ESHRE by Cypres

ESHRE Monographs July 2008

ESHRE Special Task Force on ‘Developing Countries and Infertility’

Published in association with ESHRE by Oxford University Press

The cover was designed by Belgian Artist Koen Vanmechelen

doi:10.1093/humrep/den176

Human Reproduction 2008

On the occasion of the Arusha-expert meeting on “Developing countries and infertility”, held in Arusha, 15– 17 December 2007

Editors Willem Ombelet, Paul Devroey, Luca Gianaroli, Egbert te Velde

Contents Introduction

Willem Ombelet

Photo of Arusha experts: list of speakers (with addresses)

Articles Documentation of infertility prevalence, treatment access and treatment outcomes in developing countries Karl Nygren and Fernando Zegers-Hochschild

False perceptions and common misunderstandings surrounding the subject of infertility in developing countries Willem Ombelet

Affordable assisted reproductive technologies in developing countries: pros and cons E. Oluwole Akande

Ethical issues of infertility treatment in developing countries

Guido Pennings

Is affordable and cost-effective assisted reproductive technology in low-income countries possible? What should we know to answer the question? J. Dik F. Habbema

Involuntary childlessness: a neglected problem in poor-resource areas

F. Van Balen

Infertility-related reproductive health knowledge and help-seeking behaviour in African countries Medical and socio-cultural aspects of infertility in the Middle East

S.J. Dyer

G.I. Serour

29 34

Assisted reproductive technology in Latin America: an example of regional cooperation and development Fernando Zegers-Hochschild, Juan-Enrique Schwarze and Veronica Galdames

Infertility in African countries: challenges created by the HIV epidemic

S.J. Dyer

Modern endoscopic-based exploration of the female reproductive tract: a model for developing countries? Rudi Campo and Carlos Roger Molinas

African experience with training courses on sperm examination D.R. Franken and N. Aneck-Hahn

Intrauterine insemination (IUI) as a first-line treatment in developing countries and methodological aspects that might influence IUI success Willem Ombelet, Rudi Campo, Eugene Bosmans and Martine Nijs

Assisted reproductive technologies: how to minimize the risks and complications in developing countries? Petra De Sutter, Jan Gerris and Marc Dhont

Affordable ART services in Africa: synthesis and adaptation of laboratory services

Carin Huyser

R. Frydman and C. Ranoux

INVO: a simple, low cost effective assisted reproductive technology

Four years of IVF/ICSI experience in Kampala (Uganda) P. Platteau, B. Desmet, G. Odoma, C. Albano, P. Devroey and E. Tamale Sali

Affordable ART and the Third World: difficulties to overcome A.O. Trounson on behalf of the Low Cost IVF Foundation Infertility in developing countries: funding the project

I.D. Cooke, L. Gianaroli, O. Hovatta and

Hassan N. Sallam

93 97 102

Short communications (messages) Patientsâ&#x20AC;&#x2122; voice

Rita Sembuya Namusisi

108

IVF in developing countries: an artistâ&#x20AC;&#x2122;s view

Koen Vanmechelen

110

Message from the French Ministry of Foreign Affairs Bernard Kouchner

112

Message from the government of Uganda

Alhajm Tezikuba Sajjabi

113

Message from the European Commission: the role of the developed countries, a political issue Sonia Languille

115

Recommendations Arusha-meeting 2007

116

Human Reproduction 2008

doi:10.1093/humrep/den159

Introduction

The Executive Committee of the European Society of Human Reproduction and Embryology (ESHRE) started with a new ‘Special Task Force’ dedicated to infertility in developing countries. This Special Task Force aims to encourage more and affordable infertility diagnosis and treatment in developing countries. The organization of the expert meeting on the topic of ‘Developing countries and infertility’ in Arusha, Tanzania, from 15 until 17 December 2007, was the first project. Worldwide .80 million couples suffer from infertility, the majority being residents of developing countries. Negative consequences of childlessness are experienced to a greater degree in developing countries when compared with Western societies. Childless women are often stigmatized resulting in isolation, neglect, domestic violence and even suicide. The most common cause for infertility in developing countries is bilateral tubal occlusion due to sexually transmitted diseases and pregnancy-related infections, a condition that is potentially treatable with assisted reproductive technologies (ART). New reproductive technologies are, however, either unavailable or very costly in developing countries, and as a result the large majority of the population does not benefit from ART. While recognizing the importance of prevention and education, we believe that for reasons of social justice infertility treatment in developing countries requires greater attention at national and international levels. Keystones in the successful implementation of infertility care in low-resource settings include simplification of diagnostic procedures and ART, minimizing the complication rate of interventions, providing training courses for health-care workers and incorporating infertility treatment into existing reproductive health-care programmes. The aims of the meeting were the following: (i) to register and document the problem of infertility in developing countries; (ii) to study the ethical aspects surrounding this controversial topic; (iii) to study the effectiveness of a simplified ‘one-step clinic for the diagnosis of infertility’; (iv) to study the effectiveness of simplified IVF-related procedures; (v) to develop strategies for minimizing the risks and complications of ART;

(vi) to promote the go-together of family planning, infertility treatment and safe pregnancy and motherhood; (vii) to search for the optimal strategy algorithm for subfertile couples in developing countries with emphasis on non-IVF treatment and other (surgical or medical) options before starting IVF; (viii) the organization of training courses for fertility specialists and paramedical health-care providers from developing countries: a) Reproductive endocrinology, b) Diagnosis and prevention of infertility in developing countries, c) Endoscopic surgery, d) Clinical aspects of IUI and IVF, e) Laboratory aspects of IVF/ICSI; (ix) to find the best methods to convince politicians and representatives of the industry through the media (medical and non-medical); (x) how can we work together with other non-profit organizations with common interests? (xi) search for ‘private’ and ‘non-private’ funding. The challenge will be to identify efficiently and cheaply the couples who would benefit from ART. Optimizing a concurrent and affordable infertility treatment programme will be an important challenge for developing countries in the near future. We have to liaise with the authorities and discuss the integration of infertility treatment in the public health-care system. In this Monograph, most experts of the Arusha-meeting contributed in writing their message on the topic of infertility in developing countries, and I am very grateful to all of them. As a result of this meeting, an action plan and a road plan to the future have been outlined. After a fascinating period of almost 30 years of IVF and 15 years of ICSI, we must admit that only a small part of the world population benefits from these new reproductive technologies. Time has come to give adequate attention to the issue of infertility in developing countries. Willem Ombelet Coordinator of the ESHRE Special Task Force ‘Developing countries and infertility’

doi:10.1093/humrep/den174

Human Reproduction 2008

List of participants O. Akande College of Medicine University College Hospital Oritamefa Ibadan Nigeria E-mail: akandewole@yahoo.com S. Brown Journalist (ESHRE) E-mail: sb@copgrove.demon.co.uk

Herestraat 49 3000 Leuven Belgium E-mail: thomas.dhooghe@uz.kuleuven.ac.be

N. Dhont Rwanda E-mail: dinaluju@yahoo.com

R. Campo LIFE Leuven Tiensevest 168 3000 Leuven Belgium E-mail: rudi.campo@lifeleuven.be

S. Dyer Reproductive Medicine Unit Groote Schuur Hospital and Faculty of Health Sciences Anzio Road Observatory 7925 Cape Town South Africa E-mail: silke.dyer@uct.ac.za

I. Cooke University of Sheffield 80 Grove Road Millhouses Sheffield S72GZ UK E-mail: i.d.cooke@sheffield.ac.uk

D. Franken Reproductive Biology Unit Tygerberg Hospital and University of Stellebosch Tygerberg 7505 South Africa E-mail: drf@sun.ac.za

W. Decleer Centrum Reproductieve Geneeskunde AZ Jan Palfijn Site 1 9000 Gent Belgium E-mail: ivf.centrum@janpalfijgent.be

R. Frydman Universite´ Paris XI Kremlin-Biceˆtre France E-mail: rene.frydman@abc.aphp.fr

P. De Sutter UZ Gent Centrum voor Infertiliteit De Pintelaan 185 9000 Gent E-mail: petra.desutter@ugent.be P. Devroey Centrum Reproductieve Geneeskunde Laarbeeklaan 101 1090 Brussel Belgium E-mail: paul.devroey@uzbrussel.be T. D’Hooghe Reproductive Medicine UZ Gasthuisberg

L. Gianaroli SISMER Reproductive Medicine Unit V. Mazzini 12 40138 Bologna Italy E-mail: segreterialg@sismer.it

O. Giwa-Osagie Advanced Fertility Centre 18 Boyle Street Onikan, Lagos Department of Gynaecology University of Lagos Nigeria E-mail: osatoosagie2000@yahoo.com

List of participants

S. Ghosh-Dastidar GD Institute for Fertility Research Pvt. Ltd 208, Rashbehari Avenue Kolkata 700029 India E-mail: gdifr@vsnl.com D. Habbema Public Health Erasmus MC University Medical Center Rotterdam PO Box 2040 3000 CA Rotterdam The Netherlands E-mail: j.d.f.habbema@erasmusmc.nl B. He´don Department of Medicine and Biology of Reproduction Academic Hospital A. de Villeneuve 371 Avenur Doyen G. Giraud 34295 Montpellier 05 France E-mail: bernard.hedon@9online.fr M. Hopkin Journalist ‘NATURE’ E-mail: m.hopkin@nature.com O. Hovatta Karolinska University Hospital Huddinge SE 141 86 Stockholm Sweden E-mail: outi.hovatta@ki.se Z. Merali International Finance Group Sidley Austin LLP London UK E-mail: zmerali@sidley.com R. Molinas Manuel Blinder Nro 5685 Casi Emigdia Reishofer Asuncion Paraguay E-mail: roger.molinas@lifeleuven.be H. Msuya Amani Medical Research Centre Box 4 Amani Tanga Tanzania E-mail: drmsuya@yahoo.com G. Nargund St Georges Hospital and Medical Sector Blackshaw Road

Tooting London SW170RE UK E-mail: geetanargund@gmail.com K. Nygren IVF-Clinic Sofia Hospital Sweden E-mail: karl-gosta.nygren@telia.com W. Ombelet Genk Institute for Fertility Technology ZOL Campus St Jan Schiepse Bos 6 3600 Genk Belgium E-mail: willem.ombelet@telenet.be G. Pennings Bioethics Institute Ghent (BIG) Ghent University Department of Philosophy and Moral Science Blandijnberg 2 9000 Gent Belgium E-mail: guido.pennings@ugent.be P. Platteau AZ-VUB Zonlaan 49 1700 Dilbeek Belgium E-mail: peterplatteau@telenet.be H. Sallam University of Alexandria 22 Victor Emanuel Square Smouha Egypt E-mail: hnsallam@link.net G. Schatten Departments of Zoology and Obstetrics and Gynecology Wisconsin Regional Primate Research and Waisman Centers University of Wisconsin 1117 West Johnson Street Madison WI 53705 USA E-mail: gschatten@pdc.magee.edu R. Sembuya Joyce Fertility Support Center 32 Windsor Crescent off Babiiha Avenue PO Box 28095 Kampala Uganda E-mail: joycefertility@hotmail.com

List of participants

G. Serour Department of Obstetrics and Gynaecology Al Azhar University 40 Talaat Harb Street City Center Ca覺穡ro Egypt E-mail: giserour@thewayout.net A. Tezikuba Presidential Advisor Office of the President Government of Uganda PO Box 7168 Kampala Uganda E. te Velde Abstederdijk 319 3582 BL Utrecht The Netherlands E-mail: e.r.tevelde@wanadoo.nl F. van Balen Department of Education University of Amsterdam Postbus 94208 Nwe Prinsengracht 130

1090 GE Amsterdam The Netherlands E-mail: f.vanbalen@uva.nl S. Vanderpoel WHO Geneva Switzerland E-mail: vanderpoels@who.int C. van der Flier Esaote-PieMedical PO Box 1132 NL-6201 BC Maastricht The Netherlands E-mail: cor.vanderflier@pie.nl E. Van Doorslaer Department of health Policy and Management Erasmus Medical Center Rotterdam PO Box 1738 3000 DR Rotterdam The Netherlands E-mail: e.vandoorslaer@erasmusmc.nl K. Vanmechelen Belgian Artist E-mail: koen.vanmechelen@skynet.be

doi:10.1093/humrep/den218

Human Reproduction 2008

Documentation of infertility prevalence, treatment access and treatment outcomes in developing countries Karl Nygren1,3 and Fernando Zegers-Hochschild2 1

Queen Sophia Hospital, Stockholm, Sweden; 2Clinicas Las Condes, Santiago, Chile

Correspondence address. E-mail: karl-gosta.nygren@telia.com

Background and current knowledge To set up adequate fertility services in a country, a national evaluation of the basic need of such services is desirable, i.e. an evaluation of the national prevalence of infertility. The reason is that the prevalence of infertility varies between countries mainly due to variations in lifestyle factors causing or contributing to the infertility status, dominantly the time interval between the age where sexuality is initiated and the age where first pregnancy is desired, and of course, the prevalence of sexually transmitted diseases (STDs). In urban communities, women tend to seek fertility treatment too late in their reproductive life and with difficult access to appropriate diagnostic and therapeutic facilities. The actual ‘demand’ for medical services and the obstacles encountered in seeking treatments vary considerably between countries, mainly due to wide differences in financial resources and in the recognition of infertility as a public health issue, with the corresponding absence of specific public health policies. Prevalence of infertility: potential need for treatment A recent overview (Boivin et al., 2007) of population based surveys, published since 1990, estimated the current international prevalence of infertility to be 9% in average, with a range of 3.5 –16.7% (Table 1). The Table is taken from that overview, showing current infertility prevalence from a number of less developed countries. The life-time prevalence was found to range from 5.0% to 25.7%. There was a wider range in developing countries, possibly due to different country specific factors, such as the prevalence of STDs (which per se shows important variation over time, in developed as well as in developing countries), age at delivery, political factors (e.g. the one-child family policy in China) and more. Hence, estimations of the prevalence of infertility tend to be national and time specific. An even more complex issue is to try to associate prevalence of infertility with its significance to a certain country or region. For example, a prevalence of 9% infertility in a community where the mean age of female is near 40 (Germany) is different to countries where the same prevalence stands in a population of mean age 24 (Brazil). Social and demographic impacts are different in these two

examples; therefore, the application of public health policies will necessarily consider other factors beyond prevalence before public funding is diverted to the establishment infertility services. Treatment demand: seeking-treatment behaviour and obstacles In the same overview of population-based surveys, the average tendency to seek medical help was estimated to be 56%, with relative little variation between countries. However, obstacles to treatment seeking were possibly very different in different settings, again country and time specific. Although for some communities infertility is a curse from God and should be accepted without discussion, for others infertility is a health problem needing treatment as any other health issue. The proportion of infertile women seeking medical treatment will also vary depending on the availability and access to appropriate diagnostic and therapeutic alternatives. Many women prefer to remain infertile (especially when it is a secondary infertility) if they have to travel long distances to seek therapy, when their husband have expressed no interest or when other neighbours have spent months with no solution to their problem. Actual treatment access International variation in access to the treatment of assisted reproduction technologies (ART) and of intrauterine insemination treatments (IUI) has been recorded and published annually from a number of countries, mostly from developed countries but in an increasing number also from developing countries. The International Committee of Monitoring of ART (ICMART) in its latest World Report (Adamson et al., 2006) from treatments started during 2002 and covering 1.429 clinics in 49 countries reported an access ranging from very low levels in most developing countries (60 – 200) up to over 2000 treatment cycles per million inhabitants in Denmark, and possibly even higher in Israel. It is clear that access is determined first of all by financial resources, public or private, and by legal regulation. Cross-border fertility care occurs as a result of this inequity of access; however, in the majority of cases, cross-border

Nygren and Zegers-Hochschild

Table 1: Potential need for medical care (prevalence of infertility) in less developed countries (with kind permission of Boivin et al., 2007). Authors

Less developed countries Current Che and Cleland (2002) Larsen (2005) Sundby et al. (1998) Lifetime Barden-O’Fallon (2005) Fuentes and Devoto (1994) Geelhoed et al. (2002) Unisa (1999) Zarger et al. (1997) Che and Cleland (2002) Ericksen and Brunette (1996)a Larsen (2000) Liu et al. (2005)

Country or region

Year of survey

China

Women sampled

Age of survey sample

Reproductive state defined

Time to state (months)

Period covered by survey

Population sample size

1988–1995 Newly married

25– 45

Infertilitya

Current

7872

9.3

Northern Tanzania Gambia

2003 1994

20– 44 15– 49

Infertility Infertility

24 12

Current Current

2019 2918

6.9 9.2

Rural Malawi

2000–2002 All

15– 34

Infertility

Lifetime

678

19.6

Santiago, Chile

1993

Married

15– 45

Infertility

Lifetime

474

25.7

Rural Ghana India (Pradesh) Indian Kashmir Shanghai, China

1999 1998 1997 1988–1995

All Married 3 years Married 1 year Newly married

15– 44 20– 49 15– 44 25– 45

Infertility Childlessness Infertilityb Infertilityb

12 36 12 24

Lifetime Lifetime Lifetime First 5 years

1073 6640 10 063 7872

11.8 5 15.1 3

Sub-Saharan Africa Sub-Saharan Africa China (national)

1977–1992 Newly married

20– 41

Childlessness

First 5 years WFS and DHS 14.5

1977–1997 Newly married

20– 44

Childlessness

First 7 years 66 453

16.4

2005

15– 57

Childlessness

First 7 years 21 970 120 160

1.3

All Married

Newly married

Percent infertile

DHS, Demographic and Health Surveys; WFS, World Fertility Survey; Lifetime: in pre-menopausal women this means lifetime to date of interview. Primary infertility only.

reproductive care is reachable only by those who can afford travelling, out of pocket funding of treatment. The magnitude and reasons for this phenomenon is currently under international evaluation. What further national documentation is needed? Most countries have very little access to national data. Data are country and time specific. Ideally, in order to transfer limited economic resources into sexual and reproductive healthcare, data on prevalence of infertility and on certain etiologic factors are required. However, hard data are difficult to obtain, and many times, health policies are established in the absence of epidemiologic data. The same applies for the evaluation of therapeutic interventions. What has proved to be useful is the access to international or regional data as a source of external quality control in order to build-up and maintain confidence on infertility treatments among couples, professionals and society at large. Therefore, an international effort of co-operation in this area is suggested. A draft strategic template Before promoting infertility treatment services in a developing country, and indeed in any country, an understanding is needed of the country-specific magnitude and character of the problem, as well as of already existing national resources, so that the national ‘resource gap’ can be identified. When an intervention starts, ideally based on these assessments, a system of monitoring treatment characteristics and outcomes should already be in place. For this purpose, 6

common definitions and terminology and national key data for collection need to be identified. ICMART has published an infertility glossary, endorsed by all the large international professional organisations (Zegers-Hochschild et al., 2006a,b). ICMART and WHO will hold an international conference to revise and expand this glossary, late 2008. In the first phase, before interventions, a specific ‘country profile’ on infertility should be prepared, based on a ‘needs assessment and a resources assessment’ resulting in ‘a national strategy plan’. The needs assessment should include an evaluation of the national prevalence of infertility, its country specific causes, obstacles to seeking treatment and current treatment access. The resources assessment should document national financial and organizational resources. The national strategic plan should be published, its feasibility evaluated and interventions started. In the second interventional phase, national data collection of key data should be implemented already from the start. Data should be audited and published on a yearly basis. International co-operation on data collection should be in place. ICMART has developed forms that allow each country to analyse its own data and at the same time, compare their results with the rest of the world. ICMART can assist in establishing alliances with already existing regional registries and with the co-operative IVF World Reports system. Monitoring of service activities and benefit outcomes will give feedback to clinics for clinical and laboratory policy adjustments, information to couples on clinic performance and information to society for the formulation of regulations and for resources allocation.

Documentation of infertility prevalence, treatment access and treatment outcomes

National and international comparison is made possible. Confidence can then be built and maintained. References Boivin J, Bunting L, Collins JA, Nygren KG. International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility medical care. Hum Reprod 2007;22:1506–1512.

Adamson GD, de Mouzon J, Lancaster P, Nygren KG, Sullivan E, Zegers-Hochschild F. World collaborative report on in vitro fertilization, 2002. Fertil Steril 2006;85:1586–1622. Zegers-Hochschild F, Nygren KG, Adamson DG, de Mouzon J, Mansour R, Sullivan E. The ICMART glossary on ART terminology. Hum Reprod 2006a;21:1968–1970. Zegers-Hochschild F, Nygren KG, Adamson DG, de Mouzon J, Lancaster P, Mansour R, Sullivan E. International Committee monitoring assisted reproductive technologies. Fertil Steril 2006b;86:16– 19.

doi:10.1093/humrep/den204

Human Reproduction 2008

False perceptions and common misunderstandings surrounding the subject of infertility in developing countries Willem Ombelet1,† Genk Institute for Fertility Technologies, Schiepse Bos 2, 3600 Genk, Belgium 1

Correspondence address. E-mail: willem.ombelet@telenet.be

Although the consequences of the problem of childlessness are more pronounced in developing countries when compared with Western societies, local health care providers and international organizations pay little attention on this issue. The limited budgets for reproductive health care are mostly restricted to family planning and mother care. The most common misunderstanding is the ‘overpopulation-issue’. It is generally believed that the expected growth of the world population puts a real burden on the issue of infertility treatment in resource-poor countries, although recent UN reports clearly show that in most developing countries the fertility rate is dropping significantly and will fall below the threshold of 2.0 by 2050. It seems that the expected population growth in developing countries in the next decades is rather due to population ageing and not to high fertility rates. Another important issue surrounding infertility in developing countries is the so-called ‘limited resources argument’. Because the problem of childlessness is a major health problem in most developing countries, a re-arrangement of the global reproductive health care budget should be requested from local governments and international organizations taking into account the urgent need for a go-together of more successful family-planning policies and affordable simplified ART methods. Keywords: affordable; assisted reproduction; developing countries; limited resources; population growth

Introduction In developing countries, unwanted childlessness creates a more profound problem when compared with Western societies. This is related to the fact that having children in developing countries has an important influence not only on the personal wellbeing of a couple, but also and even more pronounced on the women’s status within the couple, within the extended family and the community at large (van Balen and Gerrits, 2001). Children are highly valued for socio-cultural and economic reasons and childlessness often leads to psychological, social and economical burden, especially for women (Dyer et al., 2002, 2004, 2005). The social stigma of childlessness still leads to isolation and abandonment in many developing countries (Ebomoyi and Adetoro, 1990; Leke et al., 1993; van Balen and Gerrits, 2001; Giwa-Osagie, 2002; Daar and Merali, 2002), but the magnitude of the problem differs between different geographic areas because of different †

Chairman of the scientific committee of the Flemish Society of Obstetrics and Gynaecology. Coordinator of the ESHRE Special Task Force on ‘Developing countries and infertility’

religious, ethical and sociocultural influences (Leke et al., 1993; Serour, 2002, 2006). Although the United Nations International Conference on Population and Development in Cairo in 1994 agreed on making reproductive health care universally available no later than 2015 (Table I), the progress that was made since than has fallen a long way short of the original goal (Fathalla, 2007). Until very recently the problem of infertility in developing countries has been ignored at all levels of health care management, not only in the developing countries themselves but also from an international viewpoint. This attitude of local governments in developing countries can be explained by a serious underestimation of the problem of childlessness and a lack of facilities and affordable treatment options. Even more important is the observation that in almost all resource-poor countries infertility is not a priority for the health authorities and the only destination of the limited resources spent on reproductive health is primary health care with two main objectives: to promote family planning services and to reduce maternal mortality and morbidity. This is easy understandable by the fact that the most common underlying

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False perceptions and common misunderstandings

Table I. Important citations and recommendations by different international organizations on the issue of infertility in developing countries. Men and women of full age, without any limitation due to race, nationality or religion, have the right to marry and to found a family (UN declaration of Human Rights, Article 16.1a) Infertility should be recognized as a Public Health issue worldwide, including developing countries (WHO meeting, Geneva, 2001b) Reproductive health implies that people have the capability to reproduce and the freedom to decide if, when and how often to do so (UN International Conference for Population and Development, Cairo, 1994c) a www.un.org/rights; bVayena et al. (2002b); cUN. Report of the international conference on population and development, Cairo, Egypt, 1994 (www.iisd.ca/cairo.html).

cause for female and male infertility in developing countries, especially in sub-Saharan Africa, are sexually transmitted infections (STDs), unsafe abortions and post-partum infections (WHO, 1987; Nachtigall, 2006). Considering the international society, until now reproductive health strategies in Western countries focused on reducing total fertility rates in developing countries while infertility care received little or no attention (Hamberger and Janson, 1997). Because infertility as such is not directly life-threatening there is a widespread belief that infertility is not a pressing problem in poor developing countries where fatal and contagious diseases remain uncontrolled neglecting totally the social, psychological, economical and personal burden of childless women (Vayena et al., 2002b; Anonymous 2006). The second argument of Western societies and international organizations holds that supporting infertility treatment is unacceptable in countries struggling to decrease their fertility rate and failing to support their fast-growing populations, although recent figures of the United Nations show that in the great majority of developing countries the mean fertility rate nowadays already dropped significantly and is expected to decline to less that 2.0 by mid-century (http://esa.un.org/ unpp/). Another argument against the use of new assisted reproductive technologies (ART) in developing countries is the ‘limited resources argument’. In most developing countries, the problems of infectious diseases such as malaria, tuberculosis, gonorrhoea and HIV are still very prevalent and therefore most people believe that it should be questioned if expensive techniques with a low success rate, such as ART, can be justified in countries where poverty is still an important issue. The strong competition for funding is a reality in most resourcepoor countries leaving little space for expensive infertility treatment (Fig. 1). Consequently, international non-profit organizations will only focus on education, family planning, prevention of infertility and improvement of mother-care rather than giving support to make ART affordable and accessible for a large part of the population. Population growth perception The idea of infertility treatment in developing countries often evokes a feeling of discomfort and disbelief. There is no

Figure 1: Different factors responsible for the limited interest in the development of a ART in developing countries. HIV, human immunodeficiency virus; tbc, tuberculosis.

doubt that during the next decades the world population will grow from 6.5 billion inhabitants to .9 billion before the year 2050 (http://esa.un.org/unpp/). This increase will be most prominent in the poorest areas such as sub-Saharan Africa and South East Asia. According to the 2006 revision of the ‘World population prospects’ by the United Nations, the population of the more developed countries will decline slowly by 1 million a year by 2050, although that of the developing world would be adding 35 million annually, 22 million of whom would be absorbed by the least developed countries. The population of the less developed regions is projected to rise from 5.4 billion in 2007 to 7.9 billion in 2050. The global fertility rate (number of children per woman) in developing countries was 5.0 in 1950– 1955 and declined to 2.65 in 2000 – 2005. This rate is projected to decline further to 2.05 per woman by 2045 – 2050, i.e. below the replacement level of 2.1. In the majority of developing countries the mean fertility rate has already dropped as low as 2.58 per woman and is expected to decline to 1.92 by mid-century. The expected population growth in developing countries can therefore not be attributed to high fertility rates in the first instance anymore. As in most developed countries, an improved life expectancy, at least in the great majority of countries, will be the most important factor considering world population growth (http://esa.un.org/unpp/). Even in the least developed countries life expectancy is going to rise from an average of 51 years currently to 67 years in 2045 – 2050 which highlights the important issue of population ageing. In the context of overpopulation, another plea against the implementation of affordable infertility treatment is the argument that infertile people should adopt children instead of having their own children, given the large number of children in developing countries that are available for adoption. However, most reports indicate that adoption is not the answer in most developing countries because of socio-cultural reasons. On the other hand, proposing adoption as the only alternative for infertile couples denies the importance of reproductive anatomy and puts social responsibility for overpopulation unjustly on the infertile couples (Daar and Merali, 2002). 9

Ombelet

Competition for funding—the limited resources argument Bilateral tubal blockage and male infertility due to STDs are the leading causes of infertility in developing countries. While ART remains the most effective intervention for these conditions, funding remains a contested issue. This can be explained by the scarcity of health resources against a backdrop of limited funds. Some people believe that the infertile couple should be encouraged to courageously accept their condition of childlessness rather than be offered intervention (Tangwa, 2002). Most health care providers argue that the limited recourses should only be given to programmes focusing on reducing STDs, post-partum and post-abortion complications rather than offering high-technology treatments to infertile couples (Okonofua, 1996). According to many, training health care workers to carry out systematic evaluation and treatment protocols, making a correct diagnosis, offering counselling and conduct basic treatments might be possible and successful without adding to existing health care costs. Nevertheless, even in developed countries, the best prevention campaigns cannot entirely solve the problem of infertility. This is even more important in developing countries because the incidence of infection-related infertility is much higher resulting in a more important need for ART, unfortunately the most expensive treatment option. While prevention of STDs and pregnancy-related sepsis is a reproductive health priority, public investment in infertility treatment must also become a subject for discussion. For most developing countries, a large majority of the population cannot afford infertility treatment since new reproductive technologies are either unavailable or very costly (Malpani and Malpani, 1992; Van Balen and Gerrits, 2001; Nachtigall, 2006). Making ART less expensive, safe and affordable will be the key of success (Hovatta and Cooke, 2006; Pilcher, 2006; Ombelet and Campo, 2007). We have to acknowledge that if we do not succeed in substantially simplify ART procedures public funding of infertility-related health care will be restricted to education and preventative care because of cost-effectiveness considerations. In developing countries, even more than in developed countries, infertile couples do not have the right to the most effective treatment, regardless of cost, but to the most costeffective treatment, taking into account the cost implications for the health care system of that specific country (Pennings and Ombelet, 2007).

The go-together of infertility treatment and family planning/mother care programmes Considering the problem of infertility in developing countries, most local health care providers focus on primary health care such as the reduction of maternal mortality and the promotion of family planning. Moreover, international funding is restricted to what is thought women should have, potentially neglecting what women really want. In many rural areas of developing countries women see the problem of childlessness as far more important than the problem of excessive fertility indicating that infertility is indeed a major social and 10

healthcare problem in developing countries (Bergstrom, 1992; Daar and Merali, 2002; Aboulghar, 2005). When we succeed to develop simplified methods of infertility management and affordable ART, we will face a unique opportunity to move beyond the current status, which tends to focus on infertility prevention and health education, towards offering effective treatment. Moreover, infertility management, comprising both prevention and intervention, should be integrated into existing sexual and reproductive health care programmes. It will be very important to give the right message to the local authorities and to the international community: less children for couples with a high fertility potential, offering children for the childless couples. Importantly, the role of traditional healers should not be overlooked in this process. In many developing countries traditional healers are highly respected members of the community who often have the advantage over their Western counterparts of speaking the local language and living in the same culture as their patients (van Balen and Gerrits, 2001). Their cooperation may be pivotal to the success in the development of new health strategies.

Infertility in developing countries: the local government’s task The first priority is and should remain prevention rather than cure of infertility. It has been shown that a better education is the most effective and ethically desirable way of curtailing population growth (Macklin, 1995). On the other hand, education on reproductive health should also be promoted by the government and implemented at schools and at primary health care facilities. Education in sexuality and safe sex are the best measures to prepare the adolescent and to prevent infertility. Prevention of infertility can be organized by actions aiming at reducing the rate of STDs in the population and by improving the obstetrical and perinatal care. It is the duty of the local governments to make infertility discussable and accepted as a disease, taking into account the social and psychological suffering. Although the United Nations International Conference on Population and Development in 1994 (Cairo) clearly highlighted ‘prevention and appropriate treatment of infertility where feasible’ and despite the recommendations of the WHO meeting on ‘Medical, Ethical and Social Aspects of Assisted Reproduction’, Geneva, 2001 (Vayena et al., 2002a) almost no progress is made in education and service in South East Asia and sub-Saharan Africa due to a lack of guidelines or concrete actions and programmes (Fathalla et al., 2006). In most developing countries the public health service agenda is very distant from the people’s agenda. Due to a lack of interest of health care providers, a lot of infertile patients are prone to exploitation and potentially damaging practices (Van Balen and Gerrits, 2001; van Zandvoort et al., 2001), another important reason for asking local politicians to support the idea of simplified infertility treatment.

False perceptions and common misunderstandings

Conclusion While recognizing the important and crucial role of education and prevention, the issue of infertility in developing countries requires greater attention at national and international levels for reasons of social justice. Even if we succeed in making infertility diagnosis and treatment affordable for a large part of the population in developing countries, a lot of questions concerning this issue will remain the same and a lot of people still throw doubt upon the value of affordable ART in resource-poor countries, in most cases using the limited resources argument. With respect to public health, evidence supports the compelling need for infertility treatment beyond prevention in developing countries. Cost-effectiveness will be crucial. To examine the possibility of low-cost ART should be supported by local and international communities because ART will be the last hope to achieve a child for many couples.

References Aboulghar MA. The importance of fertility treatment in the developing world. BJOG 2005;112:1174– 1176. Anonymous. Cheap IVF needed (editorial). Nature 2006;442:958. Bergstrom S. Reproductive failure as a health priority in the Third World: a review. East Afr Med J 1992;69:174–180. Daar AS, Merali Z. Infertility and social suffering: the case of ART in developing countries. In: Vayena E, Rowe PJ, Griffin PD (eds). Current Practices and Controversies in Assisted Reproduction. Geneva: World Health Organization, 2002, 15– 21. Dyer SJ, Abrahams N, Hoffman M, van der Spuy ZM. Men leave me as I cannot have children: women’s experiences with involuntary childlessness. Hum Reprod 2002;17:1663–1668. Dyer SJ, Abrahams N, Mokoena NE, van der Spuy ZM. You are a man because you have children: experiences, reproductive health knowledge and treatment-seeking behaviour among men suffering from couple infertility in South Africa. Hum Reprod 2004;960– 967. Dyer SJ, Abrahams N, Mokoena NE, Lombard CJ, van der Spuy ZM. Psychological distress among women suffering from couple infertility in South Africa: a quantitative assessment. Hum Reprod 2005;20:1938–1943. Ebomoyi E, Adetoro OO. Socio-biological factors influencing infertility in a rural Nigerian community. Int J Gynaecol Obstet 1990;33:41 –47. Fathalla MF. Issues in Women’s Health. International and Egyptian perspectives. Assiut University Press, 2007. Fathalla MF, Sinding SW, Rosenfield A, Fathalla MMF. Sexual and reproductive health for all: a call for action. The Lancet 2006;368:2095–2100.

Giwa-Osagie OF. Social and ethical aspects of assisted conception an Anglophone sub-Saharan Africa. In: Vayena E, Rowe PJ, Griffin PD (eds). Current Practices and Controversies in Assisted Reproduction. Geneva: World Health Organization, 2002, 50–54. Hamberger L, Janson PO. Global importance of infertility and its treatment: role of fertility technologies. Int J Gynaecol Obstet 1997;58:149–158. Hovatta O, Cooke I. Cost-effective approaches to in vitro fertilization: means to improve access. Int J Gynaecol Obstet 2006;94:287– 291. Leke RJ, Oduma JA, Bassol-Mayagoitia S, Bacha AM, Grigor KM. Regional and geographical variations in infertility: effects on environmental, cultural, and socioeconomic factors. Environ Health Perspect 1993;101(Suppl 2): 73–80. Macklin R. Reproductive technologies in developing countries. Bioethics 1995; 9:276–282. Malpani A, Malpani A. Simplifying assisted conception techniques to make them universally available—a view from India. Hum Reprod 1992;7: 49–50. Nachtigall RD. International disparities in access to infertility services. Fertil Steril 2006;85:871–875. Okonofua FE. The case against new reproductive technologies in developing countries. Br J Obstet Gynaecol 1996;103:957–962. Ombelet W, Campo R. Affordable IVF for developing countries. Reprod Biomed Online 2007;15:257–265. Pennings G, Ombelet W. Coming soon to your clinic: patient-friendly ART. Hum Reprod 2007;22:2075– 2079. Pilcher H. Fertility on a shoestring. Nature 2006;442:975–977. Serour GI. Attitudes and cultural perspectives on infertility and its alleviation in the middle East area. In: Vayena E, Rowe PJ, Griffin PD (eds). Current Practices and Controversies in Assisted Reproduction. Geneva: World Health Organization, 2002, 41–49. Serour GI. Religious perspectives of ethical issues in ART. Contemporary ethical dilemmas. In: Shinfield F, Sureau C (eds). Assisted Reproduction. Informa Health Care UK 2006;99–114. Tangwa GB. ART and African sociocultural practices: worldview, belief and value systems with particular reference to francophone Africa. In: Vayena E, Rowe PJ, Griffin PD (eds). Current Practices and Controversies in Assisted Reproduction. Geneva: World Health Organization, 2002, 55–59. Van Balen F, Gerrits T. Quality of infertility care in poor-resource areas and the introduction of new reproductive technologies. Hum Reprod 2001;16: 215– 219. van Zandvoort H, de Koning K, Gerrits T. Medical infertility care in low income countries: the case of concern in policy and practice. Trop Med Int Health 2001;6:563– 569. Vayena E, Rowe PJ, Griffin PD. Current Practices and Controversies in Assisted Reproduction. Report of a meeting. World Health Organization, Geneva, Switzerland, 2002a, 383–385. Vayena E, Rowe JP, Peterson HB. Assisted reproductive technology in developing countries: why should we care? Fertil Steril 2002b;78:13– 15. World Health Organisation. Infections, pregnancies and infertility: perspectives on prevention. Fertil Steril 1987;47:944– 949.

doi:10.1093/humrep/den147

Human Reproduction 2008

Affordable assisted reproductive technologies in developing countries: pros and cons E. Oluwole Akande1 Department of Obstetrics and Gynaecology, College of Medicine, University College Hospital, Ibadan, Nigeria 1

Correspondence address. E-mail: akandewole@yahoo.com

Infertility in developing countries is pervasive and a serious concern. In addition to the personal grief and suffering it causes, the inability to have children especially in poor communities can create broader problems, particularly for the woman. Infertility services in developing countries span the spectrum from prevention to treatment. From a societal and public health standpoint, prevention is cost–effective and is considered by many governments and public health care providers to be a priority for service delivery. While prevention remains paramount, taken alone it ignores the plight of infertile couples, including those with non-infectious causes of infertility. Two key arguments are frequently used to challenge the development of new reproductive technologies in developing countries: overpopulation and limited resources. Evidence supports the conclusion that there is a compelling need for infertility treatment beyond prevention. In many instances, assisted reproductive technologies (ART) are the last hope or the only means to achieve a child for couples. In an effort to make much needed ART to developing countries accessible and affordable, developing countries should look to public–private partnerships. Governments have a responsibility to ensure safe and effective services including the control of standards for clinical procedures and the regulation of professional practice. Keywords: infertility prevention; infertility and reproductive tract infections; overpopulation; limited resources; public –private partnerships

Magnitude of the problem Sixty to 80 million people experience infertility around the world, and most of those people live in developing countries (WHO, 1991). Infertility in developing countries is pervasive and a serious concern. Further, there is evidence that the infertility rates that are generally quoted are, in fact, underestimates. In addition to the personal grief and suffering it causes, the inability to have children especially in poor communities can create broader problems, particularly for the woman, in terms of social stigma, economic hardship, social isolation and even violence. In some societies, motherhood is the only way for women to improve their status within the family and the community. On a practical level, many families in developing countries depend on children for economic survival. While many people, therefore, would not consider infertility a disease in itself, it can certainly be said to be a social and public health issue as well as an individual problem (Unisa, 1999; Papreen et al., 2000). 12

Most of the infertility in developing countries is attributable to damage caused by infections of the reproductive tract, notably gonorrhoea and chlamydial infection (Cates et al., 1985). Infertility services in developing countries span the spectrum from prevention to treatment. From a societal and public health standpoint, prevention is cost– effective and is considered by many governments and public health care providers to be a priority for service delivery. While prevention remains paramount, taken alone it ignores the plight of infertile couples, including those with noninfectious causes of infertility.

Assisted reproductive technologies ART encompasses a wide range of techniques designed primarily to aid couples unable to conceive without medical assistance. Since the birth of the first so-called ‘test-tube baby’ in 1978, more than 1.5 million children worldwide have been born following in vitro fertilization (IVF) treatment.

Pros and cons of ART in developing countries

The term ‘assisted reproductive technology’ includes techniques such as IVF and intracytoplasmic sperm injection as well as artificial insemination. It can be defined as including all treatments that include medical and scientific manipulation of human gametes and embryos in order to produce a term pregnancy. ART raise profound moral issues. Arguments for and against ART in developing countries Two key arguments are frequently used to challenge the development of new reproductive technologies in developing countries: overpopulation and limited resources. First, the argument from overpopulation suggests that an overpopulated country should not prioritize infertility management, for the overpopulation poses a demographic problem for the country and for the global community. The primary response to this argument is that individuals should be able to reproduce ‘if, when and as often as they wish,’ as it was stated in the definition of reproductive health adopted by the United Nation’s International Conference on Population and Development (United Nations, 1994). References in both the Universal Declaration of Human Rights and the Convention on the Elimination of All Discrimination against Women (1979) may also be interpreted to argue for a right to access to infertility treatment through ART. For, if infertile persons do not have access to ART because this would ‘contribute’ to overpopulation, why save lives in developing countries using medical technologies, as this too would have an ‘overpopulation effect’? If it is thought that it is justified to employ medical technologies to prevent suffering, why is it not justified to use medical technologies to alleviate suffering from infertility? Distinguishing the cases requires the assumption that the harms of disease necessitate medical technology in a way that the harms of infertility do not. The second argument, the limited resources argument, suggests that developing countries should not allocate resources for expensive technology that can benefit only a few. Proponents maintain that a country’s resources should be directed toward the prevention of infertility (Okonofua, 1996). Some critics question whether ARTs are an appropriate use of limited health care resources (Okonofua 1996; Sheth and Malpani, 1997). It has been recommended that public health policy should invest in preventing the causes of infertility and leave the establishment of new ARTs to the private sector since it is unlikely to be cost – effective in the public sector (Okonofua, 2003). As Sen (1994) observes, a careful examination of governmental budgets in both developing and developed nations frequently reveals mismanagement of funds, rather than an inability to finance social and economic rights. Others argue on the other hand, that the social, emotional, physical and economic consequences that infertile couples— and in particular, women—face justifies investing in treatment options in developing countries (Edouard and Olatunbosun, 1997; Daar et al., 2002). The idea that infertility treatment is not a health care priority is based on the fallacious assumption that it does not have devastating, material and life-threatening consequences.

Indeed, since the consequences of infertility are so severe in developing countries, infertility treatment should assume an even higher priority in developing countries than it does in developed countries. In some instances ART may be the only way to treat infertility, even if prevention programmes are successful. While the affordability of ART is a problem that needs to be assessed in the specific context of a country’s needs and economic conditions, it cannot be assumed that ART is unfeasible. Rather, given the social suffering and public health harms associated with infertility, research should be directed towards finding effective, low-cost solutions to infertility and this exploration should extend to ART. Finally, if governments cite scarce resources as the justification for not funding ART, this is a cause for governments to think creatively about infertility solutions, rather than a justification for rejecting all ART advances and development. Public – private partnerships In an effort to make much needed ARTs to developing countries accessible and affordable, developing countries should look to public – private partnerships (PPPs). These partnerships can bring technical expertise, research, equipment and supplies to low-resource settings. At the same time, PPPs can offer services at lower costs that are more realistic in developing countries. In addition, PPPs can help influence the establishment of standards, regulations and policies to safeguard the health of couples undergoing treatment (Daar et al., 2002; Giwa-Osagie, 2002). Cooperative public and private partnerships have the potential to make infertility care affordable and to make access more just. A framework that ensures knowledge transfer through PPPs would enable domestic drug companies to manufacture their own infertility drugs, especially for those drugs whose patents have expired. Furthermore, public– private clinics may be a source of revenue that may be used to support other health care objectives. Evidence supports the conclusion that there is a compelling need for infertility treatment beyond prevention. In many instances, ART are the last hope or the only means to achieve a child for couples. There is a heightened need for ART in developing countries. While developing countries have generally not established adequate infertility programmes, mainly due to arguments based on overpopulation and cost, some notable exceptions raise hope of successful and just implementation of ART, perhaps through PPPs. A failure to even consider examining low-cost models of ART will be to conceive of developing countries as perpetually developing, rather than developed, with respect to public health. Heterogeneity of the developing world The provision of ART services in developing countries could be viewed as contradictory. Such a view may be influenced by the misconception that the developing world is homogeneous. On the contrary, developing countries are heterogeneous, varying in cultural and moral values, religions, and 13

Akande

their pace of development. The health care infrastructure, including laboratory facilities and personnel, in some countries is substantially better positioned than in others to support the delivery of relatively sophisticated medical services. In some countries with economies in transition, an emerging middle class is already able to afford ART. In other countries, strong religious opposition to ART, on ethical rather than financial grounds, has led to little or no access to ART. Such differences are currently reflected in a wide variety of national policies toward infertility and its treatment, which, in turn, influences the options available to infertile couples (Vayena et al., 2002a). Conclusion Many studies have established that IVF may be cost – effective and feasible in developing nations (Olatunbosun et al., 1990; Serour et al., 1991). However, the burgeoning use of ART in developing countries raises important questions regarding the quality of services provided in terms of safety and effectiveness (Vayena et al., 2002b). Governments have a responsibility to ensure safe and effective services with constraints regarding government funding whilst the public priority to be accorded to new reproductive technologies should be established (WHO, 2003). At the very least, the involvement of government in assisted reproduction should include the control of standards for clinical procedures, regulation of professional practice and in certain countries, the waiving of import duties so as to improve the procurement of equipment and supplies. References Cates W, Farley TMM, Rowe PJ. Worldwide patterns of infertility: is Africa different? Lancet 1985;2:596– 598. Daar AS, Merali Z. Infertility and social suffering: the case of ART in developing countries. In: Vayena E, Rowe PJ, Griffin PD (eds). Current

Practices and Controversies in Assisted Reproduction: Report of a WHO Meeting, Geneva: WHO, 2002. Edouard L, Olatunbosun OA. The case against new reproductive technologies [Letter to the Editor]. Br J Obstet Gynaecol 1997;104:969. Giwa-Osagie OF. ART in developing countries with a particular reference to sub-Saharan Africa. In: Vayena E, Rowe PJ, Griffin PD (eds). Current Practices and Controversies in Assisted Reproduction: Report of a WHO Meeting. Geneva: WHO, 2002. Okonofua FE. The case against new reproductive technologies in developing countries. Br J Obstet Gynaecol 1996;103:957– 967. Okonofua FE. New reproductive technologies and infertility treatment in Africa [editorial]. Afr J Reprod Health 2003;7 Olatunbosun OA et al. Early experience with in vitro fertilization-embryo transfer and gamete intrafallopian transfer in a Nigerian Hospital. Int J Gynecol Obstet 1990;33:159–163. Papreen N et al. Living with infertility: experiences among urban slum populations in Bangladesh. Reprod Health Matters 2000;8:33 –44. Serour GI et al. In vitro fertilization and embryo transfer in Egypt. Int J Gynecol Obstet 1991;36:49– 53. Sen A. Freedoms and needs. The New RepublicJanuary 10, 1994;17: 31– 32. Sheth SS, Malpani AN. Inappropriate use of new technology: impact on women’s health. Int J Gynecol Obstet 1997;58:159–165. Vayena E, Rowe PJ, Peterson HB. Assisted reproductive technology in developing countries: why should we care? Fertil Steril 2002a;78: 13– 15. Vayena E, Rowe P, Griffin PD (eds). Current Practices and Controversies in Assisted Reproduction: Report of a WHO Meeting. Geneva, World Health Organization, 2002b. United Nations: The Convention on the Elimination of All Forms of Discrimination Against Women (CEDAW). Adopted and opened for signature, ratification and accession by General Assembly resolution 34/ 180 of 18 December 1979 entry into force 3 September 1981, in accordance with article 27(1). United Nation’s International Conference on Population and Development. Cairo, Egypt, 1994. Unisa S. Childlessness in Andhra Pradesh, India: treatment-seeking and consequences. Reprod Health Matters 1999;7:54 –64. World Health Organization. Infertility: A Tabulation of Available Data on Prevalence of Primary and Secondary Infertility. Geneva, WHO, Programme on Maternal and Child Health and Family Planning, Division of Family Health, 1991. World Health Organization. Assisted reproduction in developing countries: facing up to the issues. Progress in Reproductive Health Research, WHO, No 63, 2003.

doi:10.1093/humrep/den142

Human Reproduction 2008

Ethical issues of infertility treatment in developing countries Guido Pennings1 Department of Philosophy and Moral Science, Bioethics Institute Ghent (BIG) Ghent University, Blandijnberg 2, 9000 Gent, Belgium 1

Correspondence address. Tel/Fax: þ32-16-620767; E-mail: guido.pennings@ugent.be

The provision of infertility treatment in developing countries is controversial. Reports over the last decades have inculcated in people from Western countries the belief that overpopulation is the major problem of developing countries. This paper will analyse the different arguments advanced for and against providing infertility treatment to resource-poor countries. There are two arguments in favour: reproductive autonomy and the huge burden of infertility in these countries. Pronatalism, which reigns in almost all developing countries, is to a great extent responsible for the devastating effects of infertility. The five arguments against the application of infertility treatment are overpopulation, prioritization of limited resources, prevention rather than cure, justice and equal access and risk of abuse. The importance of a person’s reproductive autonomy demands that efforts should be made to enable people to determine how many children to have. This is equally true in developing countries. However, given the enormous difficulties of resource-poor countries to provide even the most basic goods, the contribution by society should be directed mostly at prevention and should depend on a strong cost reduction for assisted reproductive technology. Keywords: justice; low-cost IVF; overpopulation; prevention; QALY

Introduction Whenever one mentions the provision of infertility treatment in developing countries, the reaction of the people is almost unanimously negative. Reports over the last decades have inculcated in people from Western countries the belief that overpopulation is the major problem of developing countries. This conviction was and still is the main barrier to even consider infertility treatment in resource-poor countries. This conviction leads to a bias in Western people’s way of looking at the provision of contraception and fertility control in resource-poor countries. For them, these technologies are ways to reduce population growth, not means to address the needs of people to control when and how many children to have. Worries of people in rich countries about immigration and fears of being overrun by the South probably also play a role (Grimes, 1998). Nevertheless, things are very slowly changing. A pivotal point for the new evolution was the Conference on Population and Development in 1994 in Cairo on reproductive health. The conference adopted a definition of reproductive health that integrates both fertility control and infertility treatment in general family planning. ‘Reproductive health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity, in all matters relating to the reproductive system and to its functions and processes. Reproductive health therefore implies that people are able to have a satisfying and safe sex life and that they have the capability to reproduce and the freedom to decide if, when and how often to do so’ (United Nations, 1994). Family planning implies both avoiding unwanted children and having wanted children. Framing

infertility treatment in the general context of reproductive health and family planning is crucial for the ethical evaluation. Two preliminary warnings should be issued. First, we should be aware of the large heterogeneity of ‘developing’ countries in terms of wealth, population growth, health care resources etc. This point may have a huge impact on the debate as people may think of very different countries when they discuss infertility treatment in developing countries. If people think of Soudan, Sierra Leone or Rwanda, countries which have been the battlefield of civil wars for decades, lacking a central government and minimal medical infrastructure or organization, it is not surprising that they are baffled by the suggestion of introducing in vitro fertilization (IVF) there. In order to prevent such misunderstandings, we stipulate that infertility treatment can only be considered when two conditions are fulfilled, namely minimal political stability and a minimal basic structure of health care provisions. Secondly, the discussion frequently focuses on high technological interventions like IVF. However, other interventions of a lower technical nature can be offered to treat infertility. The general consensus at the Arusha meeting was that there are three levels of technical difficulty: IUI, IVF and ICSI. The technical level as well as the timing of the introduction of a technique will have to be country-specific, depending on the wealth and the general development (Van Balen and Gerrits, 2001).

Pronatalism, patriarchy and suffering Reproduction and fertility have a different meaning in Western and non-Western countries (Van Balen and Inhorn, 2002).

