan Africa are at significantly increased risk of HIV infection due to greater marital instability and higher likelihood of extramarital sexual partners.
HIV leads to physical death, while infertility leads to a kind of ‘social death’.
Lack of infertility prevention and treatment services is often justified as a form of population control in high-fertility settings.
High fertility is said to be blocking the ‘demographic dividend’.
A tacit eugenic view exists that infertile people in developing countries are unworthy of treatment.
Those parts of the world with the highest rates of infertility are least likely to offer reliable diagnosis and treatment, including IVF services; this is a global reproductive health disparity.
IVF was designed to overcome blocked fallopian tubes—the major form of female infertility in many developing countries, yet these nations are least likely served by IVF clinics.

Globalization of ART

There has been a significant increase in the number of IVF clinics and ART cycles performed worldwide over the past decade.
The IFFS has tracked this process since 1998, assessing the number of clinics, services offered, and each country’s ART legal and regulatory environment.
By 2000, IVF services were only available in ~1/4 of the world’s nations (45 of 191 WHO member states, or 24%), mostly affluent, Western nations accounting for 91% of the world’s gross domestic product.
By 2005, that number had expanded to nearly 1/3 of the world’s nations (59 of 191, or 31%).
By 2010, more than half of the world’s nations had developed, or were on the cusp of developing, IVF services (105, or 55%).
In 2010, between 4000 and 4500 IVF clinics were estimated to exist.
More than 1/4 of these clinics were located in just two countries, Japan (606–618 clinics) and India (500 clinics).
Other nations with large numbers of IVF clinics included the USA (450–480), Italy (360), Spain (177–203), Korea (142), Germany (120–121) and China (102–300).
By the mid-2000s, both the Middle East and Latin America had shown remarkable development of their IVF sectors.
Among the 48 countries performing the most ART cycles per million inhabitants, nine Middle Eastern countries could be counted, with Israel ranking first, followed by Lebanon (6th), Jordan (8th), Tunisia (25th), Bahrain (28th), Saudi Arabia (31st), Egypt (32nd), Libya (34th) and the United Arab Emirates (UAE) (35th).
Nine Latin American countries—Argentina (37th), Uruguay (38th), Brazil (40th), Chile (41st), Peru (43rd), Mexico (44th), Ecuador (45th), Dominican Republic (47th) and Guatemala (48th)—all made the list of the top 48 nations offering the most IVF cycles per capita.
Less than one-third of sub-Saharan African nations hosted an IVF clinic as of 2010 (15 of 48 nations, or 31%), and seven of these had just one IVF clinic.
Three nations—Ghana (7 clinics), Nigeria (16 –20 clinics) and South Africa (12 –15 clinics)—could be considered comparative regional success stories.
The relative absence of IVF clinics in sub-Saharan Africa in 2010--compared with Asia, the Middle East and Latin America--is clear.
Sub-Saharan Africa—with its high infertility estimates—is relatively deprived of IVF clinics, especially when compared with the IVF-saturated region of the Middle East and North Africa.
These inequalities have been described as ‘islands of high-tech infertility treatment in a sea of generalized poverty and medical neglect’.
Several other regions of the world were missing altogether in the 2010 IFFS surveillance report.
None of the large Central Asian countries of Afghanistan, Kazakhstan, Kyrgyzstan, Mongolia, Tajikistan, Turkmenistan, and Uzbekistan were included in the report.
The absence of IVF in most of Central Asia is especially troubling, given that it has the world’s highest rates of secondary infertility—probably due to unsafe abortions.
Even within ‘successful’ regions, such as the Middle East, marked disparities could be detected as a result of political isolation and violence.
South Asia also showed pronounced regional disparities in IVF clinic development.
India had become the new millennium’s emblem of IVF globalization—boasting ~500 IVF clinics, while neighboring South Asian states of Bangladesh and Pakistan had opened only 10 clinics each by 2010.
In the more recent 2013 IFFS surveillance report, only 7 of the 18 sub-Saharan Africa countries that had reported in 2010 were included.
Furthermore, these seven nations showed zero growth in their IVF sectors between 2010 and 2013.
Thus, the actual number of IVF clinics around the globe—and the ongoing IVF absences in many resource-poor regions of the world—is even more obscure than before.
As suggested by the cases of Bangladesh, Pakistan and sub-Saharan Africa overall, there remains a high ‘unmet demand’ for IVF services around the globe.
At the beginning of the new millennium, an ESHRE workgroup estimated that 1500 couples per million population required ART treatment annually. 1500 cycles per annum was considered a conservative estimate, given that many couples may need to undergo more than one ART cycle in a given year Half of couples in both the developed and developing nations are able to seek any medical assistance for their infertility problems (Boivin et al., 2007). In the end, only about one-quarter of infertile couples (22%) actually obtain help (Boivin et al., 2007).