Pennings

In developed countries, reproduction is a self-chosen goal and a largely personal choice made by an individual or couple. Although there are attempts by others to influence a couple’s family planning, these attempts have no moral basis. In nonWestern societies, having children is also a social obligation, a performance that is due to the family (-in-law) and the community. Social pressure and stigmatization are logical consequences of this position. Norm violations are generally met with repudiation or sanctions. The different meaning of infertility and parenthood is mirrored in the motives people have for wanting to become parents. Children secure one’s marriage, confer social status, guarantees rights of property and inheritance, assist with labour, offer social security in old age and provide continuity by maintaining the family name (Dyer, 2007). The significance of involuntary infertility is socially constructed and gender roles play a major role in constituting the social meaning of infertility. This is true in the developed as well as the developing world (Becker and Nachtigall, 1994). Infertility is at least in part a cultural problem, generated by pronatalist and patriarchal ideologies. A pronatalist society holds the belief that a person’s social and moral worth is linked to reproduction (Ulrich and Weatherall, 2000). The more one believes in the cultural construction of infertility, the more one will believe that infertility should be tackled not by treating the infertile but by targeting the ideologies that cause the problem (Sandelowsky and de Lacey, 2002). Still, also in largely egalitarian societies, people want children as part of their life plan and they suffer when they cannot realize this wish. However, because parenthood has deeper social roots in developing countries, the social and psychological consequences of involuntary childlessness are often more severe. Not surprisingly, the problem of infertility in developing countries is frequently introduced by pointing at the large impact on the lives of men and especially women (Ombelet and Campo, 2007). ‘Common scenarios include unstable marriages, divorce, polygamy and ostracism of the women’ (Vayena et al., 2002). Especially for women, social status and female identity depend on their ability to produce children. ‘They [the women] are usually blamed for infertility and can be ostracized and assaulted by their families, even driven to suicide or killed. By supporting the development of low-cost IVF, governments can help make such treatments more widely available’ (Editorial, 2006). As the previous quote shows, low-cost IVF is proposed as a solution to the social problems of the infertile. According to the main ethical theory, i.e. utilitarianism, one should do whatever maximizes happiness or well-being. A utilitarian could defend that it is best to cure infertility in countries with the direst consequences. More well-being would be created or more unhappiness avoided by providing assisted reproductive technology (ART) to a couple in Africa than to a couple in Europe. However, it is not clear to what extent these negative consequences of infertility in developing countries justify the provision of infertility treatment. Two reactions are possible. The first reaction is to focus on changing the existing moral and social order so that infertile people will no longer be ostracized and discriminated. We should adopt 16

measures to diminish the pronatalist ideology and its undesirable consequences. This can be done in several ways. An important step is education as a means for women to obtain a job which gives them an alternative route to increase their self-esteem and to ensure economic independence and security. The second reaction is to provide infertility treatment as a medical solution for a social problem. Many current health problems, like obesity, are solved by medical interventions. From a utilitarian position, the choice between these reactions can only be made on empirical evidence. If more well-being can be gained by avoiding the social and psychological consequences than by providing ART, the former should be done. If a pronatalist society justifies provision of infertility treatment, does a sexist society justify social sexing? Women who are unable to give birth to a son are also discriminated. Like infertility, it is a reason for a man to divorce his wife (Chan et al., 2002). Mothers who have only daughters in India and China undergo ostracism, are at risk for suicide, and often face beatings, divorce or fatal ‘accidents’ (Holmes, 1995). The main argument against this analogy is that wanting a child is acceptable while wanting a child of a certain sex is unacceptable. However, this presupposes that there are standards to judge the acceptability of wishes, rules and practices independent of the culture. The acceptance of pronatalism, however, seems to be based on the conviction that Western people should not judge other societies which attribute a different value to parenthood. Those who argue in favour of infertility treatment in pronatalist societies on the basis of cultural autonomy, should also defend social sexing in sexist, patriarchal and misogynist societies. Cultural relativism cannot be adopted whenever one agrees with a deviant practice and rejected when one disagrees. My position is that discrimination on the basis of health or disability (to have children) is unacceptable and pronatalism leads to such discrimination. Moreover, the highly negative consequences for infertile people and the fact that some people will remain infertile even with high-tech infertility treatment are good reasons to attenuate the pronatalist attitude. Overpopulation One of the demographic paradoxes is that countries with the highest overall fertility are also those in which the prevalence of secondary infertility is highest (Nachtigall, 2006). It is highly unlikely that high-tech interventions will have an impact on the population in developing countries since only a small minority of the population can afford them. However, it does not really matter whether only a small additional number of children will be created by ART. It could be argued that any child that is added to the already excessive population growth, is one too many. However, this argument would count against every new child, regardless of how it came into being. In its extreme form, the argument would lead to the conclusion that an overpopulated country should promote measures causing infertility. However, the reasoning of some authors that this implies that we would not have a reason to save people’s lives in developing countries makes little sense (Daar and Merali, 2002). There is an enormous

Ethical issues of infertility treatment

difference between letting existing people die and not bringing potential people into existence. In the latter case, no one is harmed. The overpopulation argument attributes a high value to societal benefits at the expense of the individual. The personal good is sacrificed for the sake of a collective or aggregate good. These individual rights have a very high status in their negative form. That explains why we so strongly reject coercive (eugenic) measures like forced sterilization. In fact, people who use the overpopulation argument to deny infertile persons access to ART use the same reasoning as people from the eugenics movement use to deny some people the right to reproduce for the sake of society. Nevertheless, there may be circumstances in which coercive measures to defend the public good are justified. This is the case when it can be shown with reasonable certainty that a major catastrophe can only be avoided by infringing peopleâ&#x20AC;&#x2122;s rights. This justification is not applicable to the overpopulation problem because population growth can be restricted much more effectively by other means that do not infringe peopleâ&#x20AC;&#x2122;s rights such as educating women, providing contraception and safe abortions etc. The second argument against the reference to overpopulation is related to distributive justice: the total burden of the overpopulation should not be carried by the infertile alone. Why should they alone remain childless? One could for instance encourage fertile people to have fewer children. China has given the example of an egalitarian approach to the overpopulation problem with its one-child-per-family policy. Regardless of the objections one may have against this system, it is certainly a more balanced and just measure than the proposal that infertile couples should remain childless because their neighbours have too many children (and even more than they want themselves). The child wish expresses a personal need that cannot be satisfied by the neighbours having a child (Shah, 1994). Referring to the children of others to explain the refusal to assist the infertile in having children demonstrates a serious misconception of what it means to want a child. Prioritization and limited resources Most developing countries are struggling to provide a basic minimum of care. They are confronted with immense problems of poverty and deprivation of the most basic goods like clean drinking water and food, which also affect the general health of the population. A mean life expectancy around 50 years is no exception in developing countries. The question then becomes whether governments should not spend their money trying to resolve these problems rather than embarking on expensive high-technology programmes for non-life threatening conditions like infertility. When considering this question, we have to look at the broader picture of the allocation of the total national budget. Most developing countries spend ,5% of their gross national product on health care and the largest part thereof is private money (World Health Organisation, 2007). If we accept this starting point, the provision of hightechnology infertility care obviously implies that already underfunded and essential programmes like maternal and

child care will receive even less money. However, there is no reason why we should accept the existing health care budget as fixed. On the contrary, there are very good reasons to urge the governments to increase the public health care budget. The whole resource allocation policy should be questioned and evaluated. For instance, what percentage is spend in those countries on military equipment or prestige projects? South Africa is organizing the world championship football in 2010 which will cost around 2 billion euro. Should the country not rather spend this money on helping AIDS victims or treating infertility? Generally speaking, the inability to pay for health care and other basic needs is due more to mismanagement of funds than to the lack of resources. Allocating additional funding to health care would considerable improve the global situation. Still, regardless of the amount that is directed at health care, we will still have to discuss to which treatments the money will be given (Pennings and Ombelet, 2007). The ambiguous status of infertility puts it in a disadvantaged position when different needs are ranked. Infertility is not lifethreatening and is not even considered as a disease by many people. This means that it loses against almost any other lifesaving health-related service. This is confirmed by the currently most frequently used method for ranking diseases, i.e. Quality Adjusted Life Year and its mirror concept Disability Adjusted Life Years (DALY). The DALY is a measurement technique to assess the overall burden of a disease. It includes both the time lost due to premature death (mortality) and the time lived with a disability (morbidity). One does not need much imagination to see that combining both quality of life and length of life in one single number is difficult. This index runs into serious conceptual and methodological problems (Arnesen and Nord, 1999). Nevertheless, the DALYs are put forward by the World Health Organisation and the World Bank as the basis for public health policy and resource allocation. The DALYs are used to determine the priorities for the allocation of health care resources. Given this practical use, it is extremely important to review and refine the process to make sure that infertility, and reproductive health in general, is ranked at the position it deserves. In the International Classification of Diseases (ICD), which is the basis for the calculation of the DALYs, infertility is included only as a disability outcome of sexually transmitted diseases (STD) and postpartum and post-abortal sepsis and not as a non-fatal disease in its own right (AbouZhar, 2000). The calculation method, moreover, raises a number of difficult questions when applied to infertility. For instance, the DALYs are calculated by multiplying the expected duration of the disability by a disability weight that measured the severity of the disease compared with death. This would imply that, in cases of primary infertility, a man or woman would be infertile from the age of 18 till approximately 45. It would be odd to talk of infertility before and after the natural reproductive life span. Moreover, infertility is only a disability when there is a child wish. Women becoming infertile due to abortions or pelvic inflammatory disease at an age at which they have no further child wish, will not consider themselves disabled (Vos, 2001). Nevertheless, the (primary) infertile persons will continue to 17

Pennings

suffer the consequences of their disability after the reproductive period because of a lack of support during old age. These conceptual problems are caused by the focus on ‘infertility’ as a disability while the effects are connected to childlessness. A second problem is that socioeconomic, cultural and environmental factors are excluded in determining the burden of disease. Infertility has important social (exclusion, ostracism etc.) and economic consequences (poverty in old age, divorce etc.) that are not incorporated in the DALY. Third, the disease of one person may affect the well-being of others. Infertility is a disability of a couple in Western countries, but influences the well-being of the larger family of both partners in developing countries. Fourth, the DALYs have been criticized because the burden of disease is largely determined by experts and epidemiologists while people’s own perceptions are left out of the calculation. When community members are questioned about the value of certain health states, some diseases which are fairly trivial from a clinical point of view, move up in the ranking despite their low prevalence. One study showed that socially stigmatized conditions like erectile dysfunction and infertility are considered more serious than non-stigmatized conditions (Kapiriri and Norheim, 2002). Studies in Nigeria, Mozambique and South Africa revealed that life without children is perceived as unhappy and not worth living (Dyer, 2007). The clinical criteria used in the calculation of DALYs strongly underestimate the impact of certain conditions, like infertility and skin diseases, on a person’s life. This is a plea to extend the criteria used to calculate the DALY of a disability in order to obtain a more complete picture of the global effect on a person’s quality of life.

argument can be shown by looking at the response to AIDS. Most countries spend a lot of money and health care resources providing anti-retroviral therapy to HIV positive persons. If the prevention/cure distinction would be an all or nothing question, they should spend all their money on prevention and let the infected persons die. The moderate form of the prevention argument states that priority should be given to prevention but, depending on a number of criteria, one should also direct part of the resources to cure. The criteria to determine the distribution are, among others, the degree of scarcity of the resources, the cost-effectiveness of both prevention and cure and the difference in cost between the two. I find the argument about the double benefit of preventive measures particularly strong for numerous reasons. First, the prevention of AIDS, infections etc. is realized by securing other rights of (mostly) women. Access to safe abortions not only prevents tubal infections, but also respects women’s right to control their fertility. Secondly, although the preventive measures are directed at healthy people, they are the ones most at risk of infertility due to lack of contraceptive devices and untreated STDs (Luna, 2002). Finally, cure without prevention would be a waste of effort: the number of infertile couples would continue to grow and no developing country will have the means to treat all these people by means of ART. ‘The development of expensive IVF units, whether public or private, in countries where there are no programmes for the prevention and early management of STDs, amounts to a national crime’ (Toubia, 1994). In conclusion, the government should give priority to prevention when allocating resources for public health. However, this does not mean that no money should go to infertility treatment at all, especially not when treatment can be made less expensive. One should not ignore the plight of the people who are infertile now.

Prevention The ‘prevention’ argument is a specified version of the ‘prioritization’ argument. It expresses the conviction that the available resources should be directed first towards programmes to prevent infertility. Okonofua (1996) gives three reasons for this position: (i) prevention programmes are less expensive, benefit a greater number of people and are more effective in eliminating the social consequences of infertility; (ii) prevention programmes will improve the health status of women in other ways and (iii) such programmes could provide impetus for the utilization of other prevention services, such as family planning. In general, there is little doubt that prevention is better than cure. Cure and therapy usually is more painful and burdensome. Moreover, for diseases such as AIDS, there is no cure. However, some moral points can be raised against the automatic priority given to prevention. In allocating medical treatment, one of the important criteria is medical need. People who are ill normally have priority on healthy people. When resources are allocated almost exclusively to prevention, one ignores the people who already attracted the disease (Verweij, 2007). It helps to distinguish a ‘moderate’ and a ‘radical’ form of the ‘prevention’ argument. The radical form defends the position that all available resources should be directed completely at prevention. The untenability of the radical ‘prevention’ 18

Justice Equity in health care means equal access to basic health care without excessive burdens. Health care in general is important because it secures the normal range of opportunities and allows people to flourish. The question of justice in health care is not limited to developing countries. The difference between developed and developing countries is a matter of gradation. Poor people in rich countries without insurance coverage for infertility treatment have no access to high-tech treatment either. In the United States, for instance, access to IVF is limited primarily to middle- or upper-class persons. Access to treatment can be determined by looking at the cost of infertility treatment in comparison to the mean income. In developing countries, the cost borne by the infertile patients themselves for IVF is more than half of the average annual income of the citizens (Collins, 2002). In resource-poor countries, infertility treatment is almost exclusively provided in private hospitals to the upper-class. The principle of justice contains two dimensions: equality and access. Justice can be promoted by either increasing equality (no one has access or everyone has access) of by increasing access (the more people can obtain the treatment the better). The people who focus on equality tend to conclude that when

Ethical issues of infertility treatment

access cannot be guaranteed for everyone, no one should have access. This results in what Engelhardt has called an ‘ethics of envy’: if I cannot have it, no one should. This difference in emphasis is important in the discussion. Regardless of the techniques that will be used and the cost reductions that can be realized, not every infertile person in developing countries will have access to infertility treatment. People who focus on equality believe that no action should be taken unless everyone (including the poorest) can obtain treatment. I think on the contrary that cost reduction for infertility treatment is morally defensible even if the treatment is only available to the more affluent groups in society because it increases the number of people who can afford treatment. Moreover, a small decrease in cost may result in a much higher increase in utilization (Collins, 2002). Nevertheless, the ideal situation combines equality and universal access. This can be obtained in several ways, either by reimbursement of treatment through public funding, affordable private health insurance or direct cost reduction. Given the problems encountered in resource-poor countries, the latter is the most realistic route. All parties can contribute to this goal. Pharmaceutical companies can provide cheaper drugs as they do for AIDS. Researchers and professional organizations can invest in cheaper, more effective and simpler procedures to facilitate introduction in less sophisticated health care systems and physicians can work for minimal fees. There are two considerations to keep in mind when private clinics start to offer high-technology infertility treatment. One argument is that it does not affect others when people have to pay for ART out-of-pocket. However, this is only correct when direct costs are taken into account. One should take into account the indirect costs in terms of health care resources and capacity. The private clinics will attract scarce qualified people like embryologists and gynaecologists with higher wages. The ‘health conveyor belt’ shifts qualified personnel from public to private clinics. The end result is an exodus from the public health sector (Schrecker and Labonte, 2004). Moreover, one should also beware of ‘creamskimming’: doctors in public hospitals refer public hospital patients to their private practices for follow-up and more sophisticated treatment if, of course, the patients are willing and able to pay (Sundby, 2002; Inhorn, 2007). This leaves the public hospitals with only poor patients. Finally, one should think proactively about a number of problems that will arise when low-cost IVF will be introduced without public funding. Low-cost does not mean that everyone will be able to afford it or will have access. This raises the question of which criteria (if any) should be used to rank the patients. One possibility would be to exclude, at least as long as there is great scarcity, secondary infertility. It can be argued that the scarce resources should first go to men and women who have no child of their own. A second issue is more related to cost-effectiveness. The treatment of some categories of patients will be more expensive than that of others. In the present discussion, severe male factor infertility is not included because ICSI cannot be performed for the same price as ‘standard’ IVF. The same applies to HIV positive persons who need infertility treatment. The inclusion of these

patients automatically implies that fewer patients can be treated with the same amount of money. Abuse and exploitation of patients The patient – physician relationship is characterized by a power imbalance. This is due both to the vulnerability of the sick person and to the inequality in terms of knowledge and skills. This inequality holds a possibility of abuse by the more powerful party that can only be avoided by the virtuousness of the physician (his or her integrity) combined with regulation. Several authors have expressed their concern about the high rates of medical malpractice in the management of infertility in the developing world (Macklin, 1995; van Zandvoort et al., 2001; Aboulghar et al., 2007). ‘Unregulated private practices offer considerable potential for making large profits from infertile women, and this can attract doctors who are more interested in wealth than ‘good practice’ (Aboulghar et al., 2007). This danger obviously is linked to any profit-driven practice, in developed as well as developing countries. The chance of abuse may be higher when patients are uneducated, desperate and willing to invest all their savings. The risk may be exacerbated by the lack of knowledge, experience and competence on the part of the practitioners (Macklin, 1995). However, the solution is not to prevent or block the introduction of high-technology infertility treatment but to regulate the practice by licensing providers, close monitoring of the activities and verifying results. Conclusion Most arguments against the provision of infertility treatment in developing countries cannot be sustained. On the contrary, a combination of measures such as increased investment in health care and considerable reduction of the cost of ART would justify at least some public funding. However, given the difficulties of resource-poor countries, the lion’s share of the effort should be directed at the prevention of infertility. References Aboulghar MA, Serour GI, Mansour RT. Ethical aspects and regulation of assisted reproduction in the Arabic-speaking world. RBM Online 2007;14(Suppl 1):143–146. AbouZhar C, Vaughan JP. Assessing the burden of sexual and reproductive ill-health: questions regarding the use of disability-adjusted life years. Bull WHO 2000;78:655–666. Arnesen T, Nord E. The value of DALY life: problems with ethics and validity of disability adjusted life years. BMJ 1999;319:1423–1425. Becker G, Nachtigall RD. Eager for medicalisation: the social production of infertility as a disease. Sociol Health Illn 1994;14:456– 471. Chan CLW, Yip PSF, Ng Ernest HY, Ho PC, Chan CHY, Au JSK. Gender selection in China: its meanings and implications. J Ass Reprod Gen 2002;19:426– 430. Collins J. An international survey of the health economics of IVF and ICSI. Hum Reprod Update 2002;8:265–277. Daar AS, Merali Z. Infertility and social suffering: the case of ART in developing countries. In: Vayena E, Rowe PJ, Griffin PD (eds). Current Practices and Controversies in Assisted Reproduction. Geneva, WHO, 2002, 15–21. Dyer SJ. The value of children in African countries—insights from studies on infertility. J Psychosom Obstet Gynaecol 2007;28:69–77. Editorial. Cheap IVF needed. Nature 2006;442:958.

Pennings Grimes S. From population control to ‘reproductive rights’: ideological influences in population policy. Third World Q 1998;19:375–393. Holmes HB. Choosing children’s sex: challenges to feminist ethics. In: Callahan JC (ed.). Reproduction, Ethics, and the Law: Feminist Perspectives. Bloomington: Indiana University Press, 1995, 148–177. Inhorn MC. Masculinity, reproduction, and male infertility surgery in the Middle East. JMEWS 2007;3:1– 20. Kapiriri L, Norheim OF. Whose priorities count? Comparison of community-identified health problems and burden-of-disease assessed health priorities in a district of Uganda. Health Expect 2002;5:55 –62. Luna F. Assisted reproductive technology in Latin America: some ethical and sociocultural issues. In: Vayena E, Rowe PJ, Griffin PD (eds). Current Practices and Controversies in Assisted Reproduction. Geneva: WHO, 2002, 31–40. Macklin R. Reproductive technologies in developing countries. Bioethics 1995;9:276– 282. Nachtigall RD. International disparities in access to infertility services. Fertil Steril 2006;85:871–875. Okonofua F. The case against new reproductive technologies in developing countries. Brit J Obstet Gynaecol 1996;103:957– 962. Ombelet W, Campo R. Affordable IVF for developing countries. RBM Online 2007;15:257– 265. Pennings G, Ombelet W. Coming soon to your clinic: patient-friendly IVF. Hum Reprod 2007;22:2075–2079. Sandelowsky M, de Lacey S. The uses of a ‘disease’: infertility as rhetorical vehicle. In: Inhorn MC, Van Balen F (eds). Infertility Around the Globe. Berkeley, Los Angeles, London: University of California Press, 2002, 33–51. Schrecker T, Labonte R. Taming the brain drain: a challenge for public health systems in southern Africa. Int J Occup Environ Health 2004;10:409– 415.

Shah I. Treatment of infertility: an integral part of reproductive health and a necessity. Reprod Health Matters 1994;4:96 –97. Sundby J. Infertility and health care in countries with less resources: case studies from sub-Saharan Africa. In: Inhorn MC, Van Balen F (eds). Infertility Around the Globe. Berkeley, Los Angeles, London: University of California Press, 2002, 247–259. Toubia NF. Social pressure is not the only reason people want children. Reprod Health Matters 1994;4:94–95. Ulrich M, Weatherall A. Motherhood and infertility: viewing motherhood through the lens of infertility. Feminism Psychol 2000;10:323–336. United Nations. Programme of action adopted at the International Conference on Population and Development, Cairo, 1994. Van Balen F, Gerrits T. Quality of infertility care in poor-resource areas and the introduction of new reproductive technologies. Hum Reprod 2001;16: 215–219. Van Balen F, Inhorn MC. Introduction. Interpreting infertility: a view from the social sciences. In: Inhorn MC, Van Balen F (eds). Infertility around the globe. Berkeley, Los Angeles, London: University of California Press, 2002, 3–32. Van Zandvoort H, De Koning K, Gerrits T. Medical infertility care in low income countries: the case for concern in policy and practice. Tropical Med Int Health 2001;6:563–569. Vayena E, Rowe PJ, Peterson HB. Assisted reproductive technology in developing countries: why should we care? Fertil Steril 2002;78:13 –15. Verweij M. Preventing disease. In: Ashcroft RE, Dawson A, Draper H, McMillan JR (eds). Principles of Health Care Ethics, 2nd edn. Chichester: John Wiley & Sons, 2007, 557 –562. Vos T. Ranking reproductive health problems to define service priorities. African J Reprod Health 2001;5:31 –39. World Health Organisation. The World Health Report 2006. Annex table 2. 2007. http://www.who.int/whr/2006/annex/06 annex2 en.pdf

doi:10.1093/humrep/den203

Human Reproduction 2008

Is affordable and cost-effective assisted reproductive technology in low-income countries possible? What should we know to answer the question? J. Dik F. Habbema1 Department of Public Health, Erasmus MC, University Medical Center Rotterdam, PO Box 2040, 3000 DR Rotterdam, The Netherlands 1

Correspondence address. E-mail: j.d.f.habbema@erasmusmc.nl

Decision making on infertility treatment in low-income countries (LIC) assumes answers to quite a few questions: how should the infertility problem be defined? How often does infertility occur? What is the burden-of-disease of infertility? What is the income in LIC, and what can be spend on health care? How cheap should IVF be in order to be accessible to a considerable part of the population? With what alternative health interventions should infertility treatment be compared? How cost-effective should IVF be in order to compete with those other interventions? These questions will be discussed. The emphasis is on the situation in Sub-Saharan Africa (SSA). It is concluded that a place for ART in a health care package is not straightforward. Many of the questions are not or only partially answered. Moreover, cheap and effective ART has yet to be developed and tested. From the limited evidence available for each of the questions, it could be calculated that an IVF cycle should cost between 50 and 75 dollar in order to be a candidate for the inclusion in a health package in SSA. This estimate can easily change considerably when in the future the calculations will be based on thorough research. Thus, a targeted research programme for answering the open questions, especially on quality-of-life implications of infertility in different societies, is the preferred option for facilitating the future evaluation of ART in LIC. Keywords: infertility; quality-of-life; cost-effectiveness; burden-of-disease; low-income countries

Introduction Infertility is often a personal drama in low-income countries (LIC) because of its social, cultural and religious connotations. This pleads for a rapid implementation of assisted reproductive technologies (ART) in order to solve as many infertility problems as possible. On the other hand, LIC have limited resources, and people who live in these countries often have a low income. And all medical services come at a price. This surely holds for in vitro fertilization (IVF) and other ART. One cycle of IVF-treatment in high-income countries costs several thousands of euros/dollars. This is too expensive for LIC, except for a small upper class. In spite of spectacular economic growth rates in some LIC, including the billion inhabitants countries, China and India, extreme poverty is still widespread. We will focus on Sub-Saharan Africa (SSA) because the situation there is worse than in other parts of the world. Moreover, infertility is one of the many important health problems that people face in these countries and it is well possible that more health is gained at lower costs by attacking other health problems than infertility. Therefore, the answer to the question posed in the title is not simple at all.

Before trying to answer the question, the following subjects have to be recognized and studied. † How should the infertility problem be defined and what is its occurrence in SSA? † What is the income in LIC, and what is spend on health care? † What is de burden-of-disease of infertility and how does it compare with other diseases? † How cheap should IVF be in order to compete with the cost-effectiveness of other health interventions for infertility and for other health problems? We will discuss each of the above subjects, intertwined with more technical sections in which we make some preliminary calculations.

How should the infertility problem be defined? Depending on the definition used, the number of infertile women will vary. In order to avoid confusion and misunderstanding, one should be clear about the definition that is actually used. In the first place, there is the distinction between primary and secondary infertilities. Primary infertility

Habbema

corresponds to the idea of infertility as childlessness. However, childlessness is a broader concept, because infant mortality may make a couple childless after a live-born delivery (LBD). Most important is the duration of infertility. In western countries, it is often already after 1 year of non-conception that the term infertility is used. But many couples will get pregnant after more than 1 year of trying, and for LIC it is better to use a much longer duration (e.g. 5 years). We recommend that the term infertility is not used without indicating the duration (Habbema et al., 2004). Infertility may refer to the failure to conceive (‘conception-infertility’) or to the failure to have a live-born child (‘LBD-infertility’). Duration of infertility without children corresponds to a 9 months shorter duration for nonconception. As a child is the outcome that matters to prospective parents, LBD-based infertility is usually most relevant. However, in a clinical context, or when discussing risk-factors and aetiology, the distinction between conception and livebirth can be important. See Larsen (2005) for a discussion of different concepts of infertility, including some which are based on couple perception. How often does infertility occur? There are 130 million women in the age group 20 – 44 in 2008 in SSA (U.S. Census Bureau, 2008). How many of them are infertile? For SSA, Larsen (2000) analysed the DHSþsurveys. She concluded that the percentage with primary infertility, based on the proportion childless after at least 7 years of first marriage, was on average 3%, with a range from 1 to 6%. For secondary infertility, defined as at least 5 years after the birth of the last child no further child, the percentages are much larger and steeply increasing with age. For the age group 30 – 34, the figure for the whole of SSA is 20%. The same percentage of 3% primary infertility is found in WHO (1991). It follows that there is presently a yearly incidence of roughly 300 000 primary infertility cases and two million secondary infertility cases (calculation not shown). Secondary infertility can occur for any parity of the woman. For infertility treatment, women with one child are the most important category of secondary infertility. For SSA, secondary infertility with one child at age 40þ can be estimated at about 5% from WHO (1991). For other reviews of infertility see Boivin et al. (2007) and Rutstein and Shah (2004). The below 1-year child-mortality in SSA is 9%, implying that nearly 10% of the women with a first life born child will nevertheless be childless 1 year later. Sexually transmitted infections (STI) are an important cause for infertility, both for primary and secondary infertility, via tubal occlusion and ectopic pregnancy. Unsafe abortions are estimated to contribute 2% to primary and secondary infertility (Grimes et al., 2006). Septic partum and postpartum practice will contribute the majority of the remainder, and each additional birth gives a new risk of secondary infertility. The role of HIV in biological causes of infertility is not exactly known. In a prospective study, there were less pregnancies and more pregnancy loss in the HIV positive women than in the control group, see Gray et al. (1998). For a more general 22

appraisal of the population impact of HIV on infertility, see Lewis et al. (2004) and United Nations (2002). What is the burden-of-disease of infertility? The assessment of the burden-of-infertility is an extremely complex problem and different between and within countries, because of the social, cultural and religious variations in implications of infertility for the woman or couple concerned. The reader is referred to Safarinejad (2008), Van Balen et al. (2000), Inhorn (2003) and Dyer et al. (2005) as an entry to the literature. Qualitative research is very important, and will remain the mainstay of research in this area. However, in order to compare the burden-of-infertility with the burden of other diseases, a quantified quality-of-life (QoL) judgement is needed (Dyer et al., 2005; Smith et al., 2008). More technically, the question has to be answered how many QoL adjusted life-years (QALYs) or disability adjusted life-years (DALYs) are lost by infertility. Briefly, QALYs are calculated by weighing each year of life with a QoL weight, which is scaled from 0 (dead) to 1 (perfect health). For example, a year lived with a QoL of 0.8 counts for 0.8, and 2 years lived in this health state count for 1.6 QALY. For further theory, see Gold et al. (1996). The same reasoning applies to DALYs, only the scaling is reversed, with a disability of 0 for perfect health and one for dead. On an individual level, the expected number of DALYs lost will guide individual choices, including the preparedness to spend money on infertility treatment. On a societal level, the number of DALYs lost by infertility gives an indication of the importance of the problem, and of the gain in population health obtained by solving it. It is outside the scope of the present paper to tackle the design of QoL research in infertility in any depth. However, it should be stressed that because of the long-term implications of infertility, the research should adopt a life course perspective, and QoL measurement should not stop after a few years, or only be done during the period of treatment. For DALY calculations, it has to be decided during how long a period QoL loss should be taken into account. Should it be life-long? Twenty years? Up till age 45? A second question is how to deal with secondary infertility. Should secondary infertility be a priority for infertility services or should the exclusive focus be on childlessness? Or should secondary infertility with one child be included? It is clear that the prevalence of women or couples suffering from infertility depends on the choices made. AbouZahr et al. (1998) use a disability weight of being infertile of 0.22 on a scale from 0 to 1, for an average duration of 15 years and an average starting age of the infertility problem at 25 years of age. Thus, an average case of infertility would incur a loss of 3.3 DALYs (15 0.22). These numbers would imply that for primary infertility the prevalence is 4.5 million in SSA (15 years duration times 300 000 yearly incidence) and that each year 1 million DALYs are lost (4.5 million times 0.22). For secondary infertility comparable calculations can be made. Secondary infertility percentages are very high in SSA, but when restricted to one-child, the figure is only slightly higher than for primary infertility, with

When is ART cost-effective in low-income countries?

a prevalence at age 40 of 5% (WHO, 1991), implying a yearly incidence of 500 000 cases. For a further discussion of the measurement and use of DALYs in sexual and reproductive ill-health, see AbouZahr and Vaughan (2000). An important topic for discussion is if and how children who are born as a consequence of infertility treatment are to be valued. The general population policy in SSA is trying to reduce the number of births. From this perspective, the birth of more children is unwanted which pleads against infertility treatment. This might be an important reason why infertility in LIC had little public attention, see Van Balen and Gerrits (2001). It is often a neglected issue in overviews of reproductive health services, or only mentioned as a contrast to more important health problems (Cleland et al., 2006). On the other hand, small families are encouraged because of advantages for both parents and children. And fertility services should deal with small sized families. Especially the cure of primary infertility or childlessness helps the formation of small families. And the availability of good reproductive health services, including infertility care, might be a motivation for couples to decide to have only a small number of children. Because of these complex and contradictory considerations, one might consider to restrict the effectiveness of ART to the QoL improvement for the couple concerned.

With what alternatives should infertility treatment be compared?

What is the consumption level in LIC, and what does this imply for affordable art?

How cheap should IVF be in order to compete with the cost-effectiveness of other health interventions?

A considerable fraction of the population in SSA is poor. This implies that in order to reach a large part of the population, infertility services should also be affordable to the poor. Absolute poverty is often defined as a consumption of 1 or 2 dollar a day, at 1993 international purchasing power parity (Chen and Ravallion, 2007). For SSA, the percentage absolute poverty for 2004 is estimated as 72 and 41% for ‘2$ per day’ and ‘1$ per day’, corresponding to 0.5 and 0.3 billion people. For the whole world, the numbers are 2.5 and 1.0 billion people (Chen and Ravallion, 2007). Most of private expenditure on health in SSA is out-of-pocket (WHO, 2007). This means that all but very cheap health services can be detrimental for the financial position of the household. The term ‘catastrophic health expenditure’ has been coined for cases, where health expenditures lead to total financial collapse. The level of health expenditure in order to be catastrophic has been defined as 40% of household income, after subtraction of income needed for buying food (Xu et al., 2003). It is estimated that each year a few percentage of households in LIC incur catastrophic health expenditures (see Xu et al., 2003, 2007; Van Doorslaer et al., 2006). An approach to defining affordable IVF would be that it should be so cheap that it will not lead to catastrophic health expenditure. When the income distribution and the health expenditures for a country are known, it can be calculated for what proportion of the population IVF is affordable for a given cost. The data for performing such calculations are scarce, and research is needed for filling the gaps.

Both economic theory and daily life learn that money can only be spend once, and that by spending it on one thing you forego the (health) value for your money that you could get by spending it on other things. This is the principle of ‘opportunity costs’. The consequence is that you should spend your resources such that you get the most health out of it. Costeffectiveness analysis is the discipline which deals with priorization, for an overview see Gold et al. (1996). The methodology and application of cost-effectiveness analysis of medical services in LIC is the subject of the comprehensive volume by Jamison et al. (2006). Remarkably, infertility is not included in many conditions that are treated in this volume. Laxminarayan et al. (2006) summarize the costeffectiveness of different interventions. Many important interventions for serious health problems like malaria and maternal and perinatal mortality have a cost-effectiveness of 100 dollar or less per DALY gained. Adam et al. (2005) look at cost-effectiveness of strategies for maternal and neonatal health. They combine interventions in the most cost-effective way, starting with the intervention with the best costeffectiveness ratio. Also in their results, most interventions have a better CER than 100 dollar per DALY. When applying a threshold CER of 100 dollar per DALY gained to IVF, and assuming a 20% LBD chance per IVF cycle, 20% of the earlier derived 3.3 DALY-loss per woman because of infertility will be gained per cycle. Thus, on average 0.66 DALY is gained by an IVF cycle, and therefore the costs of an IVF cycle should be 66 dollar in order to be a possible candidate for inclusion in health packages in SSA.

The main ART modalities are, in order of increasing complexity, intra-uterine insemination (IUI), IVF and intra-cytoplasmic sperm-insemination (ICSI). Infertility and childlessness can also be tackled by prevention or by mitigation of the suffering that infertility causes. Prevention of infertility includes prevention of problems caused by STI, especially chlamydia and gonorrhoea. This is possible by condom use, by improved STI treatment and by having less sexual partners. Secondary infertility is prevented by safe obstetric practice and by reducing unsafe abortions. Childlessness after LBD is prevented by reducing neonatal and child mortality. The negative impact of being infertile can be reduced by fighting the social and cultural stigma associated with childlessness, by encouraging small family size and by realizing a respected position for adoption. All interventions mentioned above will reduce the number of infertile women or couples, or reduce the adverse consequences of infertility. For overviews of maternal and child health that include the causes of infertility see (Murray and Lopez, 1998; Glasier et al., 2006). The challenge is to determine for each specific local situation which combination of interventions should be chosen in the fight against infertility.

Habbema

If the costs are much higher, ART will not be accessible to the majority of the population (see also the discussion by Nachtigall, 2006). But all this is based on rough calculations and considerably different figures may result from thorough research.

Conclusions The elements for a full evaluation of cheap ART, for judging its inclusion in health packages in LIC, especially SSA, have been discussed. For all relevant questions, evidence is available in the literature, but often too limited to provide reliable answers. In a preliminary exercise, the costs of cheap IVF for being a candidate for inclusion in health intervention packages in SSA is calculated as somewhere between 50 and 75 dollar per cycle. But much research is needed for making more valid calculations, which may change the results considerably. Most of the research efforts will have to go in Qol measurements to estimate the number of disability adjusted life years lost because of infertility in different countries in SSA. References AbouZahr C, Vaughan JP. Assessing the burden of sexual and reproductive ill-health: questions regarding the use of disability-adjusted life years. Bull World Health Org 2000;78:655–666. AbouZahr C, Ahman E, Guidotti R. Puerperal sepsis and other puerperal infections, chapter 5. In: Murray JL, Lopez AD (eds). Health dimensions of sex and reproduction. Global Burden-of-Disease and Injury Series, Vol. 3, Harvard University Press, 1998. Adam T, Lim SS, Mehta S, Bhutta ZA, Fogstad H, Mathai M, Zupan J, Darmstadt GL. Cost effectiveness analysis of strategies for maternal and neonatal health in developing countries. BMJ 2005;331:1107– 1112. Boivin B, Bunting L, Collins JA, Nygren KG. International estimates of infertility and treatment-seeking: potential need and demand for infertility medical care. Hum Reprod 2007;6:1506– 1512. Chen S, Ravallion M. Absolute Poverty Measures for the Developing World, 1981–2004. Washington, DC: World Bank, 2007. Cleland J, Bernstein S, Ezeh A, Faundes A, Glasier A, Innis J. Family planning: the unfinished agenda. Lancet 2006;368:1810–1827. Dyer SJ, Abrahams N, Mokoena NE, Lobard CJ, Van der Spuy ZM. Psychological distress among women suffering from couple infertility in South Africa: a quantative assessment. Hum Reprod 2005;20:1938– 1943. Glasier A, Gu¨lmezoglu AM, Schmid GP, Moreno CG, Van Loon PFA. Sexual and reproductive health: a matter of life and death. Lancet 2006;368: 1595–1607. Gold MR, Siegel JE, Russel LB, Weinstein MC (eds). Cost-effectiveness in Health and Medicine. New York: Oxford University Press, 1996. Gray RH, Wawer MJ, Serwadda D, Sewankambo N, Li C, Wabwire-Mangen F, Paxton L, Kiwanuka N, Kigozi G, Konde-Lule J et al. Population-based study of fertility in women with HIV-1 infection in Uganda. Lancet 1998;351:98– 103.

Grimes DA, Benson J, Singh S, Romero M, Ganatra B, Okonofua FE, Shah IH. Unsafe abortion: the preventable pandemic. Lancet 2006;368:1908–1919. Habbema JDF, Collins J, Leridon H, Evers JLH, Lunenfeld B, Te Velde ER. Towards less confusing terminology in reproductive medicine: a proposal. Hum Reprod 2004;19:1497– 1501. Inhorn MC. Global infertility and the globalization of new reproductive technologies: illustrations from Egypt. Soc Sci Med 2003;56:1837–1851. Jamison DT, Breman JG, Measham AR, Alleyne G, Claeson M, Evans DB, Jha P, Mills A, Musgrove Ph (eds). Disease Control Priorities in Developing Countries. 2nd edn. New York: Oxford University Press, 2006. Larsen U. Primary and secondary infertility in sub-Saharan Africa. Int J Epidemiol 2000;29:285–291. Larsen U. Research on infertility: which definition should we use? Fertil Steril 2005;83:846–852. Laxminarayan R, Chow J, Shahid-Salles SA. Intervention cost-effectiveness: overview of main messages. In: Jamison et al. (ed). Disease Control Priorities in Developing Countries. Chapter 2, 2nd edn, Oxford University Press, 2006. Lewis JJC, Ronsmans C, Ezeh A, Gregson S. The population impact of HIV on infertility in sub-Saharan Africa. AIDS 2004;18:S35– S43. Nachtigall RD. International disparities in access to infertility services. Fertil Steril 2006;4:871– 875. Murray JL, Lopez AD (eds). Health dimensions of sex and reproduction. Global Burden-of-Disease and Injury Series, Vol. 3, Washington, DC: Harvard University Press, 1998. Rutstein SO, Shah IH. Infecundity, Infertility, and Childlessness in Developing Countries. DHS Comparative Reports No. 9. Washington, DC: World Health Organisation, 2004. Safarinejad MR. Infertility among couples in a population-based study in Iran: prevalence and associated risk factors. Int J Androl 2008;31:303– 314. Smith KJ, Tsevat J, Ness RB, Weisenfeld HC, Roberts MS. Quality of life Utilities for pelvic inflammatory disease health states. Sex Transm Dis 2008;35:307–311. United Nations. HIV/AIDS and fertility in sub-Saharan Africa: a review of the research literature. Department of Economic and Social Affairs, 2002. U.S. Census Bureau. Population Figures, International Database. http://www. census.gov/ipc/www/idb (April 2008, date last accessed). Van Balen F, Gerrits T. Quality of infertility care in poor-resource areas and the introduction of new reproductive technologies. Hum Reprod 2001;16: 215–219. Van Balen F, Gerrits T, Inhorn M (eds). Social Science Research in Childlessness in a Global Perspective. Amsterdam: SCO-Kohnstamm Institute, 2000. Van Doorslaer E, O’Donnell O, Rannan-Eliya RP, Somanathan A, Adhikari SR, Garg CC, Harbianto D, Herrin AN, Huq MN, Ibragimova S et al. Effect of payments for health care on poverty estimates in 11 countries in Asia: an analysis of household survey data. Lancet 2006;368:1357–1364. World Health Organisation. Infertility: A Tabulation of Available Data on Prevalence of Primary and Secondary Infertility. Geneva: WHO/MCH/ 91.9, 1991. World Health organisation. World Health Statistics: 2007. http://www.who. int/whosis/whostat 2007/en/index.html. Xu K, Evans DB, Kawabata K, Zeramdini R, Klavus J, Murray CJL. Household catastrophic health expenditure: a multicountry analysis. Lancet 2003;362:111– 117. Xu K, Evans DB, Carrin G, Aguilar-Rivera AM, Musgrove P, Evans T. Protecting households from catastrophic health spending. Health Aff 2007;4:972–983.

doi:10.1093/humrep/den141

Human Reproduction 2008

Involuntary childlessness: a neglected problem in poor-resource areas F. Van Balen1 Department of Education, University of Amsterdam, Amsterdam, The Netherlands 1

Correspondence address. Nieuwe Prinsengracht 130, Gebouw G, 1018 VZ Amsterdam, The Netherlands. E-mail: f.vanbalen@uva.nl/ vabalen@hotmail.com

Childlessness is analysed on the individual, the national and the international level. On the individual level five categories of consequences are described: grief and sadness; social isolation and stigma; restricted rights; religious effects and economic aspects. The first category concerns individual feelings and the others are socio-cultural effects in broad-sense. In developing countries childlessness has consequences on individual and socio-cultural level. In the West consequences are mostly restricted to individual feelings. In poor-resource areas there are limited possibilities for modern biomedical treatment. Traditional medicine, with its easy access and cultural acceptation, is a serious ‘competitor’. On the national level there are few incentives and possibilities for development of adequate infertility treatment. Though local and national authorities might be sensitive to the problem, allocation of funds is mostly determined by international agencies, which consider other issues more important. On the international level Western perceptions about the urgency of health issues are still dominant. In the Western world there is little interest and understanding in the problem of ‘barrenness among plenty’ because a focus on population growth reduction and on other problems. Also, the perception of childlessness as an individual problem, makes it difficult to change this attitude. Possibilities for change are discussed. Keywords: involuntary childlessness; poor-resource areas; socio-cultural effects; infertility treatment; population growth

Introduction In poor-resource countries, there are many problems such as poverty, shortage of job opportunities, a high frequency of illnesses and vast expanding populations. The problem of not having children does not come to mind easily. Still ‘barrenness among plenty’ is often a very sad situation with repercussions in all areas of life. Consequences of childlessness in developing countries are usually much more dramatic, and also show a much wider impact than in Western societies. Infertility and sterility are generally looked upon as medical problems. However, it is the social and psychological consequences of infertility that make this situation so hard to bear. Therefore, I will in this article use the word childlessness, when it denotes the social side of the state of ‘barrenness’. The term infertility will be used regarding the specific medical side, for instance in relation to treatment. Childlessness may be voluntary or involuntary. The concept childless may indeed, also be used for couples who do not want to have children, or are postponing childbirth, as is a frequent phenomenon in the West. However in poor-resource countries voluntary childlessness is rarely found, and if so, mostly in the upper classes. This article is focused on poor-resource areas and developing countries where most of the world population

and also most of the childless population is found. I will analyse the situation of involuntary childlessness first by looking on the individual level, than the national level and finally the international level.

The individual level There are great differences between cultures and societies in the non-Western world. However, everywhere childlessness leads to great suffering, especially among women. Experiences and consequences may vary. Generally five interrelated aspects can be discerned: individual psychological problems, such as grief and sadness; social isolation and stigma; restricted rights; effects in the area of religious and spiritual beliefs; and economic consequences. Psychological and social aspects Grief and sadness are universal affects of involuntary childlessness, and is found in all societies, also in the Western world (Greil, 1997; Van Balen and Inhorn, 2002). Having children is very important for most humans (and other animals, too). To find that one is not being able to have children is often a shock. It means that one has to adjust the life one had imagined

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for the future of oneself into a life without children. Not having the chance to give love to a child of one’s own is for many people almost unacceptable, and is often accompanied with loss of self-esteem and the feeling of being only half a man or a woman (e.g. Van Balen and Trimbos-Kemper, 1993; Inhorn, 1994; Deyer et al., 2004; Nahar, 2007). It is not surprising that many studies reported a whole range of negative effects on women and men, such as wellbeing, health, psychological complaints, stress, loss of self-esteem, anxiety, hostility, unhappiness (e.g. Abbey et al., 1991; Stanton et al., 1991; Van Balen and Trimbos-Kemper, 1993). Though not every study showed the same effects. If we turn to developing countries, however, it appears that the importance of motherhood is often much more important than in the Western world. In the West today women are supposed to have a paid job, just like men, and men are supposed to contribute in an essential way to childrearing and household task (though this is not always done). In many other areas of the world motherhood is essential for womens’ self-esteem and social position. So this makes it even more important to have children. Associated with this importance of motherhood, is the pronatalist culture in various non-Western areas (e.g. FeldmanSavelsberger, 2002; Van Balen and Inhorn, 2002; Van Rooij et al., 2004; Kagitcibasi and Ataca, 2005). Ideals propagated by nation-states and some religions stress the value of having sons, and to a lesser extent daughters, for the continuation and importance of oneself. Self-chosen childlessness is something that is not culturally expected. Childless couples have to do their best to have children. In the last decade studies have been done regarding childlessness in the third world. It turns out that social isolation and stigma are frequently found (Inhorn, 1994; Okonafua et al., 1997; Kielman, 1998; Gerrits, 2002). There is fear of abandonment among the women (Riessman, 2002; Deyer et al., 2002), and in some cultures a man will resort to another wife (Inhorn, 1994; Sundby, 1997; Nahar, 2007). Often infertile women are accused of witchcraft. They may carry the evil eye, and are better avoided (Inhorn, 1994; Meyer, 1994; Okonofua et al., 1997). A woman without a child has often no position of significance, and has to accept the social pressure of motherhood. Even in Vietnam and China where the small or one-child family is official policy, the ones without children, are seen as failures (Handwerker, 2002; Pashigian, 2002). Besides that childless people are often ridiculed and sometimes abused (Sundby, 1997; Deyer et al., 2002; Deyer et al., 2004). Also in many areas childless persons are banned from social events, especially around marriage, childbirth, death or other ‘rites de passage’ (Inhorn, 1994; Sundby, 1999; Gerrits, 2002). Of course, in the Western world couples without children often do not attend social gatherings for children, such as school activities like graduation, sports competitions, cultural activities and celebrations. However one is not banned to attend; and frequently childless couples in the West follow closely all celebrations and special occasions in the life of children of family members or friends. 26

Legal and religious aspects Childlessness has also legal and religious consequences. In anthropological studies we find narratives about the repayment of bride-gifts, and of childless women that feel used as slaves by their in-laws to pay back ‘their debt’, that is, not producing a family heir (Bharadwaj, 2000; Riessman, 2002; Nahar, 2007). Moreover, childless women are supposed to have enough spare time to help their in-laws (family from the husband’s side). Also, especially in Islam areas, childless women have restricted heritage rights, for instance when they become a widow, they are left with just a small part of the possessions of their husbands (Sundby, 1999; Okonofua et al., 1997; Nahar, 2007). Nahar (2007) describes in her thesis about childlessness in Islamic Bangladesh that women without children are not supposed to be alone on the streets and paths, even to do simple shopping and errands. So childless women are restricted to stay at home all day, and can only move outside accompanied by their husbands. An early anthropological study on childlessness, reported that childless women were not supposed to be buried in graveyards or sacred grounds, but to be left in the open field as animal fodder (Denga, 1982). Additionally, in many areas of our world ancestor worship is very important, especially in China and Vietnam. Not to be able to produce male offspring or at least offspring means that one’s soul will not get to rest easily. Especially the in-law family tends to be concerned that these pious duties are carried out (Handwerker, 2002; Pashigian, 2002). Economic aspects Finally, childlessness often leads to poverty. There are various mechanisms involved. First there are the treatment costs, whether by traditional healers or western medicine. Traditional treatment is often relatively expensive for the couples concerned. Western biomedical treatment such as IVF however is extremely costly. Mulgaonkar (2000) mentions the fate of middle-class Indian couples, which had to move to the slums because of the treatment costs. Another mechanism is that there are no children to support their parents when they get old. In many countries the state does not provide enough support for the elderly. Even in the rich western countries the lack of social support can make the old age of childless couples difficult, because they lack the social and informal support of still able—now grown-up children (Van Balen, 1995). The lack of support by in-laws (mostly the husbands) side is already mentioned. For childless women the situation is often reversed, they have to support their in-laws, instead caring for themselves. Finally the lack of children makes social relations and networking more difficult. Studies of rich merchants in the 17th century in Holland showed for instance, that most of them were related to one and another by intermarriage of their children, more or less like the nobility (Van Balen, 1995). Marrying off a child of to another merchant is considered as a sign of trust, a guarantee for honesty and cooperation, comparable to the same thing among warring tribes, and ancient kings. In conclusion, all these mentioned aspects are much stronger than in the West. In poor-resource areas there is not only

Childlessness: a neglected problem in poor-resource areas

individual suffering, but there are mostly also huge social, legal, economic and religious consequences to childlessness. Second, the phenomenon of voluntary childlessness in the West, more or less hides the infertility, while in the other areas involuntary childlessness is conspicuous and visible. Moreover, the differences between childless women and childless men are greater, especially in patriarchal and patrilineal cultures. The modern western cultures display also relatively small differences between the world of the women and the men, as reflected in such things as military service for both genders, political demonstrations attended by women and men, mixed classes in schools, shared swimming pools and hospital wards, etc. Traditional and modern treatment Finally of course, there is the difference in treatment opportunities: it may be surprising in the light of its great achievements but for modern biomedicine it is often difficult to compete with traditional healing (Okonofua, 1996; Van Balen and Gerrits, 2001; Nahar 2007). High-tech treatment for infertility, like IVF and ICSI, is very expensive and often not available at all, or only in the capital city. Moreover many people believe in traditional explanations of infertility, explanations that are more in line with the culture and life circumstances of the areas. Doctors are often member of the upper-class or foreigners, speak in a different accent or language, and belong to a different culture, so communication is not easy, and patients often feel a large distance between them and the physician. Also the male partners are often reluctant to do tests and have examinations, because it could turn out that they might be to ‘blame’ instead of their wives. Finally success rates of high-tech treatments are still not high, especially among beginning fertility specialists. Traditional healing, on the other hand, fits in the traditional explanatory models about the causes of infertility (Sundby, 1997; Mariano, 2000; Mogobe, 2000; Gerrits, 2002; Nahar, 2007). It is mostly easily available though not always cheap. It is culturally expected and accepted to use these methods, and also can give the feeling of not ‘medically defined’ infertility. That is: one still might have the feeling of not being officially labelled as infertile and sterile, with all its consequences (Nahar, 2007). So, in conclusion, on the individual level, childlessness is an existential problem, especially for women, and modern biomedicine still has to compete for its place as treatment number one, like it is in the West. The national and international level However, it appears that on the national level in developing countries infertility still is not an important issue. Mostly the goal of the administration is to reduce the population growth, and obviously involuntary childless persons contribute to this. Moreover, other issues are considered more important, for instance maternal morbidity and mortality. Also, childless people are not a powerful and well-organized group, but mostly isolated individuals within their community. So it is difficult to put pressure on the authorities for infertility care.