ART and Changing Gender Relations

There is still a huge unmet need for ART around the globe—from the least to the most developed nations.
For many infertile women, the absence of IVF access may have significant social consequences, particularly in the realm of marriage.
Women who are married but have never given birth face divorce and separation.
Childless women are more likely to be the victims of domestic violence, and may also endure various forms of verbal and emotional abuse.
Infertile women who are abandoned may be forced to turn to prostitution.
Therefore, infertility may be both impoverishing and life threatening, putting a woman at a higher risk of violence and STIs/HIV/AIDS.
Paradoxically, women are often blamed for infertility, even when it is their husbands who are infertile.
Male infertility remains a ‘hidden’ reproductive health condition, even though it contributes to more than half of all cases of childlessness worldwide.
However, the gender relations surrounding infertility appear to have changed significantly over time, as diagnostic semen analysis techniques and ART spread around the globe.
Access to ART appears to be changing gender relations in several positive ways through:
1. increased knowledge of both male and female infertility among the general population
2. normalization of both male and female infertility problems as medical conditions that can be overcome
3. decreased stigma, blame and social suffering for both men and women
4. increased marital commitment as husbands and wives seek ART services together
5. increased male adoption of ART, especially for male infertility problems
The coming of ART to previously ART-poor settings can lead to major, positive impacts on marriage and on gender relations more generally.
Middle Eastern Muslims are among the ‘most married’ people in the world, often trying to maintain their marriages, even under the threat of infertility and childlessness.
'Conjugal connectivity' has been demonstrated across the region.
Thus, the coming of ART to the Middle Eastern region has been a major marital asset, promoting conjugal connectivity through couples’ hopes of making a ‘test-tube baby’ together.
Most significantly, the widespread emergence of ICSI as the solution for the region’s highly prevalent male infertility problems has facilitated the development of ‘emergent masculinities’.
In general, the emergence of ART has been a positive force in men’s more general attempts to overturn patriarchy, challenge negative male stereotypes, and nurture companionate marriages characterized by love, commitment and fortitude in the face of adversity.
These positive effects on gender can be seen most clearly in the Middle Eastern nation-states that have made ART most accessible, notably Turkey.
Turkey began fully funding two IVF cycles for all Turkish citizens, so the demand for IVF in Turkey has dramatically increased.
In the Middle East, Turkey has made a national commitment to overcome its unmet need for ART, providing affordable IVF for all.

The LCIVF Movement

Relatively few countries have followed the Turkish lead, which is why an alternative social movement, called the LCIVF movement, is gaining momentum.
LCIVF represents a new millennial activist attempt to respond to the Universal Declaration of Human Rights mandate (Article 16:1), which states that ‘Men and women of full age, without any limitation due to race, nationality or religion, have the right to marry and found a family’.
LCIVF is thus a reproductive justice movement, driven by the goal of helping the world’s infertile, most of whom are located in resource-poor settings.
In Europe, ESHRE has supported the LCIVF movement, which is being headed in Europe by Willem Ombelet of the Genk Institute for Fertility Technology in Belgium.
Ombelet’s non-profit organization, ‘The Walking Egg (WE)’, has invented an LCIVF method that was first announced at the ESHRE annual meeting in London in July 2013.
ESHRE issued a press release announcing, ‘IVF for 200 euro per cycle: first real-life proof of principle that IVF is feasible and effective for developing countries’.
The new LCIVF technique essentially bypasses the need for a costly IVF laboratory, by simplifying embryo culture methods and eliminating high-end equipment.
The tWE lab IVF culture system developed by The Walking Egg is a low-cost embryo culture system, ‘designed for simple assembly and to fit within a container for transport’.
LCIVF cannot mitigate the high costs of ICSI— the variant of IVF designed to overcome male infertility. As yet, ICSI la- boratory techniques cannot be replicated in a low-cost format.
A North American-based non-profit organization called ‘Friends of Low-cost IVF’ (FLCIVF) (www.friendsoflcivf.org) was created in 201 1 by Prof. Alan Trounson, emeritus professor at Monash University in Melbourne, Australia, Karin Hammarberg and a number of North American colleagues.
The two main aims of FLCIVF are:
1. to provide simplified clinical IVF services for a minimal cost to reduce the burden of childlessness
2. to deliver reproductive health education to prevent infertility and avoid transmission of HIV and other STIs
The first successful pilot initiative of social solidarity supported by FLCIVF started in Monterrey, Mexico in 2012.
Adoption of FLCIVF programmes can serve to widen access to infertility care, and the milder stimulation protocols can reduce treatment invasiveness and complications for women.
As of 2015, FLCIVF programmes are being implemented at ‘no-cost-to-patient’ clinics in Sudan and Tanzania. Sites for future programmes are being explored in South Africa, Nigeria, Tunisia, Burkina Faso, Ethiopia and Uganda.
The new global LCIVF movement is part of a reproductive justice mission being supported by many prominent IVF clinicians and organizations.
In addition to investments in LCIVF, the ESHRE Task Force has made a number of other important recommendations for providing infertility treatment in resource-poor countries.
These include:
1. increasing attention to infertility prevention, partly through national investments in reproductive health and sex education
2. research to improve the cost-effectiveness of infertility diagnosis and treatment, with technologies adapted to local conditions
3. modified ovarian stimulation protocols, using simplified and mild stimulation procedures or controlled natural cycles, to reduce the risks of ovarian hyperstimulation syndrome
4. single-embryo transfer to reduce multiple pregnancies
5. efforts by international organizations to fund research and organize infertility diagnosis and treatment training courses in low-resource settings
6. support to governments to regulate ART practice by licensing providers, monitoring clinical activities and verifying success rates of low-cost approaches.
The ultimate goal is to optimize the efficacy and safety of infertility diagnosis and treatment with ART, primarily through promoting the uptake of single-embryo transfer in all IVF facilities around the globe