Finally, of course, the developing countries are not wealthy and do not have a well-developed medical infrastructure. Therefore it is difficult to organize adequate infertility care even when there is a wish to attend to the problems of infertile persons. Moreover, international agencies and NGO’s play an important role on the national level in deciding about the attribution of funds to medical and social welfare. International organizations still do not consider infertility as a great problem. Globally 70 – 80 million couples might be currently affected by infertility (Bos et al., 2006; Boivin et al., 2007). However, these numbers are largely based on studies that also include secondary infertility. Of course secondary infertility, or at least not having another child when one wants to, has considerable less negative consequences that not having a child at all. Though the effects may be still serious, especially if a couple has only female offspring, in areas where it is utmost important to have a son. Still, a tentative breakdown of the numbers regarding primary and secondary infertility indicates that some tens of million couples are confronted with the expectation of being completely childless. However, we have keep in mind that a part of these couples might have children, spontaneously in the following years. Though large numbers of people are confronted with primary or secondary infertility, other problems are considered more important. The lack of interest in infertility might be explained by a Western vision on infertility in developing countries. If one talks about tackling this problem, people in the West often react like ‘there already so many children in these areas’. In this way individual suffering is not recognized. Moreover, being childless in the West is largely an individual experience, without the wide social consequences as described above. And indeed childlessness is often considered a question of choice, as indeed couples can choose not to have children. So a western attitude about childlessness and the difficulties to create and organize adequate treatment may explain the lack of interest. However, some related aspects of infertility may contribute to a change of attitude. First it appears that infertility may lead to STD/HIV. In some areas extra marital sex is used as a kind of ‘treatment’, or to show off potency (Bergstro¨m and Samucidine, 2000; Gerrits, 2002; Nahar, 2007). Furthermore, it might be important to focus on infertility in anti-STD programmes, because infertility is often more feared by the population than STD’s (Bergstro¨m and Samucidine, 2000). Also, as described above, childlessness may lead to poverty. But most importantly it is to recognize the problem of involuntary childlessness in its own right, considering the tremendous consequences it has for the ones concerned. It is indeed important the international donor agencies and NGO’s support programmes of infertility treatment and prevention. A first step was the Cairo conference of 1994, where infertility was accepted as part of the international public health programme (ICPD, 1994). However not much has been done to put the resolution in practice. Also, national patient organization in Western countries could play a role, for instance, each could ‘adopt’ an developing country, and help patients there. Also the international ‘infertility month’ could focus on third world problems. 27

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Besides that, social scientists could emphasize the fate and the role of the childless in poor-resource countries. Medical scientists could do the same in their field. It is important that low costs but state of the art techniques are developed, that training programmes for fertility specialists are developed and so on. Also the pharmaceutical and medical industry should become aware of their opportunities in treating millions of people, and invest in this field. Hopefully this volume will help in its own way to make infertility no longer a neglected, but an acknowledged problem, that humans try to solve. References Abbey A, Andrews FM, Halman JL. Gender’s role in response to infertility. Psychol Women Q 1991;15:295– 316. Bergstro¨m S, Samucidine M. Vulnerability of childless women to sexually transmitted infections. In: Van Balen F, Gerrits T, Inhorn M (eds). Social Science Research on Childlessness in a Global Perspective. University of Amsterdam, Amsterdam, 2000, 160–165. Bharadwaj A. Infertility and gender: a perspective from India. In: Van Balen F, Gerrits T, Inhorn M (eds). Social Science Research on Childlessness in a Global Perspective. University of Amsterdam, Amsterdam, 2000, 65–74. Bovine J, Bunting L, Collins JA, Negron KG. International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility care. Hum Report 2007;22:1506–1512. Boss HMW, Van Baleen F, Visor A. Social and cultural factors in infertility and childlessness. Patient Educ Counsel 2006;59:223–225. Denga DL. Childlessness and marital adjustment in Northern Nigeria. J Marr Family 1982;44:779–802. Deyer SJ, Abrahams N, Hoffman M, Van der Spuy ZM. ‘Men leave me as I cannot have children’: women’s experiences with involuntary childlessness. Hum Reprod 2002;17:1663–1668. Deyer SJ, Abrahams N, Mokoena NE, Van der Spuy ZM. ‘You are a man because you have children’: experience, reproductive health knowledge and treatment-seeking behaviour among men suffering from couple infertility in South Africa. Hum Reprod 2004;19:960– 967. Feldman-Savelsberger P. Is infertility an unrecognized public health and population problem, the view from the Cameroon Grassfields. In: Inhorn MC, Van Balen F (eds). Infertility Around the Globe, New Thinking on Childlessness, Gender and Reproductive Technologies. Berkeley, Los Angeles, London: UCLA-press, 2002, 215–232. Gerrits T. Infertility and matrilineality: the exceptional case of the Macua of Mozambique. In: Inhorn MC, Van Balen F (eds). Infertility Around the Globe, New Thinking on Childlessness, Gender and Reproductive Technologies. Berkeley, Los Angeles, London: UCLA-press, 2002, 233–246. Greil AL. Infertility and psychological distress: a critical review of the literature. Soc Science Med 45:1997, 1679– 1704. Handwerker L. The politics of making modern babies in China: reproductive technologies and the new eugenics. In: Inhorn MC, Van Balen F (eds). Infertility Around the Globe, New Thinking on Childlessness, Gender and Reproductive Technologies. Berkeley, Los Angeles, London: UCLA-press, 2002, 298– 314.

ICPD. ICPD Plan of Action. New York: UNICPD Secretariat, 1994. Inhorn MC. Quest for Conception, Gender, Infertility and Egyptian Medical Traditions. Philadelphia: University of Pennsylvania Press, 1994. Kagitcibasi C, Ataca B. Value of children and family change: a three-decade portrait from Turkey. Appl Psychol Int Rev 2005;54:317–337. Kielman K. Barren ground: contesting identities of infertile women in Pemba, Tanzania. In: Lock M, Kaufert PA (eds). Pragmatic Women and Body Politics. Cambridge: Cambridge University Press, 1998, 127 –163. Mariano E. Conceptions about woman’s childlessness and land’s infertility in a Rhonga community in the South of Mozambique. In: Van Balen F, Gerrits T, Inhorn M (eds). Social Science Research on Childlessness in a Global Perspective. University of Amsterdam, Amsterdam, 2000, 136– 139. Meyer B. Satan, slangen en geld. In: Driessens H, De Jonge H (eds). In de ban van de betekenis, proeven van symbolische antropologie. Nijmegen: Sun, 1994, 170–197. Mogobe K. Traditional therapies for infertility: implications for the brokerage role of the nurse in Botswana. In: Van Balen F, Gerrits T, Inhorn M (eds). Social Science Research on Childlessness in a Global Perspective. University of Amsterdam, Amsterdam, 2000, 111– 117. Mulgaonkar V. A research and an intervention programme on women’s reproductive health in slums of Mumbai. Sujeevan Trust. Mumbai: 2000. Nahar P. Childlessness in Bangladesh, Suffering and Resilience Among Rural and Urban Women. University of Amsterdam, Amsterdam, 2007. Okonofua FE. The case against new reproductive technologies in developing countries. Br J Obstet Gynaecol 1996;103:957– 962. Okonofua FE, Harrus D, Odebiyi A, Kane T, Snow RC. The social meaning of infertility in Southwest Nigeria. Health Transit Rev 1997;7:205–220. Pashigian MJ. Conceiving the happy family, infertility and marital politics in Northern Vietnam. In: Inhorn MC, Van Balen F (eds). Infertility Around the Globe, New Thinking on Childlessness, Gender and Reproductive Technologies. Berkeley, Los Angeles, London: UCLA-press, 2002, 134–151. Riessman CK. Positioning gender identity in narratives of infertility: South Indian women’s lives in context. In: Inhorn MC, Van Balen F (eds). Infertility Around the Globe, New Thinking on Childlessness, Gender and Reproductive Technologies. Berkeley, Los Angeles, London: UCLA-press, 2002, 152–170. Stanton AL, Tennen H, Affleck G, Mendola R. Cognitive appraisal and adjustment to infertility. Women Health 1991;17:1–15. Sundby J. Infertility in the Gambia: traditional and modern health care. Patient Educ Counsel 1997;31:29–37. Van Balen F. De betekenis van kinderen en de ervaring van kinderloosheid. In: Kuin Y (ed.). Levenservaringen en zinvragen Ambo: Baarn, 1995, 35–53. Van Balen F, Gerrits T. Quality of infertility care in poor-resource areas and the introduction of new reproductive technologies. Hum Reprod 2001;16: 215–219. Van Balen F, Inhorn MC. Interpreting infertility a view from the social sciences. In: Inhorn MC, Van Balen F Infertility Around the Globe, New Thinking on Childlessness, Gender and Reproductive Technologies. Berkeley, Los Angeles, London: UCLA-press, 2002, 3– 32. Van Balen F, Trimbos-Kemper TCM. Long-term infertile couples, a study of their well-being. J Psychosom Obstet Gynaecol 1993;14:s53– s60. Van Rooij FB, Van Balen F, Hermanns JMA. A review of Islamic Middle Eastern migrants: traditional and religious cultural beliefs about procreation in the context of infertility treatment. J Reprod Infant Psychol 2004;22:321–331.

doi:10.1093/humrep/den148

Human Reproduction 2008

Infertility-related reproductive health knowledge and help-seeking behaviour in African countries S.J. Dyer1 Reproductive Medicine Unit, Department of Obstetrics and Gynaecology, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, Observatory 7925, South Africa 1

Correspondence address. E-mail: silke.dyer@uct.ac.za

Data from African countries indicate that men and women attribute infertility to traditional beliefs about health and disease as well as to biomedical causes, although appropriate knowledge of the latter is frequently lacking. Infertility is a dreaded condition and as a result help-seeking is often intense and persistent. Most of the help-seeking is undertaken by women and both traditional and modern biomedical health services are accessed. There are, however, many barriers to effective and affordable biomedical infertility care, many of which are related to poor resources and lack of infrastructure, and as a result the need for infertility treatment is often unmet. Advances in the quality of care require greater commitment to the problem of infertility in African countries, the provision of health education as an integral part of infertility management, the integration of infertility services into reproductive health care programmes and defining the role of assisted reproductive technologies in low resource settings. At the same time the importance of traditional health services in infertility management should be recognized. Keywords: infertility; knowledge; health-seeking behaviour; traditional health care; Africa

Introduction Infertility has a major impact on the reproductive health of men and women living in Africa. This impact is generated through high prevalence rates, the associated burden of physical disease comprising in particular genital tract infections secondary to sexually-transmitted diseases (STDs) and pregnancy-related sepsis, and negative psychosocial consequences which are common and often severe (Cates et al., 1985; Bergstrom, 1992; Sonko, 1994; Larsen, 2000). Moreover, most couples experience their infertility in a context where access to effective and affordable infertility management is lacking due to an overall lack of resources and competing health needs. This raises the question how in the relative absence of appropriate interventions people construct and explain their inability to conceive and which avenues they pursue in order to try and overcome their childlessness. The answers to this question contribute to our understanding of the reality of infertility in African countries, provide insight into the need for infertility care and offer relevant information for the planning of future reproductive health services. This manuscript summarizes the available evidence on infertility-related reproductive health knowledge and helpseeking behaviour derived from studies conducted in African countries. Data relating to the prevalence and causes of infertility in Africa are presented as contextual information. Relevant peer-reviewed English-language publications were identified

through a MEDLINE search using the key words ‘infertility’, ‘knowledge’, ‘reproductive health’, ‘health-seeking behaviour’ and ‘Africa’. The bibliographies of identified publications were further searched for references. The body of data finally included in this manuscript had to be restricted, however, to accommodate the scope of this review.

Prevalence and causes of infertility In Africa, large-scale epidemiological studies designed to assess the prevalence of infertility according to the medical definition of non-conception after one year of unprotected intercourse are lacking. In the absence of this information prevalence rates have been estimated from national demographic surveys and world fertility surveys which utilize childlessness after a given period of marriage or a previous delivery as markers of infertility. According to these data the prevalence of primary infertility is low, while secondary infertility affects 14– 16% of women age 20– 44 years with higher rates recorded in various subgroups (WHO, 1991; Larsen, 2000; Boivin et al., 2007). The leading cause of infertility is tubal disease, which has been documented in 23– 85% of infertile couples, while male factor infertility has a reported prevalence of 9 – 45%. These wide ranges are at least in part attributable to differences in research methods and in the diagnostic process applied.

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Ovulatory disorders have been diagnosed in 18 – 29% of cases, whereas other causes of infertility are inconsistently documented (Cates et al., 1985; Wiswedel and Allen, 1989; Fiander, 1990; Chigumadzi et al., 1998; Ikechebelu et al., 2003; Larsen et al., 2005). Tubal factor infertility and, to a lesser degree, male factor infertility are closely linked to the high prevalence of STDs as well as to pregnancy-related infections, which in turn are influenced by multiple factors such as poor general health status, inadequate health care facilities, poverty, sexual behaviour and cultural traditions (Sciarra, 1997; Bambra, 1999). Traditional and biomedical health models Men and women suffering from infertility seek to explain their inability to conceive. In Africa, these explanations are commonly influenced by both traditional and Western biomedical concepts of health and disease. According to anthropological studies, traditional causes can furthermore be broadly divided into personalistic (human) or mystic causes and naturalistic causes (Janzen, 1981; Gerrits, 1997). Personalistic causes are commonly attributed to inter-personal conflicts which, through the involvement of witchcraft or spiritual forces, can generate disease. Naturalistic causes of disease include a wide range of events not attributed to witchcraft, and these may be interlinked with biomedical concepts of disease causation. It must be emphasized that from the patient’s perspective there is frequently no strict divide between traditional and biomedical explanations for infertility; rather, the two concepts tend to exist in parallel with mutual influence on each other. Moreover it should be noted that some medical anthropologists have viewed the divide between ‘modern’ and ‘traditional’ health care as simplistic as it does not pay tribute to the complex relationship between biomedical concepts of disease and African systems of health and healing (Comaroff, 1981; Janzen and Prins, 1981). Infertility-related reproductive health knowledge Several studies have described the explanations that women, and to a lesser degree men, forward as possible causes of infertility in rich detail. A study conducted among the Macua tribe, a matrilineal ethnic group in Mozambique, documented that women attributed their childlessness to both traditional and biomedical explanations, with the former being mentioned more frequently (Gerrits, 1997). Traditional causes included spirits (which possessed and had sexual contact with the human body) as well as witchcraft. Some of the cultural traditions appeared to make women vulnerable to witchcraft. The initiation rites conducted after menarche involve the burial of pubic hair, and if this was tampered with by a witch, it was believed that infertility may result. Similarly, the purposeful incorrect burial of the umbilical cord by a birth assistant after delivery was believed to cause sterility in the parturient. A commonly found naturalistic explanation was the concept that male blood could be ‘too hot’ or ‘poisonous’ causing dyspareunia and dysmenorhoea as well as infertility in their partner. Explanations influenced by biomedical 30

concepts included sperm problems, retroversion of the uterus, infections of the ovary and ‘norro’, the local term for gonorrhoea (Gerrits, 1997). An ethnographic study conducted among the Sara (a conflation of several minor ethnic groups living in the Chad) reported that women were believed to be born with an unknown number of children located within their bodies, except for a few women who were born infertile (without children inside them) and who could not be cured (Leonard, 2002). More commonly, however, infertility was explained by blood incompatibility between husband and wife, the remedy for which was changing partners. Other believed threats to female fertility included, among others, curses, multiple sexual partners, use of modern contraception, induced abortions, worm infestation, vaginal discharge and STDs. Men were considered fertile unless impotent (Leonard, 2002). An anthropological study conducted among the Yoruba, a large ethnic group in Nigeria, documented similar findings (Koster-Oyekan, 1999). According to results, the Yoruba also believed that women were born with a certain number of children within them, and that male factor infertility was restricted to impotence. Infertility was attributed to evil spirits, angered ancestors and spells. Naturalistic and biomedical causes included sexual promiscuity, gonorrhoea (which was believed to heat the womb and damage sperm), modern contraception and induced abortions. Moreover, all women were believed to have a uterine fibroid which was considered necessary for conception but which also could cause infertility in some instances. Less frequently encountered was the concept that a worm lived in the womb of every woman which despite sharp teeth was usually harmless, but at times could turn evil and prevent conception or cause a miscarriage (Koster-Oyekan, 1999). Results from qualitative studies conducted in other regions document similar as well as additional findings indicating that witchcraft, failure to adhere to cultural taboos, God’s will, partner incompatibility, weak sperm, male impotence, abortion, promiscuity and contraception are among the central causes believed to cause infertility (FeldmanSavelsberg, 1994; Sundby, 1997; Koster-Oyekan, 1999). Quantitative data on this topic are largely lacking with the exception of a study from rural Ghana involving over 2000 men and women (Geelhoed et al., 2002). In this study, approximately half of the informants had no knowledge of any possible causes of infertility, and the remainder had incomplete knowledge. The commonest explanation forwarded by men was sperm abnormalities (13.3%), while induced abortion was quoted most frequently by women (32.2%). Less than 2% of participants referred to STDs as a cause of infertility. The above studies have evaluated reproductive health knowledge of people living predominantly in rural regions. Further insight can be gained from research conducted in urban settings in South Africa, an environment which arguably has greater exposure to Western culture when compared with many other African regions. Qualitative data collected in this setting demonstrated that infertile men and women who accessed a specialist infertility clinic within the public health sector had limited knowledge of the basic biological principles

Knowledge on infertility in African countries

of reproduction and of the causes of infertility (Dyer et al., 2002b, 2004). Although biomedical causes were frequently mentioned (especially ‘blocked tubes’, weak sperm and menstrual abnormalities), individual constructs of these mechanisms often differed considerably from the actual biomedical principles. In addition, a wide range of other factors were considered to cause infertility including religious causes, life style-related factors, a ‘dirty’ womb, as well as coincidental medical conditions. Some informants mentioned traditional beliefs in conjunction with other causes. In contrast to studies from other African regions, both men and women had a high degree of awareness of male factor infertility (Dyer et al., 2002b, 2004). Collectively, these studies demonstrate that most African societies have a multifaceted construct of infertility, which involves biomedical concepts as well as spiritual and cultural dimensions. Any comparison between these studies conducted in different regions is inherently difficult. With this in mind the cautious observation may, however, be made that urbanization is not necessarily associated with adequate reproductive health knowledge, although there appears to be a shift from traditional to biomedical explanations of infertility and an overall increase in awareness of male infertility. Help-seeking behaviour Infertility-related help-seeking behaviour is influenced by the perceived causes and the social consequences of involuntary childlessness. In Africa the latter are both common and severe. They include, among others, marital disharmony, neglect, abuse, stigmatization, loss of social security and social isolation (Sonko, 1994; Gerrits, 1997; Sundby, 1997; Dyer et al., 2002a; Hollos, 2003). Driven by the hope and need to conceive, the search for treatment is frequently persistent and intense (Koster-Oyekan, 1999; van Balen and Gerrits, 2001). Most of this search is undertaken by women who are usually blamed for non-conception and who carry the main burden of the social consequences of childlessness (Mbizvo et al., 1984; Inhorn and Buss, 1993; Sundby, 1997). Moreover, failure to seek help may result in accusations of selfishness (for not wanting to contribute to the patrilineage) and irresponsible behaviour (Richards, 2002). The role of men in the health-seeking process is less well described. Existing information would suggest that men are, at best, peripherally involved although the data are conflicting (Inhorn and Buss, 1994; Gerrits, 1997; Sundby et al., 1998; Dyer et al., 2004). Further research on male participation in infertility management is required. Available evidence on infertility-related health-seeking behaviour in African countries indicates that women (and at times men) access both traditional and modern health services, and in both health sectors infertility is a leading cause for consultation (Inhorn and Buss, 1994; Shai-Mahoko, 1996; Gerrits, 1997; Sundby, 1997; Koster-Oyekan, 1999; Leonard, 2002; Richards, 2002; Stekelenburg et al., 2005). Different service providers may be accessed consecutively or concomitantly. Although such health-seeking behaviour may appear haphazard, it often follows a rational strategy based on the presumed

cause of non-conception and modified by the accessibility of health systems (in terms of cost and distance to travel) and by the reputation of individual health care providers (Gerrits, 1997; Leonard, 2002; Stekelenburg et al., 2005). Traditional health care According to an anthropological study in Nigeria, infertility may be managed by a number of different traditional healers including local reproductive health specialists, herbalists and spiritual healers (Koster-Oyekan, 1999). Treatment involves sacrifices offered to deities or ancestors, various ceremonies to lift evil curses as well as powders and medicinal soaps to treat different causes of non-conception. Linked to these interventions are preventative strategies which include charms, herbs and the adherence to cultural taboos. A further preventative strategy is the avoidance of contraceptives and vaginal speculum examination as these are believed to be possible causes of infertility (Koster-Oyekan, 1999). In southern Chad, infertility-related health-seeking behaviour is referred to as ‘looking for children’ and ‘doing research’ (Leonard, 2002). At the outset of this ‘research’ the cause of infertility has to be identified—often from a multitude of possibilities. Infertility secondary to social discord is managed through the traditional health system. Interventions involve reconciliation ceremonies, food offerings and ritual cleansing. In contrast, help is sought from the biomedical sector for most of the somatically expressed causes of infertility (such as infections, worm infestation and a ‘dirty’ womb). Marabouts, who are healers connected with the Muslim faith, play an important role in providing infertility-related health care in the Gambia (Sundby, 1997). Interventions are usually based on medicinal drinks and amulets containing writings from the Koran. Other aspects of traditional health care involve spiritual healers, herbalists, fortune tellers and visits to sacred places. Several other studies describe the important role that herbs, medicinal drinks, amulets, cleansing rituals, spiritual and religious healers play in the management of infertility in Africa (Ebomoyi and Adetoro, 1990; Gerrits, 1997; Seybold, 2002). Collectively, these studies indicate that, although traditional health systems may differ in their individual context and in the beliefs upon which they are built, their overall role and structure is remarkably similar throughout the continent (Sundby, 1997). Biomedical health care Infertility also places considerable demands on the often sparse resources of the biomedical health sector. According to studies from several countries the inability to conceive is either the leading cause or a very common reason for gynaecological consultations (Bergstrom, 1992; Okonofua, 1996). In some instances this high demand may be created by unrealistic fertility expectations which lead women to seek help after not falling pregnant within three or four months of attempting conception (Barden-O’Fallon, 2005). On the other hand, the observed demand for infertility treatment may only represent the tip of an iceberg as studies have indicated that less than half of infertile participants accessed modern health care 31

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(Gerrits, 1997; Sundby, 1997). Recognized barriers to modern infertility services include lack of appropriate resources, lack of access because of financial or geographical reasons, services which are not patient friendly, interventions which are without benefit, unwillingness of the male partner to be investigated and lack of trust or dissatisfaction with biomedical care (Inhorn and Buss, 1994; Gerrits, 1997; Sundby et al., 1998; van Zandvoort et al., 2001; Leonard, 2002). Indeed, it has been suggested that the many shortcomings of biomedical facilities in African countries sustain the persistence of traditional beliefs and health care since the success of biomedical infertility interventions is often no higher than that of alternative treatment strategies (Gerrits, 1997; Leonard, 2002). Given these limitations, many authors have highlighted the importance of preventative health strategies (Sundby et al., 1998; Geelhoed et al., 2002; Okonofua, 2003). These undoubtedly play an important role. They do, however, not help those suffering from infertility in Africa today (van Balen and Gerrits, 2001). Moreover, lessons learned from the HIV/ AIDS epidemic have highlighted the many difficulties in effecting changes in reproductive behaviour. A review on infertility-related help-seeking behaviour would not be complete without addressing the role of assisted reproductive techniques (ART). While a detailed discussion of this debate is beyond the scope of this manuscript, a few brief observations remain pertinent. In principle, the demand for ART in Africa is significant if we consider the high prevalence of infertility, the nature of the underlying pathology (which limits the success of other treatment options) and the associated human suffering (Inhorn, 2003). At the same time the barriers to ART are considerable. They include, among others, cost of treatment (against a backdrop of poor resources and competing health needs), geographical barriers (as ART can at best be offered in a few urban centres), lack of an overall infrastructure for ART (i.e. lack of staff and technical expertise, shortages in supplies and electricity), as well as physical risks (ectopic pregnancies, multiple pregnancies, ovarian hyperstimulation syndrome) which may threaten women’s lives and take up additional resources (Okonofua, 1996; Inhorn, 2003). In addition, the concern exists that cultural factors may limit the uptake of ART in African countries. Specifically, barriers may exist between physicians, who were trained in Western medicine, and their patients, who uphold traditional belief systems and who may be unfamiliar with ‘modern’ technology and medicine (Qiu, 1993). To date there are limited data to support or refute this concern. In the meantime ART has spread to many African countries, predominantly via private clinics offering high-cost treatment to a small group of people who can afford this technology (Inhorn, 2003). It would, however, appear that unless cultural factors are underpinned by religious doctrine which may prohibit or limit access to ART, cultural differences do not prevent men and women from utilizing this treatment if it is available and affordable. This observation is in keeping with the studies outlined above, which have documented that infertile couples seek help from both the traditional and biomedical health sector in a rather pragmatic way. At the same time lack of health education and knowledge may represent a relevant treatment 32

barrier as it may limit patients’ ability to access available interventions and comply with treatment. Other help-seeking strategies Apart from seeking help from traditional and modern health care providers, men and women may employ strategies, which are not related to the health sector. These include feigning pregnancies and miscarriages to avoid the worst of the stigma, claiming pregnancies with other women and polygamy (Gerrits, 1997; Sundby, 1997; Hollos, 2003). In countries with a high prevalence of HIV infection and other STDs, the latter is not without considerable risk. Another strategy is adoption and fostering, often involving children from relatives (Sonko, 1994). While this approach addresses some of the negative consequences of infertility, it often does not remove the stigma and may therefore not be a solution. Moreover, studies from Nigeria and Mozambique have documented women’s concern that foster children were unreliable in supporting family interests and providing old age support (Sundby, 1997; Koster-Oyekan, 1999; Hollos, 2003). Conclusions In African countries men and women have multifaceted constructs of infertility and its’ underlying causes. These constructs frequently comprise both traditional and biomedical elements. Lay concepts of the latter may, however, differ considerably from the actual biological model. Infertility-related help-seeking behaviour in turn is often associated with a plethora of options (Sundby, 1997). Most of the help-seeking is undertaken by women, who carry the main burden of infertility, and who often demonstrate great persistence in trying to overcome their childlessness. This persistence together with the high prevalence rates of infertility results in considerable demands being made on both the traditional and modern health sector. These findings are relevant to the delivery of infertility care. In the first instance they demonstrate that health education, based on an understanding of how men and women experience and explain their infertility, must form an integral part of infertility management in the interest of both the individual patient and the advancement of reproductive health in the community. At the same time, infertility services should be sensitive to the role of traditional health care. Greater collaboration between the two health care systems is generally considered desirable as this may increase referral of infertile couples to the biomedical sector, while the spiritual and cultural health needs can be addressed through traditional healers (Sundby, 1997). At the level of sexual and reproductive health care planning, the enormous need for infertility care must be recognized. Available evidence indicates that infertility consumes existing health resources to a considerable extent, albeit often in an ineffective way. This implies that withholding of appropriate infertility care does not necessarily protect scarce resources. The way forward needs to be based on a greater recognition of the problem of infertility in African countries and the largely unmet need for interventions. Key factors in advancing quality of care include health education as part of infertility management, the integration of infertility into existing sexual

Knowledge on infertility in African countries

and reproductive health care programmes and defining the role of ART in low resource settings. In addition, efforts should be directed at reducing the stigma of infertility in African countries as this may lessen the demand for treatment while increasing acceptability of other options such as acceptance of childlessness or adoption.

References Bambra CS. Current status of reproductive behaviour in Africa. Hum Reprod Update 1999;5:1–20. Barden-O’Fallon J. Unmet fertility expectations and the perception of fertility problems in a Malawian village. Afr J Reprod Health 2005;9:14–25. Bergstrom S. Reproductive failure as a health priority in the Third World: a review. East Afr Med J 1992;69:174–180. Boivin J, Bunting L, Collins JA, Nygren K. International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility medical care. Hum Reprod 2007;22:1506–1512. Cates W, Farley TM, Rowe PJ. Worldwide patterns of infertility: is Africa different? Lancet 1985;2:596– 598. Chigumadzi PT, Moodley J, Bagratee J. Infertility profile at King Edward VIII Hospital, Durban, South Africa. Trop Doct 1998;28:168– 172. Comaroff J. Healing and cultural transformation: the Tswana of southern Africa. Soc Sci Med 1981;15:367–378. Dyer SJ, Abrahams N, Hoffman M, van der Spuy ZM. ‘Men leave me as I cannot have children’: women’s experiences with involuntary childlessness. Hum Reprod 2002a;17:1663–1668. Dyer SJ, Abrahams N, Hoffman M, van der Spuy ZM. Infertility in South Africa: women’s reproductive health knowledge and treatment-seeking behaviour for involuntary childlessness. Hum Reprod 2002b;17:1657– 1662. Dyer SJ, Abrahams N, Mokoena NE, van der Spuy ZM. ‘You are a man because you have children’: experiences, reproductive health knowledge and treatment-seeking behaviour among men suffering from couple infertility in South Africa. Hum Reprod 2004;19:960– 967. Ebomoyi E, Adetoro OO. Socio-biological factors influencing infertility in a rural Nigerian community. Int J Gynaecol Obstet 1990;33:41 –47. Feldman-Savelsberg P. Plundered kitchens and empty wombs: fear of infertility in the Cameroonian grassfields. Soc Sci Med 1994;39:463–474. Fiander A. Causes of infertility among 1000 patients in Ghana. Trop Doct 1990;20:137–138. Geelhoed DW, Nayembil D, Asare K, Schagen van Leeuwen JH, van Roosmalen J. Infertility in rural Ghana. Int J Gynaecol Obstet 2002;79:137–142. Gerrits T. Social and cultural aspects of infertility in Mozambique. Patient Educ Couns 1997;31:39– 48. Hollos M. Profiles of infertility in southern Nigeria: women’s voices from Amakiri. Afr J Reprod Health 2003;7:46–56. Ikechebelu JI, Adinma JI, Orie EF, Ikegwuonu SO. High prevalence of male infertility in southeastern Nigeria. J Obstet Gynaecol 2003;23:657–659. Inhorn MC. Global infertility and the globalization of new reproductive technologies: illustrations from Egypt. Soc Sci Med 2003;56:1837– 1851.

Inhorn MC, Buss KA. Infertility, infection, and iatrogenesis in Egypt: the anthropological epidemiology of blocked tubes. Med Anthropol 1993;15:217– 244. Inhorn MC, Buss KA. Ethnography, epidemiology and infertility in Egypt. Soc Sci Med 1994;39:671– 686. Janzen JM. The need for a taxonomy of health in the study of African therapeutics. Soc Sci Med 1981;15:185–194. Janzen JM, Prins G. Causality and classification in African medicine and health. I. Introduction. Soc Sci Med 1981;15:169–171. Koster-Oyekan W. Infertility among Yoruba women: Perceptions on causes, treatments and consequences. Afr J Reprod Health 1999;3:13 –16. Larsen U. Primary and secondary infertility in sub-Saharan Africa. Int J Epidemiol 2000;29:285–291. Larsen U, Masenga G, Mlay J. Infertility in northern Tanzania. Int J Gynaecol Obstet 2005;90:80–81. Leonard L. ‘Looking for children’: the search for fertility among the Sara of southern Chad. Med Anthropol 2002;21:79 –112. Mbizvo MT, Chimbira TH, Mkwananzi JB. Aetiological factors of male infertility in Zimbabwe. Cent Afr J Med 1984;30:233–238. Okonofua FE. The case against new reproductive technologies in developing countries. Br J Obstet Gynaecol 1996;103:957–962. Okonofua F. New Reproductive technologies and infertility treatment in Africa. Afr J Reprod Health 2003;7:7– 11. Qiu RZ. What has bioethics to offer the developing countries. Bioethics 1993;7:108–125. Richards SC. ‘Spoiling the womb’: definitions, aetiologies and responses to infertility in North West Province, Cameroon. Afr J Reprod Health 2002;6:84 –94. Sciarra JJ. Sexually transmitted diseases: global importance. Int J Gynaecol Obstet 1997;58:107– 119. Seybold D. Choosing therapies: a Senegalese woman’s experience with infertility. Health Care Women Int 2002;23:540–549. Shai-Mahoko SN. Indigenous healers in the North West Province: a survey of their clinical activities in health care in the rural areas. Curationis 1996;19:31–34. Stekelenburg J, Jager BE, Kolk PR, Westen EH, van der KA, Wolffers IN. Health care seeking behaviour and utilisation of traditional healers in Kalabo, Zambia. Health Policy 2005;71:67–81. Sundby J. Infertility in the Gambia: traditional and modern health care. Patient Educ Couns 1997;31:29 –37. Sundby J, Mboge R, Sonko S. Infertility in the Gambia: frequency and health care seeking. Soc Sci Med 1998;46:891–899. Sonko S. Fertility and culture in sub-Saharan Africa: a review. Int Soc Sci J 1994;46:397– 411. Van Balen F, Gerrits T. Quality of infertility care in poor-resource areas and the introduction of new reproductive technologies. Hum Reprod 2001;16: 215– 219. Van Zandvoort H, de Koning K, Gerrits T. Viewpoint: medical infertility care in low income countries: the case for concern in policy and practice. Trop Med Int Health 2001;6:563– 569. Wiswedel K, Allen DA. Infertility factors at the Groote Schuur Hospital Fertility Clinic. S Afr Med J 1989;76:65 –66. World Health Organization. Infertility: a tabulation of available data on prevalence of primary and secondary infertility. WHO/MCH/91.9, Geneva, 1991.

doi:10.1093/humrep/den143

Human Reproduction 2008

Medical and socio-cultural aspects of infertility in the Middle East G.I. Serour1,2,3 1 International Islamic Center for Population Studies and Research, Al-Azhar University, 40 Talaat Harb Street, City Center, Cairo, Egypt; 2Egyptian IVF Center, Maadi, Egypt 3

Correspondence address: E-mail: giserour@thewayout.net

The Middle East (ME), an area rich in history and tradition with >300 million population, includes 18 heterogeneous countries concerning resources, income per capita, available healthcare services, population density, growth rate, birth rate, total fertility rate and life expectancy. There is a high prevalence of infertility in the ME because of post-partum infection, unsafe abortion, iatrogenic tubal and pelvic infertility, tuberculosis, schistosomiasis and high incidence of male factor infertility. It is argued that in the ME, the solution to the problem of infertility is its prevention, and population control should take precedence over infertility treatment. However, for a successful family planning program and adoption of small family norms, couples should be reassured that they will be helped to achieve pregnancy should they decide so. Prevention and treatment of infertility are of particular significance in ME because a woman social status, her dignity and self-esteem are closely related to her ability to have children. Also there is gender suffering of infertility in the ME. One of the stumbling blocks to acceptance of assisted reproductive technology (ART) as a line of treatment of infertility was the unacceptability to the main religious groups of the involvement of a third party in the act of procreation. Practices of ART in the ME have many common features and little differences. A mechanism had to be found to provide low-cost ART to the needy. Keywords: infertility; ART; Middle East; socio-cultural; medical

The â&#x20AC;&#x2DC;Middle Eastâ&#x20AC;&#x2122; definition used by the current international tax calculations and airfare determination as established by the International Air Transport Association (IATA) included as constituents of the Middle East (ME), Bahrain, Egypt, Iran, Iraq, Israel, Jordan, Kuwait, Lebanon, Pakistan, Palestinian territories, Oman, Qatar, Saudi Arabia, Somalia, Sudan, Syria, United Arab Emirates and Yemen. The ME, an area rich in history and tradition, is also a land of contemporary economic and political struggle with .300 million population. It comprises a heterogeneous group of countries concerning resources, income per capita, available state supported healthcare services, population density, growth rate, birth rate, total fertility rate and life expectancy. In the ME, the paradox is that although demographics in many countries in the region point to a struggle to control population growth, one of the highest fertility rates in the world are found in the ME countries where total fertility rate varies between 2 and 6.8 with most of countries above 3 (Population Reference Bureau, 2007) (Table I). It is often argued that in the ME with many low income and middle income countries (Table I), the solution to the problem of infertility in these countries is in the prevention of 34

post-partum infection, unsafe abortion, iatrogenic infertility, tuberculosis, schistosomiasis and ST1s which are preventable causes of infertility in the ME (Serour and Hefnawi, 1982). In low-income countries where health service resources are limited and basic health needs are unmet, if health resources are used to provide expensive advanced technology for the treatment of infertility, the opportunity is lost for using these resources to deal with other serious health problems affecting mortality and morbidity of a large sector of the population of the country. However, the physical and psychological burden the infertile couple go through and the financial cost couples are willing to pay, if they can afford it, attest to the high ranking of infertility as a perceived burden of disease, which should be alleviated by all means including assisted reproductive technology (ART) (Fathalla, 2002). Furthermore, for a successful family planning program and adoption of small family norms, the issue of involuntary infertility becomes more pressing. Couples who are urged to postpone, delay or widely space pregnancies should be reassured that they will be helped to achieve pregnancy should they decide so (Serour et al., 1991a; Serour and Omran, 1992; Fathalla, 2002).

Medical and socio-cultural aspects of infertility in the ME

Table I. ME countries: some demographic patterns.

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

Country

Population mid-2007 (Millions)

Birth per 1000 population

Rate pf natural increase (%)

Total fertility Rate

GNI PPP per capita US$ 2006

Bahrain Egypt Iran Iraq Israel Jordan Kuwait Lebanon Pakistan Palestine Qatar Oman Saudi Arabia Somalia Sudan Syria UAE Yemen

0.8 73.4 71.2 29 7.3 5.7 2.8 3.9 169.3 4 0.9 2.7 27.6 9.1 39.6 19.9 4.4 22.4

21 27 18 36 21 28 21 19 31 33 17 25 30 46 33 28 17 40

1.8 2.1 1.2 2.5 1.5 2.4 1.9 1.5 2.3 2.9 1.5 2.2 2.7 2.9 2.2 2.5 1.5 3.2

2.6 3.1 2 4.9 2.8 3.5 2.6 2.3 4.1 4.6 2.8 3.4 4.1 6.8 4.5 3.5 2.7 6.2

18.770 4.680 8.480 — 25.470 6.200 29.200 5.460 2.500 — — 14.570 16.620 —2.160 3.920 23.990 920

Source: Population Reference Bureau (2007).

ART, a necessary line of treatment for many cases of male and female infertility, was long debated in the ME whether should it be included in the armamentaria of infertility treatment or not. The use of ART to manage infertility is a contested issue in the context of the cause of the problem, the attitude to over-population and availability of scarce health resources. The challenge tasks will be to simplify ART in such a way that it becomes affordable in low and middle income countries in the ME. Simplifying should reduce the cost but not the quality, and special attention should be given to eliminating complications such as ovarian hyperstimulation syndrome and multiple pregnancy. Both complications are unacceptable in these countries (Ombelet and Campo, 2007).

Medical issues in infertility in ME The terms infertility, sterility, subfertility, childlessness and infecundity are often used loosely and differ substantially between demographic and medical usage. In demographic terminology, primary infertility is defined as the inability to bear any children either due to the inability to conceive or due to the inability to carry a pregnancy to a live birth after several years of exposure to the risk of pregnancy. In medical terminology, however, infertility is defined as the inability to conceive. Inability to conceive within 2 years of exposure to pregnancy is the epidemiological definition recommended by the World Health Organization (World Health Orgainzation, 1975, 2001). Clinical studies often use a 1 year period of exposure. It is estimated that worldwide between 70 and 80 million couples suffer from infertility, most of these are residents of developing countries including the ME (Fathalla, 1922; Boivin et al., 2007). Only a limited number of papers reported on the prevalence of subfertility and infertility in developing countries including the ME. The prevalence of infertility differs tremendously between regions and between countries. The figures are as low as 9% in some African countries as

Gambia (Sundby et al., 1998) or as high as 35% in Nigeria (Ebomoyi and Adetoro, 1990; Okonofua, 1996). The reported international prevalence of infertility ranges from 4% to 14% with a consensus estimate of 10% of married and cohabiting couples (Greenhall and Vessey, 1990; Thonneau and Spira, 1990; World Health Organization, 1991; Sciarra, 1994; Lunenfeld and Van Steirteghem, 2004; Larsen, 2005). In the ME, prevalence of infertility is expected to vary between 10% and 15% of married couples because of high prevalence of post-partum infection, post-abortive infection, iatrogenic infertility, schistosomiasis and tuberculosis (Serour and Hefnawi, 1982; Serour et al., 1991a, 1997). It should be noted that a prevalence calculation is subject of correct diagnostic process and registration modalities (Ombelet and Campo, 2007), both of which are very seldom present in many countries in the ME. Bilateral tubal occlusion is the most common underlying cause (World Health Organization, 1987; Nachtigall, 2006). Tubal and pelvic infertility is the leading cause of female infertility in many countries of ME. Several factors are responsible for the high prevalence of tubal and pelvic factors. There is a high prevalence of postpartum infection as more than 70 of all births in many countries in ME are attended by traditional birth attendants, and strict aseptic techniques are often not observed. High prevalence of unsafe abortion, iatrogenic tubal and pelvic infertility, tuberculosis and schistosomiasis are all contributing factors (Serour et al., 1991a, 1997; Serour and Hefnawi, 1982). Infertility and ART ART is one line of treatment of tubal infertility and sometimes it is the only appropriate mode of treatment as in severe tubal damage, failure of conventional endoscopic surgery, severe male factor infertility and multifactorial infertility. Several studies in the ME had shown high prevalence of male factor infertility where ART is the most effective line of treatment particularly in severe cases of oligoasthenospermia (Mansour, 35

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2004; Inhorn, 2006; Mansour and Abou Setta, 2006; Sills et al., 2007). Ethical issues in provision of ART The ethical principle of justice implies that all people should have equitable access to healthcare services. However, because of the rapidly increasing cost of medical technology and advanced healthcare services in different fields of medicine, the question of resource allocation becomes a pressing and sometimes a decisive one (Serour, 2002). If the country has adequate resources and can provide basic health services as well as advanced healthcare services, as in some ME countries, there is no problem. However, in other countries in ME where resources are limited and basic health services are lacking, implementation of advanced healthcare services as ART, though it could benefit a certain sector of the population, could be unjust, because it deprives a major sector of the population of basic health services. In this context, there is a collision between the principles of justice and equity (Serour, 1997). Legislations and guidelines of ART Statutes or law regulate the practices of ART in some countries in the ME as Israel and Saudi Arabia. In other countries, ART is regulated by guidelines as in Egypt. However, in some countries neither legislations nor guidelines exist to regulate various ART practices (Jones and Cohen, 2007). The social structure required to be accepted in ART programs varies in different countries in the ME. In Israel, marriage or stable relationship is required to be accepted for ART treatment. This permitted single women and lesbian couples access to ART treatment. In Iran and Lebanon, ART is permitted mostly for married couples. However, it is also permitted in some forms of temporary arrangements to provide oocyte donation, embryo donation or surrogacy. In most countries of the ME, a valid marriage contract is required before enrollment of the couple on ART programs. Violation of the marriage contract by death of one of the couple or divorce would prevent the use of gametes or embryos available in the ART center (Serour and Dickens, 2001; Serour, 2006). Insurance coverage Cost was an important factor which hindered early establishment of ART centers in many countries in the ME, as some of these countries have limited health resources. In the 80s, the establishment of an ART centre with accepted international standards would cost about US$ 400 000– 500 000 (Dandekar and Quigley, 1984). Today because of inflation and the rapid advancement in the technology of ART including new practices as preimplantation genetic diagnosis (PGD), cryopreservation and LASER applications in ART centers, the cost of establishment of ART center had increased by 3 or 4 folds. This relatively high cost limited the installment of such centers in governmental institutions in many countries in the ME till today. Most of the centers, in the majority of the countries in the area, are in the private sector. In low-income countries in the ME, many needy infertile patients cannot 36

have access to ART in private centers as the cost of an IVF cycle is prohibitively expensive compared with the average income of many couples. The direct patient’s cost per in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycle in the ME varies between US$ 0 and 4059 with an average of US$ 2500 (Serour et al., 1991a; Sills et al., 2007; Shahin, 2007). Two studies in Egypt showed that 90% of patients felt the price was too high, 15 –40% of patients could not afford to have the procedure and 40% only could afford to have a repeat cycle (Serour et al., 1991b; Shahin, 2007). However, the cost of ART is totally or partially covered by the State in few countries. In Israel, there is a complete coverage of cost of ART for a number of cycles and in some other countries the cost is partially covered by the state (Jones et al., 2007; Sills et al., 2007). In Egypt, there are two large centers: one at Al Azhar University Hospital and the other at El Galaa Maternity Hospital Ministry of Health where the service is provided at a subsidized cost. Government’ subsidies of ART treatment in some of the ME countries show that because of importance and meaning of infertility treatment in the ME, national health policy has tended to favor public support of costly IVF programs (Birenbaum-Carmeli, 2004) even in some low-income countries as Egypt. A recent study from nine countries in ME had shown that the provision of such advanced technology is associated with minimal delay often ,8 weeks (a range 0.3 – 3.5 months) from initial presentation to ART program (Sills et al., 2007).

Patient’s profile undergoing ART Most couples undergoing ART in most ME countries are married couples with a stable marital relationship. In Israel, single women and lesbians have access to ART programs as well. Women’s age group ,29 years old and 30 –34 years old constitute the largest age groups undergoing ART with a combined total of 59– 64% of cycles (Mansour and Abou Setta, 2006; Sills et al., 2007). There is also a trend for IVF/ ICSI in older women with 25% in the age group of 35– 39 years. Women aged 40 and more represent 8.7– 10.4% of all cycles performed (Mansour and Abou Setta, 2006; Sills et al., 2007). Most ART centers in the region do not have a policy of long-term follow-up of ART patients or the children born as a result of ART. However, few centers in some countries have implemented long-term follow-up policy of children born after ART and reported on the incidence of chromosomal aberrations and/or malformation in ART babies. Although all programs offered prenatal referrals outside their clinic by the end of the first trimester, 61.5% providers were involved in obstetrical care for their pregnant ART patients by attending them at delivery (Sills et al., 2007). This is in contrast to the practice in Europe and North America where the doctors performing ART are very rarely involved in delivery of these patients. Differences in patient comfort and satisfaction between the unified versus fragmented health provider approach have not been specifically studied from the

Medical and socio-cultural aspects of infertility in the ME

perspective of the medical consumers and form a basis for further research (Sills et al., 2007). Number of embryos transferred The financial difficulties often drive couples and the treating physicians as well to be inclined to request and apply the policy which leads to the highest pregnancy rate irrespective of the outcome of the pregnancy, i.e. the transfer of too many embryos (Serour et al., 1991b, 1998). In many countries in the ME, transferring too many embryos is still a common practice. A study had shown 25.9% of all women undergoing transfer received at least four embryos, 42% received three embryos and only 32.1% received two or one embryo (Mansour and Abou Setta, 2006). Transfer of too many embryos resulted in an exceptionally high rate of multiple pregnancy and high-order multiple pregnancy (HOMP) (Serour et al., 1998; Mansour, 2004; ICMART, 2006, Mansour and Abou Setta, 2006; Jones et al., 2007). Studies in the ME had shown that multiple pregnancy and HOMP vary between 28% and 32.6% (Serour et al., 1998; Mansour, 2004; Mansour and Abou Setta, 2006). In 16 340 initiated cycles and 15 193 oocyte pick-up, the number of embryos transferred were one, two, three and more than three embryos in 10%, 24%, 39.4% and 26.6%, respectively. The incidence of twins and triplets and more was 27.4% and 5.2%, respectively (Mansour, 2004). In another study from 13 centers in nine countries in ME, the average number of embryos transferred was 2.4 (+0.4) for patients ,35 years and 2.9 (+0.8) for patients .41 years. For these age categories, twinning was observed in 22.6 (+10.8)% and 13.7 (+10.4)%, respectively (Sills et al., 2007). Because of the high incidence of HOMP, multifetal pregnancy reduction (MFPR) is widely practiced in many countries of the ME (Jones et al., 2007). Cryopreservation Cryopreservation service is available in most centers in the ME. A study had shown that frozen thawed embryos were transferred in 17.2% of cycles performed in 13 ART centers in nine ME countries during the year 2005 (Sills et al., 2007). An earlier study showed that only 7% of transfers were from cryothawed embryos (Mansour, 2004) which may reflect a gradual increase in the use of cryopreservation in ART programs in the region. It is expected that installment of good cryopreservation programs in ART centers in the region would encourage physicians to minimize the number of embryos transferred per cycle and cryopreserve the surplus embryos. Micromanipulation ICSI as a successful modality of treatment male infertility was introduced and widely practiced in the ME in the early 90s. Studies from the ME had shown that male factor infertility is the most common indication for ART varying between 50.3% and 72.1% (Mansour, 2004; Mansour and Abou Setta, 2006; Inhorn, 2006; Sills et al., 2007). However, ICSI is widely practiced in many centers in the ME for non-male factor infertility. A registry from 32 centers

from eight countries in the ME showed a total of 15 193 aspirations during the year 2000, 13 533 (82.4%) and 1660 (17.6%) were subjected to ICSI and IVF, respectively (Mansour, 2004). During the year 2001, a Registry from 30 centers in nine countries in the ME showed of 13 979 oocyte aspirations, 12 684 (90.7%) and 1249 (8.9%) were subjected to ICSI and IVF, respectively (Mansour and Abou Setta, 2006). This represents an increasing trend in most ART centers in ME to use ICSI for virtually all causes of infertility and not only male factor infertility. ICSI is widely used in ME to avoid the risk of failure of fertilization and because of the prevalence of male factor infertility (Mansour, 2004; Mansour and Abou Setta, 2006; Inhorn, 2006; Sills et al., 2007). Preimplantation genetic diagnosis PGD is legally available in at least nine countries in the region. Sex selection for medical indications is performed in all countries where PGD service exists. However, sex selection for social indications, although is associated with a heavy demand in the region, is only performed in very few centers because of the ethical dilemma surrounding this practice (Serour and Dickens, 2001; Serour, 2006). In one country in ME, PGD for sex selection for social reasons had shown that the greatest demands were for male embryos to be transferred. In countries which provide such service, tight ethical guidelines are needed to avoid discrimination against the female child (FIGO Committee for the Ethical Aspects of Human Reproduction and Womenâ&#x20AC;&#x2122;s Health, 2006a; Serour, 2006). Wide disparities exist in the quality, availability and access to infertility service in various countries in ME. However, several common factors can be identified in ART practices in the ME. Government registry or oversight of clinical IVF practice is limited or non-existing in most countries. None of the programs identified any local ordinance or regulations prohibiting advertisement of ART services to the public. Number of embryos transferred is fairly high, .2 or .3 embryos. MFPR is a common practice in ME. Sophisticated reproductive health service in ME is associated with a minimal delay. Most centers do not maintain a comprehensive IVF database. However, some independent agencies collect transnational data on IVF clinics (IFFS; ICMART; ME Registry, MER). However, all these bodies cover only a small number of ART centers which markedly flourished in ME during the past few years (Table II). Socio-cultural aspects of infertility Prevention and treatment of infertility are of particular significance in the ME area because a womanâ&#x20AC;&#x2122; social status, her dignity and self-esteem are closely related to her ability to have children. Childbirth and rearing are regarded as family commitments and not just biological and social functions. Furthermore, adoption as a possible solution to the problem of infertility is not widely acceptable in the region of the ME for various cultural and religious reasons (Serour et al., 1995). There is gender suffering in infertility in many of the ME countries. Women are often blamed for infertility even if 37

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Table II. ART Practices in some ME countries. Country

No. of centres

Guidelines/statutes

Requirement for ART

Coverage or reimbursed

Gamete donation

1. 2. 3. 4.

Bahrain Egypt Iran Israel

4 50– 51 No data 24– 27

Guidelines Guidelines Statutes Guidelines/statutes

coverage No coverage NA + complete

Not allowed Not allowed Allowed Allowed

5 6 7 8 9 10

Jordan Lebanon Qatar Saudi Arabia Syria UAE

16 13 NA 23 6 4

Guidelines Guidelines Guidelines Guidelines/statues Guidelines Guidelines

Marriage Marriage Marriage Marriage or stable relationship. Permitted for single women and lesbian couples Marriage Marriage Marriage Marriage Marriage Marriage

No coverage No coverage Coverage Coverage No Coverage Coverage

Not allowed Allowed Not allowed Not allowed Not allowed Not allowed

NA, not available. Source: Middle East Registry, 2006; Collaborative transnational pilot survey of IVF in the ME 2007 and IFFS surveillance 2007.

they are not the cause of infertility. If infertility occurs, it is the female partner who is anxious, frustrated and suffers from grief, fear, marital distress, domestic violence, economic deprivation, social stigma, community ostracism, divorce, polygamy and may even undergo life-threatening medical intervention (Serour, 2002). In all modalities of treatment of infertility except ART, conception occurs only after sexual act between the male and the female partners and is not of particular ethical concern in any of the countries in the region. With the advent of ART since the birth of Louise Brown in UK on 25 July 1978, it became possible to separate the bonding of reproduction from sexual act (Steptoe and Edwards, 1978). ART enabled women to conceive without having sex. This challenged the age-old ideas and provoked discussion all over the world including ME. When ART was first introduced in ME, there was a tremendous societal rejection based on social, cultural and religious backgrounds. The introduction of ICSI in ME for male infertility played a role in the change of attitudes of many couples to ART. Husbands in the structure of the family in many countries in the ME are usually more influential in decision-making in family affairs particularly reproduction. When the female factor was the cause of infertility, husbands often had been reluctant to seek medical advice, especially when the treatment was not conventional. Husbands were very reluctant to participate in or to agree to their wives to undergo ART for female factor infertility. Also, the fact that polygamy in some countries in the ME is a possible solution for husbands to father children if the wife was the cause of infertility made many husbands reluctant to agree to undergo ART, especially in the rural areas. However, when ICSI was introduced, it offered great hope to many infertile men, especially those with severe oligoasthenospermia or azoospermia. Husbands became very enthusiastic about ART and they took the initiative and encouraged their wives to undergo this new modality of treatment once it became available. The objections and resistance of the males to their wives to undergo ART almost disappeared. This encouraged many couples in the area to make use of ART for the treatment of their infertility (Serour, 2002). 38

In a part of the world like the ME, where the three major religions, namely Judaism, Christianity and Islam, emerged, religion still means and influences a lot of social behaviors, attitude, practices and policy making (Serour, 2000).

Religious aspects of infertility in ME One of the stumbling blocks to acceptance of the ART was the unacceptability to the main religious groups of the involvement of the scientist in the act of procreation (World Health Organization, 2003). The handling of the human gametes in the laboratory by the scientists in the process of conception created the most bizarre and inconsistent attitudes in many countries all over the world and particularly in the ME area. The Jewish attitude to infertility treatment is based on the fact that the first commandment from God to Adam was ‘Be fruitful and multiply and replenish the earth and subdue it’ [Holy Bible: 1:28(1)]. This is expressed in a Talmudic saying from the second century, which says ‘Any man who has no children is considered a dead man’. This attitude arises from the Bible itself and refers to the words of Rachel to Jacob, who was barren, ‘Give me children or else I die’ [Holy Bible: 30:1(1)]. The Mishnah emphasizes that only prohibitive, strict decisions require juridical substantiation whereas permissibility or leniency needs no supportive precedent. Some individual rabbis have taken a strict position, and suggested that legal and biological ties be severed with the removal of the oocyte from the body, but both chief Rabbis of Israel (of Ashkenazi or European origin and Sephardic/Oriental origin) support ART. In general, there is near unanimity of opinion that the use of semen from the husband is permissible and masturbation should be avoided if at all possible, and coitus interruptus or the use of a perforated condom seems to be the preferred methods for provision of sperm. All orthodox Jewish legal experts agree that sperm donation using the semen of a Jewish donor is forbidden, but some rabbinical authorities (reform and conservative) permit sperm donation when the donor is non-Jew. Oocyte donation is acceptable, as only the offspring of a Jewish mother may be regarded as a Jew.

Medical and socio-cultural aspects of infertility in the ME

Donation is also permitted for single women. Cryopreservation of embryos is permitted with the consent of the parents for a period of 5 years, which is renewable if requested by the couple. In case of death of the husband (or of divorce), the embryos may be transferred to the wife within 1 year after death of her husband, if supported by the recommendation of a social worker (or written permission in case of divorce) (Schenker, 2005). Jewish religion does not forbid the practice of surrogacy, whether complete or partial, as indeed the practice is described in the Bible in the case of Sarah and Abram with Hagar who bore Abram a son, Ishmael, and Rachel, who used her slave girl Bilha to bear a child for Jacob as indicated in Genesis 19 and Genesis 30. Halachic authorities would allow fetal reduction, if it is absolutely certain that all fetuses would be lost otherwise. Some fetuses are being sacrificed in an attempt to save the others. Christianity does not speak with one voice on infertility treatment and the technology of ART. What some would permit and regulate others would forbid. Rome puts absolute value on an unbreakable nexus between the fully human contest of the conjugal act and conception. Although it permits all conventional lines of treatment of infertility, it forbids to its members all practices of ART as they bypass the sexual union of man and woman (Donum Vitae, 1987). Although ART is not accepted by the Vatican, it may be practiced by the Protestant, Anglican and other Denomination’s. In the Protestant Churches, moral reasoning is the perennial task, establishing the acceptable limits in the application of new developments in science and technology, including ART (Dunstan, 1996). It is thought that infertile people have a proper claim on medical technology, and must be informed and counseled as they are vulnerable and therefore prone to exploitation. Many protestant churches would allow ART with spouse gametes and no embryo wastage. The Eastern Orthodox Church does not oppose ART for couples. However, gametes donation or surrogacy, like the church of Alexandria, are not approved (Serour 2006). In Islam, the primary sources of Sharia encouraged marriage, family formation and procreation (Holy Quran: Sura El Shoura: 49–50; El Nahl: 27; El Raad: 38). Thus, infertility management and its prevention to preserve humankind are encouraged in Islam [Gad El Hak AGH (H.E.), 1980]. ART was not mentioned in the primary sources of Sharia; however, ART within the frame of marriage was encouraged by the secondary sources of Sharia, in otherwise incurable infertility. It was not until Fatwas from Al-Azhar in 1980 (Gad El Hak AGH (H.E.) 1980), the Islamic Fikh Council in Mecca in 1984 and the Church of Alexandria in 1989 (Gregorios, 1989) that the procedure gained popularity and became widely acceptable to the medical profession, patients, religious leaders and policy makers in most countries of the area. These bodies and organizations issued guidelines which were adopted by the National Medical Councils and Ministries of Health in the various countries and controlled the practices of ART centers (Serour, 2002). The guidelines encouraged couples to seek infertility treatment including (ART), as long as there was a medical

indication for its use. Most of the guidelines indicated that gametes of a third person should not be used and the fertilized oocytes should be transferred to the uterus of the wife from whom the oocytes were obtained within a valid marriage contract. Oocyte donation, sperm donation, embryo donation or surrogacy were not allowed in most of these guidelines. The Islamic Fikh Council of Mecca previously allowed surrogacy to be performed on the second wife of the same husband (Proceeding of the 7th meeting of Islamic Fikh council, 1984). The council soon after denied surrogacy and the guidelines became identical with those of Al-Azhar. The promulgation of these guidelines was just a response to the needs of the community, and the discussions and debates which arose in the area, as well as the problems anticipated with the practice of surrogacy with special reference to the cultural and religious background of the people in the area (Serour, 2002). The Shi’aa Guidelines has ‘opened’ the way to a third-party donation, via Fatwa from Ayatollah Ali Hussein Khomeini in 1999. This Fatwa allowed third-party participation, including oocyte donation, sperm donation, embryo donation and surrogacy. Recently, there has been some concern about sperm donation among Shi’aa. All these practices of third-party participation in reproduction are based on the importance of maintaining the family structure and integrity among the Shi’aa family. These guidelines and legislation played a major role in comforting patients and physicians. In the 80s, seeking ART for infertility treatment was associated with secrecy, feelings of shame, doubt and even sometimes guilt, but in the 90s such feelings were replaced by openness about seeking infertility treatment and ART in particular (Serour et al., 1991a). Most of the observant believers of the three major religions in the ME countries abide by these guidelines. However a small minority, which cannot be estimated, may ask for some modalities of ART outside this frame as oocyte donation, embryo donation or surrogacy. It becomes an ethical obligation of the treating physician to refer them where they can have this treatment provided if he/she has conscientious objection to provide such evidence-based treatment (FIGO Committee for the Ethical Aspects of Human Reproduction and Women’s Health, 2006b). Conclusions and recommendations Infertility does not threaten the life or endanger physical health. However, as health is not merely the absence of disease or infirmity and is a state of complete physical, mental and social well-being, infertility sufferings are very real. As fertility and childbirth are of particular significance in the ME, it is recommended that: † Women should be empowered so that when infertility occurs they are not to suffer from its consequences including economic deprivation, social isolation, unstable marriage, domestic violence polygamy, stigmatization and even ostracism. † Reproductive health education and improvement of the standards of basic healthcare services would prevent a substantial part of infertility. 39

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† Infertile couples present levels of distress should be assessed by psychologists and coping strategies should be assessed prior to initiating treatment to provide the couple with opportunities to learn and practice new adaptive behaviors. This could enhance their ability to cope with infertility and the associated medical procedures. † Efforts should be made to convince governments to include treatment of infertility and ART in their health service programs. Infertility treatment and its prevention serves rather than conflicts with population control policy. † Ethicists, physicians, scientists, psychiatrists, social scientists, consumer’s groups and religious leaders should have continuous updated dialogue and debate about development and new knowledge in ART. This would help to revise old guidelines and develop new guidelines. † Reproductive medicine physicians should be aware of ethical issues involved in ART. When offering this service for their patients, it is the duty of the physician to provide the needs of his/her patients according to patient’s ethical percept if this does not conflict with the accepted standards of healthcare. If the physician has a conscientious objection to treatment, it is the duty of the physician to refer the couple to where their needs can be met. † Every effort should be made to reduce ART cost. The service to the needy may be provided through: donation, charitable projects, drug companies, research projects, health insurance and low cost IVF. Satellite clinics may cooperate with ART centers in larger cities to reduce the cost of establishing, many ART centers and reduce the overhead cost for the patients. References Birenbaum-Carmeli D. Cheaper than a newcomer: on the social production of IVF policy in Israel. Social Health Illn 2004;26:897–924. Boivin J, Bunting L, Collins JA, Nygren KG. International estimates of infertility prevalence and treatment-seeking: potential need and demand for infertility medical care. Hum Reprod 2007;22:1506– 1512. Dandekar PV, Quigley MM. Laboratory set up for human IVE. Fertil Steril 1984;42:1–12. Donum Vitae. Vol. 11. Vatican City: Polyglot Press, 1987,A,1. Dunstan GR. Diagnosis and treatment of infertility: a religious and ethical discussion. Christian moral reasoning. EAGO Congress Budapest, 20th June 1996. EAGO Newsletter 2:29– 31. Ebomoyi E, Adetoro OO. Socio-biological factors influencing infertility in a rural Nigerian community. Int J Gynaecol Obstet 1990;33:41 –47. Fathalla MF. Reproductive health: a global overview. Early Hum Dev 1992;29:35– 42. Fathalla MF. Current challenges in assisted reproduction. In: Vayena E, Rowe PJ, Griffin PD (eds). Current Practices and Controversies in Assisted Reproduction. Geneva, Switzerland: World Health Organization, 2002, 3 –12. FIGO Committee for the Ethical Aspects of Human Reproduction and Women’s Health. Ethical guidelines on conscientious objection. Int J Gynaecol Obstet 2006a;92:333–334. FIGO Committee for the Ethical Aspects of Human Reproduction and Women’s Health. Ethical guidelines on sex selection for non-medical purposes. Int J Gynaecol Obstet 2006b;92:329–330. Gad El Hak AGH (H.E.). Islamic Fatwa of Dar ELEftaa, Cairo, Egypt: Dar EL Eftaa, 1980;9,1225:3213– 3228. Greenhall E, Vessey M. The prevalence of subfertility: a review of the current confusion and a report of two new studies. Fertil Steril 1990;54:978– 983. Gregorios Archbishop. General for high Coptic studies, culture and scientific research. Christianity views on IVF and ET in ‘Treatment of infertility’ and test tube babies. In: Kamal R (ed). Akhbar El Youm, Vol. 82, 1989, 131.

Holy Bible. Genesis 1:28(1). Holy Bible. Genesis 30:1(1). Holy Quran. Sura El Nahl: 27. Holy Quran. Sura El Raad: 38. Holy Quran. Sura El Shoura: 49–50. ICMART. Fertil Steril 2006;85:1586– 1622. Inhorn MC. Making Muslim babies: IVF and gamete donation in Sunni vs. Shi’s Islam. Cult Med Psychiatry 2006;30:427– 450. Jones H, Cohen J. IFFS surveillance. Fertil Steril 2001;76:1–35. Jones HWJR, Cohen J, Cooke I, Kempers R. IFFS surveillance 2007. Fertil Steril Suppl 2007;87 (Suppl 1):1– 67. Larsen U. Research on infertility: which definition should we use? Fertil Steril 2005;83:846–852. Lunenfeld B, Van Steirteghem A. Infertility in the third millennium: implications for the individual, family and society: condensed meeting report from the Bertarelli Foundation’s second global conference. Hum Reprod Update 2004;10:317–326. Mansour R. The Middle East IVF registry for the year 2000. Middle East Fertil Soc J 2004;9:181–186. Mansour R, Abou Setta A. The Middle East IVF Registry. Middle East Fertil Soc J 2006;11:145– 151. Nachtigall RD. International disparities in access to infertility services. Fertil Steril 2006;85:871–875. Okonofua FE. The case against new reproductive technologies in developing countries. Br J Obstet Gynaecol 1996;103:957– 962. Ombelet W, Campo R. Affordable IVF for developing countries. Reprod Biomed Online 2007;15:257– 265. Proceeding of 7th Meeting of the Islamic Fikh Council in IVF & ET and AIH, Mecca. Kuwait Siasa Daily Newspaper, 1984. Population Reference Bureau. 2007 World Population Data Sheet. PRB USAID, 2007. www.prb.org Schenker JG. Women’s reproductive health: monotheistic religious perspectives. Int J Gynaecol Obstet 2000;70:77– 86. Schenker JG. Assisted reproductive practice: religious perspectives. Reprod Biomed Online 2005;10:310– 319. Sciarra J. Infertility—an international health problem. Int J Gynaecol Obstet 1994;46:155–163. Serour GI. Islamic development in bioethics. In: Lustig BA (ed). Bioethics Yearbook, Vol. 171. The Netherlands: Baylor College of Medicine Kluwer Academic Publishers, 1997,188. Serour GI. Ethical considerations of assisted reproductive technologies: a Middle Eastern perspective. Middle East Fertil Steril J 2000;5:13– 18. Serour GI. Attitudes and cultural perspectives on infertility and its alleviation in the Middle East area. In: Vayena E, Rowe PJ, Griffin PD (eds). Current Practices and Controversies in Assisted Reproduction. Geneva, Switzerland: World Health Organization, 2002,41– 49. Serour GI. Religious perspectives of ethical issues in ART. Contemporary Ethical Dilemmas In Assisted Reproduction: In: Shinfield F, Sureau C (eds). Informa Health Care UK 2006; pp. 99–114. Serour GI, Hefnawi FI. Diagnostic laparoscopy for infertile patients as a training program. Int J Gynaecol Obstet 1982;20:19– 22. Serour GI, Omran AR (eds). Ethical Guidelines for Human Reproduction Research in the Muslim World. International Islamic Center for Population Studies and Research (IICPSR), 1992,29– 31. Serour GI, Dickens B. Assisted reproduction developments in the Islamic world. Int J Gynaecol Obstet, Ethical Legal Column 2001;74:187–193. Serour GI, El Ghar M, Mansour RT. Infertility: a health problem in the Muslim world. Popul Sci 1991a;10:41–58. Serour GI, Aboulghar MA, Mansour RT. In vitro fertilization and embryo transfer in Egypt. Int J Gynaecol Obstet 1991b;36:49– 53. Serour GI, Aboulghar MA, Mansour RT. Bioethics in medically assisted conception in the Muslim world. J Assist Reprod Genet 1995;12: 559–565. Serour GI, Aboulghar M, Mansour R. Tubal and pelvic iatrogenic infertility in the female. Egypt J Fertil Steril 1997;1:31–40. Serour GI, Aboulghar M, Mansour R, Sattar M, Amin Y, Aboulghar H. Complications of medically assisted conception in 3,500 cycles. Fertil Steril 1998;70:638–642. Shahin A. The problem of IVF cost in developing countries: has natural cycle IVF a place? Reprod Biomed Online 2007;15:51 –56. Sills ER, Qublan HS, Blumenfeld Z, VT Dizaj A, Revel A, Coskun S, Abou Jaoude I, Serour GI, Eskandar M, Ali Khalili M et al. Regional clinical practice patterns in reproductive endocrinology: a collaborative

Medical and socio-cultural aspects of infertility in the ME transnational pilot survey of in vitro fertilization programs in the Middle East. J Exp Clin Assist Reprod 2007;4:3. Steptoe PC, Edwards RG. Birth after the reimplantation of a human embryo. Lancet 1978;2:366. Sundby J, Mboge R, Sonko S. Infertility in the Gambia: frequency and health care seeking. Soc Sci Med 1998;46:891– 899. Thonneau P, Spira A. Prevalence of infertility: international data and problems of measurement. Eur J Obstet Gynecol Reprod Biol 1990;38: 43– 52. World Health Organization. The epidemiology of infertility. Report of WHO Scientific Group on the Epidemiology of Infertility. Technical Report series No. 582. Geneva: WHO, 1975.

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doi:10.1093/humrep/den151

Human Reproduction 2008

Assisted reproductive technology in Latin America: an example of regional cooperation and development Fernando Zegers-Hochschild1, Juan-Enrique Schwarze and Veronica Galdames Unit of Reproductive Medicine, Clinica Las Condes, Lo Fontecilla 441, Santiago 7550000, Chile 1

Correspondence address. E-mail: fzegers@clc.cl

BACKGROUND: Since 1990, the Latin American Registry of Assisted Reproduction covers more than 80% of the assisted reproductive technology (ART) cycles performed regionally. METHODS: 130 centers enter their data online, and after collection, it is analyzed and published regionally. RESULTS: This paper analyses trends in ART procedures initiated between 1990 and 2004, and babies born up to 2005. Overall, the data include 150,000 embryo transfer (ET) cycles, 33,500 deliveries and the birth of 44,978 babies. The yearly increment in initiated cycles is below other regions of the world. The economic, religious and social factors explaining this limited access to ART are discussed. Major trends include: an increase in the age of female partner undergoing treatments; a marked shift towards an increase in the use of ICSI; and a steady increase in the delivery rates per ET reaching 24.6% in IVF/ICSI cycles, and 30.7% in OD cycles. Despite a slight decrease in the mean number of ET (2.9), almost half of all births are either twins or triplets. CONCLUSIONS: Our region is confronted with two main issues: limited access to those who can afford it; and a high number of embryos transferred resulting in almost 50% of babies born from multiple births. Keywords: ART; registry; Latin America

Introduction The first birth of an in vitro fertilization (IVF) baby was reported in Latin America in 1984. During the next 5 – 6 years, the use of this technology expanded rapidly in Argentina, Brazil, Mexico, Colombia and Chile, but little is known on the number of attempts and the number of babies born until 1990 when the Latin American registry of assisted reproduction (RLA) was established. This initiative was the first multinational/regional registry, which had mainly five objectives in mind; to develop an educational tool to serve the medical profession and infertile couples during their processes of decision making; to develop a robust regional database; to serve as an external quality control for centres in the region; to build a large database for epidemiological studies; to promote the formation of national assisted reproductive technology (ART) registries in the region; and to monitor trends in efficacy and safety of ART procedures in the region. Nineteen IVF centres from 12 countries initiated this registry. Seventeen years later, the majority of centres performing ART procedures in Latin America report to RLA every year. Operating such an international project had to overcome several problems. The vast geographical extension of ART centres located in Latin America—from Mexico in the North to Chile in the South—plus the multiplicity of languages (Spanish, Portuguese) spoken in the region made 42

communication a relevant issue. Another major issue was the understandable distrust of directors of competitive institutions to share their data. To gain their trust, RLA ensured that the information provided by each individual centre would never be disclosed or used for purposes other than those stated previously. The last major issue was the limited experience of (mostly) private ART centres—with little or no academic background—in adhering with consistency and rigor to scientific research protocols. Thus, RLA started as a voluntary activity, publishing summary regional data on a yearly basis. With no existing national registries in the region, the first step was to develop standardized forms and distribute them among the different centres. The first forms used for data collection were adapted from those developed by the international working group for registers on assisted reproduction, today, International Committee Monitoring ART (ICMART). In 1990, 21 centres from eight countries reported a total of 2491 procedures. During the fourth year, the coverage of the registry was sub-optimal and there were concerns about the reliability of the information provided by certain institutions. To address this issue, the clinical director and laboratory director of each of the 59 RLA-reporting centres met in 1995 in Chile, and founded the Latin American Network of Assisted Reproduction (RED). Latin America was divided into five subregions and a director was appointed for each one. Human and

Assisted reproductive technology in Latin America

economic resources were allocated to start a regional educational programme focused on preparing embryologists and clinicians for the process of centre accreditation, which started the following year. Since 1996, all centres willing to be members of RED undergo a periodic accreditation process whereby infrastructure, equipment, personnel, use of consent forms, and veracity of the information provided to the RLA are checked for quality and consistency. After 15 years, the number of participating centres has increased from 21 to 130, reaching almost 25 000 initiated cycles per year, which represents .80% of ART cycles performed in the region. Today, Brazil contributes with 45% of the initiated cycles, Argentina with 21% and Mexico with 15.8%; with the remaining cycles coming from Colombia, Chile, Uruguay, Venezuela, Peru, Ecuador, Guatemala and Bolivia (Zegers-Hochschild et al., 2007). This manuscript covers ART procedures (fresh non-donor IVF/intracytoplasmatic sperm injection (ICSI) cycles, donor cycles and frozen – thawed embryo transfers) initiated between January 1990 and December 2004; and babies, born due to these procedures, up to September 2005. Data collection, analysis and communication Initially, data were compiled using printed forms, sent by mail or fax. Each centre required an average of five phone calls from the administrative office before their data could be cleared of inconsistencies. To improve this, in 1991 special software was developed for electronic collection of data. Although it had a built-in system to check for inconsistencies, it still required excessive interaction between the administrative office and each individual centre. Today, participating institutions enter their data directly online (www.redlara.com). The administrative office in Santiago, Chile, periodically recovers and analyses the data for consistency. Once all the information are cleared, and the centre is checked as accredited by the RED, the data are included and published as part of RLA’s yearly report. The terminology used in the registry is that contained in the ‘ICMART glossary of ART terminology’ (Zegers-Hochschild et al., 2006a,b). Along with every report, each individual centre receives an electronic file prepared by RLA, containing their own data as well as the corresponding national data. As a result of the RLA initiative, today, every participating country in Latin America has a national ART database with information analysed, verified and summarized by RLA. After approval of the participating centres, national data are also sent to the ICMART for inclusion in the publication of the world report (International Committee for Monitoring Assisted Reproductive Technology et al., 2006).

embryo transfer cycles, with 33 500 deliveries and the birth of 44 978 newborns. Of these newborns, 82.8% correspond to non-donor fresh cycles (51.9% ICSI, 27.8% IVF and 3.1% GIFT); 4.2% to FET cycles; and 13.0% to OD cycles. Age of female partner and mode of fertilization The age of women undergoing ART in Latin America is increasing: in 1990, 66.5% of women were 34 years old and only 8.7% were 40 years old; in 1998 half of women undergoing FIV/ICSI were 35 years old, and 14% were 40 years old. In the last 5 years, the proportion of embryo transfers in women 35 years old increased from 49.2% in 2000 to 53.2% in 2004. Furthermore, the proportion of transfers in women 40 years old increased from 14.8 to 16.3% (Table I). These trends need to be taken into account when analysing success rates over the years. The mode of fertilization has experienced a dramatic shift towards the use of micromanipulation techniques. In 1990, IVF represented 63.3% of procedures, while GIFT and other techniques (ZIFT etc.) represented 36.7% of procedures. In year 2000, GIFT and other techniques represented only 2% of procedures. Conversely, ICSI represented 6.3% of procedures in 1994, increasing to 42.0% in only 2 years. Finally, in 2004, ICSI includes 74.0% of all procedures despite the fact that only 11– 15% of cases of infertility are reported as attributable to a male factor (Fig. 1). If we compare these data to the 52.4% of ICSI procedures performed in Europe during 2003, there is clearly a regional tendency for greater use of micromanipulation. Success rates Success rates can be expressed as clinical pregnancy rate (CPR), delivery rate (DR) and live birth rates by initiated cycles, oocyte pick-up attempts or embryo transfer cycles. Furthermore, these indicators can be analysed by the type of procedure, number of embryos transferred and age of the female partner. Overall, CPR and DR per transfer in fresh, non-donor IVF/ ICSI cycles remained unchanged until 1994 with a mean of 24.5 and 17.8%, respectively. Subsequently, CPR and DR increased steadily until 1999, when they stabilized at 29.7 and 22.4%, respectively. The next significant increase took place throughout the last 5 years where CPR and DR increased from 28.6 and 20.5% in 11 287 embryo transfers performed in 2000, to 32.7% (P ¼ 0.0001) 24.6% (P ¼ 0.0001) in 16 183 embryo transfers performed in 2004 (Fig. 2).

Table I. ETs* according to age of woman (2000– 2004).

Outcome of ART in Latin America RLA keeps a complete registry of ART procedures that includes IVF, gamete intrafallopian transfer (GIFT), ICSI, assisted hatching (AH), oocyte donation (OD) and the transfer of frozen – thawed embryos (FET), starting in 1990, with babies born up to September 2005. Overall, the data include 150 000

Transfers Women 34 years or less Women 35– 39 years Women 40 years or more

2000

2001

2002

2003

2004

11 269 50.9 34.3 14.8

12 780 50.0 35.0 15.0

12 822 48.4 35.0 16.6

14 220 49.5 35.0 15.5

16 183 46.8 36.9 16.3

*includes IVF, ICSI, IVF þ ICSI, AH.

Zegers-Hochschild et al.

Table II. Outcome of pregnancies, Latin America IVF and ICSI (1998– 2004).

Babies born (total) Live births Stillbirths Early neonatal death Perinatal mortality

Singletons

Twins

Triplets

14 608 14 333 102 (0.7%) 173 (1.2%) 1.9%

1038 9918 235 (2.3%) 227 (2.2%) 4.5% (2.4)

4127 3712 180 (4.4%) 235 (5.7%) 10.1% (5.3)

Total number of babies born ¼ 29 115. Singletons, 50.2%; Twins, 35.7%; Triplets and more, 14.2%). Table III. Babies born from ART according to multiplicity, Latin America (2000–2004).

Number of babies born Single (%) Twin (%) Triplet or more (%)

Figure 1: Mode of fertilization as a percentage of all procedures. Latin America (1990–2005).

Figure 2: Delivery rate per transfer according to type of procedure; Latin America, (1990–2005).

OD cycles experienced a similar trend during the last 5 years, with CPR reaching 39.7% in 3115 transfers performed in 2004. The DR increased from 24.3 to 30.7% (P ¼ 0.0001) results that are similar to those obtained in non-donor fresh IVF/ICSI performed in women 34 years old. FET cycles were first reported in 1995, with CPR and DR of 17 and 13.3%, respectively. Although the overall success rate between 2000 and 2004 remain low, CPR increased from 15.1 to 20% (P ¼ 0.008) and DR from 11.2 to 14.3% (P ¼ 0.008). 44

2000

2001

2002

2003

2004

2521 51.3 36.4 12.3

3661 51.1 34.9 14.0

4540 50.5 35.9 13.6

4530 49.8 37.0 13.2

4776 53.6 35.4 11.0

Multiple births and perinatal outcome The number of embryos transferred and the age of female partner have the highest predictive value for multiple gestation. There has been a slight decrease in the mean number of embryos transferred over the last 5 years—from 3.2 to 2.9— with no differences among different age groups of female partners. Between 2003 and 2004, out of 14 450 transfers in women 34 years, 25.4% were twin pregnancies and 7.4 were triplets and quadruplets. In women 35– 39 years, and 40 years, high order multiple gestation decreased to only 6.0 and 5.7%, respectively. Contrary to trends in other regions of the world, in the last 5 years, multiple births in Latin America have remained unchanged. This means that approximately half of the babies born have co-habited with at least one more fetus throughout gestation with increasing risks of morbidity and mortality (see Tables II and III). Access to ART The latest report by ICMART (International Committee for Monitoring Assisted Reproductive Technology et al., 2006) presents worldwide information about ART procedures performed in 2000. The number of cycles reported by Latin-American centres represented only 2.9% of the 667 711 procedures performed worldwide. Expressed as the ratio of ART cycles per million inhabitants, the disparity in access to ART is even more striking. Countries like Sweden, Denmark and Belgium have between 1000 and 2000 cycles per million inhabitants, whereas countries in Latin America perform between 33 and 109 cycles per million inhabitants. When using this indicator to look at differences between countries, age distribution in different regions can be a source of bias. For example, the need for infertility treatment should be different in countries where the majority of women are 30 years and seeking pregnancy (Latin America), and countries where the majority of women are 35, many of which no longer wish to become pregnant. Nowadays, 130 centres in 12 countries report their ART data to the RLA. As stated previously, this number represents .80%

Assisted reproductive technology in Latin America

Figure 3: Access to ART cycles in Argentina, Brazil, Chile, Colombia and Mexico (1990–2004).

of the cycles performed in the region. This number has increased steadily since the beginning of the registry, in part due to an increase in the number of the centres and countries reporting, but mainly due to an increase in the number of cycles initiated in each individual centre. Only Argentina has experienced a steady increase in the access to ART (Fig. 3), but still far below that of developed countries. The majority of countries in the region have experienced little growth despite a worldwide increment in ART procedures. Several factors are responsible for this low access to ART treatment; the most important are the high costs involved. Since infertility is not recognized as a disease, coverage of fertility treatments is not a part of public health policies, and couples need to cover expenses from private resources. Furthermore, many legislators in Latin America struggle morally with procedures, such as IVF and embryo cryopreservation, whereas others view them as a luxury that should not be sponsored with limited public resources. Consequently only a small proportion of the population can afford paying for ART either in their country or abroad. This lack of governmental support is paradoxical in countries like Chile and Uruguay, where the fertility rate (number of children per woman) declined from 2.3 and 2.4 in 1995 to 2.0 and 2.1 in 2005, respectively (i.e. below the replacement level). Furthermore, the population growth rate in these countries declined from 1.5 to 1.0% and from 0.7 to 0.2% during the same period. From another perspective, the Roman Catholic tradition is by far the most outspoken and influential religious body in Latin America. Its moral teachings concerning sexual and reproductive issues are against any form of reproduction outside the natural means. Following this guidance, the majority of countries in the Americas signed the ‘American Convention on Human Rights, Pact of Costa Rica’. This document states that ‘Laws should protect the lives of those to be born, in general, from conception onwards’. This statement has been used by the Supreme Court in Costa Rica to consider IVF as morally unacceptable and illegal, forbidding its practice.

Conclusions and challenges As the first regional registry, with over 15 years of data, RLA has contributed significantly in the development of ART in Latin America. Some of its major contributions include: (i) Annual data that allow comparisons and conclusions at different levels: individual centre, country and regional. (ii) Support for centres with little scientific background; assisting with technical analysis of their results compared with those of their respective country and region. (iii) A rigorous and systematic accreditation process has helped centres to establish quality control programs that directly benefit infertile couples. (iv) RLA has contributed to the development and publication of national registries in several countries in the region. Today, five countries publish national registries with data provided by RLA. (v) RLA has facilitated the transfer of technology and the strengthening of human resources between centres of neighbouring countries, thus eliminating occasional cultural and language barriers to foreign assistance. Latin America currently faces several challenges, as identified and highlighted by RLA. The first challenge is to increase the limited access to ART procedures. As discussed earlier, although the number of ART procedures has increased significantly, it is by far under the estimated need of the population. As shown by RLA, there is a great disparity in the access to ART procedures among the different countries member of RED. Furthermore, the influence of the Catholic Church, which opposed any ART procedure, is growing in the region, and contributes to increase inequality in the access to this form of treatment. The second challenge is to reduce the number of embryos transferred and decrease the high rate of multiple births. At a regional level, RLA demonstrates comparable results to those of developed countries, as measured by CPR and DR. However, these results are obtained by transferring more embryos, regardless of the age of the female partner. Out of 29 115 babies born between 1998 and 2005, 35.7% were twins and 14.2% were triplets or more. This condition produced a 2.4- to 5.3-fold increase in perinatal mortality in twins and triplets over singletons, increase in family disorders mainly absorbed by the female partner, and high neonatal expenses. Although this problem has been consistently demonstrated by data published by RLA over the past 15 years, there has been seemingly little reaction. In the absence of public health policies regulating ART, the education of consumers on the risks of multiple births may be the only key to reduce excessive multiple gestation in the region. Acknowledgements The authors wish to acknowledge the continuous contribution of today’s 130 centres reporting to the Latin American registry of assisted reproduction (see Appendix).

Funding The Latin American Registry (RLA) gratefully acknowledges the support of Merck Serono and Schering Plough-Organon in the accomplishment of this multinational registry. 45

Zegers-Hochschild et al.

Appendix: list of contributors ARGENTINA: Buenos Aires: Centro de Estudios en Ginecologıá y Reproduccioń (CEGYR); Centro de Investigaciones en Medicina Reproductiva (CIMER); Centro de Reproduccioń, Servicio de Ginecologıá del Hospital Italiano; CER Instituto Me´dico; GENS— Centro Especializado en tratamientos para la mujer; FECUNDITAS—Instituto Me´dico Integral de Fertilidad; FERTILAB; Halitus Instituto Me´dico; Prefer—Instituto Me´dico de Ginecologıá y Fertilidad; PROCREARTE; Unidad de Fertilidad San Isidro; Co´rdoba: Centro Integral de Ginecologıá, Obstetricia y Reproduccioń (CIGOR); FECUNDART—Instituto Integral de Reproduccioń Asistida; La Plata: Centro de Reproduccioń y Planificacioń Familiar—FERTILEQUIP; Mar del Plata: Centro de Estudios en Reproduccioń y Procedimientos de Fertilizacioń Asistida (CRECER); Mendoza: Instituto de Medicina Reproductiva; Centro de Estudios en Reproduccioń Humana (CERH); Rosario: Centro para la Fertilidad de la Pareja (CEFEP); Programa de Asistencia Reproductiva (PROAR); Salta: Salud Reproductiva Salta (SARESA). BRAZIL: Belo Horizonte- Minas Gerais: Clıńica ORIGEN; Clıńica Pro-criar Hospital Materdei; Instituto de Sau´de da Mulher; Brasilia: Instituto Verhum (anteriormente, Centro de Endoscopio e Assisteˆncia a Fertilidade-CENAFERT); GEŃESIS—Centro de Assisteˆncia em Reproduçao Humana Ltda.; Hospital Regional da ASA Sul; Campinas-SP: Centro de Reproduçaõ Humana de Campinas; Clıńica Androfert Cuiaba-Mato Grosso: Instituto Pe´rola de Reproduçaõ Humana; Curitiba-Parana´: ANDROLAB—Clıńica e Laboratorio de Andrologıá; FELICCITA—Instituto de Fertilidade (anteriormente, Centro Me´dico da Mulher S/A Ltda.); HUNTINGTON—Centro de Medicina Reproductiva; Floriano´polis: CLINIFERT—Centro de Reproduçaõ Humana; Fortaleza, Ceara´: CRIAR-Centro de Reproduçaõ Humana; CONCEPTUS—Centro de Reproduçaõ Humana do Ceara´; Goiania-Goias: CRAF—Centro de Reproduçaõ Assistida Fe´mina Maternidade; Fe´rtile Diagno´sticos—Reproduçaõ Humana Juiz de Mora, Minas Gerais: Pro-criar, Monte Sinai, Clıńica de Reproduçaõ Humana Londrina-Parana´: CEDILON—Laboratorio de Reproduçaõ Humana; Maringa, Parana´: Materbaby—Reproduçaõ Humana e Gene´tica; Passo Fundo-Rio Grande do Sul: GEŃESIS— Clıńica de Reproduçaõ Humana; Porto Alegre: Centro de Reproduçaõ Humana Nilo Frantz; FERTILITAT—Centro de Medicina Reproductiva; Nućleo de Reproduçaõ Humana do Hospital Moıńhos de Vento GERAR (anteriormente, GERAR-Centro de Reproduçaõ Assistida); PROGEST; SEGIR—Servicio de Ecografıá, Gene´tica e Reproduçaõ Humana Recife, Pernambuco: Clıńica de Fertilidade GERAR; Ribeiraõ Preto-SP: Centro de Reproduçaõ Humana Prof Franco Junior (anteriormente, Fundaçao Maternidade de ‘Sinha´ Junqueira’—CRH); Clıńica Matriz; Laboratorio de Reproduçaõ Humana, Hospital das Clıńicas de Ribeiraõ Preto; Rio de Janeiro-SP: Centro de Medicina da Reproduçao Ltda; Clıńica ORIGEN; Clıńica Pro´ Nacer; G&O Ginecologıá e Obstetricia da Barra; HUNTINGTON—Centro de Medicina Reproductiva; Salvador Bahia: Centro de Reproduçaõ Humana, Endoscopia e Medicina Fetal; GEˆNESE—Reproduçaõ Humana; Santos-SP: CLINIMATER; Saõ Jose´ dos Campos-SP: Clıńica REPROFERTY; Saõ Jose´ do Rio Preto-SP: IMR—Centro Instituto de Medicina Reprodutiva e Fetal; Centro de Reproduçaõ Humana do Saõ Jose´ do Rio Preto; Sao Paulo-SP: Centro de Reproduçao Humana FERTIVITRO Ltda. (anteriormente, Associaçaõ para o Estudo da Fertilidade); Centro de Investigaçaõ en Reproduçaõ Humana; Centro de Reproduçaõ Humana Monteleone; Centro de Referencia da Saude da Mulher—Hospital Pe´rola Byington; Clıńica e Centro de Pesquisa em Reproduçaõ Humana R. Abdelmassih; CEERH—Centro Especializado em Reproduçaõ Humana (anteriormente, Diagno´stico Sonogra´fico, Divisaõ de Fertilizaçao Assistida - DIASON); CEPERH—Centro de

Endoscopio Pelvica e Reproduçaõ Humana; FERTILITY—Centro de Fertilizaçaõ Asistida; FERTICLIN—Clıńica de Fertilidade Humana; HUNTINGTON—Centro de Medicina Reproductiva; PROFERT— Programa de Reproduçaõ Asistida; Projecto ALFA; Serviço de Reproduçaõ Humana do Hospital e Maternidade Santa Joana; Teresina-Piaui: CRIAR—Clıńica de Reproduçaõ Humana Ltda.; Uberlaˆndia-Minas Gerais: FECUNDA—Instituto de Reproduçaõ Humana; Vitoria: HUNTINGTON—Centro de Medicina Reproductiva. CHILE: Concepcioń: Centro de Fertilidad y Medicina Reproductiva Concepcioń S.A.; Santiago: Centro de Estudios Reproductivos; Programa de Fertilizacioń Asistida, Instituto de Investigaciones Materno Infantil (IDIMI), Universidad de Chile. Hospital Clıńico San Borja Arriarań; Unidad de Medicina Reproductiva, Clıńica Alemana; Unidad de Medicina Reproductiva, Clıńica Las Condes; Unidad de Medicina Reproductiva, Clıńica Las Nieves; Vinã del Mar: Unidad de Medicina Reproductiva, Clıńica de la Mujer. COLOMBIA: Barranquilla: Instituto de Reproduccioń Humana PROCREAR Ltda.; Bogota´: Asociados en Fertilidad Humana; MEDI FE´RTIL; Programa de Reproduccioń Asistida. Profamilia—Fe´rtil; Unidad de Fertilidad del Country Ltda. (CONCEPTUM); Unidad de Fertilidad, Procreacioń Me´dicamente Asistida Ltda.; Cali: Centro FECUNDAR Cali; Centro Me´dico Imbanaco; Medellıń: IN SER—Instituto Antioquenõ de Reproduccioń. ECUADOR: Guayaquil: Unidad de Esterilidad y Fertilidad (UDEFER), Clıńica Alcı´var Quito: Centro Me´dico de Fertilidad y Esterilidad (CEMEFES); CONCEBIR—Unidad de Fertilidad y Esterilidad. GUATEMALA: Ciudad de Guatemala: Centro de Reproduccioń Humana ‘CER’. MEXICO: Ciudad de Jua´rez-Chihuahua: Instituto de Reproduccioń Humana y Gene´tica; Guadalajara-Jalisco: Centro de Reproduccioń Asistida del Occidente; Instituto de Ciencias en Reproduccioń Humana— VIDA; Instituto de Medicina Reproductiva del Bajıó (IMER); Instituto Mexicano de Infertilidad (IMI); Hermosillo: Clıńica de Biologıá de la Reproduccioń, Hospital CIMA; Matamoros: Instituto de Ciencias en Reproduccioń Humana—VIDA; Mexico-D.F: Centro especializado para la atencioń de la mujer; Clıńica Lomas Altas; Grupo de Reproduccioń y Gene´tica AGN y Asociados; Ginecologıá y Reproduccioń Humana S.C.; Centro Especializado en Esterilidad y Reproduccioń Humana; Instituto Valenciano de Infertilidad; Monterrey: Centro Universitario de Medicina Reproductiva, Universidad Autońoma de Nuevo Leoń; CREASIS; Instituto para el Estudio de la Concepcioń Humana; Quere´taro: Me´dica Fe´rtil; San Luis de Potosı´: OBGIN S.C., SLP; Tijuana Baja California: Instituto para el Estudio de la Concepcioń Humana de Baja California (IECH & BC); Veracruz: Centro de Diagno´stico Ginecolo´gico. PERU: Lima: Clıńica Miraflores—Instituto de Ginecologıá y Fertilidad; Grupo PRANOR—Instituto de Ginecologıá y Reproduccioń. DOMINICAN REPUBLIC: Santo Domingo: Programa de Fertilizacioń Asistida y Medicina Perinatal (PROFERT). URUGUAY: Montevideo: Centro de Reproduccioń Humana del Interior (CERHI); Centro de Esterilidad Montevideo (CEM), Clıńica del Parque. VENEZUELA: Caracas: Centro Me´dico Docente La Trinidad; EMBRIOS—Centro de Fertilidad y Reproduccioń Humana, Hospital de Clıńicas Caracas; FERTILAB—Clıńica El Avila; GEŃESIS—Unidad de Fertilidad y Reproduccioń; UNIFERTES—Clıńica El Avila Maracaibo:. Laboratorio In Vitro de Venezuela.

References Sullivan E. International Committee for Monitoring Assisted Reproductive Technology; Adamson GD, de Mouzon J, Lancaster P, Nygren KG, Sullivan E, Zegers-Hochschild F. World collaborative report on in vitro fertilization, 2000. Fertil Steril 2006;85:1586–1622.

Assisted reproductive technology in Latin America Zegers-Hochschild F, Nygren KG, Adamson GD, de Mouzon J, Lancaster P, Mansour R, Sullivan EInternational Committee Monitoring Assisted Reproductive Technologies. The ICMART glossary on ART terminology. Hum Reprod 2006a;21:1968–1970. Zegers-Hochschild F, Nygren KG, Adamson GD, de Mouzon J, Lancaster P, Mansour R, Sullivan EInternational Committee Monitoring Assisted

Reproductive Technologies. The International Committee Monitoring Assisted Reproductive Technologies (ICMART) glossary on ART terminology. Fertil Steril 2006b;86:16– 19. Zegers-Hochschild F, Galdames V, Schwarze JE. Registro Latinoamericano de Reproduccio´n Asistida 2003– 2004. Santiago, Chile. Red Latinoamericana de Reproduccio´n Asistida, 2007.

doi:10.1093/humrep/den157

Human Reproduction 2008

Infertility in African countries: challenges created by the HIV epidemic S.J. Dyer1 Reproductive Medicine Unit, Department of Obstetrics and Gynaecology, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town 7925, South Africa 1

Correspondence address. E-mail: silke.dyer@uct.ac.za

HIV infection and infertility are two common reproductive health disorders in Africa. From the perspective of infertility-related reproductive health care, the HIV epidemic has created several challenges which include reduction of fecundity, depletion of scarce health resources, creation of barriers to infertility treatment and increased suffering. Infertility in turn is a risk factor for HIV acquisition and a possible force in the spread of the HIV epidemic. Recognition of the reproductive health needs and desires of HIV-infected infertile men and women is a prerequisite for addressing these challenges. Subsequent strategies comprise the development of treatment guidelines for low-resource environments and a greater integration of HIV and sexual and reproductive health services. Where resources for infertility treatment are not available, the consequences must be critically assessed. Keywords: infertility; HIV; assisted conception; reproductive health; Africa

Introduction Africa carries a high burden of reproductive ill health. Among this, infertility has been a relatively neglected problem for many years, overshadowed by seemingly greater concerns such as high rates of total fertility, maternal mortality, sexually transmitted diseases and genital tract malignancies (Bambra, 1999; Van Balen and Gerrits, 2001; Hollos, 2003). In recent years, greater attention to infertility and the attendant negative psychosocial consequences has rectified this situation to a certain extent. Several calls have been made for countries to show greater political willingness to address the problem of infertility, to integrate infertility care into existing reproductive health services and to develop guidelines for effective and affordable treatment options (Okonofua, 1999; Rowe, 1999; Van Balen and Gerrits, 2001). This progress in infertilityrelated reproductive health care is currently threatened by the HIV/AIDS epidemic, which, although a global disease, disproportionably affects men and women living in Africa. It is the aim of this review to outline the negative impact of HIV/AIDS on infertility and, to a lesser extent, childlessness (comprising infertility, pregnancy failure and infant death) in the context of African countries and to make recommendations how to address this. The review is underpinned by a MEDLINE search which identified relevant peer-reviewed Englishlanguage publications. Unless stated, the reproductive health needs of HIV-positive individuals who are presumed to be fertile are not addressed in the manuscript. The issues at hand are examined from the perspective of a health care worker involved in providing infertility care against a backdrop of a 48

high HIV prevalence rate in a resource-restricted environment. The existence of other perspectives from fields, such as ethics, health politics and health economics, is acknowledged.

The impact of HIV/AIDS on infertility Reduction of human fecundity Several studies have documented a reduction of human fecundity secondary to HIV infection. The mechanisms involved include greater susceptibility to pelvic inflammatory disease (with resultant tubal factor infertility), weight loss-related anovulation and amenorrhoea (although this has not been consistently documented), male hypogonadism (characterized by a decrease in serum testosterone levels and increased sex hormone-binding globulin) and impaired spermatogenesis. In addition, behavioural factors may also contribute (Zaba and Gregson, 1998; Lyerly and Anderson, 2001; Gilling-Smith et al., 2006). The clinical relevance of these mechanisms has been documented. A meta-analysis incorporating findings from both developing and developed world countries calculated an odds ratio for spontaneous spontaneous abortions of 4.05 (95% confidence interval 2.75â&#x20AC;&#x201C; 5.96) in HIV-positive women when compared with healthy controls (Brocklehurst and French, 1998). Large population-based studies conducted in East and Central Africa documented substantially lower pregnancy rates in HIV-positive women when compared with HIV-negative controls (Gray et al., 1998; Glynn et al., 2000). According to the data from the Ivory Coast, lower pregnancy rates and

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reduced live birth rates have been observed in HIV-positive women with low CD4 counts when compared with HIVinfected women with better immune status (Loko et al., 2005). Complications in the later stages of pregnancy include prematurity, low birthweight and of course neonatal HIV infection, all of which carry an attendant risk of early infant death (Gray and McIntyre, 2007). Collectively, these data indicate that in the presence of HIV, fertility is reduced and pregnancy outcome is compromised. It must be anticipated that the resultant increase of involuntary childlessness will further burden existing infertility and antenatal health services. Depletion of scarce health resources According to UNAIDS 18 billion US dollars were required for an expanded response to the HIV/AIDS epidemic in middle- and low-income countries in 2007 (UNAIDS, 2006). Although actual spending fell short of this target, the amount raised by governments and donors remains considerable. Funds, however, are not infinite and the prominent interest from donors in HIV/AIDS work has, unfortunately, been paralleled by a decrease in funding for sexual and reproductive health services (Gruskin et al., 2007). Barriers to infertility treatment Several arguments have been advanced for excluding HIV-infected infertile couples from infertility treatment. Briefly, they include the risk of horizontal and vertical transmission, the future morbidity and reduced lifespan of the prospective parent(s), and the risk of accidental HIV transmission to staff and of contamination in a gamete laboratory (Lyerly and Anderson, 2001; Ethics Committee of the American Society of Reproductive Medicine (ASRM), 2002). In resource-rich environments, the advent of antiretroviral therapy paralleled by other strategies to further reduce the risk of HIV transmission has largely nullified the above concerns. As a result, the categorical exclusion of HIV-positive infertile couples from infertility interventions is increasingly deemed unjustified (Ethics Committee of the ASRM, 2002; Gilling-Smith et al., 2006). Treatment protocols have been formulated stipulating the use of antiretroviral therapy in order to lower viral load in serum and semen (thereby minimizing the risk of vertical and horizontal transmission), the need for appropriately trained staff, adequate laboratory facilities which should be separated in time or in space from those facilities serving HIV-negative patients, as well as the importance of long-term follow-up (Lyerly and Anderson, 2001; GillingSmith et al., 2006). The bioethical arguments for and against infertility treatment of HIV-infected individuals do not differ between resource-rich and -poor environments. The tension between them seems, however, to be greater in developing countries and especially in Africa, where the prevalence of both HIV and infertility is very high. A leading argument in favour of infertility treatment is the importance of parenthood which, although a central life goal in most societies, appears to be of particular relevance in African countries where children have many roles in the lives of their parents and the community

(Okonofua et al., 1997; Dyer et al., 2007). In this context, infertility is associated with negative social consequences, which are both frequent and severe. They include, among others, marital instability, domestic abuse and neglect, loss of gender identity, loss of social status and security, stigmatization, social isolation and poverty (Gerrits, 1997; Okonofua et al., 1997; Sundby, 1997; Runganga et al., 2001; Dyer et al., 2002; Hollos, 2003; Dyer et al., 2004). These findings suggest that children facilitate the integration of adult men and women into a social network, which appears essential for life and survival in resource-poor environments. Denying couples access to infertility treatment based on their HIV status is therefore likely to have implications beyond those encountered in resource-rich environments. On the other hand, the rates of HIV/AIDS are high, reaching 15â&#x20AC;&#x201C; 30% of the adult population in many sub-Saharan countries. At the same time, access to antiretroviral therapy by people in need of treatment is 25% and lower in most of the region. Life expectancy has dramatically decreased in many countries and maternal mortality rates are rising secondary to HIV infection (UNAIDS, 2006; Gray and McIntyre, 2007). In the absence of government-led social security networks, communities are heavily affected by the HIV epidemic, not infrequently resulting in the collapse of family and community structures because of inordinate social and economic demands. Women, and increasingly also girls, are particularly burdened by the need to provide care, household labour and supplement income (Mehta, 2006; Gruskin et al., 2007). Moreover, 10 million HIV/AIDS orphans who live in Africa exceed the capacity of families and communities to care for them, and as a result many of these children face neglect and poverty (Hunter, 1990). Against this backdrop the up-regulation of fertility in HIV-positive individuals may be considered ill advised. While, as already stated, this debate around the provision of infertility services for HIV-infected couples is not unique to Africa, the greater divide between the arguments in favour and those opposing infertility treatments makes agreement and solutions more difficult to find. Distress and suffering The experiences of infertile HIV-positive men and women living in African countries are poorly documented. A qualitative study from South Africa showed that the combination of infertility and HIV infection was associated with considerable distress and suffering as well as anger and despair over the denial of access to infertility treatment (the study was conducted at a time when HIV-positive patients were excluded from infertility interventions because of lack of antiretroviral therapy). Study participants varied in their degree of knowledge regarding HIV-related risks in pregnancy, their assessment of personal vulnerability to these risks and their willingness to accept these (Dyer, 2006). In contrast to the lack of data on HIV and infertility, the psychosocial implications of HIV infection have been documented. Studies from Ghana and Uganda have born testimony to the crisis that the diagnosis of HIV can evoke and to the many personal and social difficulties that follow (Withell, 49