Catastrophic Expenditure and CBRC

LCIVF initiatives hold great promise, but the techniques and strategies of LCIVF are still in the formative stages
In the absence of LCIVF, a huge unmet need for IVF exists in both developed and developing countries.
Only about half of all infertile couples in either developed (56%) or developing countries (51%) seek any form of infertility care.
Because of the high cost of IVF, few governments have been able or willing to subsidize ART cycles, meaning private medical sector.
Problems of accessibility, cost, and rationing of IVF services create ‘an almost insurmountable obstacle to adequate reproductive health care’.
'Financial access' describes the problem of IVF affordability, playing a critical role.
According to John A. Collins, IVF and ICSI treatments are costly technologies that involve several pro- fessions and expensive laboratory facilities expenses.
To pay for high-cost IVF treatments, many couples engage in a form of financial sacrifice called ‘catastrophic expenditure’--out-of-pocket payment exceeding 40% of annual non-food expenditures.
Infertile couples, particularly women from resource-poor countries, are at high risk of catastrophic expenditure
A study in South Africa found that 22% of couples attending a public-sector IVF clinic had incurred catastrophic expenditures.
To cope, couples reduced expenditures on basic items, depleted savings, borrowed money, and took on extra work.
High cost of IVF has been deemed one of the most important factors fueling ‘CBRC’, or the movement of mostly middle-to-upper-class infertile couples across borders.
Scholars point to four broad sets of factors:
* resource constraints
* legal and religious prohibitions
* quality and safety concerns
* socio-cultural barriers
Many countries lack IVF clinics altogether, especially in sub-Saharan Africa. In settings where the costs of IVF are prohibitive, travel to another country is a decision that increasing people take. Global cross-border appears to be a growing global phenomenon.
The study estimated a minimum of 24 000 –30 000 cross-border IVF cycles in Europe each year and global is hard to track and assess, due to absence of reliable international statistics about IVF clinics and minimal international monitoring of cross-border IVF cycles.

Future Directions

If constraints and absences of IVF facilities are fuelling the cross-border movements of thousands of infertile couples each year, then the provision of safe, affordable and reliable IVF services around the globe is far from realized in the 21st century.
What can be done to achieve reproductive justice for the world’s infertile population?
Three suggestions:
1. Infertility prevention—eclipsing the preventable forms of infertility before they can take hold, through the early detection and treatment of RTIs and through health education.
  - Infertility prevention involves the early detection and treatment of RTIs, including STIs such as gonorrhea and chlamydia, which can wreak havoc on the male and female reproductive organs, as well as postpartum, post-abortion and medically iatrogenic infections, which are a major cause of secondary in- fertility in women (Mascarenhas et al., 2012b).
  - Arab Gulf and South Asia, a new infertility ‘epidemic’ and is linked to the triad of overweight/obesity, insulin resistance/diabetes and polycystic ovary syndrome (PCOS), the global solution of which remains obscure (Gambineri et al., 2002; Mehta et al., 2013; Inhorn, 2015).
2. Support of the infertile--de-stigmatizing infertility and supporting infertile men and women who find themselves ostracized, and creating new routes to social parenthood.
  - Global effort must be directed at de-stigmatizing infertility, and supporting the infertile men—but especially the infertile women—who find themselves ostracized within societies where parenthood is socially mandatory (Cui, 2010).
  - Efforts should be directed at creating new routes to social parenthood, particularly through the encouragement of adoption and fostering (Inhorn, 1996, 2003a, 2012a).
  - Assurance of basic human rights for girls and women—especially in education and career opportunities—would diminish the agony of infertility and provide alternative pathways for infertile women, alone and in need of economic support.
3. LCIVF initiatives--embracing the LCIVF initiatives that have emerged in the IVF community, to make safe, affordable, and effective IVF accessible to all of those in need.

Conclusion

Infertility remains an ongoing global challenge, particularly for women in low-resource settings.
Despite the massive global expansion of ART, ART services remain inaccessible in many parts of the world, especially sub-Saharan Africa, where IVF clinics are absent in most countries.
An LCIVF movement is emerging to bring LCIVF to the Global South.
Without access to affordable IVF, many couples must incur catastrophic expenditures to fund their IVF cycles, or seek lower-cost IVF services outside their home countries.
Three forms of 21st-century activism are important:
1. address the preventable causes of infertility
2. provide supports and alternatives for the infertile, especially in resource-poor settings
3. make common cause with the growing LCIVF movement, which seeks reproductive justice.