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2000; Mill, 2003). According to the data from South Africa and Zambia, the latter may include intimate partner abuse following women’s disclosure of their HIV status (Semrau et al., 2005; Sethosa and Peltzer, 2005). Closely linked to these consequences is a high level of stigmatization, which, although a global problem, appears to be particularly severe in many African communities (Withell, 2000; Mill, 2003). Contributing factors are the high mortality of HIV/AIDS in Africa, the relative lack of cure and treatment, and a belief that HIV/AIDS may be caused by supernatural forces or evil spirits (Mill, 2003). For the HIV-infected infertile couple, these negative implications of HIV/AIDS, to which frequently the experience of physical disease must be added, are combined with many negative consequences of infertility, which have already been outlined. Further research is urgently required in order to determine, how this combination of reproductive ill health impacts on the lives of men and women in Africa. The impact of infertility on the HIV epidemic Although for the above reasons, the HIV/AIDS epidemic has created several challenges for infertility-related reproductive health care, the corollary also applies. Infertility is a serious threat to marital stability in African countries as children are frequently considered the purpose of marriage (Sonko, 1994; Okonofua et al., 1997). Polygamy secondary to infertility has been documented in several studies (Gerrits, 1997; Sundby, 1997; Hollos, 2003; Dyer et al., 2004). Against a backdrop of high prevalence rates of both infertility and HIV/AIDS, the concern that infertility might be a driving force of the HIV epidemic in Africa appears justified (Favot et al., 1997). This implies that infertility may represent a relevant threat to the Millenium Development Goal of halting and starting to reverse the spread of HIV/AIDS by 2015. According to an ethnographic study from Botswana, both infertility and HIV were interpreted as an incurable illness of the female blood that could be caused by a number of factors including contraception (Upton, 2002). Men, according to belief, could contract the illness from women but could obtain cure through sexual intercourse with other women, especially virgins. The existence of this virgin cleansing myth has also been documented in other regions (Bambra, 1999). In Tanzania, higher HIV prevalence rates have been reported among infertile women when compared with pregnant women (18.25 versus 6.6%) (Favot et al., 1997). In this study, infertile women had a higher number of sexual partners and were less confident about the sexual fidelity of their current partner. Fear of contraception is a further mechanism through which infertility may increase the risk of HIV acquisition. The belief that contraception can cause (permanent) infertility is widespread in Africa (Okonofua et al., 1997; Upton, 2002; Dyer et al., 2004). As childlessness is a dreaded condition for which there is frequently no cure, this belief creates a relevant barrier to the use of contraception including barrier methods. Recognizing infertility as a risk factor for HIV infection is of importance as the universal advice of ‘safer sex’ does not 50

address the needs of the involuntarily childless and will thus do little to contain the spread of the epidemic in this setting. Addressing the challenges Combating the HIV epidemic A central strategy for addressing the negative impact of HIV/ AIDS on human reproduction is to combat the HIV epidemic. Prevention of HIV infection through the promotion of safer sexual practices will also help to prevent infertility. Owing to the widespread lack of accessible and effective treatment, infertility prevention is very important. Primary prevention of HIV and infertility will in turn help to reduce the rate of involuntary childlessness in the region. HIV/AIDS intervention strategies, centred on antiretroviral therapy, will remove most of the arguments upheld against providing infertility treatment to HIV-infected couples, as we have observed in Western industrialized countries. Furthermore, it can be speculated that antiretroviral therapy may reduce the risk of pregnancy-related sepsis, which is a prominent risk factor for infertility in Africa (Okonofua, 1999). Whether the low pregnancy and live birth rates documented in women with low CD4 counts can be improved through antiretroviral therapy remains to be demonstrated (Loko et al., 2005). Relative drawbacks of this approach include the time span required for the implementation of appropriate and effective HIV/AIDS health programmes and, as previously mentioned, the attendant depletion of limited health resources. It would seem, however, that the advantages outweigh these disadvantages. Health care workers involved in the management of infertility should therefore strengthen the HIV-related health services, wherever possible, while at the same time motivating for appropriate reproductive health services which include infertility care. The need for the convergence of HIV and sexual and reproductive health services is increasingly recognized (Gruskin et al., 2007). Recognizing reproductive desires and health needs To date, the desire of HIV-infected men and women to have children has frequently been overlooked or indeed opposed. In South Africa, negative attitudes toward spontaneous and assisted conception in HIV-infected individuals have been observed in local communities, among health care workers and among HIV-negative infertile couples (De Bruyn, 2004; Dyer, 2006). Violations of women’s reproductive rights secondary to HIV infection have been documented in Asian countries (UNAIDS, 2006). A study from Brazil reported the lack of counselling of HIV-positive patients on issues related to relationships and fertility (Paiva et al., 2003). In contrast, several authors have documented the wish for a child among HIV-positive men and women in both developing and developed countries. In a review of HIV and reproductive health, Temmerman et al. (1994) noted that many women living with HIV in Africa choose to become pregnant and that the presence of AIDS defining illnesses or a previous HIVpositive child were not deterring factors in this regard. A study from Rwanda observed low contraceptive usage and similar pregnancy rates in HIV-positive women when compared with

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HIV-negative participants, although the former had received counselling on prevention of HIV transmission and contraception and had been discouraged from childbearing because of the associated risks (Allen et al., 1993). This finding was attributed to the need to ensure family survival and to women’s desire to lead a ‘normal’ life despite HIV infection. A French survey conducted among 1200 HIV participants documented a wish for a child in 33% of women and 20% of men. This desire was positively influenced by childlessness, living with an HIV-negative partner and being of African origin, but not by HIV-related health status (Heard et al., 2007). Clearly, an important prerequisite for addressing the reproductive needs of HIV-positive men and women is to acknowledge that some will desire children and that this desire is, in principle, legitimate. Only when this reproductive right is recognized can further strategies be developed subject to available resources. Even in the absence of resources for infertility treatment, health education and compassionate counselling based on an understanding of the dual burden of HIV and infertility is likely to relieve some of the suffering. The importance that infertile patients attach to information and emotional support has been documented in developed countries (Malin et al., 2001). It can be speculated that this is of even greater relevance in developing countries where access to health information through avenues other than health care workers is limited and where the psychosocial consequences of HIV and infertility are particularly severe. Looking for opportunities Most challenges also harbour opportunities and these need to be identified. The reproductive health needs of the presumed fertile HIV-infected couple may represent such an opportunity. Presumed fertile couples can make an autonomous decision to conceive and do not per se require medical intervention to do so. They may, however, request assistance in order to minimize the risks associated with conception and pregnancy. Refusal of medical assistance would appear morally wrong since reduction of risk and prevention of harm are essential to medical practice (Pennings, 2003). In contrast, infertile couples require assistance for conception and not only for risk reduction. As a result, the physician carries responsibility for the pregnancy outcome and may, in principal, refuse cooperation if this assistance is considered morally unacceptable (Pennings, 2003). This implies that there may be a greater moral imperative to offer fertility assistance to HIV-positive fertile couples when compared with infertile couples. This may represent an opportunity and indeed the obligation to put services in place (through HIV/AIDS-related funds rather than through the scarce funds available for infertility), which may ultimately benefit all patients in need of fertility treatment. A different opportunity has arisen in South Africa, where the Department of Health has initiated a National Policy and Guidelines on Fertility Options with the aim to ‘provide fertility services to all who need them’ and, specifically, to protect the reproductive rights of HIV-positive women. To date, fertility services in South Africa remain very limited especially in the public health sector, and greater political

commitment is likely to improve this shortcoming. This serves as another example how the HIV/AIDS epidemic may create positive spin-offs for infertility-related reproductive health services. Formulating management guidelines In the Western industrialized world, protocols and/or treatment guidelines have been formulated for the management of HIV-infected infertile couples (FIGO Committee for the Ethical Aspects of Human Reproduction and Women’s Health, 2006; Gilling-Smith et al., 2006; Practice Committee of the ASRM, 2006). Published data on the availability of protocols or guidelines in African countries are lacking. It can therefore be speculated that health care workers either operate without protocols or adapt international guidelines to their local setting as considered suitable. As a result, patients’ experiences with infertility management are likely to vary considerably, ranging between refusal of treatment, treatment that is not modified by HIV infection, and best practice infertility care. Guidelines for infertility management of HIV-infected couples in resource-poor environments are urgently required. Although this process should draw on the experience and evidence gained in developed countries, it also requires critical evaluation as to what constitutes minimum standard of care in the resource-poor environment. This evaluation must take cognizance of the suffering associated with infertility and HIV/AIDS and of the related need for intervention. Interventions should, however, not put the health and life of women or their children at risk. They should also be culturally feasible, economically sustainable, and accepted by the community in order to ensure that treatments, or their outcomes, are not discredited (Hamberger and Janson, 1997). Moreover, these guidelines should be incorporated into existing sexual and reproductive health care programmes which in turn, as previously stated, require convergence with HIV-related health services. In order to achieve this goal, input is needed from various role players including, among others, infertility specialists, reproductive scientists, obstetricians, HIV physicians, health politicians and the public. Once the minimum standard of care has been formulated for a specific region, the discrepancy between available and required resources can be assessed. Small gaps should be overcome relatively easily and health care delivery can follow. The problem lies in areas where the gap is too wide, and as a result infertility treatment to HIV-infected individuals may not be considered feasible at present. Future efforts should of course be directed at reducing this gap, but depending on resources and competing health needs this may be a lengthy process. In this instance, the consequences of denied infertility treatment due to inadequate resources (including antiretroviral therapy) must be evaluated. ‘Positive’ consequences may include avoidance of HIV-related risks in pregnancy, avoidance of adding to the community burden through fertility up-regulation in HIV-positive individuals and, arguably, the saving of resources. Negative consequences are likely to comprise an increased risk of horizontal transmission to an uninfected partner and/or to other partners through polygamy, 51

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spontaneous conceptions without any form of medical risk reduction, patients’ disillusionment with the modern health sector with possible implications on future health-seeking behaviour, loss of social support and security commonly rendered by children, as well as an overall loss of hope and sense of future for the men and women affected. These consequences, both positive and negative, should be assessed on an ongoing basis, evaluated against available resources and brought to the attention of health care planners and politicians in order to inform the process of resource allocation.

Conclusions The HIV/AIDS pandemic has compounded the problem of infertility in Africa by reducing fecundity, absorbing precious health resources on a large scale and creating barriers to the access of infertility treatment. In addition, the stigma associated with both conditions is likely to cause considerable suffering as well as socio-economic deprivation. Infertility in turn is a risk factor for HIV acquisition and, because of the high prevalence of infertility, a relevant threat to health strategies aimed at containing the HIV epidemic. To date, the debate on HIV and infertility has been argued predominantly in the developed world. There is now an urgent requirement to explore and address the challenges associated with HIV and infertility in Africa, which overwhelmingly bears the major burden worldwide of both conditions. Central strategies include recognizing reproductive health needs and desires, developing management guidelines and finding an integrated approach to HIV and sexual and reproductive health services.

Acknowledgements The author would like to thank Professor Zephne M van der Spuy for the support of her research interests and for editorial assistance with this manuscript.

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Human Reproduction 2008

doi:10.1093/humrep/den162

Modern endoscopic-based exploration of the female reproductive tract: a model for developing countries? Rudi Campo1,2,4 and Carlos Roger Molinas1,3 1 3 4

European Academy of Gynaecological Surgery, Leuven, Belgium; 2Leuven Institute for Fertility and Embryology, Leuven, Belgium; Centre for Gynaecological Endoscopy, Centro MeÂ´dico La Costa, AsuncioÂ´n, Paraguay Correspondence address. E-mail: rudi.campo@lifeleuven.be

Introduction Infertility has been notorious for its time-consuming and prolonged explorations and the resultant delay in diagnosis. This delayed diagnosis adds to the burden of the patient and, in spite of the higher pregnancy rate and lower cost reported with traditional treatment algorithm as first-line therapy compared with liberal referral to assisted reproduction technologies (ART) (Karande et al., 1999), has stimulated physicians and specialized centres to promote the latest approach. This strategy has the additional problem, especially for developing countries, that ART carry a higher risk of neonatal and maternal morbidity than natural conception, even in the absence of multiple pregnancy (Helmerhorst et al., 2004; Ombelet et al., 2005, 2006). Recent observations demonstrate that exploration of the female reproductive tract is not only useful for diagnosis and treatment but also necessary for enhancing the in vitro fertilizationâ&#x20AC;&#x201D;embryo transfer (IVF-ET) results. Indeed, a Cochrane review including three RCT shows that laparoscopic salpingectomy prior to IVF-ET in patients with hydrosalpinges improves pregnancy, ongoing pregnancy and live birth rates (Johnson et al., 2002). Furthermore, the incremental cost of the surgical intervention to achieve this higher live birth rate was reported to be beneficial (Strandell et al., 2005). Everybody agree on the value of an accurate exploration of the female reproductive tract for the management of infertility but opinions greatly differ as how and to which extent these investigations should be performed. In current practice hysterosalpingography (HSG) is still used as a first-line investigation, although it is not a pain-free (Tur-Kaspa et al., 1998) and riskfree procedure and even when its sensitivity, specificity and prognostic values for the management of the infertility are debatable (Glatstein et al., 1997; Swart et al., 1995; Mol et al., 1997, 1999). This option is largely based on the absence of alternatives since endoscopic procedures (e.g. conventional laparoscopy and hysteroscopy) demanding high skills and sophisticated equipments do not fulfil the criteria of being minimally invasive, affordable and accessible. Although conventional laparoscopy is considered the gold standard for the exploration of the female reproductive tract, 54

it is for several reasons not suitable as a first-line investigational technique. Laparoscopy is an expensive procedure requiring hospitalization, operating room and general anaesthesia, as in open abdominal surgery. The procedure is invasive and not without morbidity and mortality. Indeed, even in experienced hands the blind transabdominal access can cause major blood vessel and bowel injury (Jansen et al., 1997; Brosens et al., 2003), whereas the distension medium (i.e. CO2 pneumoperitoneum) causes discomfort and additional hazards (Molinas and Koninckx, 2000; Molinas et al., 2001; Nguyen et al., 2002; Kissler et al., 2004). Furthermore, the see-and-treat possibility of laparoscopy requires the presence of a high skilled reproductive surgeon at the diagnostic screening procedure, which is not always feasible. The exploration of the female reproductive tract should be as easy as HSG and as accurate as standard laparoscopy. No conclusive answer has been given until now, but the transvaginal ultrasound and endoscopic procedures offer probably the most efficient and accurate solution to the problem. The challenge is for both developed as developing countries identical: to find a low cost and easily accessible diagnostic procedure with operative possibilities for offering the fastest and minimal invasive lane to pregnancy. In this article we outline a challenging concept for the management of infertility in both developed and developing countries: a model based on ambulatory endoscopic techniques (i.e. modern mini-hysteroscopy and transvaginal laparoscopy) for the exploration of the female reproductive tract, describing their diagnostic and operative possibilities and limitations.

Ambulatory endoscopic exploration of the female reproductive tract In order to propose the systematic use of transvaginal endoscopic procedures, such as mini-hysteroscopy and transvaginal hydro-laparoscopy (TVL), and to avoid the still wellestablished delay in indication, it is mandatory to perform the technique in an easily accessible ambulatory environment, ideally at the same time as the transvaginal sonography (TVS). The most important challenge for this approach is to

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be able to perform the procedure with an acceptable patient compliance, high accuracy and low complication rate. The scientific evidence gathered over the last years and the major technical improvements in the manufacturing of high-quality small-bored scopes have indicated how diagnostic hysteroscopy should be performed in the office. Although TVL requires advance endoscopic skills, the required basic skills and instrumentation are similar to those required for hysteroscopy. Endoscopic materials and instruments Distension media Low viscosity fluids with electrolytes (e.g. saline, Ringer lactate) are used for uterine or abdominal distension during hysteroscopy and TVL, respectively. In contrast with CO2, fluids are easier to use and offers better patient compliance and excellent visualization capacity due to the rinsing and the hydroflotation (i.e. lesions floating in the watery low pressure environment) effects. To control pressure and flow a simple gravity fall system or a pressure cuff can be used. Endoscopic hardware All-in-one equipments are available for ambulatory procedures. They have the advantages of being easily transportable with acceptable cost– efficiency ratio. The TELE PACK (Karl Storz) is a comprehensive, multifunctional and compact documentation terminal that can be used as a compact system in the doctor’s office or as a secondary system in the operating room consisting of an input unit (inbuilt, high-quality membrane keyboard and text generator for entering patient data), documentation (flexible, all-purpose PCMCIA memory card for recording still images; easy transfer of data to AIDA and PC), camera control unit, illumination (HiLux high-performance light source) and image display (foldaway LCD colour monitor). Endoscopes and diagnostic shafts The optics available are the 2.9 and the 2.0 mm (for minihysteroscopy) 308 forward-oblique rigid telescopes. For diagnostic purposes the former is used with a single-flow diagnostic sheath of 3.7 mm (hysteroscopy and TVL), whereas the latter is used with a single-flow diagnostic sheath of 2.8 mm (hysteroscopy). Both diagnostic sheaths have a round shape. Operative shafts for hysteroscopy For operative purposes the mentioned optics can be assembled in a single- or double-flow operative sheath of 4.2 or 5.0 mm, respectively. Theses operative sheaths have an oval shape to reduce the instrument diameter as much as possible and a working channel for 5 Fr instruments. System for diagnostic TVL The system includes a puncture needle (diameter 1.5 mm, length 30 cm) with automatic spring mechanism, the dilation sheath (diameter 3.8 mm, length 30 cm) and the trocar sheath (diameter 4.4 mm, length 20 cm). The system is assembled with the needle inside the dilation and both inside the trocar. The length of the needle tip can be preset at 10 – 25 mm.

Operative shaft system for TVL For operative procedures an operative sheath (diameter 6.6 mm) with an atraumatic tip and a working channel for 5 Fr instruments is used. A guide mandrin (diameter 2.9 mm) is used to replace the diagnostic sheath for the operative one. Accessory 5 Fr instruments for both operative hysteroscopy and TVL Mechanical (e.g. crocodile grasping forceps, spoon and punch biopsy forceps, sharp and blunt scissors) and electrical (e.g. bipolar needle, bipolar coagulation probe) instruments are available. Disinfection of instruments Although the vagina is a non-sterile environment the implementation of ambulatory hysteroscopy depends on the inter-procedure instrument disinfection capacity. The disinfection procedure should be rapid and suitable for performing in the same room where the endoscopic procedure is performed. The disinfection product should be non-toxic (i.e. aldehydefree), biodegradable, effective against all kinds of microorganisms, inclusive resistant spores, cheap, easy to use, instrument friendly. Tristel fusion (Tristel Solutions Limited) is a disinfecting solution for medical devices including instruments such as endoscopes and it is proven to be effective against bacteria, fungi, viruses and even the most resistant spores in a very short contact time (5 min). The ambulatory approach reduces cost significantly Infertility exploration is a demanding condition both personally and financially. Current estimates are that 10.7% of couples in the US between 18 and 45 years seek care for infertility and that the total costs for evaluating and caring for the infertile couple amounts to 3 billion US$ (Wilcox and Mosher, 1993). Laparoscopy has a high yield but can amount up to 70% of the total infertility evaluation cost (Bates and Bates, 1996). Undoubtedly, the impact and actual monetary expense of the infertility evaluation could be reduced by prompt and efficient office evaluation. The above described instrumentation set up provides a full operational endoscopic unit for not more than the price of a cheap ultrasound machine. The running costs are moreover very low when only reusable instrumentation is used and the fast low cost disinfection procedure offers the possibility to reduce the total amount of instruments necessary for a working day. The primary use of TVL for infertility management would eliminate hospital costs. The benefit depends on the rate of conversion to standard laparoscopy. The increasing use of office operative TVL (e.g. ovarian drilling) (Fernandez et al., 2001; Moore and Cohen, 2001; Gordts et al., 2002, 2004) is likely to boost the cost – benefit of TVL over laparoscopy. Hysteroscopy Technique The examination starts with TVS to evaluate the uterus and the adnexal region. Then, vaginal disinfection with a 55

Campo and Molinas

non-irritating watery solution is performed without placing a speculum. The tip of the mini-hysteroscope is positioned in the vaginal introit and the vagina is distended with the same medium used for the uterine cavity. The scope is driven to the posterior fornix to visualize the portio and slowly backwards to identify the external cervical os. When this is visible, the scope is introduced into the cervical canal and after achieving its distension the scope is carefully moved forward to the internal cervical os and then to the uterine cavity. The anatomical landmarks (i.e. tubal ostia) and the uterine fundus and walls (i.e. laterals, anterior and posterior) are systematically explored by rotating the 308 fore-oblique scope. The technique requires a good knowledge of the physics and instrumentation as well as dexterity from the operator (i.e. the correlation between what is seen in the screen and the actual position of the 308 scope) to avoid unnecessary movements and to reduce patient discomfort (Campo et al., 1999a, b). Immediately after the hysteroscopy, a second TVS is performed taking advantage of the intracavity fluid for a contrast image of the uterus.

Feasibility of diagnostic hysteroscopy To evaluate the factors influencing the success rate of office diagnostic hysteroscopy, we have conducted a RCT including 480 patients (Campo et al., 2005). The effects of instrument diameter (conventional hysteroscopy: 4.0 mm optic with 5.0 mm sheath or mini-hysteroscopy: 2.7 mm optic with 3.5 mm sheath), patient parity (with or without vaginal deliveries) and surgeon’s experience (with or without experience in office hysteroscopy) were evaluated. The following variables were assessed: pain [10-cm visual analogue scale, 0 (no) – 10 (intolerable)], quality of visualization of the uterine cavity (0, no; 1, insufficient; 2, sufficient; 3, excellent) and complication rate. The procedure was considered successful only when pain was ,4, visualization was sufficient or excellent and when no complications occurred. In comparison with conventional hysteroscopy, mini-hysteroscopy was associated with less pain and better visualization. Due to the overall low complication rates, no differences could be detected between both groups. The success rate of minihysteroscopy (87%) was significantly higher than of conventional hysteroscopy (44%). In a multifactorial analysis, pain, visualization and success rate were highly influenced by instrument diameter and patient parity and only slightly influenced by surgeon’s experience. A better performance was observed with the use of mini-hysteroscopy, in patients with vaginal deliveries and in procedures performed by experienced surgeons. The effects of patient parity and surgeon’s experience were even more significant when conventional hysteroscopy was performed. This was not surprising since in those patients and in those surgeons an easier access to the uterine cavity and less traumatic manoeuvres, respectively, can be expected. Interestingly, both patient parity and surgeon’s experience were no longer important when mini-hysteroscopy was performed, indicating that a small diameter endoscope can counteract the difficulties determined by the anatomy and by the operator (Campo et al., 2005). 56

Hysteroscopic findings The findings are recorded in a standardized pre-design form. A complete visualization of cervical canal, uterine cavity and tubal ostia and absence of any anatomical alterations is required to categorize the examination as normal. It is considered abnormal when major or minor lesions, regardless their clinical significance, are detected (Molinas and Campo, 2006). If the visualization is insufficient for any reason, it is stated that the examination failed to achieve a diagnosis. Major lesions Major lesions are arbitrarily defined as those that structurally change the normal hysteroscopic anatomy (e.g. cervical stenosis, endocervical polyps, submucous myoma, endometrial polyps, congenital malformations, adhesions, necrotic tissue, tubal os stenosis, foreign bodies) (Molinas and Campo, 2006). Minor lesions Minor lesions or subtle lesions are those changes of the appearance without deformation of the normal anatomy, where the clinical significance is not always proven but where the hysteroscopic picture is different from the normal situation (e.g. diffuse polyposis, hypervascularization, strawberry pattern, moderate/marked localized/generalized mucosal elevation, endometrial cysts or greets) (Molinas and Campo, 2006). In the infertile patient these lesions can be the (co)factor of the infertility or at least impairs the results of ART treatments. In a recently published RCT including 480 infertility and AUB patients we observed normal findings in 55% of the cases and abnormal findings in 41% of the cases, whereas no diagnosis could be obtained in 4% of the cases (Campo et al., 2005). Interestingly, normal and abnormal findings were not equally distributed in patients with infertility or AUB. Indeed, in infertility patients the findings were normal in 67% of the cases and abnormal in 29% of the cases, whereas no diagnosis could be obtained in 4% of the cases. In AUB patients, however, the findings were normal in only 46% of the cases and abnormal in 51% of the cases, whereas no diagnosis could be obtained in 3% of the cases. Furthermore, the specific findings were significantly different in both groups of patients (Molinas and Campo, 2006). Operative hysteroscopy Pathologies causing or contributing to the infertility, or at least impairing the ART results, detected during diagnostic hysteroscopy can be, depending on the nature and severity of the abnormality, either treated in the same set up or scheduled for treatment in the conventional operating room. Cervical stenosis, small endocervial or endometrial polyps, lost foreign bodies (e.g. IUD), some uterine adhesions and congenital anomalies (i.e. uterine septum and T-shaped uterus) can be treated in an ambulatory setting with or without some sort of analgesia or sedation, according to the severity of the pathology, the characteristics of the patient, the experience of the surgeon and the available facilities. Since treatment is done with the same distension medium only bipolar instruments can be used for thermal energy.

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Transvaginal hydro-laparoscopy Indications for diagnostic TVL TVL, one of the earliest examples of Natural Orifice Transluminal Endoscopic Surgery (NOTES) (Gordts et al., 1998), is indicated for the exploration of the reproductive tract in patients with primary or secondary infertility without any obvious pathology at an early stage of the infertility exploration, making the use of HSG unnecessary. Contraindications for the procedure are intact hymen, narrow vagina, acute infections, obliterated cul de sac, fixed retroverted uterus, extreme obesity, haemoperitoneum and tumours prolapsed in the pouch of Douglas. Technique for diagnostic TVL The procedure is performed in the same ambulatory setting with the patient in dorsal lithotomy position. A vaginal examination and TVS are performed to assess the size and position of the uterus and to exclude any contraindications of the procedure. The vagina is disinfected and a hysteroscopy is performed, as described above (Campo et al., 1999a, b). Then, a Collin speculum is placed in the vagina and local anaesthesia is applied in the centre of the posterior fornix and in the posterior lip of the cervix, which is grasped and pushed forwards. The specially designed needle-dilating-trocar system is placed in the midline at 10 â&#x20AC;&#x201C; 15 mm below the insertion of the vaginal wall on the cervix. According to the characteristics of the patient, the needle is pre-set (usually at 15 mm) and inserted using the spring load system. Then, dilator and trocar are pushed forward to enter into the abdominal cavity using the needle as a guide. The right intra-abdominal position of the trocar is confirmed visually and then the fluid distension medium is slowly introduced (Gordts et al., 1998). In contrast to standard trans-umbilical CO2 laparoscopy, panoramic view cannot be obtained, making necessary a strict standardization of the procedure, as described previously (Gordts et al., 1998; Campo et al., 1999a, b). After recognition of the posterior uterine wall (primary anatomical landmark), the optic is rotated and directed towards either the left or the right side to individualize the utero-ovarian ligament and the istmical portion of the tube (secondary anatomical landmark). Then, the tube is inspected going downwards in direction of the fimbria. The entire ovarian surface and the pelvic side wall, including the ovarian fossa, are also examined. A salpingoscopy is also performed when feasible. The same procedure is performed to explore the contra-lateral side. Finally, the utero-sacro ligaments are inspected and the tubal patency is checked by the intra-uterine instillation of diluted methylene blue. The fluid used during the procedure (normally 200â&#x20AC;&#x201C; 400 ml) should be removed at the end of the examination through the trocar. The puncture site in the posterior fornix is not sutured unless there is active bleeding. Patients are informed that some vaginal leakage or bleeding may occur and are advised to do not use vaginal tampons and to abstain from intercourse for some days. Feasibility of diagnostic TVL The initial experience with diagnostic ambulatory TVL under local anaesthesia was evaluated to determine the feasibility of

the procedure (Gordts et al., 2000). Out of the first 157 patients with primary or secondary infertility undergoing the procedure, access to the abdominal cavity was achieved in 94.5% of the cases and not possible in 4.6% of the cases. In 0.9% of the cases the procedure was aborted due to complications. The feasibility has then been confirmed by several authors (Watrelot et al., 1999; Bajzak et al., 2000; Darai et al., 2000; Dechaud et al., 2001; Moore and Cohen, 2001; Verhoeven et al., 2004). Patient compliance for diagnostic TVL During the initial experience with TVL, 60 consecutive patients were asked to rank the pain experienced during the examination at the end of the procedure on a 10 cm visual analogue pain scale. The pain score (mean + SD) was 2.7 + 1.5, in 8% of the cases the score being .5. Ninety-six per cent of the patients agreed to repeat the procedure under the same circumstances if this would be required (Gordts et al., 2000). Other authors reported similar figures (Moore et al., 2003) and concluded that TVL together with hysteroscopy under local anaesthesia was better tolerated than HSG (Cicinelli et al., 2001). Accuracy of diagnostic TVL The accuracy of the technique for the diagnosis of tubo-ovarian pathology in infertility has been widely reported (Watrelot et al., 1999; Bajzak et al., 2000; Darai et al., 2000; Dechaud et al., 2001; Moore and Cohen, 2001; Shibahara et al., 2001). In a prospective study, 10 patients were explored by two different endoscopists with both TVL and standard laparoscopy. The inter-observer agreement for ovarian adhesions was 75% for standard laparoscopy and 90% for TVL (Campo et al., 1999a, b). In patients with mild endometriosis more ovarian adhesions were detected with TVL than with standard laparoscopy (Brosens et al., 2001). These non-connecting filmy adhesions, which clinical significance still requires further investigation, could be detected with TVL due to the hydroflotation, but not with standard laparoscopy because the pneumoperitoneum flattered and masked them against the surface of the ovary or the abdominal wall. For the diagnosis of tubal patency, 95% of agreement between TVL and HSG was reported (Cicinelli et al., 2001). In the same study a bilateral spilling of the methilen blue was seen at TVL in a case of bilateral proximal obstruction previously diagnosed at HSG. Other authors failed to find differences for tubal patency between HSG and TVL but found that TVL was superior for the diagnosis of peritubal adhesions (Shibahara et al., 2001). Safety of diagnostic TVL The transvaginal access for pelvic endoscopy was initially used in culdoscopy, but due to the higher incidence of bowel injury and risk of sepsis it was abandoned in favour of standard laparoscopy (Copenhaver, 1970). Although the access of TVL is similar to culdoscopy, the technique differs because of the use of small instruments, the patient position, the nonirritant saline distension medium and the absence of exteriorization for surgical procedures. Nevertheless, concern has been 57

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expressed for the risk of bowel injury and sepsis. The TVL needle-dilator-trocar system was specially designed to minimize the injury by the blind insertion of the instruments and the consequences of possible injuries, such as infection, rectum perforation, bleeding and uterus puncture. A multinational survey evaluating the risk and outcome of bowel injury during TVL registered 24 bowel injuries in 3667 procedures (0.65%). After the initial experience, the prevalence of this complication decreased to 0.25%. There was no delayed diagnosis and all injuries were managed expectantly without complications (Gordts et al., 2001). To evaluate the risk of infection after TVL, a large prospective study has to be performed but other transvaginal needle techniques, such as ovum retrieval, carry a low risk of infection, which is estimated at 0.4% whether or not vaginal disinfection is performed (Dicker et al., 1993; Roest et al., 1996). Operative TVL In addition to the pure diagnostic procedure, TVL allows some operative procedures, taking advantages of the direct access to the pelvis and the internal genital organs without the need for any supplementary manipulation, the hydroflotation and the close contact with the organs. These procedures are limited to those not requiring a panoramic view of the total pelvis and are performed under general anaesthesia or sedation in a one day care centre. The fluid distension medium demands a meticulous haemostasis during the interventions, since any minor bleeding might severely impair the visualization. The operative possibilities of TVL are still being evaluated and promising results were observed so far for PCOS and mild endometriosis and intra-peritoneal adhesions (Gordts et al., 2002, 2004). Other lesions must be referred to standard laparoscopy for appropriate treatment. Conclusions Since both the number and the age of patients with infertility is increasing, the probability of finding intra-uterine pathology in infertile patients is also increasing, which is consistent with the high incidence of intra-uterine pathology reported after several IVF failures (Oliveira et al., 2003). This indicates the necessity to revisit the time and form for evaluating the uterine factor. The characteristics of modern hysteroscopy (mini-instruments, atraumatic technique and fluid distension medium) (Nagele et al., 1996; Bettocchi and Selvaggi, 1997; Campo et al., 1999a, b, 2005) makes the technique a suitable first-line office diagnostic procedure for the investigation of the infertile patients, and permits to conclude that it is unacceptable not to implement the diagnostic hysteroscopy in the routine exploration of the infertile patient. Due to the close vision and the hydro-flotation principle TVL allows detailed examination of the reproductive organs in their natural position and full evaluation of the tubal factor (salpingoscopy and patency test). In the absence of contraindications it can be offered as a first-line diagnostic procedure since it is better predictor of future fertility than HSG. Both hysteroscopy and TVL allows the detection of major and minor lesions that can cause or contribute to the infertility, or at 58

least impairs the results of ART treatments. Major lesions diagnosed at hysteroscopy can be treated in the same ambulatory setting or referred to the operating room, depending on the characteristics of the pathology and the patient and on the facilities available. The clinical significance of the minor lesions detected at hysteroscopy is still unclear and under evaluation and therefore no systematic treatment can be proposed. In conclusion, the available data indicate that an endoscopybased model has a major role and is feasible for the management of infertility. This role is even more important in developing countries where the vast majority of the population is younger than in developed countries and with limited access to ART and where the incidence of surgical pathologies, such as hydrosalpinx and myomas, is higher. Since endoscopic surgery demands specific skills that are usually not acquired during the residence programme in Obstetrics and Gynaecology, the establishment of standardized training programme for endoscopic surgery, at least for the diagnostic procedures, in the frame of a general training system for all aspects related with the management of infertility, will greatly benefit patients and society.

References Bajzak KI, Winer WK, Lyons TL. Transvaginal hydrolaparoscopy, a new technique for pelvic assessment. J Am Assoc Gynecol Laparosc 2000;7:562–565. Bates GW, Bates SR. The economics of infertility: developing an infertility managed-care plan. Am J Obstet Gynecol 1996;174:1200– 1207. Bettocchi S, Selvaggi L. A vaginoscopic approach to reduce the pain of office hysteroscopy. J Am Assoc Gynecol Laparosc 1997;4:255– 258. Brosens I, Gordts S, Campo R. Transvaginal hydrolaparoscopy but not standard laparoscopy reveals subtle endometriotic adhesions of the ovary. Fertil Steril 2001;75:1009– 1012. Brosens I, Gordon A, Campo R, Gordts S. Bowel injury in gynecologic laparoscopy. J Am Assoc Gynecol Laparosc 2003;10:9– 13. Campo R, Gordts S, Rombauts L, Brosens I. Diagnostic accuracy of transvaginal hydrolaparoscopy in infertility. Fertil Steril 1999a;71:1157–1160. Campo R, Van Belle Y, Rombauts L, Brosens I, Gordts S. Office minihysteroscopy. Hum Reprod Update 1999b;5:73–81. Campo R, Molinas CR, Rombauts L, Mestdagh G, Lauwers M, Braekmans P, Brosens I, Van Belle Y, Gordts S. Prospective multicentre randomized controlled trial to evaluate factors influencing the success rate of office diagnostic hysteroscopy. Hum Reprod 2005;20:258–263. Cicinelli E, Matteo M, Causio F, Schonauer LM, Pinto V, Galantino P. Tolerability of the mini-pan-endoscopic approach (transvaginal hydrolaparoscopy and minihysteroscopy) versus hysterosalpingography in an outpatient infertility investigation. Fertil Steril 2001;76:1048–1051. Copenhaver EH. A critical assessment of culdoscopy. Surg Clin North Am 1970;50:713–718. Darai E, Dessolle L, Lecuru F, Soriano D. Transvaginal hydrolaparoscopy compared with laparoscopy for the evaluation of infertile women: a prospective comparative blind study. Hum Reprod 2000;15:2379– 2382. Dechaud H, Ali Ahmed SA, Aligier N, Vergnes C, Hedon B. Does transvaginal hydrolaparoscopy render standard diagnostic laparoscopy obsolete for unexplained infertility investigation? Eur J Obstet Gynecol Reprod Biol 2001;94:97 –102. Dicker D, Ashkenazi J, Feldberg D, Levy T, Dekel A, Ben-Rafael Z. Severe abdominal complications after transvaginal ultrasonographically guided retrieval of oocytes for in vitro fertilization and embryo transfer. Fertil Steril 1993;59:1313–1315. Fernandez H, Alby JD, Gervaise A, de Tayrac R, Frydman R. Operative transvaginal hydrolaparoscopy for treatment of polycystic ovary syndrome: a new minimally invasive surgery. Fertil Steril 2001;75:607–611. Glatstein IZ, Sleeper LA, Lavy Y, Simon A, Adoni A, Palti Z, Hurwitz A, Laufer N. Observer variability in the diagnosis and management of the hysterosalpingogram. Fertil Steril 1997;67:233– 237.

Endoscopic exploration of the infertile patient Gordts S, Campo R, Rombauts L, Brosens I. Transvaginal hydrolaparoscopy as an outpatient procedure for infertility investigation. Hum Reprod 1998;13: 99–103. Gordts S, Campo R, Brosens I. Office transvaginal hydrolaparoscopy for early diagnosis of pelvic endometriosis and adhesions. J Am Assoc Gynecol Laparosc 2000;7:45 –49. Gordts S, Watrelot A, Campo R, Brosens I. Risk and outcome of bowel injury during transvaginal pelvic endoscopy. Fertil Steril 2001;76:1238–1241. Gordts S, Campo R, Brosens I. Experience with transvaginal hydrolaparoscopy for reconstructive tubo-ovarian surgery. Reprod Biomed Online 2002; 4(Suppl 3):72–75. Gordts S, Brosens I, Gordts S, Puttemans P, Campo R. Progress in transvaginal hydrolaparoscopy. Obstet Gynecol Clin North Am 2004;31:631–639. x. Helmerhorst FM, Perquin DA, Donker D, Keirse NJ. Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ 2004;328:261. Jansen FW, Kapiteyn K, Trimbos-Kemper T, Hermans J, Trimbos JB. Complications of laparoscopy: a prospective multicentre observational study. Br J Obstet Gynaecol 1997;104:595–600. Johnson NP, Mak W, Sowter MC. Laparoscopic salpingectomy for women with hydrosalpinges enhances the success of IVF: a Cochrane review. Hum Reprod 2002;17:543–548. Karande VC, Korn A, Morris R, Rao R, Balin M, Rinehart J, Dohn K, Gleicher N. Prospective randomized trial comparing the outcome and cost of in vitro fertilization with that of a traditional treatment algorithm as first-line therapy for couples with infertility. Fertil Steril 1999;71:468–475. Kissler S, Haas M, Strohmeier R, Schmitt H, Rody A, Kaufmann M, Siebzehnruebl E. Effect of humidified and heated CO2 during gynecologic laparoscopic surgery on analgesic requirements and postoperative pain. J Am Assoc Gynecol Laparosc 2004;11:473–477. Mol BW, Swart P, Bossuyt PM, van der Veen F. Is hysterosalpingography an important tool in predicting fertility outcome? Fertil Steril 1997;67:663– 669. Mol BW, Collins JA, Burrows EA, van der Veen F, Bossuyt PM. Comparison of hysterosalpingography and laparoscopy in predicting fertility outcome. Hum Reprod 1999;14:1237–1242. Molinas CR, Campo R. Office hysteroscopy and adenomyosis. Best Pract Res Clin Obstet Gynaecol 2006;20:557– 567. Molinas CR, Koninckx PR. Hypoxaemia induced by CO(2) or helium pneumoperitoneum is a co-factor in adhesion formation in rabbits. Hum Reprod 2000;15:1758–1763. Molinas CR, Mynbaev O, Pauwels A, Novak P, Koninckx PR. Peritoneal mesothelial hypoxia during pneumoperitoneum is a cofactor in adhesion formation in a laparoscopic mouse model. Fertil Steril 2001;76:560– 567. Moore ML, Cohen M. Diagnostic and operative transvaginal hydrolaparoscopy for infertility and pelvic pain. J Am Assoc Gynecol Laparosc 2001;8: 393 –397.

Moore ML, Cohen M, Liu GY. Experience with 109 cases of transvaginal hydrolaparoscopy. J Am Assoc Gynecol Laparosc 2003;10:282– 285. Nagele F, Bournas N, O’Connor H, Broadbent M, Richardson R, Magos A. Comparison of carbon dioxide and normal saline for uterine distension in outpatient hysteroscopy. Fertil Steril 1996;65:305–309. Nguyen NT, Furdui G, Fleming NW, Lee SJ, Goldman CD, Singh A, Wolfe BM. Effect of heated and humidified carbon dioxide gas on core temperature and postoperative pain: a randomized trial. Surg Endosc 2002;16:1050–1054. Oliveira FG, Abdelmassih VG, Diamond MP, Dozortsev D, Nagy ZP, Abdelmassih R. Uterine cavity findings and hysteroscopic interventions in patients undergoing in vitro fertilization-embryo transfer who repeatedly cannot conceive. Fertil Steril 2003;80:1371–1375. Ombelet W, Peeraer K, De Sutter P, Gerris J, Bosmans E, Ruyssinck G, Defoort P, Molenberghs G, Gyselaers W. Perinatal outcome of ICSI pregnancies compared with a matched group of natural conception pregnancies in Flanders (Belgium): a cohort study. Reprod Biomed Online 2005;11: 244 –253. Ombelet W, Martens G, De Sutter P, Gerris J, Bosmans E, Martens G, Ruyssinck G, Defoort P, Molenberghs G, Gyselaers W. et al. Perinatal outcome of 12,021 singleton and 3108 twin births after non-IVF-assisted reproduction: a cohort study. Hum Reprod 2006;21:1025–1032. Roest J, Mous HV, Zeilmaker GH, Verhoeff A. The incidence of major clinical complications in a Dutch transport IVF programme. Hum Reprod Update 1996;2:345–353. Shibahara H, Fujiwara H, Hirano Y, Suzuki T, Takamizawa S, Sato I. Usefulness of transvaginal hydrolaparoscopy in investigating infertile women with Chlamydia trachomatis infection. Hum Reprod 2001; 16:1690–1693. Strandell A, Lindhard A, Eckerlund I. Cost– effectiveness analysis of salpingectomy prior to IVF, based on a randomized controlled trial. Hum Reprod 2005;20:3284–3292. Swart P, Mol BW, van der Veen F, van Beurden M, Redekop WK, Bossuyt PM. The accuracy of hysterosalpingography in the diagnosis of tubal pathology: a meta-analysis. Fertil Steril 1995;64:486–491. Tur-Kaspa I, Seidman DS, Soriano D, Greenberg I, Dor J, Bider D. Hysterosalpingography with a balloon catheter versus a metal cannula: a prospective, randomized, blinded comparative study. Hum Reprod 1998; 13:75–77. Verhoeven H, Gordts S, Campo R, Puttemans P, Brosens I. Role of transvaginal hydrolaparoscopy in the investigation of female infertility: a review of 1,000 procedures. Gynecol Surg 2004;1:191–193. Watrelot A, Dreyfus JM, Andine JP. Evaluation of the performance of fertiloscopy in 160 consecutive infertile patients with no obvious pathology. Hum Reprod 1999;14:707–711. Wilcox LS, Mosher WD. Use of infertility services in the United States. Obstet Gynecol 1993;82:122–127.

Human Reproduction 2008

doi:10.1093/humrep/den140

African experience with training courses on sperm examination D.R. Franken1,3 and N. Aneck-Hahn2 1 2 3

Department of Obstetrics and Gynaecology, University of Stellenbosch, 3rd floor, Tygerberg Hospital, Tygerberg 7505, South Africa; Department of Urology, University of Pretoria, Pretoria Academic Hospital, Pretoria, South Africa Correspondence address. E-mail: drf@sun.ac.za

In conjunction with the World Health Organization’s Department of Health and Research, the Department of Obstetrics and University of Stellenbosch, South Africa presented since 1997 hands-on semenology workshops for 87 health care workers from 16 Sub-Sahara African countries. The programme consists of a five-day workshop, during which participants underwent a pre-training test after which they received intensive hands-on training on sperm concentration, motility, vitality and sperm morphology. Following the workshop, all the participants were enrolled in a continuous quality control programme for sperm morphology. The morphology reading skills of 53 workshop participants that enrolled for the external quality control programme were analysed and classified over an extended period. The reading skills were monitored using 36 slides (18 sets over 48 months). Three participants (5.7%) had a poor standard of reading, 6 participants (11.3%) had a marginal standard of reading and 45 participants had an acceptable reading standard (83%). An external quality control programme can be highly successful, on condition that it is presented continuously with a 3–4 month interval between tests. Our results underline the importance of hands-on training and moreover the crucial role that follow up external quality control programmes plays in the maintenance of a technicians reading skills. This observation can be validated for all semen parameters. Keywords: sperm; morphology; training

Background The analysis of human semen, at least, in developing countries still remains the cornerstone of the male fertility investigations. Male-related disorders of are probably present in up to 40– 50% of childless couples, alone or in combination with female factors (Consensus Workshop 1996; Oehninger et al., 2000). Depending on the available health care services and health care insurance plans for infertility in a specific country or region, clinicians are often restricted to one or two specialized assisted reproductive clinics in the region. Although advanced assisted reproductive techniques such in vitro fertilization and intracytoplasmic sperm injection constitute validated formidable therapies that can help the majority cases with so called male factor infertility, the identification of specific sperm defects should allow the development of simpler, less expensive, directed therapies. This is especially important for couples in developing countries where we usually find restricted health insurance options. Therefore, depending on the health care services in a specific country, infertility management should be more successful and practical if administered according to stratified diagnostic schemes for both male and female investigations.

Regarding semen analysis as an important part of the male fertility investigation and recognizing sperm morphology per se as a parameter that is consistently correlated with fertilization success, clinicians in developing countries should find the results of a standard semen analysis extremely helpful. Needless to say this is only true in cases where the results of the semen investigations are recorded by individuals that are using standardized operating procedures to analyse the semen. Since analysis of semen is an inexpensive technique that only needs the basic laboratory equipment to perform, i.e. student type microscope, plastic ware, pipettes, dyes, blood cell counting chamber (Kruger et al., 1986; Oehninger, 1995, 2001), regional health care centres in developing countries should ensure that at least one individual at the centre is trained to perform a routine semen analysis. In contrast to the above our experience in Sub-Sahara Africa, India and South America countries have indicated that health care workers in these areas do not have an idea how to perform a semen analysis according World Health Organization’s standards. This observation is also demonstrated in Figs 1 and 2, where the recorded percentage difference from mean is in some cases up to 600% from the reference value.

Sperm training courses

Figure 1: Sperm concentration values recorded by laboratory technologists’ pre- and post-training. Box –Whisker plots illustrating the percentage difference for from the reference value for sperm concentration during pre- and post-training as well as during a practical examination.

providing capacity of the region. The latter goal can be reached by setting up satellite reference laboratories managed by technologists that attended a Tygerberg training course and that are linked to the continuous quality control programme. Recruitment of health care workers for the workshops is normally done through the regional WHO offices or support centres. The format of the workshops includes practical as well theoretical sessions during a five-day course. In order to establish the technical skill of the participants prior to training, we request all to perform a semen analyses on the first day of the workshop. The analyses include recordings of sperm concentration, motility, vitality and morphology. During this session we provide the standard equipment recommended by the WHO’s manual for the analysis of human semen. The results of the first day are then used to establish the individual learning curve of each participant. Reference laboratory values are used to compare the difference between reference and participant. Figures 1 and 2 clearly illustrate the total lack of knowledge on the one hand, but also the dramatic increase in their understanding of the correct methodology and apparatus.

External quality control for sperm morphology The morphology reading skills of 53 workshop participants who enrolled for an external quality control programme were analysed and classified over an extended period. Each participant received on a quarterly basis 2 Papanicolaou stained slides to monitor their technical ability to record the percent normal morphology per slide. Typically one of these coded slides contained sperm from men with an elevated percentage normal forms (.14%), while the second slide had ,4% normal forms. The reading skills were monitored using 36 slides, i.e. 18 sets of 2 slides per set over 48 months.

Figure 2: Percentage normal sperm recorded by laboratory technologists’ pre- and post-training. Box-Whisker plots illustrating the percentage difference for from the reference value for sperm morphology during pre- and post-training as well as during a practical examination.

Semenology workshops Since 1997, 87 individuals from 16 Sub-Sahara African countries, i.e. Benin, Cameroon, Ethiopia, Kenya, Nigeria, South Africa, Tanzania, Uganda, Tunisia, Zambia, Tunisia, Ghana, Sudan, Egypt, Senegal and Zimbabwe were invited to participate in semenology workshops at Tygerberg Hospital. Due to the intensity of the training sessions we invite not more than 10 individuals per annum to attend the workshops. The semenology workshops presented in conjunction with the World Health Organization’s Special Programme of Research, Development and Research Training in Human Reproduction (HRP, Geneva, Switzerland) aimed not only to provide training opportunities for individuals in reproductive health on the one hand, but also to strengthen the service

Statistical analysis Statistical evaluation was performed with Statistica for Windows Release 5.1 (Statsoft Inc., 1997) and consisted of evaluation of individual scatter plots for each participant’s data and pairwise comparisons of differences at and between evaluation times with the Wilcoxon matched pairs test (Franken et al., 2000). In order to record the technical reading ability of the participants and keeping in mind that the morphology slides used for evaluation of trainee standards were random samples from different individuals, standardization was needed with respect to an index that is independent of the morphological level. The count for strict criteria for normal morphologic sperm is a binomial random variable and the variance of this variable is dependent on the mean. Let p denote the morphology score (%) for p a slide. The standard deviation (SD) of this outcome is p(1002p) which clearly shows the dependence. Under the assumption that the reference laboratory’s morphology reading is the gold standard the index is the following standardized score: SD score ¼ Trainee score 2 Reference laboratory score/SD Reference laboratory (Franken et al., 2000). 61

Franken and Aneck-Hahn

Participants had to record the percentage normal cells and forward the results (% normal cells) to the reference, where the information were recorded and analysed (Franken et al., 2000, 2004, 2007, Franken, 2003, Franken and Kruger, 2006). In order to classify the outcome of the external quality control programme, participants were divided into three groups according to their accuracy of the reported results. These groups were classified as those with (i) Marginal reading skills: if on two consecutive evaluations the SD score of the duplicate readings fall outside the set limits then marginal reading standards can be assumed. If on two consecutive evaluations the single SD scores fall outside the limits then marginal reading standards can be assumed; (b) Good reading skills: if on two consecutive evaluations one of the duplicate readings fall outside the limits then infer marginal reading standards can be assumed and (c) Excellent reading skills: if on two consecutive evaluations both duplicate readings fall inside the limits, then excellent reading skills can be assumed. Three participants (5.7%) had a marginal standard of reading, 6 participants (11.3%) had a good standard of reading and 44 participants had excellent reading skills (83%) (Franken, 2003). These observations are important and underline the role of not only training, but also that of continuous quality assurance testing. Furthermore, we have concluded that apart from basic training (Franken and Kruger, 2006), technologist benefit extremely well from refresher courses to maintain their sperm morphology reading skills.

Discussion The scatter plots (Fig. 1 and 2) can be used as an indication of the level of technical skills and knowledge as far as the methodology for a standard semen analysis is concerned. The information should be seen as a wake-up call for institutions that provide semen analyses for referring clinicians. If we regard the present findings as representative of medical laboratory scientistâ&#x20AC;&#x2122;s technical ability, clinicians in Third-World countries should be concerned about the diagnostic quality as far as male infertility is concerned. It is well known that the evaluation of the percentage of normal sperm morphology features with light microscopy is subjective and therefore difficult to compare between laboratories, even within laboratories. Different means of assessing sperm morphology have been described (Freund, 1966; Eliasson, 1971; Kruger et al., 1986; Enginsu et al., 1993; Ombelet et al., 1994, 1998). The results from the external sperm morphology quality control programme provided useful information in connection with the distribution of research capacity in each of the African regions. Based on our success in Africa the authors feel confident to advocate the establishment of similar reference laboratories on each continent. These laboratories can be linked and thus can data be shared as far as technician standards are concerned. This will provide useful information for funding organizations that wish to perform clinical trails on men especially where changes in semen parameters are the outcome to be measured. 62

The most prominent problem in morphology classification and morphology scoring is the large variation coefficient that exists between and among different technicians in different laboratories. Despite the problems associated with the preparation of slides and staining methods, the use of different classification systems and the subjective nature of visual sperm morphology assessment, we still believe in the power of this important parameter in the routine semen analysis. This is especially true for laboratories in developing countries where the lack of sophisticated diagnostic laboratories is not readily available. Even basic material such as sperm stains can be difficult to obtain in certain areas of the continent. The lack of proper stains was basically the only reason why the majority of the workshop participants used unstained wet preparations for the morphology evaluations. The use of wet preparations is not acceptable, since not all the morphological details, i.e. acrosome size, mid-piece and tail defects, can be observed. The inability of the participants to recognized sperm aberrations is clearly demonstrated by the findings of this report. The group pre-training percentage difference from the reference value reported for sperm concentration, e.g. ranged from 221 to 557% (median 235) and 225 to 12% (median 0) during the post-training sessions. Similar values were recorded for motility, vitality and morphology. These results demonstrate the total lack of knowledge among untrained health care workers in developing countries. In order to solve this problem, policy makers should invest in setting up regional reference laboratories in developing countries not only for andrology, but preferably for all clinical laboratory work. This would not only enhance the diagnostic outcome of infertility couples, but it will also strengthen the research capacity of the region. We initiated a project to record the feasibility of establishing a satellite training laboratory for semen analyses in Nigeria. The project aimed to record the (i) technical abilities of the participants that attended the WHO semenology workshops in Tygerberg Hospital and (ii) to evaluate the possibility to use these trained technicians to establish a satellite training laboratory in their own area. The Centre for Research in Reproductive Health, Ogun State University Teaching Hospital (Sagamu, Nigeria) started training sessions in their area. Subsequently, 16 technologists were trained during three sessions. Papanicolaou stained slides, supplied by Tygerberg were used as test and training material. Pre- and post-training results were used to calculate the mean percentage normal cells as well as the percentage deviation from the reference laboratory (Franken and Dada, 2004, 2007). The mean percentage normal spermatozoa recorded during pre-training evaluations differed 38% from the reference value, compared with post-training difference of 16% (P . 0.001). These results illustrate the value of satellite training centres in Africa. During a infertility management workshop organized by the World Health Organization in 2002 (Franken, 2002) in Nairobi it was suggested that andrology services should be stratified in 3 levels, namely; (i) The first level of the assessment should include the basic semen analysis. This service should be available

Sperm training courses

at primary health care clinics in order to empower the health care service provider. Annual semenology workshops will ensure that an adequate number of trained technicians are available to supply the services. Analysis of semen is an inexpensive technique that only needs the basic laboratory equipment to perform, i.e. student type microscope, plastic ware, pipettes, dyes, blood cell counting chamber. The analysis comprises of (i) assessment of physical semen characteristics (volume, pH agglutination and viscosity), (ii) evaluation of sperm concentration, progressive motility, normal morphology (strict criteria) (iii) determination of sperm vitality by dye exclusion, detection of antisperm antibodies and (iv) a bacteriologic investigation. If abnormalities are found during the basic investigation, the work up should progress to the examination of specific sperm functions. Isolation of the motile sperm fraction is also an integral part of the initial evaluation. (ii) The second level should facilitate functional testing of spermatozoa. This advanced andrology service should be available at academic institutions or central hospitals. The second level of the andrological investigation includes (i) bioassays of gamete interaction (sperm – zona binding, acrosome reaction and hamster ovum penetration) (ii) test that evaluate defective sperm functions indirectly through the use of biochemical tests, i.e. measurement of reactive oxygen species production, creatine phosphokinase activity. (iii) The third level comprises of genetic testing of referred cases and should also be available at academic institutions or central hospitals. This level should include the evaluation of genetic disorders that are associated with male infertility. Chromosomal aberrations can be diagnosed by peripheral karyotyping and should be performed among oligozoospermic men and cases of non-obstructive azoospermia. At the gene level infertility might be associated with cystic fibrosis mutations and with Y-micro deletions. At nuclear level a variety of tests are available to test alterations in abnormal chromatin structure, aneuploidy and DNA strand breaks (Oehninger, 2001). During a separate study conducted in Singapore, Malaysia and Switzerland 19 technologists from 12 different andrology laboratories were enrolled to a sperm morphology quality control programme after initial training sessions. Four of the 19 participants attended annual refresher courses. Two limits of error, namely +0.5 and +0.2 SD were used to record technician deviation from the reference laboratory over a 4 month period. Fifteen of the 19 individuals (78%) consistently reported sperm morphology readings over a 40 month period that was within +0.5 SD limits of error. However, the four of the participants, who attended annual refresher training courses, consistently reported results that were within the +0.2 SD limits of error. For the first time it has been illustrated that excellent sperm morphology reading skills can be achieved

by initial training sessions followed up with a continuous external quality control programme and annual refresher courses. This observation can also be true for all the parameters as far as semen analysis is concerned (Franken and Kruger, 2006). The authors firmly believe that global quality control measurements in andrology laboratories will eventually become mandatory. A high-quality semen analysis still represents the cornerstone in the investigation of the infertile couple. In order to maintain low intra- and inter-technician variation and high-quality proficiency testing among laboratory technicians, continuous teaching programmes should be available to all.

Acknowledgements The World Health Organization’s Special programme for Research Development and Training (HRP). Department of Biostatistics, The South African Medical Research Council.

References Consensus Workshop on Advanced Diagnostic Andrology Techniques. ESHRE Andrology Special Interest Group. Hum Reprod 1996;11: 1463– 1479. Eliasson R. Standards for investigation of human semen. Andrologie 1971;3:49 –64. Enginsu ME, Dumoulin JCM, Pieters MHEC, Evers JLH, Geraedts JPM. Predictive value of morphologically normal sperm concentration in the medium for in vitro fertilization. Int J Androl 1993;16:113–120. Franken DR. Andrology Laboratory in the management of infertility in Africa and Eastern Mediterranean regions, A World Health Organization workshop, Nairobi, Kenya. In: Sekadde-Kigondu C, Chikamata D, Franken DR (eds). Nairobi: Noni Publicity, 2002, 142–150. Franken DR. African experience with sperm morphology training courses. Reprod Med Online 2003;7:114–119. Franken DR, Dada OA. The establishment of sperm morphology satellite training laboratories in Africa. Andrologia 2004;37:57– 60. Franken DR, Dada OA. Does training assist medical laboratory scientists with better evaluation of sperm morphology. Afr J Reprod Health 2007;11:1– 7. Franken DR, Kruger TF. Lessons learned from a sperm morphology quality control programme. Andrologia 2006;3:225– 229. Franken DR, Smith M, Menkveld R, Kruger TF, Sekadde-Kigondu C, Mbizvo M, Akande EO. The development of a continuous quality control (CQS) programme for strict sperm morphology among sub-Sahara African laboratories. Hum Reprod 2000;15:667– 671. Franken DR, Menkveld R, Kruger TF, Sekadde-Kigondu C, Lombard C. Monitoring technologist reading skills in a sperm morphology quality control program. Fertil Steril 2004;79(Suppl 3):1637–1643. Freund M. Standards for rating human sperm morphology. Int J Fertil 1966;11:97–118. Kruger TF, Menkveld R, Stander FSH, Lombard CJ, van der Merwe JP, van Zyl JA, Smith K. Sperm morphologic features as a prognostic factor in in vitro fertilization. Fertil Steril 1986;46:1118– 1123. Oehninger SC. An update on the laboratory assessment of male fertility. Hum Reprod 1995;10(Suppl 1):38–45. Oehninger SC. Strategies for the Infertile Man. Semin Reprod Med 2001;19:231. Oehninger SC. Clinical and laboratory management of male infertility: an option on its current status. J Androl 2000;3:814–821. Ombelet W, Fourie FL, Vandeput H, Bosmans E, Cox A, Janssen M, Kruger T. Teratozoospermia and in-vitro fertilization: a randomized prospective study. Hum Reprod 1994;9:1479– 1484. Ombelet W, Bosmans E, Janssen M, Cox A, Maes M, Punjabi U, Blaton V, Gunst J, Haidl G, Wouters E et al. Multicenter study on reproducibility of sperm morphology assessments. Arch Androl 1998;4:103–114.

doi:10.1093/humrep/den165

Human Reproduction 2008

Intrauterine insemination (IUI) as a first-line treatment in developing countries and methodological aspects that might influence IUI success Willem Ombelet1,2,4, Rudi Campo1,3, Eugene Bosmans1 and Martine Nijs1 1

Genk Institute for Fertility Technologies, Department of Obstetrics and Gynaecology, Ziekenhuizen Oost-Limburg, Schiepse Bos 2, 3600 Genk, Belgium; 2Flemish Society of Obstetrics and Gynaecology, Belgium; 3Leuven Institute for Fertility and Embryology, Leuven, Belgium 4

Correspondence address. E-mail: willem.ombelet@telenet.be

It is generally accepted that intrauterine insemination (IUI) should be preferred to more invasive and expensive techniques of assisted reproduction and be offered as a first-choice treatment in cases of unexplained and moderate male factor subfertility. Scientific validation of this strategy is rather difficult because literature is rather confusing and not conclusive. IUI is proven easier to perform, less invasive and less expensive than other methods of assisted reproduction. Effectivity has been documented in controlled studies under the condition that the inseminating motile count exceeds more than 1 million motile spermatozoa. Risks are minimal, provided the multiple gestation incidence can be reduced to an acceptable level and provided at least one tube is patent. Therefore, in developing countries, reflection on the implementation and use of IUI as a first-line treatment for most cases of non-tubal infertility seems mandatory. The costs are minimal, training is easy, quality control possible and severe complications are almost non-existing. In cases of unexplained infertility or combined male subfertility and ovulatory dysfunction, correction and/or ovarian stimulation with clomiphene citrate (CC) is probably the best strategy from a cost â&#x20AC;&#x201C;benefit point of view unless CC-resistancy has been proven in which the use of low-dose gonadotrophins is necessary. Keywords: affordable; assisted reproduction; cost-effectiveness; developing countries; intrauterine insemination

Introduction The rationale behind intrauterine insemination (IUI) with homologous sperm is bypassing the cervical â&#x20AC;&#x201C; mucus barrier and increasing the number of motile spermatozoa with a high proportion of normal forms at the site of fertilization. A few decades ago, homologous artificial insemination was only performed in cases of male subfertility and psychologic dysfunction, such as retrograde ejaculation, vaginismus, hypospadias and impotence. With the routine use of post-coital tests, other indications were added such as hostile cervical mucus and immunologic causes. This interest in IUI is undoubtedly associated with the refinement of techniques for the preparation of washed motile spermatozoa. These washing procedures are necessary to remove prostaglandins, infectious agents, antigenic proteins, non-motile spermatozoa, leucocytes and immature germ cells. This may enhance sperm quality by decreasing the formation of free oxygen radicals after sperm preparation. The final result is an improved fertilizing capacity of the sperm in vitro and in vivo (Aitken and Clarkson, 1987). From a scientific point of view, controversy still surrounds the effectiveness of this very popular treatment procedure. 64

This may be explained by the fact that most studies are retrospective and not only vary in the comparison of the study group but also in the use or non-use of different ovarian superovulation regimen, the number of inseminations per treatment cycle, different methods of timing ovulation, different sites of insemination, various methods of sperm preparation and the well or not use of additives such as antioxidants, platelet-activating factor (PAF), etc (Fig. 1). If IUI is promoted as a first-line treatment in case of unexplained and male factor subfertility, it has to be weighed against other treatment options such as expectant management, medical and surgical treatment, IVF and ICSI. This comparison should not only involve success rates but should also include a costâ&#x20AC;&#x201C; benefit analysis, an analysis of the complication rate of the different treatment options, the invasiveness of the techniques and patient compliancy. Healthcare cost consciousness has become an integral part in the attitude of policy makers worldwide. Evidence related to the cost and effectiveness of infertility treatment exists, but most studies only deal with IVF. Published data comparing cost of IVF versus IUI indicate that initiating treatment with

IUI as a first-line treatment in developing countries

Figure 1: Diagram showing the many different variables influencing success rates in IUI programmes (AIH, artificial insemination with homologous semen).

IUI appeared to be more cost-effective than IVF in most cases of unexplained and moderate male subfertility (Ombelet et al., 2003; Ombelet, 2005). Surprisingly and despite evidencebased arguments, data from Australia and New Zealand clearly show that almost 80% of fertility centres are convinced of the cost-effectiveness of IUI, but nearly one-third of these centres still promote IVF as a first-line treatment even with patent tubes and normal semen (Miskry and Chapman, 2002). Since IUI programmes are easy to run, this method can be extremely interesting for resource-poor countries. The techniques and methods are easy to learn, the direct and indirect costs are minimal compared with IVF/ICSI and severe complications are very rarely seen. The use of affordable and safe washing techniques and the value of natural cycle or clomiphene citrate (CC) stimulation also adds to the value of IUI in developing countries. The topics highlighted in this paper are summarized in Table I.

Effectiveness of IUI Cervical factor subfertility Bypassing the hostile cervix should increase the probability of conception. The results of a meta-analysis of randomized controlled trials comparing IUI with timed intercourse (TI) for

couples with cervical factor infertility showed a significant improved probability of conception for IUI (Cohlen, 2005). Unexplained subfertility If an infertility work-up is unable to detect a plausible explanation for couples with a history of subfertility of at least 1 year, we use the term ‘unexplained infertility’. Because a good explanation for the subfertility is lacking, the treatment is often empiric. A meta-analysis comparing IUI and TI in natural cycles showed no difference in results; therefore, IUI in natural cycles seems ineffective in case of unexplained infertility. When controlled ovarian hyperstimulation (COH) is used, IUI becomes effective compared with TI (Cohlen, 2005). There is evidence that IUI with COH increases the live birth rate compared with IUI alone. The likelihood of pregnancy was also increased for treatment with IUI compared with TI in stimulated cycles (Verhulst et al., 2006). Male factor subfertility In case of longstanding infertility caused by reduced sperm quality, expectant treatment seems to be disappointing with a spontaneous conception rate of only 2% per cycle (Collins et al., 1995). Therefore, this strategy is not applicable in clinical practice. For IUI, with or without COH, a pregnancy rate (PR) of 10– 18% per cycle has been reported (Ombelet et al., 1995, 1997a; Stone et al., 1999). A Cochrane review showed 65

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Table I. Summary of topics highlighted in this paper. † Introduction † Effectiveness of IUI Cervical factor subfertility Unexplained subfertility Male factor subfertility † Cost of ART-related services † Risks and complications of IUI versus IVF/ICSI † Couple compliancy † Treatment strategy in developing countries: a proposal † Factors influencing IUI success Natural cycle versus controlled ovarian hyperstimulation Site of insemination Exact timing of IUI Factors affecting embryo-implantation ) Endometrial thickness/polyps ) Which catheter to use ) The use of aspirin and luteal phase support Laboratory factors ) Sperm washing methods ) Addition of substances in sperm preparations ) Fallopian sperm perfusion ) The effect of the abstinence period ) Immunologic male subfertility Number of inseminations Number of IUI treatment cycles † Conclusion

that IUI is superior to TI, both in natural cycles and in cycles with COH (Cohlen et al., 2000). According to this review, IUI in natural cycles should be the treatment of choice in case of male subfertility, providing an inseminating motile count (IMC) of more than 1 million can be obtained after sperm preparation and in the absence of a triple sperm defect (according to WHO criteria). In the selection of couples to be treated with IUI, it would be interesting to establish cut-off values of semen parameters above which IUI is a real alternative for IVF/ICSI in male subfertility. According to the literature, IMC and sperm morphology are the most valuable sperm parameters to predict IUI outcome (Duran et al., 2002; Ombelet et al., 2003). There is a trend towards increasing conception rates with increasing IMC, but the cut-off value above which IUI seems to be successful, however, varies between 0.3 and 20 106. A large retrospective analysis in a selected group of patients with normal ovarian response to clomiphene (CC) stimulation showed a comparable cumulative ongoing PR after three IUI cycles for all couples, providing the IMC was more than 1 million (Ombelet et al., 1997a). Furthermore, in cases with ,1 million motile spermatozoa, IUI remains successful provided the sperm morphology score using strict criteria is 4% or more (cumulative ongoing PR of 21.9% after three IUI cycles). Acceptable PR can be achieved with IUI, even in severely oligozoospermic men (Centola, 1997). A significant improvement in PR was reported when the morphology score was more than 5% using strict criteria in a meta-analysis by Van Waart et al. (2001). A cut-off level of 0.8 million motile spermatozoa after washing was reported in a meta-analysis by van Weert et al. (2004). For total sperm motility before sperm preparation, cut-off levels vary between 30% and 50% (Ombelet et al., 1996; Dickey et al., 1999; Montanaro et al., 2001; Lee et al., 2002). 66

Cost of ART-related services In a meta-analysis, Peterson et al. (1994) showed that the PR for three cycles of gonadotrophins and IUI in a population group with unexplained infertility was superior to IVF and comparable with gamete intra-Fallopian transfer. Many other studies reported on the cost-effectiveness of IUI compared with IVF (Van Voorhis et al., 1997, 2001; Zayed et al., 1997). In a prospective randomized controlled trial, Goverde et al. (2000) concluded that three cycles of IUI offer the same likelihood of a successful pregnancy as one trial of IVF. They concluded that IUI is a more cost-effective approach, not only for unexplained subfertility, but also for moderate male factor subfertility. This important message was confirmed in another study performed in the UK (Philips et al., 2000). In this study, the authors complemented existing clinical guidelines by including cost-effectiveness of different treatment options for infertility in the UK. A series of decision-analytical models were developed to reflect current diagnostic and treatment pathways for the different causes of infertility. According to this study, stimulated IUI for unexplained and moderate male factor infertility is a cost-effective approach. In a systematic review, Garceau et al. (2002) also showed that initiating treatment with IUI appears to be more cost-effective than IVF in most cases of unexplained and moderate male subfertility. For couples with unexplained and mild male factor subfertility, Pashayan et al. (2006) showed that primary offering a full IVF cycle was less costly and more cost-effective than providing IUI followed by IVF. In their mathematical model, the assumed LBR (live birth-producing pregnancy) was only 3% for CC-stimulated IUI and 7% for gonadotrophin-stimulated IUI, although most centres worldwide have a significantly higher LBR (Ombelet et al., 2003). This might explain the opposite findings in their study.

Risks and complications of IUI versus IVF/ICSI in developing countries Transmission of life-threatening sexually transmitted diseases, infectious diseases such as HIV, HCV and Hepatitis B, constitutes particular risk in developing countries since these diseases may be highly prevalent in subfertile couples. It is estimated that nearly 40 million people worldwide are infected with HIV and prevalence among young people under age of 25 years account for approximately half of all new infections (Sauer, 2005). Most HIV patients are of reproductive age and many desire to have children. Many studies have shown that appropriate sperm processing may reduce the risk of HIV transmission through IUI and IVF/ICSI (Balet et al., 1998; Ohl et al., 2005; Manigart et al., 2006; Garrido et al., 2006; Savasi et al., 2007). Sperm washing techniques appear to be relatively safe and effective, offering HIV-serodiscordant and couples where both partners are infected an opportunity to have children, provided antiretroviral therapy and HIV monitoring are available. The challenges created by the HIV epidemic versus reproductive desires and health needs of a large HIV infected population are well described elsewhere in this monograph (Dyer et al; this monograph).

IUI as a first-line treatment in developing countries

In this context, semen decontamination through sperm processing is very important in countries with a high rate of seminal infection, since IUI and ART may become important tools, not only in the recognition of the reproductive rights of HIV-infected parents but also in the prevention of the transmission of HIV among partners and towards the fetus. The use of a novel washing method combining multiple density gradients and trypsin for removing human immunodeficiency virus-1 and hepatitis C virus from semen seems to be very promising (Loskutoff et al., 2005; Huyser et al., 2006). Ovarian hyperstimulation syndrome (OHSS) may complicate all methods of treatment in which gonadotrophins are used; however, OHSS seems to be rare after COH – IUI compared with IVF due to the fact that lower dose stimulation protocols are more often used (Dodson and Haney, 1991; Bergh and Lundkvist, 1992; Ombelet et al., 1995). The incidence of pelvic inflammatory disease after intrauterine catheterization and/or transvaginal oocyte-aspiration has been estimated to be 0.2% for IVF (Bergh and Lundkvist, 1992) and 0.01– 0.2% for IUI (Dodson and Haney, 1991; Ombelet et al., 1995). The major complication of assisted reproductive technology remains, however, the high incidence of multiple pregnancies, responsible for considerable mortality, morbidity and costs (Ombelet et al., 2005). The prediction of multiple gestation is highly uncertain, especially when gonadotrophins are used, despite careful monitoring of the cycle with ultrasonography and serum estradiol determinations. Careful monitoring remains essential and cancellation of the insemination procedure, escape IVF and follicular aspiration before IUI are reasonable options. Transvaginal ultrasound-guided aspiration of supernumerary ovarian follicles increases both the efficacy and the safety of COH – IUI with gonadotrophins (De Geyter et al., 1998; Albano et al., 2001). This method represents an alternative for conversion of overstimulated cycles to in vitro fertilization (escape IVF). Natural cycle IUI, CC

and minimal dose regimen with gonadotrophins are valuable options to prevent the unacceptable high multiple gestation rate described after ovarian hyperstimulation. Considering obstetric and perinatal outcome after IUI, to our knowledge only four papers have been published. According to Nuojua-Huttunen et al. (1999) and using the data obtained from the Finnish Medical Birth Register, IUI treatment did not increase obstetric or perinatal risks compared with matched spontaneous or IVF pregnancies. The three other studies observed a higher risk for prematurity and (very) low birth weight for IUI singletons when compared with naturally conceived singletons (Wang et al., 2002; Gaudoin et al., 2003; Ombelet et al., 2006).

Couple compliancy Since IUI is a simple and non-invasive technique, it can be performed without expensive infrastructure with a good success rate within three or four cycles, making this method of assisted reproduction very appealing for developing countries. On the other hand, we have to admit that in some areas, such as subSaharan Africa, the majority of patients suffer of tubal factor infertility. In these cases, only IVF can be proposed. Nevertheless, IUI is a safe and easy treatment with minimal risks and monitoring, at least if multiple PR can be avoided. Subsequently, a high couple compliancy is reported for IUI compared with IVF. We previously described a low dropout rate of 19.6% in a series of 1100 IUI cycles (Ombelet et al., 1996). A much higher dropout rate and long time interval between treatment cycles for IVF and ICSI have been described before (Comhaire, 1995). It is obvious that IUI must be considered as a very important first-line treatment in selected cases in developing countries. Table II gives an overview of the pros and cons of IUI compared with IVF/ICSI.

Table II. Overview of the pros and cons of IUI compared with IVF and ICSI.

IUI

IVF/ICSI

PROS

CONS

† Less equipment necessary † Easy method: less complex † Less invasive: more physiological † Less expensive † Reduced psychological burden † Good couple compliancy ) low dropout rate † Low risk for OHSS, thrombo-embolism † Low to moderate MPR with NC, CC and low-dose gonadotrophin protocols † Minimal transmission of infection (IVF) † Moderate to high success-rate per cycle

† + success-rate per cycle † + success if IMC,1 million † + success if morphology,5% † High MPR with gonadotrophins † Risk for antisperm antibodies

† High costs (direct and indirect) † Complex stimulation protocols † * patient discomfort † Time-consuming † Invasive procedure † * risk for OHSS, thrombo-embolism † High multiple pregnancy rate † * Risk for LBW, prematurity † * Risk for genetic disorders † Lower couple compliancy ) High dropout rate

IMC, inseminating motile count; OHSS, ovarian hyperstimulation syndrome; NC, natural cycle; CC, clomiphene citrate; LBW, low birth weight (,2500 g); MPR, multiple pregnancy rate.

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Treatment strategy in developing countries: a proposal Figure 2 shows the treatment strategy used for more than 10 years at the Genk Institute for Fertility Technology. In most cases, we start with CC ovarian stimulation, although the cumulative ongoing PR is significantly lower compared with rec-FSH or (purified) urinary gonadotrophins, but with the benefit of a low multiple PR (,7%) because of intensive monitoring of the number of follicles. If more than three follicles with a mean diameter of .13 mm are present, the cycle is cancelled (Ombelet et al., 1996). Although the cumulative ongoing PR after three IUI cycles is comparable with only one IVF cycle (25%), more than 90% of our couples agree to follow our protocol being aware of the better success rate per cycle after IVF. Excellent counselling is mandatory and crucial. The strategy of using CC â&#x20AC;&#x201C; IUI as a first-line treatment in most cases of non-obstructive subfertility (male and female) is of outstanding importance for developing countries.

Factors influencing IUI success The duration of subfertility, primary or secondary subfertility, endometriosis and the use or non-use of ovarian hyperstimulation are important factors influencing the success rate of IUI significantly (Crosignani and Walters, 1994; Steures et al., 2004). Other variables might be the site of insemination, the use of antioxidants, factors influencing intra-tubal environment and factors influencing embryo implantation (Iberico et al., 2004).

Figure 2: Proposed algorithm of male subfertility treatment at the Genk Institute for Fertility Technology (IMC, inseminating motile count or the number of motile spermatozoa after washing procedure; HSG, hysterosalpingography; HSCS, hystero-salpingo-contrastsonography).

Natural cycle versus controlled ovarian hyperstimulation Poor results have been described when IUI was performed in natural cycles for unexplained and cervical factor subfertility (DiMarzo et al., 1992; Ombelet et al., 1995). The rationale behind the use of ovarian hyperstimulation in artificial insemination is the increase of the number of oocytes available for fertilization and to correct subtle unpredictable ovulatory dysfunction (Arici et al., 1994). Comparing the effect of COH on PR after IUI, ovarian stimulation with gonadotrophins or rec-FSH results in a significantly higher monthly fecundability compared with CC treatment, but at the expense of a higher multiple PR (Ombelet et al., 1995, 1996). This statistical difference is not influenced by the indication for IUI. Considering the risk for multiple pregnancies and OHSS, mild COH regimen with the aim of monofollicular growth should be used. The aromatase inhibitor letrozole and CC are associated with similar PR in IUI (Al-Fozan et al., 2004). The ideal dose of letrozole remains unknown, and further studies are needed. Since letrozole is more expensive than CC, we still believe that the use of CC â&#x20AC;&#x201C; IUI is the best option in developing countries, at least in the absence of bilateral tubal block and CC resistancy. Site of insemination Artificial inseminations can be done intravaginally, intracervically (ICI), pericervically using a cap, IUI, transcervical intrafallopian (IFI) or directly intraperitoneal (IPI). Most studies refer to IUI, which seems to be an easy and better way of treatment. In a donor insemination programme, Hurd et al. (1993) reported a significantly better cycle fecundity rate for IUI compared with ICI or IFI. More sperm was found in the peritoneal cavity after IUI when compared with ICI (Ripps et al., 1994). Studies comparing pregnancy outcome after IUI versus cervical cap insemination (Williams et al., 1995) and transuterotubal insemination (Oei et al., 1992) also favoured the intrauterine method. In a large randomized controlled trial, it was shown that among infertile couples, treatment with induction of superovulation and IUI is three times as likely to result in pregnancy as is intracervical insemination and twice as likely to result in pregnancy as is treatment with either superovulation and intracervical insemination or IUI alone (Guzick et al., 1999). Exact timing of IUI Exact timing is probably crucial in IUI treatment cycles. On the other hand, conflicting data are reported in the literature on which methodology is to be used. Ultrasound and hormonal monitoring with human chorionic gonadotrophin (hCG) induction probably allows the most exact timing but is relatively expensive and time-consuming. Urinary luteinizing hormone (LH) timed IUI is commonly used but has the disadvantage that the LH surge can last for up to 2 days before ovulation in some patients (Cohlen et al., 1993). A prospective, randomized cross-over study of Zreik et al. (1999) could not demonstrate an increased PR when ultrasound monitoring and hCG were used compared with urinary LH-timed inseminations. In a prospective randomized study (Lewis et al., 2006), all patients received CC and were randomized into a LH

IUI as a first-line treatment in developing countries

(urinary LH) surge group or a follicle monitoring/hCG group. Patients in the LH surge group underwent IUI on the day after a home test for the LH surge was positive, whereas those in the hCG group received hCG according to ultrasound parameters and underwent insemination 33 â&#x20AC;&#x201C; 40 h later. Similar results were found between groups in PR per patient or per cycle. After ovarian stimulation with CC, IUI is equally effective 24 h after a spontaneous LH surge or 36 h after administration of hCG (Vlahos et al., 2005). It seems that being aware of the importance of exact timing is essential in IUI, independent of the method being used. In developing countries, the advisable method of monitoring is probably the regimen of one or two ultrasound examinations after CC stimulation combined with hCG injection, this means prefect timing and avoidance of multiples by cancellation the cycle if three or more follicles of 14 mm or more are found. The use of gonadotrophin-releasing hormone antagonists to overcome the problem of unexpected premature LH surges is effective but too expensive to be routinely used in developing countries. Factors affecting embryo implantation Endometrial thickness/polyps A trilaminar image rather and a greater endometrial thickness provide a favourable prediction of pregnancy in IUI (Hock et al., 1997; Esmailzadeh and Faramarzi, 2007). Treatment should not be cancelled because of inadequate endometrial thickness (De Geyter et al., 2000). The use of ethinyl estradiol in clomiphene-stimulated cycles looks promising but requires confirmation (Gerli et al., 2000). If polyps are present, hysteroscopic polypectomy before IUI is an effective measure to enhance pregnancy results (PeÂ´rez-Medina et al., 2005). Which catheter to use In IUI programmes, most studies indicate that the catheter type does not affect the outcome after (Lavie et al., 1997; Smith et al., 2002; Fancsovits et al., 2005). On the other hand, Proctor and Boone (2007) recently showed that although the flexible catheter costs more than the rigid catheter, it is associated with a higher PR, which decreases costs of IUI treatment because fewer cycles are needed. The use of aspirin and luteal phase support There is no evidence so far that luteal support with progesterone and/or hCG affects the conception rate in IUI programmes with the exception of treatment regimen making use of GnRH analogues. Low-dose aspirin may improve uterine perfusion in women, but its value in assisted reproduction remains very controversial (Gelbaya et al., 2007; Khairy et al., 2007; Ruopp et al., 2007). Therefore, it should not be routinely recommended in assisted reproduction. Laboratory factors Sperm washing methods Preparation and washing will remove reactive oxygen species (ROS) and prostaglandines. The prostaglandines have to be removed since they will cause severe uterine cramps when a

raw semen sample is used for IUI. The preparation will concentrate morphologically more normal and motile spermatozoa, essential for good results in IUI. Most popular are the swim-up procedures, the density gradient centrifugation and the use of Sephadex columns. Conflicting data are found on the superiority of any one preparation technique in terms of fecundity (Dodson et al., 1998; Ren et al., 2004). This can be explained by the fact that almost all methods of sperm washing and preparation surpasses the low threshold number of motile spermatozoa (.1 106) needed for conception in vivo with no added benefit of additional sperm. According to a Cochrane review, there is insufficient evidence to recommend any specific preparation technique (Boomsma et al., 2007). Addition of substances in sperm preparation Whether the addition of substances such as pentoxyphylline, kallicreine, follicular fluid etc. may improve the results remains unclear and certainly unproven. On the other hand, it is important to recognize that sperm preparation methods may induce damage to spermatozoa by increasing ROS generation by spermatozoa and by removing the scavengers from the seminal plasma. More studies that investigate whether treating spermatozoa with solutions containing antioxidants during sperm preparation can improve PR with IUI in selected cases are needed. Two double-blind randomized studies evaluated the effect of PAF exposure on sperm during semen processing for IUI (Roudebush et al., 2004; Grigoriou et al., 2005). They demonstrate a significantly higher PR for the PAF-treated group in a subpopulation of couples without male factor subfertility. Until now, there is no evidence that one specific sperm washing procedure is superior to the other methods in IUI programmes, but comparative studies are urgently needed. Fallopian sperm perfusion In Fallopian tube sperm perfusion (FSP), a large volume of a sperm suspension is inseminated intrauterine with excellent results in cases of unexplained infertility (Kahn et al., 1992, 1993). A Cochrane review showed that FSP gives rise to higher PR in couples with unexplained subfertility (Cantineau et al., 2004). Results suggested the possibility of differential effectiveness of FSP depending on catheter choice. For other indications, FSP has not been proven more effective compared with IUI. The effect of the abstinence period Abstinence did not influence sperm morphology, total or grade A motility, or sperm DNA fragmentation in a prospective study described by De Jonge et al. (2004). A short (24 h) abstinence period negatively influenced chromatin quality. An abstinence interval of 3 days or less was associated with higher PR following IUI (Jurema et al., 2005). Immunologic male subfertility Most studies demonstrate a clear association between sperm surface antibodies and the fertility potential of the male (Adeghe, 1992; Acosta et al., 1994). In 1997, we published a prospective study comparing the effectiveness of the first-line IUI approach versus IVF for 69

Ombelet et al.

male immunological subfertility (Ombelet et al., 1997b). The objective of this prospective study was to compare success rates after two different treatment protocols, COH –IUI versus IVF. Both IUI and IVF yielded unexpected high PR in this selected group of patients with long-standing subfertility due to sperm surface antibodies. Since cost– benefit analysis comparing COH – IUI with IVF may favour a course of four IUI cycles, we concluded that IUI can be used as the first-line therapy in male immunological subfertility. Although most fertility centres use IVF/ICSI in case of immunological male subfertility (Lombardo et al., 2001, 2004), a well-organized prospective study is mandatory to examine the real value of IUI for this specific indication. Number of inseminations Theoretically, improved chances for conception may be expected when two consecutive inseminations are performed since ovulation of oocytes does not occur in a synchronized pattern but rather in waves of release after hCG administration (Abbasi et al., 1987). A Cochrane review, based on the results of two trials, double IUI showed no significant benefit over single IUI in the treatment of subfertile couples with partner semen (Cantineau et al., 2003). The authors admitted that there are no meaningful data to offer advice on the basis of this review. According to this report, a large randomized controlled trial of SIUI versus DIUI is mandatory. In a cross-over study, we previously showed that double insemination provided a significant better cycle fecundity after superovulation with gonadotrophins but not after ovarian stimulation with CC, but at the expense of a higher multiple PR (Ombelet et al., 1995). Number of IUI treatment cycles A significant decline in cycle fecundity after the third or fourth IUI cycle was reported in several studies (Dodson and Haney, 1991; Friedman et al., 1992; Nan et al., 1994). The remaining couples do not seem to benefit from this method of treatment when compared with other methods of assisted reproduction. Conclusion IUI is a simple, non-invasive and cheap treatment modality which can be used as a first-line treatment in most subfertility cases including male subfertility. The technical requirements necessary and the current scientific evidence on the success and complication rate provides sufficient evidence to promote IUI as a first-line treatment modality in developing countries. Especially in developing countries, the classical algorithm of diagnosis and treatment should be followed and preference should be given to those treatment modalities with the lowest complication rate, best obstetrical outcome, affordable cost and cultural acceptance. In this view, proper diagnosis and treatment of the female reproductive tract, proper semen analysis and possibility of simple ovarian stimulation and IUI should be promoted as the best first-line treatment in most cases of subfertility. IUI should be provided to all patients with at least one patent tube and an IMC after sperm preparation of more than 1.0 million. 70

In this selected group of patients, it is unwise to start with assisted reproductive techniques such as IVF and ICSI since these techniques are more invasive, more expensive and more at risk for genetic disorders and obstetric complications. Promoting IVF and ICSI to result in pregnancy ‘as quick as possible’ ignores the advantages of IUI completely.

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doi:10.1093/humrep/den160

Human Reproduction 2008

Assisted reproductive technologies: how to minimize the risks and complications in developing countries? Petra De Sutter1, Jan Gerris and Marc Dhont Centre for Reproductive Medicine, Department of Obstetrics and Gynecology, University Hospital, De Pintelaan 185, B-9000 Gent, Belgium 1

Correspondence address. E-mail: petra.desutter@ugent.be

In 2% of assisted reproductive techniques (ART) cycles complications occur. Some are preventable, some are not. In this paper, we will discuss risks and complications of the standard â&#x20AC;&#x2DC;Westernâ&#x20AC;&#x2122; approach in ART today and point to some measures to be taken when implementing ART in developing countries, where resources and access to medical care may be limited. Ovarian hyperstimulation syndrome (OHSS, and its thrombo-embolic complications) is responsible for the majority of cycle-related complications, followed by bleeding and infection at oocyte retrieval. ART pregnancies are complicated by first-trimester bleeding more often than spontaneous pregnancies, they are more often ectopic, but the major complication is the very high incidence of multiple pregnancies, when more than one embryo is transferred. OHSS can be prevented by screening patients at risk and by using mild or no stimulation. Simple measures can minimize the risks of bleeding or infection. Obviously single embryo transfer is the only way to avoid multiple pregnancies, which have a highly increased risk for severe maternal and neonatal morbidity and mortality (mainly due to prematurity). Special attention should be given to pre-existing pathologies. Risk minimization of ART in developing countries is not only mandatory from an economical but also an ethical point of view. Keywords: ART; risks; complications; multiple pregnancies; developing countries

Introduction Assisted reproductive techniques (ART), such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), are not free of risks. More than 20 years of experience have taught us how to minimize the risks and complications, but safety and quality of ART are still not considered to be high-priority issues. It is clear that the large scale introduction of ART in developing countries cannot be done in an isolated way, and that high-quality facilities for general gynecological and obstetrical care must be available in order to deal with specific problems surrounding ART treatments. It would, for instance, not be very ethical to perform IVF and creates high numbers of multiple pregnancies in countries that have no possibilities to offer good neonatal care. The present paper will discuss some of the known risks and complications in ART and offer strategies to minimize these risks in countries with limited resources and access to medical care. In the literature, the figures of cycle-related short-term complications after ART are remarkably congruent. The mean complication rate as calculated from the available data in literature is around 2%, including hospitalizations for ovarian hyperstimulation syndrome (OHSS) (Baber et al., 1988; Bergh and Lundkvist, 1992; Roest et al., 1996; Govaerts et al., 1998; Serour et al., 1998; El-Shawarby et al., 2004). OHSS is

responsible for about half of all complications and it is well known that casualties related to ART are most often resulting from OHSS and its thrombo-embolic complications. The true death rate after ART is unknown and this is due to underreporting in the literature. In the series of Serour et al. (1998) on 3500 cycles, one mortality case was reported following hepatorenal failure in a patient with OHSS. Lethal complications of ART have been described by Braat et al. (2006) and amount to no more than 11 documented cases. It is very likely that deaths due to complications of ART treatment occur in countries, where there is anything but basic attendance to the patients. Although deaths of course are the most extreme of all possible complications, complications do occur as a result of ART. In general, one may distinguish between the risks related to the ovarian stimulation, the surgical procedure or the pregnancy itself. Although severe complications are uncommon, they may be potentially life threatening. In this paper, we will not address congenital, genetic and epigenetic anomalies of children following ART. Although this issue obviously needs our attention and follow-up of the children is of utmost importance in this respect, it is not yet clear whether these risks are preventable, because they are probably related to patient characteristics and the infertility itself, rather than to the procedure.

De Sutter et al.

Risks related to the ovarian stimulation OHSS is by far the most important risk of ART stimulation, being responsible for a 1% hospitalization rate in Western countries. An excellent review of the thrombo-embolic complications following OHSS is given in a recent paper by Chan and Dixon (2007). From the list of risk factors (young age, low body weight, PCOS or PCO-like patients, use of GnRH agonists, use of hCG for luteal support, size and number of mature follicles, history of OHSS, high estradiol (E2) levels, allergies), it is clear that both patient profile and stimulation protocol are important. Although the trigger for the development of OHSS is the administration of hCG, the number of follicles is a major predictor. Since the long agonist protocol yields a higher number of follicles than mild, short agonist or antagonist protocols, it may be wise to use milder protocols, or even just clomiphene citrate, in order to prevent OHSS. In a recent meta-analysis comparing the agonist with antagonist protocol by Al-Inany et al. (2007), it was shown that the incidence of severe OHSS was significantly reduced with the antagonist protocol (P ¼ 0.01; OR ¼ 0.60, 95% CI 0.40– 0.88), and measures to prevent OHSS were taken more frequently in the agonist group (P ¼ 0.03; OR ¼ 0.43, 95% CI 0.20– 0.92). Thrombotic complications related to the ovarian stimulation have, however, also been described in the absence of OHSS. Ludwig et al. (1999) described a patient with activated protein C (APC) resistance who developed deep calf vein thrombosis on the eighth day of hMG administration. Another patient with antithrombin III deficiency developed a massive deep vein thrombosis as a result of ovarian stimulation for ART (Kligman et al., 1995). Thrombosis always is the result of hypercoaguability and/or defective anticoagulant mechanisms. Rising E2 levels may lead to increased liver fibrinogen synthesis and thus hypercoaguability in all stimulated women. If a patient has APC resistance or antithrombin III deficiency, she has a much higher thrombotic risk. Also the use of a high-dose oral contraceptive prior to the stimulation cycle in order to synchronize the treatment may be a risk factor in such patients. Proper family and personal history taking and heparin prophylaxis may prevent thrombotic events in these patients at risk. One should not forget that the risk continues to be increased during pregnancy as well, and quite some cases have been reported of thrombotic events during the first trimester of an ART pregnancy (Arya et al., 2001; Belaen et al., 2001). Screening of patients at risk for thrombo-embolic complications, even in the absence of OHSS, seems indicated prior to ART. Seligsohn and Lubetsky (2001) advise to screen all women intending to become pregnant (a fortiori infertility patients) if they have a personal of family history of venous thrombosis. They also propose screening if they have had three unexplained spontaneous abortions in the past, abruptio placentae, stillbirth, recurrent fetal growth retardation or possibly pre-eclampsia. Complications following oocyte retrieval These complications mainly follow from puncturing a blood vessel, traumatizing an anatomically related structure (bowel, 74

ureter) or introducing an infection into the peritoneal cavity. Bleeding and infections both occur in less than 1% of all ultrasound-guided oocyte retrievals. Dicker et al. (1993) report a total of 14 out of 3656 (0.4%) patients presenting with acute abdomen after transvaginal oocyte puncture, due to pelvic infection or bleeding. Kelada and Ghani (2007) performed a recent literature review and report an incidence rate between 0.4% (Govaerts et al., 1998) and 1.3% (Tureck et al., 1993). They state that generalized prophylactic administration of antibiotics remains controversial and of unproven benefit, but should be considered in patients at risk of inadvertent puncture and inoculation, such as patients with known adhesions, endometriosis and pseudocysts. Also another recent case report and literature review by Sharpe et al. (2006) conclude that there still is no consensus on the general prophylactic administration of antibiotics in all patients. Finally, after embryo transfer without previous oocyte retrieval, as in oocyte donation or frozen–thawed cycles, pelvic infection has been described, although it is an extremely rare event (Friedler et al., 1996). Bennett et al. (1993) reviewed 2670 ultrasound-directed transvaginal follicle puncture procedures and they reported 8.6% cases of vaginal hemorrhage, with significant blood loss (.100 ml) in 0.8%. In two cases (0.1%) they recorded retroperitoneal bleeding from the ovary and in one case this necessitated an emergency laparotomy. In one case, an iliac vessel was punctured but the resulting pelvic hematoma settled without intervention. Azem et al. (2000) reported a case of massive retroperitoneal bleeding from the sacral vein, necessitating an emergency laparotomy. To reduce the risks of hemorrhage at the time of oocyte retrieval, Serour et al. (1998) advise to limit vaginal punctures to two, to visualize the peripheral follicles with ultrasound in a cross-section before puncture and to use color Doppler if available. The vaginal blood loss 24 h after non-complicated ultrasound guided transvaginal oocyte pick-up was calculated by Dessole et al. (2001) to be around 230 ml. These authors describe a drop in hematocrite of 5% or hemoglobin of 1.6 g% as normal. They conclude that if the blood loss is estimated to be normal using their calculation method, any postoperative acute abdomen must be infectious in origin. Specific pregnancy complications after ART Up to 4% of all IVF pregnancies are ectopic (Strandell et al., 1999). Ectopic pregnancies especially occur in patients with tubal disease, and it may therefore be expected that the ectopic rate may be well above 4% in ART pregnancies in developing countries, because of the high incidence of tubal infertility in these countries. Strandell et al. (1999) further performed a stepwise logistic regression analysis to identify risk factors for ectopic pregnancy after ART and they found that a previous myomectomy was also a risk factor for ectopic pregnancy, besides tubal damage. These authors suggest that changes in uterine contractility may contribute to the risk for ectopic implantation in patients having had uterine surgery. Quite typical for IVF are the heterotopic pregnancies, which present an even higher risk because of the danger of not being recognized early (Tal et al., 1996). A review by Rojansky

Minimizing risks of ART in developing countries

and Schenker (1996) mention the same risk factors as for ectopic pregnancy (especially tubal disease) together with a high number of transferred embryos. Although two embryos could in theory suffice to lead to a heterotopic pregnancy, the more embryos transferred, the higher the risk (Tummon et al., 1994). The risk is estimated to be as high as 1 – 3% of all ART gestations, but one may hope that this rate will drop in parallel with a drop in the number of transferred embryos. Because of the vital intrauterine pregnancy, diagnosis of a heterotopic pregnancy often is delayed and patients usually present with symptoms of abdominal pain, vaginal bleeding and often shock because of rupture of the pregnancy. Ultrasound and hCG monitoring do not help to diagnose a heterotopic pregnancy and in almost all instances diagnosis is only suspected when symptoms occur. However, most of the involved pregnancies end with the birth of a living child, if adequate emergency care is available. In case no treatment is available, heterotopic pregnancies may well be fatal. Also specific for ART pregnancies is the cornual or interstitial implantation site. Such ectopic localization, occurring alone or combined with an intrauterine gestation sac, represents about 2 – 6% of all ectopic localizations (Rojansky and Schenker, 1996). The diagnosis is difficult, often delayed and a cornual implantation may lead to the loss of pregnancy and in rare occasions even to hysterectomy because of uterine rupture, hemorrhage and shock. Interstitial pregnancies typically occur in patients having undergone salpingectomy and necessitate a high index of suspicion and close follow-up to avoid obstetrical catastrophes. Even in the absence of a cornual pregnancy, salpingectomy itself represents a risk factor for rupturing of the uterus in an ongoing intrauterine pregnancy in the second or third trimester (Inovay et al., 1999). Another complication that occurs quite typically in pregnancies after hormonal hyperstimulation is adnexal torsion. In the series of Roest et al. (1996), the incidence was around 0.1%. Kemmann et al. (1990) reviewed 1303 women who had a total of 6919 gonadotrophin-induced cycles. Four women developed adnexal torsion, all of whom were pregnant, representing an incidence of 1 in 162 pregnancies. In patients developing OHSS, however, the incidence of adnexal torsion seems to be much higher. Mashiach et al. (1990) reported an overall incidence of adnexal torsion of 7.5% in patients with OHSS. Torsion of a stimulated ovary can be managed by laparoscopic untwisting, even when the ovary seems to have become ischemic. Before detorsion, it may be necessary to aspirate as much fluid as possible, which allows safe rotation of the ovary without any damage. Another approach may be a transvaginal aspiration of the cysts to relieve the tension on the ovarian pedicle. Multiple pregnancies The last two decades, there has been a global increase in the incidence of multiple pregnancies, mainly resulting from the widespread application of assisted reproductive technologies. It is estimated that IVF and ICSI account for half of the increase while non-IVF treatments are responsible for the other half. According to national reports, the incidence of multiple pregnancy after IVF varies between 20 and 30%. The vast

majority of multiple pregnancies after ART are dizygotic twins and result from the transfer of multiple embryos. The risk of severe complications and sequelae per child belonging to a set of twins is 10% (Wennerholm and Bergh, 2000), and apart from severe complications, e.g. cerebral palsy, there are other physical and mental complications, as well as nonmedical problems, such as educational, emotional, (neuro)linguistic, financial, familial and sexual consequences that usually accompany the raising of twins (Dhont et al., 1999). A reasonable solution to the pandemic of ART twins would be to transfer only one embryo. Often, the pressure on both doctors and patients to increase the success rate of an expensive and stressful treatment has made the transfer of two or more embryos the standard of care. Many clinicians are reluctant to introduce single embryo transfer (SET) because of the fear of lowering their results. However, the judicious application of elective SET is a feasible option that has been demonstrated to reduce substantially the high incidence of twins following IVF/ICSI (Gerris et al., 2002; De Sutter et al., 2003a,b; Tiitinen et al., 2003). It has been shown that the combination of strict embryo selection with SET in twin-prone patients, i.e. women ,38 years of age in their first treatment cycle, can decrease the twinning rate to ,50% of its current incidence without reducing the overall efficacy of the program. Easily applicable selection criteria for both twin-prone patients and for good quality embryos with a putative high competence for implantation used to this effect have been described and validated in both retrospective and prospective studies (Gerris et al., 1999; Van Royen et al., 1999, 2001; Strandell et al., 2000). Since 2003 SET is mandatory in first and second cycles in patients up to the age of 35 in Belgium (Ombelet et al., 2005) and in several Scandinavian countries, it is applied even more widely. In countries that have adopted SET the overall results have merely changed, but multiple pregnancy rates have seriously gone down (Gordts et al., 2005; Karlstrom and Bergh, 2007). Even if pregnancy rates per cycle may be lower when applying SET in all patients (in cases of less good embryo quality or higher maternal age), as in the study by van Montfoort et al. (2006), one has to ask the question whether the outcome should not be measured in terms of healthy singleton babies per time period, rather than in terms of pregnancy rate per cycle. Success should not only be measured in terms of efficacy, but also in health-economic and even ethical terms. In countries where facilities for neonatal intensive care are lacking, deliberately creating multiple pregnancies is simply unethical. Now that ART technology has reached maturity and a high efficacy level in Western countries, quality and safety issues must retain our attention more than mere ‘success’. This is especially the case if we want to ‘export’ our technologies to countries which are not able to deal with the risks and complications, such as multiple pregnancies. ‘Primum non nocere’ has to remain our leading principle. Conclusion The two major complications of ART are OHSS and multiple pregnancies. Both can almost completely be avoided by using mild stimulation protocols, such as clomiphene citrate 75

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and by transferring only one embryo. If we do not want to create more problems than we want to solve, there should be no exceptions to this strategy. Acknowledgement The first author is the holder of a fundamental clinical research mandate by the Flemish foundation of scientific research (FWO-Vlaanderen).

References Al-Inany HG, Abou-Setta AM, Aboulghar M. Gonadotrophin-releasing hormone antagonists for assisted conception: a Cochrane review. Reprod Biomed Online 2007;14:640–649. Arya R, Shehata HA, Patel RK, Sahu S, Rajasingam D, Harrington KF, Nelson-Piercy C, Parsons JH. Internal jugular vein thrombosis after assisted conception therapy. Br J Haematol 2001;115:153– 155. Azem F, Wolf Y, Botchan A, Amit A, Lessing JB, Kluger Y. Massive retroperitoneal bleeding: a complication of transvaginal ultrasonography-guided oocyte retrieval for in vitro fertilization-embryo transfer. Fertil Steril 2000;74:405–406. Baber R, Porter R, Picker R, Robertson R, Dawson E, Saunders D. Transvaginal ultrasound directed oocyte collection for in vitro fertilization: successes and complications. J Ultrasound Med 1988;7:377–379. Belaen B, Geerinckx K, Vergauwe P, Thys J. Internal jugular vein thrombosis after ovarian stimulation. Hum Reprod 2001;16:510– 512. Bennett SJ, Waterstone JJ, Cheng WC, Parsons J. Complications of transvaginal ultrasound-directed follicle aspiration: a review of 2670 consecutive procedures. J Ass Reprod Genet 1993;10:72–77. Bergh T, Lundkvist O. Clinical complications during in-vitro fertilization treatment. Hum Reprod 1992;7:625– 626. Braat D, Bernardus R, Gerris J. Anonymous reports of lethal cases of OHSS. In: Gerris J, Olivennes F, Delvigne A (eds). Ovarian Hyperstimulation Syndrome. UK: Informa Healthcare, 2006,59– 70. Chan WS, Dixon ME. The “ART” of thromboembolism: a review of assisted reproductive technology and thromboembolic complications. Thromb Res 2008;121:713–726. Dessole S, Rubattu G, Ambrosini G, Miele M, Nardelli GB, Cherchi PL. Blood loss following noncomplicated transvaginal oocyte retrieval for in vitro fertilization. Fertil Steril 2001;76:205–206. De Sutter P, Gerris J, Dhont M. A health-economic decision-analytic model comparing double with single embryo transfer in IVF/ICSI: a sensitivity analysis. Hum Reprod 2003a;18:1361. De Sutter P, Van der Elst J, Coetsier T, Dhont M. Single embryo transfer and multiple pregnancy rate reduction after IVF/ICSI: a 5-year appraisal. Reprod Biomed Online 2003b;18:464– 469. Dhont M, De Sutter P, Ruyssinck G, Martens G, Bekaert A. Perinatal outcome of pregnancies after assisted reproduction: a case –control study. Am J Obstet Gynecol 1999;181:688– 695. Dicker D, Ashkenazi J, Feldberg D, Levy T, Dekel A, Ben-Rafael Z. Severe abdominal complications after transvaginal ultrasonographically guided retrieval of oocytes for in vitro fertilization and embryo transfer. Fertil Steril 1993;59:1313– 1315. El-Shawarby SA, Margara RA, Trew GH, Lavery SA. A review of complications following transvaginal oocyte retrieval for in-vitro fertilization. Hum Fertil 2004;7:127–133. Friedler S, Ben-Shachar I, Abramov Y, Schenker JG, Lewin A. Ruptured tubo-ovarian abscess complicating transcervical cryopreserved embryo transfer. Fertil Steril 1996;65:1065– 1066. Gerris J, De Neubourg D, Mangelschots K, Van Royen E, Van de Meerssche M, Valkenburg M. Prevention of twin pregnancy after in-vitro fertilization or intracytoplasmic sperm injection based on strict embryo criteria: a prospective randomized clinical trial. Hum Reprod 1999;14:2581–2587. Gerris J, De Neubourg D, Mangelschots K, Van Royen E, Vercruyssen M, Barudy-Vasquez J, Valkenburg M, Ryckaert G. Elective single day-3 embryo transfer halves the twinning rate without decrease in the ongoing pregnancy rate of an IVF/ICSI programme. Hum Reprod 2002;17:2621–2626. Gordts S, Campo R, Puttemans P, Brosens I, Valkenburg M, Norre J, Renier M, Coeman D, Gordts S. Belgian legislation and the effect of elective single embryo transfer on IVF outcome. Reprod Biomed Online 2005;10:436– 441.

Govaerts I, Devreker F, Delbaere A, Revelard P, Englert Y. Short-term medical complications of 1500 oocyte retrievals for in vitro fertilization and embryo transfer. Eur J Obstet Gynecol Reprod Biol 1998;77:239–243. Inovay J, Marton T, Urbancsek J, Kadar Z, Altdorfer K, Papp Z. Spontaneous bilateral cornual uterine dehiscence early in the second trimester after bilateral laparoscopic salpingectomy and in-vitro fertilization. Hum Reprod 1999;14:2471– 2473. Karlstrom PO, Bergh C. Reducing the number of embryos transferred in Sweden-impact on delivery and multiple birth rates. Hum Reprod 2007;22:2202– 2207. Kelada E, Ghani R. Bilateral ovarian abscesses following transvaginal oocyte retrieval for IVF: a case report and review of literature. J Assist Reprod Genet 2007;24:143– 145. Kemmann E, Ghazi DM, Corsan GH. Adnexal torsion in menotropin-induced pregnancies. Obstet Gynecol 1990;76:403– 406. Kligman I, Noyes N, Benavida CA, Rosenwaks Z. Massive deep vein thrombosis in a patient with antithrombin III deficiency undergoing ovarian stimulation for in vitro fertilization. Fertil Steril 1995;63:673–676. Ludwig M, Felberbaum RE, Diedrich K. Deep vein thrombosis during administration of hMG for ovarian stimulation. Arch Gynecol Obstet 1999;263:139– 141. Mashiach S, Goldenberg M, Bider D, Ben-Rafael Z, Moran O. Adnexal torsion of hyperstimulated ovaries in pregnancies after gonadotropin therapy. Fertil Steril 1990;53:76– 80. Ombelet W, De Sutter P, Van der Elst J, Martens G. Multiple gestation and infertility treatment: registration, reflection and reaction– the Belgian project. Hum Reprod Update 2005;11:3– 14. Roest J, Mous H, Zeilmaker G, Verhoeff A. The incidence of major clinical complications in a Dutch transport IVF programme. Hum Reprod Update 1996;2:345–353. Rojansky N, Schenker JG. Heterotopic pregnancy and assisted reproduction an update. J Ass Reprod Genet 1996;13:594–601. Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med 2001;344:1222–1231. Serour GI, Aboulghar M, Mansour R, Sattar MA, Amin Y, Aboulghar H. Complications of medically assisted conception in 3,500 cycles. Fertil Steril 1998;70:638–642. Sharpe K, Karovitch AJ, Claman P, Suh KN. Transvaginal oocyte retrieval for in vitro fertilization complicated by ovarian abscess during pregnancy. Fertil Steril 2006;86:219.e11– 213. Strandell A, Thorburn J, Hamberger L. Risk factors for ectopic pregnancy in assisted reproduction. Fertil Steril 1999;71:282– 286. Strandell A, Bergh C, Lundin K. Selection of patients suitable for one-embryo transfer may reduce the rate of multiple births by half without impairment of overall birth rates. Hum Reprod 2000;15:2520– 2525. Tal J, Haddad S, Gordon N, Timor-Tritsch I. Heterotopic pregnancy after ovulation induction and assisted reproductive technologies: a literature review from 1971 to 1993. Fertil Steril 1996;66:1–12. Tiitinen A, Unkila-Kallio L, Halttunen M, Hyde´n-Granskog C. Impact of elective single embryo transfer on the twin pregnancy rate. Hum Reprod 2003;18:1449– 1453. Tummon IS, Whitmore NA, Daniel SA, Nisker JA, Yuzpe AA. Transferring more embryos increases risk of heterotopic pregnancy. Fertil Steril 1994;61:1065– 1067. Tureck RW, Garcia CR, Blasco L, Mastroianna L Jr. Perioperative complications arising after transvaginal oocyte retrieval. Obstet Gynecol 1993;81:590–593. van Montfoort AP, Fiddelers AA, Janssen JM, Derhaag JG, Dirksen CD, Dunselman GA, Land JA, Geraedts JP, Evers JL, Dumoulin JC. In unselected patients, elective single embryo transfer prevents all multiples, but results in significantly lower pregnancy rates compared with double embryo transfer: a randomized controlled trial. Hum Reprod 2006;21:338–343. Van Royen E, Mangelschots K, De Neubourg D, Valkenburg M, Van de Meerssche M, Ryckaert G, Eestermans W, Gerris J. Characterization of a top quality embryo, a step towards single-embryo transfer. Hum Reprod 1999;14:2345– 2349. Van Royen E, Mangelschots K, De Neubourg D, Laureys I, Ryckaert G, Gerris J. Calculating the implantation potential of day 3 embryos in women younger than 38 years of age: a new model. Hum Reprod 2001;16:326– 332. Wennerholm UB, Bergh C. Obstetric outcome and follow-up of children born after in vitro fertilisation (IVF). Hum Fertil (Camb) 2000;3:52 –64.

doi:10.1093/humrep/den139

Human Reproduction 2008

Affordable ART services in Africa: synthesis and adaptation of laboratory services Carin Huyser1 Department of Obstetrics and Gynaecology, University of Pretoria, Pretoria Academic Hospital, PO Box 667, Pretoria 0001, South Africa 1

Correspondence address. E-mail: carin.huyser@up.ac.za.

The aim of this paper is to provide information, opinions and suggestions on affordable laboratory-orientated fertility screening and treatment. Resource management to provide such services in developing countries, basic and advanced assisted reproductive services and assisted reproduction treatment (ART) of patients with sexually transmitted infections are addressed. Alternative viewpoints and parallel thinking should be encouraged to synthesize and adapt firstworld ART guidelines and recommendations into safe and workable directives for developing regions. Affordable African ART programmes, devoid of commercialism, can provide essential sexual health screening services en route to safe fertility services for human immunodeficiency virus type-1 (HIV-1) serodiscordant couples (male HIV-positive), who wish to have their own biological child. Keywords: affordable; Africa; assisted reproduction; semen decontamination; HIV-1

Introduction Treatment for the infertile couple in a first-world setting evolved rapidly through access to high technology procedures and equipment, ready-made culture media and the finest monitoring systems in a controlled environment. A very different scenario however, shapes the lives and future of individuals, as well as health workers from the developing countries. Barriers to reproductive treatment are mostly financial in nature, influenced by regional, ethnical, social and political aspects. The question arises if past, present or alternative reproductive procedures can be applied and utilized within a simplified and, therefore affordable, assisted reproduction programme in developing countries? Furthermore, how the complex relationship between infertility and HIV-1, especially in Sub-Saharan Africa would direct or influence such a programme? The reproductive profile, affordability of care and resources available within the region will determine the selection of fertility screening procedures, as well as ‘new reproductive technologies’ treatment programmes. The aim of this paper is to provide information, opinions and suggestions on affordable laboratory-orientated fertility screening and treatment. Three sections will be discussed, i.e. basic and advanced laboratory assisted reproductive services, resource management to provide such services in developing countries and assisted reproduction treatment (ART) of patients with sexually transmitted infections in developing countries.

Assisted reproduction care in developing countries Workforce expertise, physical and financial resources available, together with the general sexual health profile of patients in a developing region, will determine the prospective reproductive care models. It is accepted that the political stability within the region, public support and a certain level of infrastructure, must be available to support reproductive healthcare deployment. (i) Levels of reproductive care Existing health services should either be remodelled or new amenities within a region could be created, to facilitate different levels of healthcare. Three levels of care are presently applicable, i.e. (i) a large number of primary centres/clinics performing initial inexpensive diagnostic fertility assessments, including a basic semen analysis and screening for viral diseases; (ii) a smaller number of intermediary practices that should offer screening and essential reproductive healthcare treatments and (iii) tertiary care centres providing advanced assisted reproductive technologies within an established academic setting. A simple semen analysis, as part of a ‘basic affordable fertility’ work-up, is mandatory for couples seeking fertility treatment in a developing country (Ombelet and Campo, 2007). This evaluation according to the latest edition of World Health Organization (WHO) guidelines should include macroscopic and microscopic assessment together with a basic semen culture (World Health Organization, 1999). Equipment, such as

Huyser

Figure 1: Adaptation of an Isolette. (A) Side view, (B) front view, (C) loading an embryo transfer catheter (Photos taken at Dallas In vitro associates, Dallas, Texas, 2002).

light microscopes, micropipettes, counting chambers and disposables including a small bio-flow/enclosed micro-chamber or ‘humidicrib’, to perform basic semen analyses are fundamental and simple (see Fig. 1) (Pilcher, 2006) to pipette semen samples and to safeguard the operator. An intermediary or secondary facility could extend basic service provision to include fundamental sperm preparation techniques and intra-uterine inseminations (IUIs) (Ombelet et al., 2003). Microorganisms, non-sperm cells, cell detritus, senescent and immature sperm should all be removed during sperm preparation, retaining only quality sperm. Basic sperm processing preparation techniques, such as the conventional swim-up procedure is easy to perform, inexpensive and recovers a good fraction of highly motile spermatozoa. Glasswool filtration is slightly more costly, but provides a good yield directly from the ejaculate, eliminates leucocytes and reactive oxygen species and is relatively easy to perform (Henkel and Schill, 2003). ‘Tertiary care centres’ can provide either sophisticated services with high-technology equipment, or use basic equipment and culturing techniques generally employed in a veterinary setting. Alternatives for laminar flow cabinets include the use of a ‘humidicrib’ (Pilcher, 2006), replacement of a water-jacketed incubator with a modular incubator chamber (www.thermo.com/forma), or use of the sealed-bag culture method (Pilcher, 2006). A dish containing the embryos can be placed inside special plastic bags, or a circular modular incubator, and purged with a pre-mixed gas mixture to create a mini-incubator. The bags can be placed in a water bath and the modular chamber inside a warm oven or incubator. Expensive gas manifolds are not needed, and gas tanks running empty or incubator malfunctioning are avoided with this system (Bavister and Poole, 2005). Present technology, alternatively, can perhaps be adapted for the use in a clinical in vitro fertilization (IVF) setting in Africa. Smaller modular bench-top-like K-MINC (Cook Co., Australia) incubators, ‘simple’ media specifically formulated to be easy to use with an extended shelf-life, should be investigated. Pilot studies and/or surveys are needed to validate alternative techniques, and to determine the views of African-females on participating in alternative protocols. The use of devices that reduce the 78

requirements for sophisticated laboratory equipment such as the INVOcellTM , an intra-vaginal culturing capsule (Bonaventura et al., 2006) should be considered, once the device is tried and accepted in economically developed countries. The application of ICSI techniques and cryopreservation as part of tertiary care centres has important financial and management implications. Cryopreservation should only be considered if the physical security of the vessels, specimens and liquid nitrogen supply as well as staff-safety could be secured. Patients should be screened for sexual transmitted infections (STIs); sperm purified and stored in hermetically sealed ionomeric resin straws (CryoBioSystems, CBSTM ) to safeguard cryopreservation conditions (Tomlinson, 2005). Networking and collaboration between regional assisted reproduction units should minimize costs through the acquisition of consumables in bulk, whereby batch quality could be compared and stock or equipment shared between laboratories. A mobile reproductive healthcare service could also optimize scarce resources, such as micromanipulators, through basic screening and treatment of patients in groups at set days/weeks. Intraand inter-region networking, training and continuous quality control is especially important when technological advanced techniques and equipment are used during assisted reproductive treatments. The embryology special interest group of the European Society for Human Reproduction and Embryology (ESHRE) (Gianaroli et al., 2000) could provide a best practice quality control framework to guide established or future IVF laboratories worldwide. Adaptation of these guiding principles together with the clinical quality guidelines and indicators (Mourad et al., 2007) should be considered for different subfertility levels of care, taking into account the existing healthcare system and socio-cultural beliefs of a developing country. (ii) Training Existing training courses (Franken et al., 2000; Bjo¨rndahl et al., 2002) could be adapted and customized into three practical and theoretical courses, i.e. a basic primary screening level that includes a semen analysis; an intermediary level including semen processing techniques and IUI, and a third advanced level that includes most assisted reproduction

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techniques. However, knowledge exclusivity and exorbitant costs (with regards to monetary exchange rates) to attend international meetings and workshops are a reality for embryologists from developing countries, who do not enjoy conference sponsorships from companies. This could change if on-line peer-reviewed educational support for continuous learning in spermatology, embryology and related procedures is freely available. Condensed theoretical and practical information should be readily available in atlas-formats, and health workers from developing countries should have free on-line access to international applicable recommendations and guidelines of ART procedures and methodologies. The introduction of inter-continental regional ‘twinning’ of reproductive facilities could further provide assistance and support. Access to peer-reviewed meetings can also be aided through charging of minimal or no registration fees to selected applicants from developing countries to attend WHO or ESHRE training, pre-congress courses and conference proceedings. Another possibility is to extend the annual ESHRE award to include a specific category at entre´e level to enable the presentation of data at a meeting. Abstracts for the presentation could be selected, extended abstracts requested and power point presentations or posters could be peer-reviewed for presentation at the annual meeting. An ESHRE taskforce training sponsorship could also support deserving health workers to visit dedicated European ART Units, or reproductive specialists from interest groups (Alpha Scientists for Reproductive Medicine/Centres for Reproductive Assistance Techniques to HIV-1-seropositive Individuals in Europe (CREAThE) network) could organize different training courses at functional African ART units. Furthermore, a supportive network of mentors and the implementation of continuous training and quality control programmes, through dedicated ESHRE taskforces, could strengthen collaboration and support. (iii) Obstacles Barriers to provide basic or advanced reproductive technologies in developing regions (Van Balen and Gerrits, 2001) are numerous and complex. Notwithstanding financial and logistic difficulties, evaluations and treatments should meet the requirements of the patient and the environment, e.g. 25% of males participating in our local assisted reproduction programme are unable to provide semen samples at the Unit. Options to provide a home-collection and/or use non-toxic polyurethane condoms are therefore offered to some patients. Inadequate transportation of patients and medical goods, antiretroviral (ARV) therapy and drugs that are not freely available, sub-optimal storage conditions and/or shortages of consumables and disposables, unavailability of adequate laboratory facilities (with specific reference to air quality, aseptic conditions and uninterrupted power supply), and inexperienced reproductive specialists, are highly relevant in some regions. Access to consumables, stable electricity supply to the laboratory and working within a dust and disaster free laboratory environment, should not be taken for granted in some developing regions. Therefore, back-up systems, laboratory consumables with a long shelf-life, durable equipment and applicable quality control assurance mechanisms should be

adapted and implemented to alleviate the restricted access to reproductive care. Advanced reproductive technologies also require patients to understand and comply with prescriptions for medications and instructions and must be on time for appointments. Unrealistic expectations or misunderstanding of processes and procedures by patients will cause a high voluntary or involuntary dropout rate. In addition, patient’s attitudes and lack of knowledge will result in the provision of incorrect sexual history and males may choose not to be part of the evaluation process. Repeated tests and investigations may be performed on the female partner, finally to discover that the couple’s infertility was due to a male factor (Leke, 2005). Resource management for effective ART management in developing countries Various internal and external resources should be considered, i.e. human, physical, financial, organizational and operational resources, to initiate spermatology and embryology-associated procedures. It is accepted that expectations, knowledge, needs, and norms of the regional community, wherein prospective reproductive healthcare centres will operate, must be the central focus to determine the format of prospective services. Special support, by trained local counsellors, will be needed at healthcare centres for couples living with HIV-1 or those patients with failed assisted reproduction attempts, especially in the locations where infertility and/or HIV are stigmatized. In addition, gender and professional inequalities in developing communities could have medical and social implications for infertility treatment. It is the author’s opinion that special attention should be given to the training and retention of paramedical staff within the African continent. Nursing staff, counsellors and biomedical scientists and technologists are most likely to be female, while clinical staff tends to be male, and will reflect the same gender, income and class, as well as influential position, in some developing societies. Experienced clinical embryologists and spermatologists who are not academically motivated, or who do not have a strong personal belief in the goals of the reproductive health centre, will either be part of the ‘brain-drain’ to developed countries (at present) and in future, lured financially into large pathology enterprises operating within the continent, or employed by gynaecologists in private assisted reproduction practices. Motivation through training opportunities and research initiatives, recognition and long-term goals, such as career path development, should however, provide a framework to retain creative, energetic and goal-orientated health workers (Mortimer and Mortimer, 2005). Financial support of assisted reproductive procedures in developing countries remains a contested issue (Ombelet and Campo, 2007). Assisted reproduction laboratory techniques as part of the ‘new reproductive technologies’ treatment can, however, be considered by some as prohibitively expensive and difficult to implement in developing countries (Inhorn, 2003). Ombelet and Campo (2007) outlined a custom-designed cost-effective infertility care programme as an alternative approach, i.e. utilizing assisted reproductive technologies 79

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complementary to family planning and perinatal care programmes in developing countries. Care should be taken that proper financial guidelines are available and regular audits are in place, together with proper legislation and official authorized documentation to guide fertility management. Patients as well as healthcare workers will be vulnerable without legal protection. Many African countries currently do not have guidelines or official national reproductive health policies to regulate or control assisted reproduction services or practitioners, or to ensure the safety of laboratory staff and patients when treating patients with chronic viral diseases. In addition, the commercialization of gametes and embryos and exploitation of resource poor communities within a developing region could jeopardize and tarnish the integrity of current reproductive healthcare initiatives. Treatment of patients with STIs in developing countries Although information on STIs and infertility management in Africa is inadequate and scarce (Leke, 2005), most international health strategies focus predominantly on the decline of population growth (Van Balen and Gerrits, 2001). There are many obstacles to the management of not only infertility, but also to implement appropriate screening and treatment of patients with STIs on the African continent. Globally, HIV infections are geographically unequally distributed. The majority of infections occur in Sub-Saharan Africa (15.4 million individuals), South and East Asia (7.1 million individuals). HIV-1 group M, with strains A, C and D together with two circulating recombinant forms, dominates the African epidemic. The HIV-2 epidemic remains limited and is located in West Africa, but is believed to be less infectious and pathogenic than HIV-1 (McCutchan, 2006). Besides HIV, the most common STIs reported in Africa include chancroid, human papiloma virus, herpes simplex, trichomoniasis and candidiasis, while gonorrhoea, syphilis and chlamydia also contribute to damages of Fallopian tubes (Bambra, 1999). Local infections of the male reproductive tract may also impact on HIV-1 shedding and thus the HIV load in semen (Dejucq-Rainsford and Je´gou, 2004). The possible origin, clinical presentation and transmission through semen of other sexual transmitted agents, such as cytomegalovirus (CMV), Hepatitis B, C, D (HBV, HCV, HDV) and human Tlymphotrophic virus (HTLV-I) have been reviewed elsewhere (Dejucq-Rainsford and Je´gou, 2004; Elder et al., 2005). Sub-Saharan Africa is reported to have the highest HCV prevalence rate in the world, compared with European and North American populations (Madhava et al., 2002). The mode of hepatitis transmission and implications for infertile patients as well as health workers have also been described in detail by the Practice Committee of the American Society for Reproductive Medicine (2006). (i) Screening of patients, laboratory adaptations and risk reduction The risk to introduce infectious conditions into the laboratory can be reduced through the screening of patients and health workers for various infectious agents. Routine testing of 80

patients will reduce the risk of infections in the ART laboratory. Testing should be governed by the prevalence of the disease in a specific patient population, medical history and physical examination of both partners (Elder et al., 2005). Should patients with STIs qualify for ART, then post-test counselling should be provided as well as a referral to facilities equipped to handle infectious body fluids. Patients should be persuaded to know their HIV status with the understanding that participation in ART implies agreement to disclose their status to the participating partner (ESHRE Ethics and Law Task force, 2004). Various national and international guidelines stipulate that patients should be tested annually for Hepatitis B and C (HBV/HCV). Screening for HIV-1 and -2 should be performed within 3–6 months of initiating a treatment cycle, to permit time for seroconversion. Screening for HTLV-I, which is endemic in central Africa, and general genital infections should be assessed within the context of the patient population (Elder et al., 2005; ASRM Practice Committee, 2006a,b). Viral reproduction, adaptations and intermitted shedding within the male genital tract (Pillai et al., 2005), as well as the concomitant occurrence of several viruses or sexual transmitted pathogens, have important implications for sperm washing procedures and viral detection methods. The ASRM Ethics Committee (2002) and ASRM Practice Committee (2006a,b) recommend health practitioners to counsel patients infected with a sexually transmissible pathogenic virus on the potential risks of transmission and to recommend the safest procedures for conception and delivery. They also stated that fertility services could not deny treatment to individuals with chronic infections if a centre has the resources to provide care. Inclusion criteria for ART in HIV-1-infected persons, results after treatment and the impact of ARV treatment on male and female fertility are discussed in detail by Van Leeuwen et al. (2007). It is, however, more complex to accommodate patients with chronic viral infections in an ART programme in a developing country, without all the necessary first-world resources. Only a very small number of South African units have separate laboratory facilities, dedicated equipment and/or cryocontainers and staff trained in semen decontamination procedures (for details on ART laboratory adaptations and safety, see Englert et al., 2004; Gilling-Smith et al., 2005). Several South African ART centres without such facilities are, however, treating HIV-1-infected patients using universal precautions. Questions therefore arise as to the frequency with which persons (with blood-borne viruses) approach ART centres seeking assisted reproduction, as well as the strategies that are in place to deal with such cases. A survey of South African infertility centres (Mphele, 2006) brought to light a number of worrying findings. There is a high probability of patients with undiagnosed HIV receiving ART without the knowledge of healthcare practitioners. This possibility raises significant ethical and legal concerns. The survey, which was conducted in 2003– 2004, demonstrated that some ART centres in South Africa treat HIV/HCV infected patients yet they lack facilities, skills and protocols that include risk reduction measures. Routine screening of both partners for HIV prior to ART were generally performed once during the couples’ first

ART services in Africa

attempt. Hepatitis B and C viral testing was however, seldom performed. We anticipate that a follow-up survey will indicate a change in attitude, policies and communication within ART units, due to HIV/acquired immune deficiency syndrome (AIDS) awareness campaigns in South Africa, as well as strong international views of compulsory and specialized approaches when handling specimens from ART patients who are HIV infected. At present, 32% of all new HIV-1 infections and AIDS deaths globally occurred in Southern Africa in 2007, with the largest number of HIV-1 infections recorded in South Africa (UNAIDS & WHO on-line report, 2007). These findings emphasize the need for relevant expertise and the development of applicable affordable laboratory protocols, as well as risk reduction strategies within the African continent that comply with internationally accepted safety standards. An affordable solution (within the African-context) would be to separate patients that tested (HIV/HCV) positive and negative in time, if space and funds are lacking (Devaux et al., 2003; Gilling-Smith et al., 2005). All laboratory procedures should be performed in a Class 2 biosafety cabinet with vertical flow, using sterile disposables and aseptic techniques and appropriate equipment to reduce the risk of infection (Elder et al., 2005). The crosscontamination incident of HBV that leaked from straws in a liquid nitrogen tank (Tedder et al., 1995) emphasized the importance of container selection and sealing system, for cryopreservation of gametes and embryos (Letur-Ko¨nirsch et al., 2003). The safety of heat-sealed shatterproof CBSTM ionomeric resin straws for the cryopreservation of semen containing HCV (Maertens et al., 2004) and HIV-1 RNA (Letur-Ko¨nirsch et al., 2003) have been demonstrated. Separate tanks to house straws containing gametes and embryos from seropositive patients would provide additional security (Devaux et al., 2003; Gilling-Smith et al., 2005). ART centres should always consider risks to other patients and staff when treating patients with known infections. Even if universal precautions are practised, zero risk does not exist (Gilling-Smith et al., 2005). (ii) Semen decontamination Contamination in a laboratory setting can occur through patients and health workers, specimens, such as semen, supplies and through the environment. Poor hygienic conditions, inadequate maintenance, cleaning and waste disposal may increase the risk of infection transmission to equipment, health workers, patients, gametes and embryos (Elder et al., 2005). All assisted reproduction techniques should reduce the risk of viral transmission to the uninfected partner, offspring, medical staff and other non-infected patients treated in the same laboratory. Adoption and the use of donor sperm are two reproductive options that are available for viral carriers seeking ART (ASRM Ethics Committee, 2002; Bujan et al., 2007). These options may, however, not be culturally or for religious reasons acceptable in many regions of the developing world (Van Balen and Gerrits, 2001; Inhorn, 2003). The ultimate sperm separation and washing method should be simple, performed in a short time, be cost-effective, resulting in the harvesting of a highly motile fraction without causing sperm damage or non-physiological changes to the separated

fraction. Non-sperm cells, as well as dead spermatozoa and harmful decapacitating factors should be removed during sperm processing (Henkel and Schill, 2003). It is clear that the type, origin, viral load and nature of infected cells in semen will, however, impact on the efficiency of a specific sperm washing procedure (Dejucq-Rainsford and Je´gou 2004; Elder et al., 2005; Fiore et al., 2005). The choice, as well as proven efficiency of a density gradient (Kuji et al., 2008) and washing technique (Fiore et al., 2005; Loskutoff et al., 2005; Kato et al., 2006) must be well established before any attempt can be made to perform semen decontamination for ART treatment. Agreement, however, has not been reached on the presence of HIV-1 DNA in sperm and the possible adherence of viral particles to the sperm plasma membrane. Muciaccia et al. (2007) confirmed the presence of HIV-DNA in purified sperm samples by nested PCR and in situ PCR after chromatin decondensation. A recent retrospective multicentre study by the CREAThE network (Bujan et al., 2007), however, demonstrated the efficiency of sperm-washing techniques in HIV-1-serodiscordant couples during different ART procedures. These researchers are of opinion that the technique can possibly be part of a worldwide health initiative to combat HIV in developing countries. The question arises whether the application of the above is of relevance with regards to reproductive treatment of HIV-infected patients in a developing country. Semen and purified samples are usually couriered to pathology laboratories in major cities (in South Africa) for viral validation using commercial assays, with small volumes undergoing only a quantitative RNA test. Results are usually received within 24– 72 h depending on transport distances. Sperm washing procedures (density gradient purification, with washing and swim-up steps) to eliminate the virus can also result in low number of sperm influencing the choice of ART procedure. IVF or ICSI using frozen spermatozoa can therefore be performed once the negative status of the sperm sample is confirmed. Special attention should also be given to motivate and train naı¨ve laboratory-staff that are not accustomed to handle potentially infected biological material (especially semen and follicular fluids from HIV-1-positive patients). Furthermore, a revised minimum standards document for practices that offer ART (Practice Committee of the Society for Assisted Reproductive Technology and the Practice Committee of the American Society for Reproductive Medicine, 2006) in developing countries could be used to assist with the specialized training of laboratory-staff, record keeping and basic information on informed consent and ethical aspects. From the above, it is clear that semen decontamination should be performed in only specific dedicated ART laboratories in developing countries, with access to reputable viral validation assays. These laboratories should have the dedicated facilities and staff should be trained to treat patients with STIs (Englert et al., 2004; ESHRE Ethics and Law Task Force, 2004; Gilling-Smith et al., 2005). Units that aspire to treat HIV-infected individuals should collaborate and interact with ART Units experienced in the treatment of such patients, according to international safety standards. Our Unit gained insight in the semen decontamination procedure through benchmarking and experimentation over time. 81

Huyser

It would therefore be advisable to adopt a HIV/ART policy for African Units that no ART can be performed if the viral load in semen is 10 000 RNA copies/ml (Pasquier et al., 2006) and .1 106 white blood cells/ml present in semen (World Health Organization, 1999). However, financial constraints and logistics will probably preclude viral-validations of most seminal and possibly purified sperm samples in most African ART laboratories. Therefore, an undetectable or low blood viral load with ARV therapy, together with a robust semen decontamination procedure that is repeatable, easy to perform, cost-effective and safeguards the patient, as well as the operator, should be promoted for the African continent.

Figure 2: Schematic presentation of a conical test-tube with a ProInsert-15TM and density gradient layers after centrifugation of seminal plasma. An elongated micropipette is inserted through an inner channel and bypass contaminated layers.

Using a centrifuge tube insert (ProInsert-15TM , Nidacon; Fig. 2) combined with a discontinuous density gradient containing a recombinant serine protease and inhibitor (PureSpermwPro Top and Bottom Layer, Nidacon), we have illustrated that HIV-1, HCV and CMV and white blood cells can be removed from spiked semen samples (Loskutoff et al., 2004, 2005; Huyser et al., 2006). Recent (unpublished) results indicated that the insert also removed various bacteria concentrations efficiently when compared with traditional density gradient centrifugation. Semen samples were spiked with a range of bacteria (Coagulase negative staphylococci, Staphylococcus aureus, Enterococcus faecalis, Enterobacter species, Escherichia coli and Candida albicans) that were commonly cultured in samples during diagnostic semen analyses. The design of the insert facilitated precise layering of density gradients and semen, allowing access to the treated sperm pellet post-centrifugation directly, without exposure to the upper gradient layers with possible pathogens and cell debris. The addition of recombinant protease to the density gradient ameliorated the viral infectivity, augmented sperm velocities and had no negative impact on sperm vitality. Most importantly, potential contaminated layers can be tightly capped within the conical tube and discarded after use. When evaluating seminal HIV-1 RNA and DNA viral loads of HIV-infected males, we observed a large disparity between blood and semen viral loads. A patient receiving ARVs can, e.g. present with .25 higher viral RNA levels in semen than in blood. We were able to confirm the removal of elevated (.8 106 copies/ml) seminal viral loads with negative quantitative (HIV-1 RNA reverse transcriptase polymerase chain reaction [RT – PCR]) and qualitative (proviral DNA RT-PCR) tests after the decontamination procedure at our laboratory. 82

Conclusion It is well known that unhindered access to information, reproductive health screening and associated therapies are of primary importance to address inequities between the developing and developed worlds. A recognized cohesive EuroAfrican partnership could further empower developing regions within the African continent to launch, sustain or expand existing reproductive health programmes. Integrating established academic-orientated reproductive laboratories from within the continent as partners to communicate, support and validate upcoming reproductive health screening centres, could further strengthen and provide intra-continental supportive networks. Regional partnerships can utilize and transfer indigenous knowledge and possibly link resources to the benefit of the continent. Matching inter- and intracontinental ART expertise and requirements to the benefit of African countries will be the bedrock of reproductive healthcare development on the continent. Past, present and validated alternative reproductive procedures can be applied within a controlled environment in developing countries. Simplified and therefore, affordable assisted reproduction programmes can be achieved through the design of three levels of reproductive care, with the first and second levels providing basic semen analyses and screening for STIs, and IUI procedures, respectively. Tertiary levels of ART care should be associated with selected academic institutions, using basic equipment and culturing techniques. Cryopreservation and micromanipulation procedures should be offered including possible treatment of patients with STIs. This possibility relies on the infrastructure of the surroundings and the accessibility to reliable pathology services to support ART procedures. Affordable ART services are attainable in Africa, if an African ‘brain-drain’ could transform into an African ‘brainbank’, to support and promote scientific knowledge and talent within the continent. Alternative viewpoints should be encouraged to synthesize and adapt first-world ART guidelines and recommendations into safe and workable directives for developing regions. Participation in a continuous quality assurance programme, data monitoring and training are essential to establish efficient ART laboratories in developing countries. The relationship between infertility and HIV/HCV, especially in Sub-Saharan Africa should receive special attention through networking with ART Units experienced in treating HIV/ HCV-infected persons. Evidently, the economic and

ART services in Africa

demographic impact of HIV/AIDS on the African continent should be counteracted through counselling, knowledge dissemination and proactive services to predominantly resource poor Africans. Affordable African ART programmes, devoid of commercialism, can provide essential sexual health screening services en route to safe fertility services for HIVserodiscordant couples (male HIV-positive), who wish to have their own biological child.

Acknowledgements Semen decontamination procedures were performed in part by Mr Jozef M. Fourie, Department of Obstetrics and Gynaecology, University of Pretoria. The semen decontamination research has been funded by the South African Medical Research Council (MRC). The views expressed by the author do not necessarily reflect the views of the MRC. Graphics provided by Creative Studios, University of Pretoria.

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Gilling-Smith C, Emiliani S, Almeida P, Liesnard C, Englert Y. Laboratory safety during assisted reproduction in patients with blood-borne viruses. Hum Reprod 2005;20:1433– 1438. Henkel RR, Schill W-B. Sperm preparation for ART. Reprod Biol Endocrinol 2003;1:108–130. Huyser C, Loskutoff NM, Singh R, Webber L, Franken DR. Enhanced sperm quality using advanced density gradient technology. Hum Reprod 2006;21(Suppl.):i58. Inhorn MC. Global infertility and the globalization of new reproductive technologies: illustrations from Egypt. Soc Sci Med 2003;56:1837–1851. Kato S, Hanabusa H, Kaneko S, Takakuwa K, Suzuki M, Kuji N, Jinno M, Tanaka R, Kojima K, Iwashita M et al. Complete removal of HIV-1 RNA and proviral DNA from semen by the swim-up method: assisted reproduction technique using spermatozoa free from HIV-1. AIDS 2006;20:967– 973. Kuji N, Yoshii T, Hamatani T, Hanabusa H, Yoshimura Y, Kato S. Buoyant density and sedimentation dynamics of HIV-1 in two density-gradient media for semen processing. Fertil Steril 2008 (in press). Leke RJI. The prevalence of infertility and its preventative measures in Sub-Saharan Africa. In: Sekadde-Kigondu CB, Chikamata DM, Franken DR (ed.) Infertility Management In African and Eastern Mediterranean Region. Nairobi, Kenya: A WHO Workshop, 2005. 53–59. Letur-Ko¨nirsch H, Collin G, Sifer C, Devaux A, Kuttenn F, Madelenat P, Brun-Vezinet F, Feldmann G, Benifla J-L. Safety of cryopreservation straws for human gametes or embryos: a study with human immunodeficiency virus-1 under cryopreservation conditions. Hum Reprod 2003;18:140– 144. Loskutoff NM, Huyser C, Singh R, Morfeld KA, Walker D, Thornhill AR, Smith M, Morris L, Webber L. A novel and effective procedure for removing HIV-1 RNA from human semen. In: Daya S, Pierson R, Gunby J (eds). International Congress Series; Special Issue: Research Papers in Fertility and Reproductive Medicine. Proceedings of the 18th World Congress on Fertility and Sterility (IFFS) 2004;1271C:200–204. Loskutoff NM, Huyser C, Singh R, Walker DL, Thornhill AR, Morris L, Webber L. Use of a novel washing method combining multiple density gradients and trypsin for removing human immunodeficiency virus-1 and hepatitis C virus from semen. Fertil Steril 2005;84:1001– 1010. Madhava V, Burgess C, Drucker E. Epidemiology of chronic hepatitis C virus infection in sub-Saharan Africa. The Lancet Inf Dis 2002;2:293– 302. Maertens A, Bourlet T, Plotton N, Pozzetto B, Levy R. Validation of safety procedures for the cryopreservation of semen contaminated with hepatitis C virus in assisted reproductive technology. Hum Reprod 2004;19: 1554– 1557. McCutchan FE. Global Epidemiology of HIV. J Med Virol 2006;78:S7– S12. Mortimer D, Mortimer S. Quality and Risk Management. UK: University Press, 2005. Mourad SM, Hermens RPMG, Nelen WLDM, Braat DDM, Grol RPTM, Kremer JAM. Guideline-based development of quality indicators for subfertility care. Hum Reprod 2007;22:2665–2672. Mphele SP. Human Immunodeficiency Virus (HIV) and Hepatitis in Assisted Reproduction in South Africa. Pretoria, South Africa: Tshwane University of Technology, 2006. Muciaccia B, Corallini S, Vicini E, Padula F, Gandini L, Liuzzi G, Lenzi A, Stefanini M. HIV-1 viral DNA is present in ejaculated abnormal spermatozoa of seropositive subjects. Hum Reprod Update 2007;22: 2868– 2878. Ombelet W, Campo R. Affordable IVF for developing countries. Reprod Biomed Online 2007;15:257–265. Ombelet W, Deblaere K, Bosmans E, Cox A, Jacobs P, Janssen M, Nijs M. Semen quality and intrauterine insemination. Reprod Biomed Online 2003;7:485–492. Pasquier C, Anderson D, Andreutti-Zaugg C, Baume-Berkenbosch R, Damond F, Devaux A, Englert Y, Galimand J, Gilling-Smith C, Guist’hau O et al. Multicenter quality control of the detection of HIV-1 genome in semen before medically assisted procreation. J Med Virol 2006;78:877– 882. Pilcher H. Fertility on a shoestring. Nature 2006;442:975–977. Pillai SK, Good B, Pond SK, Wong JK, Strain MC, Richman DD, Smith DM. Semen-specific genetic characteristics of human immunodeficiency virus type 1 env.. J Virol 2005;79:1734–1742. Practice Committee of the American Society for Reproductive Medicine. Hepatitis and reproduction. Fertil Steril 2006;86:S131–S141.

Huyser Practice Committee of the Society for Assisted Reproductive Technology and the Practice Committee of the American Society for Reproductive Medicine. Revised minimum standards for ART programs. Fertil Steril 2006;86: S53–S56. Tedder RS, Zuckerman MA, Goldstone AH, Hawkins AE, Fielding A, Briggs EM, Irwin D, Blair S, Gorman AM, Patterson KG et al. Hepatitis B transmission from contaminated cryopreservation tank. Lancet 1995;346:137–140. Tomlinson M. Managing risk associated with cryopreservation. Hum Reprod 2005;20:1751–1756. United Nations Programme on HIV/AIDS (UNAIDS) and World Health Organization (WHO), 2007 AIDS epidemic update, viewed 15 January

2008, http://www.unaids.org/en/KnowledgeCentre/HIVData/EpiUpdate/ EpiUpdArchive/2007. Van Balen F, Gerrits T. Quality of infertility care in poor-resource areas and the introduction of new reproductive technologies. Hum Reprod 2001;16: 215–219. Van Leeuwen E, Prins JM, Jurriaans S, Boer K, Reiss P, Repping S, van der Veen F. Reproduction and fertility in human immunodeficiency virus type-1 infection. Hum Reprod 2007;13:197–206. World Health Organization. WHO Laboratory Manual for the Examination of Human Semen and Sperm-cervical Mucus Interaction. 4th edn. Cambridge: Cambridge University Press, 1999.

doi:10.1093/humrep/den163

Human Reproduction 2008

INVO: a simple, low cost effective assisted reproductive technology R. Frydman1,2,3 and C. Ranoux4,5 1

Univ Paris-Sud, Clamart F-92140 Paris, France; 2AP-HP, Service de Gyne´cologie-Obste´trique et Me´decine de la Reproduction, Hoˆpital Antoine Be´cle`re, Clamart, F-92141 Paris, France; 3INSERM, U782, Clamart, F-92140 Paris, France; 4BioXcell Inc, 100 Cummings Center, Suite 421E, Beverly, MA 01915 USA 5

Correspondence address. E-mail: clauderanoux@bioxcell.com

INVO procedure is a simple and effective infertility treatment that uses a new device, the INVOcell. INVO can be performed in a physician’s office or in a satellite facility of an IVF center. The INVO procedure consists of fertilization of oocyte(s) and early embryo development in the INVOcell placed into the maternal vaginal cavity for incubation. The vaginal cavity replaces the complex in vitro fertilization (IVF) laboratory. This study presents the specially designed device, INVOcell that has received CE Certification. INVOcell overcomes the disadvantages of the previously used prototype and makes the procedure simpler and reproducible. INVO is a proven procedure that has demonstrated comparable results to conventional IVF when comparative studies were performed. Over 800 cycles have been published worldwide that showed a clinical pregnancy rate of 19.6%. The INVO technology can be performed in an office setting with minor capital equipment. INVO is a simple low-cost procedure that can be available almost everywhere. INVO allows the treatment of a new population of infertile couples who could not benefit from IVF due to cost and availability. The participation of the patient in the process of fertilization and early embryo development is a psychological benefit that creates a high level of acceptance of INVO. Keywords: INVOcell device; intravaginal culture; in vitro fertilization; office setting procedure; low cost

Introduction In vitro fertilization (IVF) is now an established treatment for infertility. IVF and variations such as intra cytoplasmic sperm injection (ICSI) requires complex laboratory equipment and very experienced laboratory personnel. Consequently, these treatments are expensive and are only available for a small fraction of the infertile population. The INVO technique, IVC (Ranoux et al., 1988), is a simple alternative to IVF, where the vaginal cavity of the patient substitutes the complex IVF laboratory. This study will describe a new device, the INVOcell, specially designed for the vaginal incubation. The INVOcell prevents the technical problems that were described during the use of a prototype. INVO could transform the treatment of infertility. Materials and Methods The principle of the INVO technique consists of oocyte fertilization and early embryo development in an air-free plastic device permeable to gas. The device placed into the maternal vaginal cavity utilizes the pCO2 of the vagina to equilibrate the pCO2 of the culture medium and maintain the pH of the medium during the period of incubation (Fukuda et al., 1996). INVO has been used with mild ovarian stimulation or no stimulation and allows the physician to perform an

IVF-like procedure in an office setting or in a satellite facility of an IVF center. Mild ovarian stimulation or no stimulation Several protocols have been used successfully: (i) FSH/hMG with or without GnRH antagonist, with ovulation induction triggered by hCG: Patients are injected with 1–2 ampoules of follicle-stimulating hormone (FSH) or human menopausal gonadotropin (hMG) every day starting at Day 3 of the cycle. Gonadotropin-releasing hormone (GnRH) antagonist is given late in the follicular phase (Days 8–10). Five to ten thousand international units (IU) of human chorionic gonadotropin (hCG) are used to trigger ovulation. This protocol allows recruiting an average of 10 follicles. (ii) CC alone, CC and FSH/hMG with ovulation induction triggered by hCG: Clomiphene citrate (CC, 50 or 100 mg) is given from Day 3 to Day 7, FSH, 75 IU is injected every day or 150 IU every two days from Day 6. This protocol allows recruiting an average of 5– 6 follicles. (iii) Natural cycle, natural cycle with GnRH antagonist with ovulation induction triggered by hCG: Cycles without ovarian induction have been performed, but premature ovulation and onsets of luteinizing hormone (LH) surge (Taymor et al., 1992) have complicated the protocol and lowered the pregnancy rate (10% per cycle, see Table I). The use of antagonist

Frydman and Ranoux

Table I. Summary of the results obtained in publications concerning INVO. Publication

Location

Ranoux et al. (1988) Sterzik et al. (1989) Ranoux and Seibel (1990) Wiegerinck et al. (1990) Freude et al. (1990) Taymor et al. (1992)

France 100 Germany 22 France 100 The Netherlands 43 Germany 15 USA 51

Sharma and Hewitt (1993) UK Fukuda et al. (1996) Japan Batres et al. (1997) USA Total

No. Cycles Clinical pregnancy rate per cycle

334 58 92 815

20% 22.7% 22% 14% 20% 10% Natural cycle 20.7% 20.7% 19.6% 19.6%

at Day 8 to Day 10 prevents the LH surge and dramatically increases the pregnancy rates (Rongie`res-Bertrand et al., 1999; Mendez-Lozano et al., 2008). Generally 1 to 2 follicles are recruited. These mild stimulation protocols allow to retrieve few follicles and to minimize the discomfort of the patient during the follicle retrieval. Follicle retrieval Thirty-four to thirty-six hours after the hCG injection the follicle aspiration is performed transvaginally using ultrasound vaginal probe guidance. A light sedation, with or without local vaginal anesthesia, replaces the general anesthesia and allows the retrieval to be performed in an office setting. INVO procedure The INVO procedure is a major simplification for fertilization and embryo development. The principle is simple. The vagina of the future mother replaces the complex laboratory as the site of incubation. (i) The procedure: The sperm preparation is generally performed 1 h prior to the oocyte retrieval to allow the biologist to perform the insemination immediately after oocyte retrieval. Gradients of density are used to wash the sperm and select the most motile spermatozoa. The device should be filled with medium without interposition of air. Air bubbles could be trapped in the cumulus of the mature oocytes and bring them to the surface and therefore prevent fertilization by spermatozoa. A small fraction of the motile spermatozoa (30 000) is used to inseminate the oocytes in the device. After follicle aspiration, oocyte(s) are identified in the follicular fluid. As no pre-incubation of the oocytes is necessary, oocytes are immediately placed into the device, the fraction of motile sperm is added before or after transfer of the oocytes. The device is closed, placed into a protective outer rigid shell and then positioned into the vaginal cavity for 2 or 3 days. A retention system is used to secure the device in the vagina during incubation. No activity restriction is required for the patient, but baths are not recommended as they may modify the temperature of incubation. After incubation the retention system and the device are removed from the vagina in the physicianâ&#x20AC;&#x2122;s office. The outer rigid shell is removed, the device is opened and the contents observed under microscope to find the embryos. The two best ones are loaded into a catheter and transferred immediately into the uterine cavity. Ultrasound guidance may be used in order to improve the quality of the transfer.

(ii) The Device: (a) Prototype. A prototype was used during the first development and in the publications concerning the INVO procedure. The prototype was chosen because it showed the best sealed closure among the prototypes that were initially tested. To avoid air bubbles the corpus and the plug of the prototype tube were filled with culture medium, then the gametes were introduced and the tube was closed. Several disadvantages were described such as: (1) only one sterile opening and closing were possible. (2) During the closing of the prototype oocytes could be lost in the overflow of medium and the culture medium could be easily contaminated by errors in manipulation. (3) A large opening of the tube could rapidly modify the pH of the medium. (4) A plastic envelope was sealed thermally around the prototype to protect the contents of the tube from the vaginal secretions. During the sealing of the envelope with heat, the increase of temperature could affect the gametes. (5) Openings of prototypes have been reported during its placement or removal from the vaginal cavity. (6) To prevent expulsion of the device, a diaphragm was used to maintain the device in the vagina during the period of incubation. A risk of bacterial vaginosis was increased as vaginal secretions were retained behind the membrane of the diaphragm. (7) One major advantage of the INVO technique is that corona cells surrounding the zona pellucida and the cumulus cells are spontaneously removed after 2 or 3 days of vaginal incubation. The disadvantage of these spontaneously denuded embryos was the difficulty to find them rapidly under microscope in the large volume of medium even for a trained embryologist (chamber volume of the prototype equals 3 ml). (b) INVOcell. The new device has been specially designed for the INVO procedure which addresses the disadvantages described above (Figs 1â&#x20AC;&#x201C; 3). (iii) Disposable equipment: other disposable equipment than the INVOcell device are necessary to perform the INVO procedure such as: (a) Needle for oocyte retrieval (b) Cover for the vaginal probe (c) Petri dishes, tubes, pipettes, container to collect the sperm, slides and gloves used to prepare the gametes (d) Embryo transfer catheter (e) Culture media: saline solution to wash the vaginal cavity, medium to flush the follicle if used, gradient density for sperm preparation, culture medium to wash the sperm and used in the INVOcell. (iv) Capital equipment: (a) Rapid hormonal assay instrument. Hormonal assays are important to evaluate the follicle growth and the timing of ovulation. Instrumentation for rapid hormonal assays is generally available in clinical laboratories. Small instruments with individual disposable test units are also available. Leasing of the instrument is generally included in the cost of the disposable test units. (b) Ultrasound machine with vaginal probe and vacuum pump. Ultrasound is also valuable in the monitoring of ovulation and is necessary for the follicle retrieval. The ultrasound machine with vaginal probe is generally available in the

Intravaginal culturing

Figure 1: INVOcell fully assembled device, before positioning in the vagina. This device is made of two parts, the inner chamber that contains the culture medium [Complete P1 SSS (Synthetic Serum Substitute) from Irvine Scientific, Irvine, CA, USA, was used successfully in a clinical trial] and the gametes and the outer rigid shell that keeps the orifice of the valve sterile and protects the inner chamber from the vaginal contaminations.

Figure 3: Outer rigid shell. The external surface is smooth to prevent any lesion or irritation of the vaginal or the cervical epithelium during the 3 days of vaginal incubation. The wall of the INVOcell is permeable to CO2. The rigid wall protects the inner chamber but allows the physician to grasp the device with a forceps to place it or remove it from the vagina. A locking system prevents any unexpected opening of the outer rigid shell. The retention system has been improved. Holes have been perforated in the membrane of the diaphragm for elimination of the vaginal secretions during the incubation. observation can be performed successfully without clean environment. However, we recommend the use of a laminar flow hood for the INVO procedure to decrease the risk of contamination and major variations in temperature of the culture media and gametes. The investment varies from $7000 to $30 000.

Figure 2: Inner chamber. A rotating valve allows several openings and closings of the inner chamber without interposition of air or contamination of the culture medium. A small orifice prevents major variations in pH of the culture medium and looses the gametes due to overflow. The volume of the chamber has been reduced (1.1 ml). A micro-chamber collects the embryos after incubation, by placing the inner chamber in a vertical position during 15 min. Embryos can be observed in the micro-chamber under microscope without transferring them to a culture dish and therefore can be loaded in a catheter for their immediate transfer to the uterus of the patient.

office of a physician who treats infertility. The investment to get the ultrasound machine with the vaginal probe, its needle guides and the vacuum pump to aspirate the follicular fluid may vary from $7000 to $30 000, depending of the age of the instrument and where it is purchased. (c) Laminar flow including warm bench, small incubator and stereomicroscope with video system and bench centrifuge. This capital equipment is desired to perform the biologic steps of the INVO procedure. Identification of oocytes in the follicular fluid, sperm preparation and embryo

Results The INVOcell device has been ISO 10993 tested (and mouse embryos tested) to assess toxicity and biocompatibility. Clinical tests have been performed to evaluate the comfort and retention of INVOcell within the vagina. Preliminary analysis of a clinical trial performed in an infertile population has shown the INVOcell to be a well accepted, non-traumatic, effective device with births of normal babies. Complete results from the clinical trial will be published in the future. This clinical trial also demonstrated that Complete P1 SSS could be used for 3 days of incubation without medium change. Over 800 cases of IVC performed by infertility groups around the world (France, Germany, Netherlands, England, USA, Japan) have been documented in peer-reviewed journals, demonstrating success rates (average clinical pregnancy rate of 19.6% per cycle) which were comparable to success rates of conventional IVF reported by the user of INVO at this time (Table I). The clinical pregnancy rate per cycle that went to oocyte retrieval was reported in most of the publications on IVC or could be easily calculated. We used this clinical pregnancy rate to allow pooling the results of all these different publications and calculate the average clinical pregnancy rate per 87

Frydman and Ranoux

cycle (19.6%) presented in Table I. When comparative studies were performed, pregnancy rates obtained by IVC were comparable to those observed in IVF (Sterzik et al., 1989; Ranoux and Seibel, 1990). Another publication on IVC by Costoya et al. ( 1991) is not reported in Table I. This publication concerned 23 cycles of which 18 proceeded to retrieval but could not be used, as only a fraction of the retrieved oocytes (78 on 102) were inseminated by IVC. The method for selecting these 78 oocytes was not defined. Costoya et al. (1991) achieved only an average 10.2% fertilization rate as other publications generally reported an average fertilization rates between 50.3 and 69.5% for IVC. This abnormally low fertilization rate suggests a toxic factor, methodological problem or a wrong utilization of the prototype as suggested by three fertilized oocytes blocked at the pronuclei stage and two diagnosed contaminations of the culture medium by Candida albicans. On the five cleaved embryos transferred one birth was achieved, demonstrating the efficacy of the INVO technique when performed correctly. Discussion The results from over 800 clinical cases of IVC and preliminary studies of the INVO procedure using the INVOcell device indicate that INVO provides a simple and effective alternative to conventional IVF. Disadvantages and advantages of a cycle using an INVO procedure are discussed below. Potential disadvantages of the INVO procedure Two major criticisms have been made to the INVO technique: (i) The culture medium is not changed during the 2 or 3 days of incubation. Therefore, the oocytes are in contact with dead spermatozoa and the products of degradation related to the metabolism of the cells. (ii) The absence of the embryo check at 16 â&#x20AC;&#x201C; 20 h postinsemination could omit polyspermic embryos that could develop normally and be transferred to the uterus. The low sperm concentration used in IVC or INVO reduces the products of degradation in the medium as well as the rate of polyspermic embryos without any decrease of the fertilization rates. Improvements in stimulation protocols with a better maturity of the retrieved oocytes have also contributed to a decrease in the rate of polyspermic embryo. In addition, higher miscarriage rates were not observed by the users of the INVO procedure. The use of mild stimulation protocols presents several advantages (i) It eliminates the side effects related to the high estrogen levels of an ovarian hyperstimulation such as hot flushes, discomfort, abdominal pain or complications such as an ovarian syndrome of severe hyperstimulation that could lead to the hospitalization of the patient in intensive care or even to her death. (ii) It reduces the monitoring of the stimulation. (iii) It decreases the time and discomfort of the follicle retrieval due to the small number of follicles retrieved. It 88

allows the physician to perform the retrieval under light sedation in the office. (iv) It prevents using embryo cryopreservation. Generally two embryos with the best quality will be transferred. If more embryos are obtained, embryos of lesser quality will be discarded. This policy will help to decrease the rate of multiple pregnancies that creates a huge financial burden for the society. The use of INVO procedure adds other advantages (i) The INVO procedure does not need major capital equipment. This capital equipment can be easily stored in the office of a physician (12 square feet or 1.14 m2) and does not need extensive maintenance and quality controls. (ii) In INVO, embryos are not stored in the office therefore sophisticated incubator with CO2, air filtration system, alarm system and embryologist on call are not necessary. In a busy IVF center, sperm preparation, oocytes retrieval, oocyte insemination, change of culture medium, embryo denudation, check for fertilization and embryo cleavage are spread over several hours and even days. For evident reasons of organization and efficiency, a technician will prepare sperm samples of different patients at the same time, perform retrieval, IVF/ ICSI fertilization, medium change or check fertilization for several different couples in a row. Very rarely the same embryologist will be able to perform all these steps for the same patient. This complex organization requires a strict patient identification but increases the risk of errors in labeling or handling of the gametes and embryos. The simplicity of the INVO procedure allows a single technician to carry out all the tasks of INVO in the same period of time (60â&#x20AC;&#x201C; 90 min) without any assistance. It allows the technician to complete the treatment of one couple before starting the treatment of another couple and dramatically decreases the risk for mislabeling and mishandling. (i) In an IVF center, incubation of gametes and embryos of several different couples in the same incubator may create the opportunity for errors. In the INVO procedure, the incubation of the gametes and embryos in the maternal vagina and the transfer of the embryo(s) immediately after INVOcell removal eliminate any risk of errors. The INVO procedure can be performed in an office setting, which is a familiar environment, at a lower cost. INVO can be available almost everywhere with less travel expenses for the infertile couple. One limitation for a more generalized application of the technique in Europe is the actual EU guidelines for the manipulation of gametes and embryos, which favor certified and legally controlled IVF centers. These guidelines do not allow the manipulation of gametes and embryos outside these protected environments. The creation of INVO low-cost satellite units in physician offices that are trained, affiliated and controlled by IVF centers is one of the most economical solution to answer the increasing demand of the infertile population and to reverse the falling birth rates of European countries (Rand Research Brief, 2005). Down-sized capital equipment, mild stimulation protocols and simplifications brought by INVO which requires less

Intravaginal culturing

expertise and time consuming from the operators contribute to lower the overall cost of an INVO cycle. INVO procedures have been performed for 1/3 to 1/2 of the cost of a conventional IVF.

Conclusion IVC is a well researched and simple alternative to conventional IVF. The INVO procedure and INVOcell device represent significant advancements of IVC. BioXcell has received ISO 13485 certification and a CE Certification for the INVOcell device. The INVOcell is specifically designed to address the challenges faced by clinicians using earlier prototype devices. For example, the INVOcell uses a precisely designed rotating valve to eliminate the risk of gametes loss and medium degradation. In addition, the design of the inner chamber, which contains gametes and medium, provides for easy identification and transfer of the embryos to the mother. Combined with the mild or no stimulation protocol, the INVO procedure is an attractive infertility treatment option for patients who cannot afford conventional IVF or who live too far away from a clinic that offers IVF. Further, in developing countries, where infertility rates are high and access to cost-effective infertility treatment is low, INVO provides an excellent treatment option.

Acknowledgements We thank BioXcell Inc. which sponsored the study.

References Batres F, Mahadevan M, Maris M, Miller M, Moutos D. Stimulated cycle and intravaginal culture fertilization in an office setting. A preliminary study. Poster presentation (P-196) at the annual meeting of ASRM, Cincinnati, Ohio, 1997. Costoya AL, Cafatti CM, Gadan AA. Experience with intravaginal culture for in vitro fertilization (IVF). J Vitro Fert Embryo Transfer 1991;8:360– 361. Freude G, Artner B, Leodolter S. Intravaginal culture–simplification of IVF. Wien Med Wochenschr 1990;140:498– 501. Fukuda M, Fukuda K, Ranoux C. Unexpected low oxygen tension of intravaginal culture. Hum Reprod 1996;11:1293– 1295. Mendez-Lozano D, Brum Scheffer J, Frydman N, Fay S, Fanchin R, Frydman R. Optimal reproductive competence of oocytes retrieved through follicular flushing in minimal stimulation IVF. RBM Online 2008;16:119–123. Rand Research Brief. Population Implosion? Low Fertility and Policy Responses in the European Union. Rand Online RB-9126-EC, 2005. Ranoux C, Seibel MM. New techniques in Fertilization: Intravaginal culture and microvolume straw. J Vitro Fert Embryo Transfer 1990;7:6–8. Ranoux C, Foulot H, Aubriot FX, Poirot C, Dubuisson JB, Chevallier O, Cardone V. A new in vitro fertilization technique: intravaginal culture. Fertil Steril 1988;49:654– 657. Rongie`res-Bertrand C, Olivennes F, Righini C, Fanchin R, Taieb J, Hamamah S, Bouchard P, Frydman R. Revival of the natural cycles in in-vitro fertilization with the use of a new gonadotropin-releasing hormone antagonist (Cetrorelix): a pilot study with minimal stimulation. Hum Reprod 1999;14:683– 688. Sharma S, Hewitt J. Intravaginal culture for IVF. Bombay Hosp J 1993;35:155– 160. Sterzik K, Rosenbusch B, Sasse V, Wolf A, Beier HM, Lauritzen C. A new variation of in vitro fertilization: intravaginal culture of human oocytes and cleavage stages. Hum Reprod Suppl 1989;83– 86. Taymor M, Ranoux C, Gross G. Natural oocyte retrieval with intra vaginal fertilization: a simplified approach to in vitro fertilization. Obstet Gynecol 1992;80:888– 891. Wiegerinck MAHM, Moret E, Van Dop PA, Wijnberg M, Beerendonk CDMB. Intra vaginal culture (IVC), the Eindhoven experience. In: Evers JHL, Heineman MJ (ed). Ovulation to Implantation. Elsevier Science Publishers, BV, 1990, 349–351.

doi:10.1093/humrep/den161

Human Reproduction 2008

Four years of IVF/ICSI experience in Kampala (Uganda) P. Platteau1,4, B. Desmet1, G. Odoma2, C. Albano1, P. Devroey1 and E. Tamale Sali3 1

Centre for Reproductive Medicine, University Hospital, Dutch-speaking Brussels Free University (vrije universiteit Brussel), Brussels, Belgium; 2G-Systems ltd, House 51, Gwarimpa Abuja, Nigeria; 3Womenâ&#x20AC;&#x2122;s Hospital International, PO Box 16233, Kampala, Uganda 4

Correspondence address. Zonlaan 49, 1700 Dilbeek, Belgium. E-mail: peterplatteau@telenet.be

We all know that starting and running an ART clinic is not so easy as some people might perceive from outside. Doing the same thing in the middle of Africa is even more challenging as some evidences in the Western world are not so obvious in this part of the world. We started our clinic in Kampala in 2004. The clinic was a converted apartment from a four flat building. In the beginning, we had difficulties with importing drugs, culture media and consumables; we had the feeling everybody was against us. We overcame multiple power failures, night intruders and a 20% masturbation failure, but once the first IVF/ICSI babies were born, people started to believe in the project. At present, 250 IVF/ICSI cycles a year are done in batches, we have a successful embryo freezing programme, offer IUI/ICSI for sero discordant HIV couples and have the first babies after IVF, ICSI, testicular biopsy, embryo freezing, oocyte donation and surrogacy in Central Africa. The results are comparable to the ones in the Western world. Keywords: IVF; ICSI; Uganda; first IVF baby

Introduction We started our IVF clinic in Kampala in 2004; this was the result of an initial idea of my old friend and colleague Dr Edward Tamale Sali, who went to medical school in Kampala, but had to move to the UK to finish his obstetrics and gynaecology training, due to the political turmoil at the time in Uganda. He always had the idea to go back and talking to Ugandan colleagues, family members and a local patient organization, realized that infertility in Central Africa was a serious and unrecognized problem. Now, starting an IVF clinic in a country, with one of the highest birth rates in the world (Blacker et al., 2005) might raise some eyebrows; especially as treatment and prevention of malaria, HIV, malnutrition and vaccination programmes are top list priorities in Uganda. Second, introducing IVF, which is expensive and far from full prove, in a third world country seems to be prone for failure. We have proved the contrary up till now! It is true that viewed from a society perspective (Ombelet and Campo, 2007), there is no need for fertility treatment in a country where an average family has more than six children; but on an individual basis, we know that up to 30% of the couples in Uganda suffer from primary or secondary infertility (Larsen, 2000). For these couples and especially for the female partners, the fact that they are unable to conceive is a social drama. They risk rejection from their husband, family and socio-economic deprivation; they are also at higher risk for domestic violence and might end-up in prostitution (Dyer et al., 2005). 90

Infertility increases, on top of this, also the propagation of HIV; a high proportion of Ugandan men will after a certain period of unsuccessful trying with their partner, start a second and even more extramarital relationships (especially if it is a male problem), exposing themselves, their partners and wife to a high risk of HIV infection, as they will never use protection. They will either succeed to have a pregnancy with a different partner, which will lead to a divorce and terrible stigma of their wife, or after a few relationships, realize that they themselves suffer from male infertility.

The start We started our clinic in Kampala in 2004 with the help of a Danish company called Nordica; they sold and transported the necessary second-hand lab material (for a good price) from a 15-year-old IVF clinic in Copenhagen who just closed. The clinic was an apartment from a four-flat building, which was converted in a consultation room (the old kitchen), an oocyte retrieval room and laboratory (two-old bedrooms) and a recovery room (the old-living room). The first batch of patients was a disaster as medication did not arrive on time in Kampala, culture media and other utensils were not released at the airport and everybody seemed to be against us. Most patients were cancelled, but we learned a lot and knew that the next time we had to get it right. The second batch of 12 patients were well prepared (drugs were imported from Kuwait) and 10 were ready for oocyte retrieval. Culture media were smuggled into Kampala as well

IVF/ICSI in Uganda

as all the consumables. Three patients became pregnant and delivered three healthy babies. We overcame multiple power failures, a check-up of the incubator at night by intruders, a 20% masturbation failure of the patients and all in non-ideal circumstances. From then on, it only became better, we adapted the lab and oocyte retrieval room, we bought new equipment, we got major support from the local press and President Museveni, we could import all necessary material without any delays at the airport and we installed electricity converters and back-up engines. We now do 250 IVF/ICSI cycles a year in batches and have the first babies after IVF, ICSI, testicular biopsy, embryo freezing, oocyte donation and surrogacy in Central Africa. Our results are comparable with the ones in the Western world. The patients From the 4 years the IVF clinic is running, we realize that the majority of couples, presenting at our clinic, are suffering of severe male infertility; most husbands are in fact not surprised (Dyer et al., 2004), when they are confronted with the diagnosis. A small proportion of couples are diagnosed with tubal infertility of which most are HIV positive, especially if they have hydrosalpinges. This is most probably due to the fact that sexually transmitted diseases, which cause hydrosalpinges, also facilitate the transmission of HIV and go often together. Another proportion of patients are older couples (often with children from a first marriage), who suffer from secondary infertility due to the age of the female partner. These couples have usually less economical problems (a standard IVF/ICSI treatment with medication costs from $3000 onwards at our clinic) and participate in our anonymous oocyte-sharing programme, where they receive half of the oocytes of younger patients (who are screened for infectious diseases) and in compensation pay for the IVF treatment of the younger and economically poorer patients. In this way, we managed to offer also fertility treatment to a category of patients who would have never been able to pay for it (50% of the couples that consult at the clinic, cannot afford IVF treatment). We also see a lot of patients from neighbouring countries (Kenia, Tanzania, Rwanda, Congo, Sudan, Somalia and Ethiopia) who cannot afford to go to South Africa, Europe or USA for IVF treatment. The fact that our clinic is close by and transport and accommodation are cheap made IVF treatment affordable for these couples. A last category of patients at our clinic are expatriate patients for whom treatment at our clinic is much cheaper than in their home country and Europeans from African origin, who are in need of oocyte donation, which is in Europe more difficult to find and three times more expensive. The clinic At the moment, we are extending our project by building a tree storey house, adjacent to the existing building. In the near future, we will move the IVF unit to the new building, and

we will have a maternity unit, operation theatre and neonatal care unit; the latter is very important as neonatal care services in Uganda are scarce and we have a multiple pregnancy rate of 20%. We are doing our best to lower this high rate of multiple pregnancies, but it is very difficult due to the pressure of the patients; most of them will be able to afford only one treatment cycle in their entire life, so a single embryo transfer is for them difficult to accept, as it is in all health systems, where the patient has to pay for the full treatment themselves. Embryo reduction is culturally difficult to accept in Uganda, although offered at our clinic. The staff There are about 30 people employed by the clinic: round the clock security guards (Kampala is very safe, but before employing them, we had some intruders at night, who probably came more out of curiosity than to steal something), nurses, administration personnel, one pharmacist, two chauffeurs, cleaning personnel, one cook and tree embryologists; the latter were locally trained by a senior Belgian and Nigerian embryologist. We opted for local training as we think that working circumstances in the Western IVF world are quite different, it is cheaper and we know that a high number of trainees in Europe do not come back as they are offered locally a job (if they are good) for a higher salary or being young, meet a partner and prefer to stay. Our most experienced embryologist left for a foreign NGO working on an HIV project in Kampala, who offered her the triple of her salary she was getting at our clinic. We realize that this is a frustrating situation, which might repeat itself in the future. We cannot compete with Western salaries and there is no legislation that organizes compensation for previous investment in training. We have a very high turn over of personnel, most of them dismissed after a while due to small theft; most of it is very obvious and is admitted very swiftly by the responsible person; the main reason is usual acute unforeseen financial problems within the family. We regularly have meetings with the paramedical personal to review procedures, discuss problems and complications to make sure that the standards are maintained. The cost We feel that our project lowered the access threshold for infertility treatment for infertile couples in Uganda and neighbouring countries. We are well aware that for most people this treatment is still unaffordable, but we believe that in the near future we will be able to lower this threshold even further; the costs of gonadotrophin preparations will decrease by at least 50% when generics will be allowed; better communication and collaboration between centres in Africa and other countries of the developing world should result in cheaper consumables (by buying them in bulk) and equipment [most IVF equipment is overpriced and some can be made by some local craftsmen (e.g. our ICSI stabilization table was made locally and costed ,$50)]. We fully support further research in low cost IVF projects with minimal stimulation protocols. We fear, however, that it might give false expectations to 91

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a very poor group of patients for whom even $100 is a lot of money. To extrapolate pregnancy results after minimal stimulation from the Western world to Central Africa is not possible due to the different working circumstances. We also fear that the initial investment for the basic IVF equipment (ultrasound machine, incubator, theatre table, etc.) to start such a project (estimated at 25.000 Euros and fully subsidized by the Western world) might be taken over at the end of the project by a local private centre; this would be unfair to other existing private centres, who had to invest in all the equipment themselves. Education Our clinic in Kampala generated through the media, after the birth of the first IVF babies, a general awareness about infertility, the fact that it can be solved and that the babies born after IVF are quite similar to natural conceptions (although as mentioned in the local press ‘they were conceived without sex’). In the future, we hope to extend this in a fertility prevention programme and start a well needed education programme (Byamugisha et al., 2006) in collaboration with the local universities.

years, with the building of two new dams on the Nile river (personal communication by Mr Alhaj M. Tezikuba Sajjabi, senior presidential adviser industrial matters) and the exploitation of large oilfields near Albert lake. Conclusion Although we encountered many unexpected problems, we now have a successful IVF/ICSI program in Central Africa. We learned from experience that starting and running an IVF clinic is very different than in the Western World. We believe that thanks to our clinic more couples have access to infertility treatment, and we are confident that this will only increase in the future. Starting the first IVF clinic in Central Africa was not always easy, but retrospectively it was more than worth it. Acknowledgements We like to thank H.E. President Museveni, Mr K.E. Bagger and the staff of the centre for Reproductive Medicine of UZ-Brussel for their support.

References Human immunodeficiency virus We decided from the beginning to treat also HIV positive patients. The reasons for this are multiple: first of all there is a high prevalence of HIV in the infertile population of Uganda (Gray et al., 1998; Bebell et al., 2007), although we have a feeling this is decreasing over the last years (Fabiani et al., 2001); second, refusing these patients would just propagate the HIV spread even more, as they tend to infect new partners; third, all patients in Uganda have easy access to retroviral drugs, which will reduce vertical transmission to minimal levels. The future We plan to join an international registry of ART data, to monitor better our own data (which we know from each individual batch of patients that has been done, but which is fading away due to the increasing workload) and to be able to provide more accurate data to our patients, media and local politicians. We are also expecting that the electricity problems in Uganda (which is a major headache, when you use high-technology equipment) will be solved in the coming

Bebell LM, Gasasira A, Kiggundu M, Dokomajilar C, Kamya MR, Charlebois ED, Havlir D, Rosenthal PJ, Dorsey G. HIV-1 infection in patients referred for malaria blood smears at government health clinics in Uganda. J Acquir Immune Defic Syndr 2007;46:624–630. Blacker J, Opiyo C, Jasseh M, Sloggett A, Ssekamatte-Ssebuliba J. Fertility in Kenya and Uganda: a comparative study of trends and determinants. Popul Study (Camb) 2005;59:355–373. Byamugisha JK, Mirembe FM, Faxelid E, Gemzell-Danielsson K. Emergency contraception and fertility awareness among University Students in Kampala, Uganda. Afr Health Sci 2006;6:194–200. Dyer SJ, Abrahams N, Mokoena NE, van der Spuy ZM. ‘You are a man because you have children’: experiences, reproductive health knowledge and treatment-seeking behaviour among men suffering from couple infertility. Hum Reprod 2004;19:960– 967. Dyer SJ, Abrahams N, Mokoena NE, Lombard CJ, van der Spuy ZM. Psychological distress among women suffering from couple infertility in South Africa: a quantitative assessment. Hum Reprod 2005;20:1938– 1943. Fabiani M, Accorsi S, Lukwiya M, Rosolen T, Ayella EO, Onek PA, Declich S. Trend in HIV-1 prevalence in an antenatal clinic in North Uganda and adjusted rates for the general female population. AIDS 2001;15:97. Gray RH, Wawer MJ, Serwadda D, Sewankambo N, Li C, Wabwire-Mangen F, Paxton L, Kiwanuka N, Kigozi G, Konde-Lule J et al. Population-based study of fertility in women with HIV-1 infection in Uganda. Lancet 1998;351:98–103. Larsen U. Primary and secondary infertility in sub-Saharan Africa. Int J Epidemiol 2000;29:285–291. Ombelet W, Campo R. Affordable IVF for developing countries. Reprod Biomed Online 2007;15:257– 265.

doi:10.1093/humrep/den145

Human Reproduction 2008

Affordable ART and the Third World: difficulties to overcome I.D. Cooke1,2,6,7, L. Gianaroli1,3, O. Hovatta1,4 and A.O. Trounson1,5 on behalf of the Low Cost IVF Foundation1 1

The Low Cost IVF Foundation, c/o B G Trust Company SA - Massagno, PO Box 132, Via San Gottardo 77, CH 6908 Massagno, Switzerland; 2Department of Obstetrics and Gynaecology, University of Sheffield, UK; 3S.I.S.Me.R., via Mazzini 12, Bologna 40138, Italy; 4 Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden; 5California Institute for Regenerative Medicine, 210 King Street, San Francisco, CA 94107, USA; 6 Present address: 80 Grove Road, Millhouses, Sheffield S7 2GZ, UK 7

Correspondence address. Tel: þ44 (0) 114 262 0718; E-mail: I.d.cooke@sheffield.ac.uk

A coherent strategy is required, donors to cover the costs of a business plan and personnel to provide advice and training and the country must be chosen. An urban environment is preferred with a local link, ideally a University Department with an existing ART programme and a willingness to be involved. Premises, a clinician and an embryologist must be identified, appropriate training arranged and excellent communication systems put in place. Apart from arranging equipment and servicing supplies, management systems and transparent data collection processes must be established. The protocol and local variations have to be agreed. The clinic needs to be related to the local health system, referral patterns must be created and screening processes set up to develop a waiting list of suitable patients. The nature of prior treatments must be defined. At some point, there needs to be a visit of an agreed scientific adviser with or without a donor representative. The number of patients treated in an initial cohort and review details should be determined. A longer term programme, the creation of a local professional network and clear relations with the state health system need to be explored. Any of these stages may constitute difficulties to be overcome. Keywords: low cost ART; strategy; low resource; developing world; difficulties

Introduction The stimulus to develop Assisted Reproductive Technology(ies, ART) in the developing world began at a World Health Organization meeting in September, 2001 arranged to review progress in the field over the preceding 10 years and define areas for closer attention. The meeting developed a series of recommendations in public health with regional relevance. They invoked action by governments, policy makers, professionals and the public. One of these was that ‘research is needed on innovative, low-cost ART procedures that provide safe, effective, acceptable and affordable treatment for infertility’ (Vayena et al., 2002). Subsequently, WHO adopted as policy the implementation of a programme on low-cost ART. To address this defined need, the Low Cost IVF Foundation was established independently in 2006 and has begun to develop a protocol and explore ways in which it might be implemented. It is not immediately obvious that the Millennium Development Goals (http://www.un.org/millennium/declaration/ ares552e) can include such a programme, however the last

one is to ‘evolve a global partnership for development in co-operation with the private sector, make available the benefits of new technologies—especially information and communications technologies’. And clearly such technologies can include ART. Although it may not be difficult to establish a new ART centre in a developed economy, it is rather more challenging to do so in a low resource economy, especially where there is little experience of such organizations. Much thought has gone into planning an inaugural clinic by the members of the Low Cost IVF Foundation and this paper addresses some of the issues that have been foreseen as potential problems. Steps in the establishment of a clinic will be described, recognizing that each one may be a source of significant difficulty. When these steps have been implemented, it will be interesting to see whether all problems have been effectively anticipated and forestalled or whether new and taxing issues conspire to compromise our early efforts. Prior to the Mexico summit on Health Services Research, Travis et al. (2004) in an invited contribution, emphasized that the major barriers in establishing a service in the

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developing world are the lack of human resources, financing, drugs and supply systems together with the failure to use information that is already available. They went on to point out that the overall policy environment, political instability and the quality of governance pose greater barriers than do resource constraints. These caveats have been kept very much in mind.

little more restricted if one uses the UN Human Development Report, 2007, which highlights much of Africa, especially subSaharan Africa, most of southern Africa and the horn of Africa. But even within such large regions one country needs to be selected and within that one city. 7.

Planning steps 1. A coherent strategy is required The whole process from initial soundings through to the funding of an established clinic needs to be planned with appropriate emphasis being given to each step. The details come later, but the feasibility of developing a sophisticated reproductive medicine service in a low resource economy with perhaps little previous experience of complex and meticulous organization must be explored and documented. 2. A business plan with costings must be formulated The physical facilities, staff, equipment and consumables over a defined time period must be estimated. The cost of training, transport, servicing of equipment, provision of educational material, patient recruitment and screening must be allowed for. Documentation and communication with supervisors need to be covered. 3.

Personnel are required for advice and training, recognising travel demands There will need to be one or more experts, say, embryologist and clinician, who have the responsibility for training and supervising new staff in a clinic. There will need to be a system for immediate contact in case urgent problems need to be resolved. These experts may not work close by, so arrangements will need to be made for visits and the cost of travel and accommodation supplied. 4. Protocols and management policies must be defined Although a standard protocol may be desirable, there are likely to be local idiosyncrasies that suggest alterations are necessary. If elements are already practised locally, these should be incorporated if feasible. There should be a clear understanding of the reasons for all steps with local anxieties being addressed. 5.

Donors need to be recruited to cover the costs for a specified time Before definitive negotiations with a specific location are begun, costings must be available, so that potential donors can be appraised of likely candidate clinics to support. There may be special reasons for a donor to have interests in a particular part of the world or specific links between experts and donors that can be developed. 6. Locations need to be decided The potential is huge. Developing countries comprise North Africa, sub-Saharan Africa and southwest Africa, the northern and eastern countries of South America, Eastern Europe and countries of the former USSR, the Middle East, Iran and Myanmar, South East Asia and Indonesia. This becomes a 94

Choose an urban environment, linked to an existing infertility clinic framework It is tempting to think in terms of providing ART to the huge numbers of the urban poor, but apart from being a logistic nightmare, many such regions have poor infrastructure, such as roads and transport, water, sewage and communications, which should all take priority, as should issues of obstetric services and prevention of maternal mortality, over the more complex forms of assisted reproduction. It would be better to think in terms of a capital city with an established University, where there is already considerable experience of fertility management and where supply chains for equipment, drugs and consumables have been established. Further, the skills of such staff may be crucial in dealing with local supply problems, staff recruitment and in due course, in providing advice and partnership in dealing with government. 8.

Patient screening and selection mechanisms must be in place to create a waiting list When the treatment phase begins, it should provide a significant work load for the staff. The best way to arrange this is to bulk up the patients so that batches of patients are treated for a period of time. This will allow reflection, modification of systems, guaranteeing supplies and repairs and permit prediction of future workload. It is imperative that appropriate patients are treated and treated with relevant techniques. To ensure that this happens, a substantial screening process will need to have been operating for some time. That time will depend on the experience of the original infertility clinic, for how long it has been operating and the types of treatment offered. Record systems must be in place so that those placed on a waiting list have known why they were placed on it, have been counselled and can be readily contacted. The level of treatment will need to have been determined, so that only those who have failed simpler methods or initially have more complex problems that require the higher level of treatment offered. Strict criteria will need to be applied, such as for age and duration of infertility, so that the initial candidates have a reasonable prospect of pregnancy. This is to ensure that the method is properly tested and that early successes help to raise the clinic profile. Once these early parameters have been established it will be possible to address more complex problems, but there will be confidence in the system and morale and public confidence will be sustained. 9. Appropriate premises and staff training must be arranged The precise details in relation to the original clinic must be agreed. The physical relations of the existing clinic must be established, whether it is in the same clinic, but an adjacent area, an extension or new premises. Both clinician and laboratory staff must reach an agreed standard. It may be necessary to send trainees away for training or training on

Likely problems

site can be arranged. Details of local or distant supervision and continuing contact must be arranged. There should be some relation to an existing formal training programme, so that upon completion, a successful trainee can use such criteria for validation. 10. Enthusiasm and altruism are required of staff It is evident that, when discussing these concepts in various places, some personnel are doubtful or sceptical and do not wish to participate in such a programme. It should be clear to participating personnel that these techniques will be offered to those who cannot afford the more costly methodology frequently available elsewhere. They will not be offering, at least initially, the methods to those who can afford more costly interventions. It is essential that all participants recognize that their offering treatments to their society members is an exercise in goodwill, a move to spread medical skills to a larger segment of their society and that they are proud to be able to participate. 11. Excellent communication with supervisors is necessary It is vital that all variations in management and outcome are identified and recorded, so that trouble shooting can be effective. Efficient communications with supervisors are crucial to engender confidence in each party and ultimately in the data generated. This must certainly be by e-mail, and ideally by mobile phone. 12.

Reliable delivery of equipment and consumable supplies is essential Initial setting up of the clinic is one thing, but reliable supplies and equipment maintenance and repair processes are essential for longer term functioning. This is where the experience of an established clinic in a capital city is more likely to be critical in achieving these aims. Experience will also indicate the nature of likely future problems and allow appropriate anticipatory responses. 13.

Systems for records and data management are mandatory A laptop should be used to enter data into a simple spreadsheet to document basic information. The data are to be used for patient monitoring, later review and analysis when the data bulk up. Care must be taken in organising the original data input to ensure that the format is compatible with larger databases, such as the international collation system of the International Committee for Monitoring of ART data (ICMART). When a number of these clinics have been set up, hopefully with methodology that allows the data to be integrated, analyses can be carried out to evaluate the data from low cost systems. These data should also be entered into the ICMART regional and world databases in due course, and ideally from early days. It is also important to have systems that allow trouble shooting when programmes fail to reach expected standards, and particularly for a programme that may fall some way short of the â&#x20AC;&#x2DC;successesâ&#x20AC;&#x2122; trumpeted by the more aggressive and expensive systems.

14. Relations with other infertility services It is likely that other providers will be working in the same locality. The parent clinic may already be in the same Department or hospital. Competition is not the way to describe their respective activities. They are targeting completely different strata of society and will continue to do so until ART has been fully integrated into the health services and funded by the government, which may be a long way off. There may be opportunities for exchange of information, and staff, educational activities in common and social interchange, which should sustain morale, allowing appreciation of a common enterprise. Rather than competition for resources, it would be better to share knowledge and administrative effort to obtain better services for each. It may be necessary for the incoming clinic, as the less well established, to promote communication and co-operation. Patient education could be a shared activity leading to better public information and, indirectly, is a way to enhance political awareness of change and opportunity. 15.

Initial cohort size and the review process should be agreed It will take some time to screen patients both economically and healthwise. It is important that those who can afford conventional ART, often the more articulate, do not exploit the new service. Those initially offered the low cost regime should not have had previous ART, as failure of previous treatment would compromise valid appraisal of prospects for pregnancy. A group of say 50 patients should be the initial cohort, to ensure an appropriate workload for the laboratory and nursing support. Perhaps a regular clinic would offer this service intermittently, having screened all their patients to select those appropriate for the new system. Between batches the nature of the clinicâ&#x20AC;&#x2122;s work would be different and planning of these contrasting phases would be separate. Ultimately, there could be continuous activity, but this would depend on actual and perceived success and longer term funding. 16.

Integrate data collection from centres to facilitate early comprehensive review It will be essential that the external advisor/supervisor reviews the data. This is to ensure integrity, credibility and selfconfidence for the clinic. Data must be able to be sent to a central point for analysis and comparison with other similar centres. It will be a learning experience for all. Recognition of the need for compatibility of datasets is fundamental. Hopefully, the data can be merged and analysed in a meaningful way. That should lead to the presentation and publication in the usual media, a process to be encouraged from the beginning. Only in that way will the possibilities for the extension of the concept and expansion of the facilities become possible. 17. Modify the programme in the light of results Self-critical reflection is crucial to the development of a robust system, so that modifications of the original protocols and techniques can improve results and the patient experience. The more the clinics work on their systems to improve them the richer will be the experience become as information and attitudes are exchanged. This could lead to a major change in 95

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the perception by the community that could affect greater numbers of prospective patients. 18. Develop links with other health service areas There is a concept of Reproductive Health Centres, which includes family planning, management of sexually transmitted infections (STIs), even linking to maternity and neonatal services. The idea is to emphasize the continuity of care and the relationship between these elements. Effective family planning, public and patient education to reduce the blight of illegal abortion and STI and the preparation from puberty for a rewarding reproductive life are the important denominators of a society developing toward fulfilment of each personâ&#x20AC;&#x2122;s potential. These processes should reduce the prevalence of infertility by emphasizing prevention with its feedback on to reducing the overall cost of reproductive health care. Begin the broader political campaign to promote acceptance If and when a Low Cost ART programme can be effective and provide acceptable outcome, then the data must be available for the presentation not only in medico-scientific circles, but also to the wider public. This means not simply patient groups, but the media for public reproductive health education and to sensitize government. Officials of the health service should see the data and should be given the case for integration into the publicly funded provision. A political case will also need

to be presented to become a part of the aspirations of sitting and candidate members of the administration. This argument has been won in few affluent countries, but the impact could be much greater in low resource environments. To conclude, this list of points is a start. When a number of clinics have established Low Cost programmes, they may be quite different, but more likely in the detail than the principles. There are three steps: firstly, to identify efficiently and cheaply the 50% of couples with infertility who would benefit from ART and concentrate the Low Cost programmes on those that cannot afford the more expensive services; secondly, to deliver effective treatment in the local context and thirdly, to publicise quality data and use it to influence the health systems. Perhaps the more affluent countries could learn from this approach and offer such a system to their own impoverished populations, which have the same problems.

19.

References Low Cost IVF Foundation. Massagno. http://www.lowcost-ivf.org Travis P, Bennet S, Haines A, Pang T, Bhutta Z, Hyder AA, Pielemeier NR, Mills A, Evans T. Overcoming health-systems constraints to achieve the Millenium Development Goals. Lancet 2004;364:900â&#x20AC;&#x201C;906. Vayena E, Rowe PJ, Griffin PD (eds). Current practices and controversies in Assisted Reproduction. Report of a WHO Meeting. Geneva, Switzerland: Department of Reproductive Health and Research, Family and Community Health, World Health Organization, 2002.

doi:10.1093/humrep/den144

Human Reproduction 2008

Infertility in developing countries: funding the project Hassan N. Sallam1,2,3 1

Department of Obstetrics and Gynaecology, The University of Alexandria, Alexandria, Egypt; 2Suzanne Mubarak Regional Center for Women’s Health and Development, Alexandria, Egypt 3

Correspondence address. E-mail: hnsallam@link.net

Assisting developing countries in establishing infertility services is not a uniform exercise and depends on the stage of development of each country. Three levels of assistance are suggested: providing basic (level 1), advanced (level 2) or tertiary referral infertility services (level 3). At each of these levels, four activities are needed: equipping the clinics, training the staff, educating the public and running the services. Basic (level 1) clinics can be equipped by international donors, whereas level 2 and 3 clinics can be funded through a partnership between an international scientific body (WHO, ESHRE, etc.) and an international bank (World Bank, African Development Bank, etc.). Training of the medical and paramedical staff should be the responsibility of the non-profit organizations (NPOs) preferably in regional training centers. An awareness campaign is necessary to educate the public and inform them of the range of treatment available in their community and can also be funded by NPOs. Finally, the running cost of the services including the staff salaries, the cost of the investigations and medication should be the responsibility of the local government, although in many countries, this has to come from out of pocket payments. Keywords: funding; developing countries; low-cost IVF; non-profit organization; infertility

Introduction Infertility is a universal health issue and it has been estimated that 8– 12% of the couples worldwide are infertile (Inhorn, 2003; Lunenfeld et al., 2004). In developing countries, the situation is worse and it has been reported that up to 30% of the couples are infertile in some areas of the developing world (Giwa-Osagie, 2004; Aboulghar, 2005; Rizvi and Zuberi, 2006; Ombelet and Campo, 2007). It has also been argued that infertility in not a health problem and that infertile couples are not really ill. However, this narrow interpretation of the problem is refuted by the world community. The WHO defines health as a “state of complete physical, mental and social wellbeing and not merely the absence of disease or infirmity”. It has also been argued that overpopulation is the main problem in the developing countries and that helping infertile couples contradicts the interests of the countries and the world at large. However, this narrow approach contradicts human rights in general and reproductive rights in particular (Fathalla, 2001). The concept of reproductive health was endorsed by the United Nations International Conference on Population and Development (ICPD) held in Cairo in 1994 by the representatives of the 179 nations participating in the conference. The definition endorsed at the International Conference on Women held in Beijing in 1995, confirms ‘the right of men and women to . . . the best chances of having a healthy child’. In 2004, the WHO sexual and reproductive health

package was adopted by the World Health Assembly with its five core aspects: (i) improving antenatal, perinatal, postpartum and newborn care, (ii) providing high-quality services for family planning, ‘including infertility services’, (iii) eliminating unsafe abortion, (iv) combating sexually transmitted infections including human immunodeficiency virus, reproductive tract infections, cervical cancer and other gynecological morbidities; and (v) promoting sexual health (Fathalla, 2001). Subsequently, at the World Summit in 2005, the largest-ever gathering of world leaders, heads of governments called for achieving these goals by the year 2015. The right to infertility treatment is therefore an integral part of human rights adopted by the international community (Rao, 2005). In addition, infertility in developing countries is a gender inequality issue, as in many cases, the burden of the problem lies on the female partner (Chapman and Gordon, 1999). In many of these communities, women are stigmatized, ostracized and become targets of psychological abuse or domestic violence, even if infertility is due to the male partner (Dyer, 2002; Orji et al., 2002; Araoye, 2003; Inhorn, 2003; Dhaliwal et al., 2004).

Developing countries For operational and analytical purposes, the World Bank classifies countries according to their gross national income (GNI) per capita into low-income, middle-income (subdivided into

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lower-middle and upper-middle), or high-income countries. Low-income countries are those with a GNI of US$ 905 or less, lower-middle income with a GNI of US$ 906 – 3595, upper-middle income with a GNI of US$ 3596 – 11 115, and high-income countries are those with a GNI of US$ 11 116 or more. Low- and middle-income countries are sometimes referred to as developing countries. Although the use of the term is convenient for financial purposes, it does not necessarily reflect the development status of the country in question (Table I). Accordingly, other measures for the classification of developing countries have been used by other international agencies. The United Nations Development Programme (UNDP) takes

into consideration three criteria for the evaluation of countries’ development: the low-income criterion, the human resources weakness criterion and the economic vulnerability criterion. On the basis of these criteria, the UNDP has compiled a list of the least developed countries (LDCs) shown in Table II. Regardless of the classification used, many of these countries need assistance in establishing or upgrading their infertility services. Plan for action As developing countries differ in their status of development, three levels of assistance are suggested:

Table I. World Bank classification of countries by GNI per capita. Low-income economies (53) Afghanistan Bangladesh Benin Burkina Faso Burundi Cambodia Central African Republic Chad Comoros Congo, Dem. Rep Coˆte d’Ivoire Eritrea Ethiopia Gambia, The Ghana Guinea Guinea-Bissau Haiti Lower-middle-income economies (55) Albania Algeria Angola Armenia Azerbaijan Belarus Bhutan Bolivia Bosnia and Herzegovina Cameroon Cape Verde China Colombia Congo, Rep. Cuba Djibouti Dominican Republic Ecuador Egypt, Arab Rep. Upper-middle-income economies (41) American Samoa Argentina Belize Botswana Brazil Bulgaria Chile Costa Rica Croatia Dominica Equatorial Guinea Gabon

India Kenya Korea, Dem Rep. Kyrgyz Republic Lao PDR Liberia Madagascar Malawi Mali Mauritania Mongolia Mozambique Myanmar Nepal Niger Nigeria Pakistan Papua New Guinea

Rwanda Sa˜o Tome´ and Principe Senegal Sierra Leone Solomon Islands Somalia Sudan Tajikistan Tanzania Timor-Leste Togo Uganda Uzbekistan Vietnam Yemen, Rep. Zambia Zimbabwe

El Salvador Fiji Georgia Guatemala Guyana Honduras Indonesia Iran, Islamic Rep. Iraq Jamaica Jordan Kiribati Lesotho Macedonia, FYR Maldives Marshall Islands Micronesia, Fed. Sts. Moldova Morocco

Namibia Nicaragua Paraguay Peru Philippines Samoa Sri Lanka Suriname Swaziland Syrian Arab Republic Thailand Tonga Tunisia Turkmenistan Ukraine Vanuatu West Bank and Gaza

Kazakhstan Latvia Lebanon Libya Lithuania Malaysia Mauritius Mayotte Mexico Montenegro Northern Mariana Islands Oman

Poland Romania Russian Federation Serbia Seychelles Slovak Republic South Africa St. Kitts and Nevis St. Lucia St. Vincent and the Grenadines Turkey Uruguay Continued

Funding the project Table I. Continued Grenada Hungary High-income economies (60) Andorra Antigua and Barbuda Aruba Australia Austria Bahamas, The Bahrain Barbados Belgium Bermuda Brunei Darussalam Canada Cayman Islands Channel Islands Cyprus Czech Republic Denmark Estonia Faeroe Islands Finland

Palau Panama

Venezuela, RB

France French Polynesia Germany Greece Greenland Guam Hong Kong, China Iceland Ireland Isle of Man Israel Italy Japan Korea, Rep. Kuwait Liechtenstein Luxembourg Macao, China Malta Monaco

Netherlands Netherlands Antilles New Caledonia New Zealand Norway Portugal Puerto Rico Qatar San Marino Saudi Arabia Singapore Slovenia Spain Sweden Switzerland Trinidad and Tobago United Arab Emirates United Kingdom United States Virgin Islands (U.S.)

Developing countries comprise low-income (53), lower-middle-income (55) and upper-middle-income countries (41). This classification does not necessarily reflect the development status of the country. Reference: http://web.worldbank.org/WBSITE/EXTERNAL/DATASTATISTICS/0,contentMDK:20420458~menuPK:64133156~pagePK:64133150~piPK: 64133175~theSitePK:239419,00.html

Table II. List of the LDCs according to the UNDP. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Afghanistan# Angola Bangladesh Benin Bhutan# Burkina Faso# Burundi# Cambodia Cape Verde* Central African Republic# Chad# Comoros* Democratic Republic of the Congo Djibouti Equatorial Guinea Eritrea Ethiopia# Gambia Guinea Guinea-Bissau* Haiti* Kiribati* Lao People’s Democratic Republic# Lesotho# Liberia

26 27 28 29 30 31 32 33 34 35

Madagascar Malawi# Maldives* Mali# Mauritania Mozambique Myanmar Nepal# Niger# Rwanda#

36 37 38

Samoa* Sa˜o Tome´ and Principe* Senegal

39 40 41 42 43 44 45 46 47 48

Sierra Leone Solomon Islands* Somalia Sudan Timor-Leste´* Togo Tuvalu* Uganda# United Republic of Tanzania Vanuatu*

49 50

Yemen Zambia#

See Appendix for criteria of inclusion. *Also SIDs (Small island developing countries). # Also LLDCs (Land locked developing countries). Reference: http://www.un.org/special-rep/ohrlls/ldc/list.htm

Level 1—A basic infertility clinic capable of offering the following services: basic infertility workout including semen analysis, hormonal assays, follicular scanning, PCT in addition to ovulation induction and IUI;

Level 2—An advanced infertility clinic capable of offering the following services in addition to level 1: IVF and diagnostic endoscopy; Level 3—A tertiary level infertility clinic capable of offering the following services in addition to level 2: ICSI, cryopreservation and operative endoscopy. Helping developing countries at each of these levels entails four activities: (i) Equipping the clinics—Infertility clinics in developing countries should be provided with low-cost and easy serviceable equipment taking into consideration the local problems often encountered (e.g. fluctuating voltage, frequent power cuts, unavailability of servicing facilities, irregular supply of consumables, etc.). This may require negotiations with various manufacturers to supply these tools at affordable prices, particularly if large quantities are ordered. Equipping the clinic depends on the level of service required. (a) Level 1—At this level, the following equipment is necessary: a basic ultrasound machine with a vaginal probe (with electric battery), a basic binocular microscope, a basic ELISA reader for hormonal assays, a regular or submarine (Vajta et al., 1997) incubator, a centrifuge and a laboratory pipette set and a refrigerator, in addition to 2 UPS (uninterrupted power supply) units. It is estimated that equipping a Level 1 clinic would cost 15.000 to 20.000 USD. (b) Level 2—At this level, the following equipment is necessary in addition to level 1: a stereo microscope for oocyte recognition, a simple inverted microscope for checking the 20 PN embryos, a laminar flow hood, a CO2 incubator and a hot plate, in addition to 4 UPS units. A diagnostic laparoscope is also necessary with 99

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Table III. Suggested funding options for various activities involved in the project. Equipment

Level 1 (IUI) Level 2 (IVF) Level 3 (ICSI)

Running services

Public sector

Private sector

Public sector

Private sector

Government or Donor agencies or WHO/ World Bank partnership Donor agencies or WHO/World Bank partnership WHO/World Bank partnership

WHO/World Bank partnership WHO/World Bank partnership WHO/World Bank partnership

Government or Donor

Out of pocket Out of pocket Out of pocket

simple manipulation tools. It is estimated that equipping a Level 2 clinic would cost 40.000 to 50.000 USD. (c) Level 3—At this level, the following equipment is necessary in addition to Level 2: an inverted microscope with advanced optics, a micromanipulation unit, a second CO2 incubator, embryo freezing equipment (or vitrification facilities), with 2 more UPS units. In addition, an operating laparoscope and a hysteroscope are necessary, as well as an electricity generator. It is estimated that equipping a Level 3 clinic would cost 150.000 to 180.000 US$. (ii) Training the staff—This includes the training of the medical, paramedical as well as the administrative staff. Training courses should be tailored to the local conditions and the possible difficulties encountered in developing countries. ESHRE will be very important in the coordination and organization of these courses. (iii) Educating the public—This necessitates establishing contacts and working relationships with schools, community leaders, traditional healers as well as the media, producing and distributing educational materials (brochures, posters and audio-visual material) and even dispatching convoys to the areas in need. (iv) Running the services—This should take into consideration staff salaries, regular purchasing of consumables, cost of equipment maintenance, cost of investigations, cost of medical interventions and the cost of medication. Special servicing contracts should be negotiated with the manufacturers. In addition, simplification of the consumables should be taken into consideration and laboratory reagents and culture media should have a long shelf life. Special prices for the medications needed should be negotiated with the drug manufacturers and simple treatment protocols should be put into action in order to reach the best costeffective therapies.

Funding the project Funding the project will depend on the level of service needed as well as the local conditions of the country in question and will require the services of professional financial advisors (van Balen and Gerrits, 2001; Dyer, 2002). However, as a general plan, the following plan for funding is suggested and is shown in Table III: 100

Government or Donors or Out of pocket Out of pocket

Training personnel

Public education

NPO

Donors or NPO Donors or NPO Donors or NPO

NPO NPO

(i) Equipping the clinics—Purchasing equipment for a Level 1 or 2 clinics working in the public sector can be funded by a donating agency. On the other hand, a private Level 1 or 2 clinics can be funded by a commercial bank or partnership. Such a partnership already exists between the World Bank and the World Health Organization. A similar partnership can be negotiated between the European Society for Human Reproduction and Embryology (ESHRE) on one hand and an international bank on the other hand (e.g. the World Bank or the African Development Bank). It will be difficult to fund Level 3 clinics working in the public or private sector through international donors, and these will probably need to be funded by an NPO/international bank partnership. (ii) Training the staff—This should be the responsibility of the non-profit organizations (NPOs), and in particular the international scientific societies such as ESHRE and IFFS, which have a lot of expertise in organizing training courses. Training should be provided to the physicians, the laboratory staff, the nursing staff as well as the administrative and counseling staff. International donor agencies are usually happy to sponsor these training activities. In order to minimize costs and maximize the benefits, training can be provided at regional centers appointed for such activities. Training syllabi will be formulated by ESHRE and IFFS, whereas trainers and trainees can be sponsored to travel to the regional centers by international donors. This training can be supplemented by field visits by the experts to help solve any technical problems on-site. (iii) Educating the public (information, education and counseling)—These activities can also be sponsored by international donors or NPOs in order to educate the public on the prevention and treatment of infertility in simple terms and to inform them on the range of treatment modalities available in their own communities. (iv) Running the services—This consists of various components: (a) Staff salaries—In the public sector, this is the responsibility of the country in question, whereas in the private sector, it is the responsibility of the administration.

Funding the project

(b) Cost of maintaining the equipment—Purchasing contracts should include a 2– 5 years service contracts and a comprehensive plan for providing spare parts if needed. (c) The steady supply of consumables should be secured and special prices for developing countries should be negotiated with the manufacturers. Laboratory supplies and culture media should have a long shelf life. (d) The cost of investigations and medication is also the responsibility of the country in question in the public sector, although in some countries, the patients have to pay for the medication. In the private sector, the above mentioned cost-reducing steps should ensure a low-cost for services at the private sector.

Conclusion Infertility is a universal problem and is more pronounced in developing countries. Despite the problem of overpopulation, infertile patients in these countries deserve to have access to treatment options available to their counterparts in the developed world. Assistance can be provided at three levels depending on the services required by the specific country/ community. A plan for action is drawn and funding options are suggested. References Aboulghar MA. The importance of fertility treatment in the developing world. BJOG 2005;112:1174– 1176. Araoye MO. Epidemiology of infertility: social problems of the infertile couples. West Afr J Med 2003;22:190– 196. Chapman K, Gordon G. Reproductive health technologies and gender: is participation the key? Gend Dev 1999;7:34– 44. Dhaliwal LK, Gupta KR, Gopalan S, Kulhara P. Psychological aspects of infertility due to various causes—prospective study. Int J Fertil Womens Med 2004;49:44– 48. Dyer SJ. The conflict between effective and affordable health care—a perspective from the developing world. Hum Reprod 2002;17:1680– 1683. Fathalla MF. Reproductive rights and reproductive wrongs. Curr Womens Health Rep 2001;1:169–170. Giwa-Osagie OF. The need for infertility services in the developing world: the WHO point of view. Gynecol Obstet Invest 2004;57:58. Inhorn MC. Global infertility and the globalization of new reproductive technologies: illustrations from Egypt. Soc Sci Med 2003;56:1837– 1851. Lunenfeld B, Van Steirteghem A, Bertarelli Foundation. Infertility in the third millennium: implications for the individual, family and society: condensed meeting report from the Bertarelli Foundation’s second global conference. Hum Reprod Update 2004;10:317–326. Ombelet W, Campo R. Affordable IVF for developing countries. Reprod Biomed Online 2007;15:257–265. Orji EO, Kuti O, Fasubaa OB. Impact of infertility on marital life in Nigeria. Int J Gynaecol Obstet 2002;79:61 –62. Rao KA. Infertility treatment is a human right. Indian J Med Ethics 2005;2:128. Rizvi JH, Zuberi NF. Women’s health in developing countries. Best Pract Res Clin Obstet Gynaecol 2006;20:907– 922.

Vajta G, Holm P, Greve T, Callesen H. The submarine incubation system, a new tool for in vitro embryo culture: a technique report. Theriogenology 1997;48:1379–1385. van Balen F, Gerrits T. Quality of infertility care in poor-resource areas and the introduction of new reproductive technologies. Hum Reprod 2001;16: 215– 219.

Appendix 1: Criteria used for the identification of least developing countries according to the UNDP

The Criteria for the identification of the LDCs In its latest triennial review of the list of LDCs in 2003, the Economic and Social Council of the United Nations used the following three criteria for the identification of the LDCs, as proposed by the Committee for Development Policy (CDP):

(i) a low-income criterion, based on a 3-year average estimate of the GNI per capita (under $750 for inclusion, above $900 for graduation); (ii) a human resource weakness criterion, involving a composite human assets index based on indicators of: (a) nutrition, (b) health, (c) education and (d) adult literacy; (iii) an economic vulnerability criterion, involving a composite economic vulnerability index based on indicators of: (a) the instability of agricultural production, (b) the instability of exports of goods and services, (c) the economic importance of non-traditional activities (share of manufacturing and modern services in GDP), (d) merchandise export concentration and (e) the handicap of economic smallness (as measured through the population in logarithm); and the percentage of population displaced by natural disasters (E/2004/33). To be added to the list, a country must satisfy all three criteria. To qualify for graduation, a country must meet the thresholds for two of the three criteria in two consecutive triennial reviews by the CDP. In addition, since the fundamental meaning of the LDC category, i.e. the recognition of structural handicaps, excludes large economies, the population must not exceed 75 million. In the 2000 review, Senegal was included in the list of LDCs. Timor-Leste was added to the list in 2003, bringing the total number of LDCs to 50. With regard to the 2003 triennial review of the list, the CDP concluded that Cape Verde and Maldives qualified for graduation and recommended that they be graduated from the LDC category. The CDP also concluded that Samoa was eligible for graduation in 2006. On the basis of the CDP report, the ECOSOC will make a recommendation to the General Assembly, which is responsible for the final decision on the list of LDCs. Reference: http://www.un.org/special-rep/ohrlls/ldc/ldc%20 criteria.htm

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doi:10.1093/humrep/den164

Human Reproduction 2008

Reproductive research in non-human primates at Institute of Primate Research in Nairobi, Kenya (WHO Collaborating Center): a platform for the development of clinical infertility services? Thomas M. D’Hooghe1,2,3, Atunga Nyachieo1,2, Daniel C. Chai2, Cleophas M. Kyama1,2, Carl Spiessens1 and Jason M. Mwenda2 1 Leuven University Fertility Centre, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium; 2Institute of Primate Research, Reproductive Biology Division, PO Box 24481, Karen, Nairobi, Kenya 3

Correspondence address. Tel: þ32-16-34-36-24; Fax: þ32-16-34-36-07; E-mail: thomas.dhooghe@uz.kuleuven.ac.be

The Institute of Primate Research (IPR; www.ipr.or.ke) is a WHO collaborating center for research in reproductive biology, infectious diseases and ecology/conservation. It includes a fully equipped surgical complex, >5000 square feet of laboratory space, a quarantaine facility, library, conference room, administrative offices, etc. More than 500 primates can be housed at IPR, mainly baboons. Reproductive research at IPR is applied to endometriosis, assisted reproduction, prevention of heterosexual transmission of HIV and includes the investigation of immunocontraceptives and placental retroviruses. Reproductive research capacities of IPR include: videolaparoscopic surgical equipment, surgical experience, endometrial biopsies and uterine flushes, ovarian stimulation, laparoscopic oocyte aspiration, hormonal analyses in baboon blood and urine, sperm assessment, in vitro culture and reproductive immunological investigations. During the last years, simultaneously with the development of baboon IVF, there have been contacts with several Kenyan gynecologists at the level of KEMRI (Kenya Medical Research Institute), KOGS (Kenyan Obstetrical and Gynecological Society), Kenyatta National Hospital and Aga Khan Hospital in Nairobi to develop clinical infertility services including low-budget high-quality IVF in Nairobi. The logic behind this initiative is that the Kenyans trained in non-human primate embryology, and IVF would be natural partners to develop human IVF in Kenya. Keywords: infertility; baboon; non-human primate; endometriosis; poor resource countries

Introduction One in four ever-married women of reproductive potential in most developing countries is infertile because of primary or secondary infertility (DHS Comparative Report 9). The WHO has defined the provision of high-quality services for family planning, including infertility services as a core element of its policy in reproductive health for low-resource settings. Available data indicate that countries in sub-Saharan Africa have some of the highest rates of infertility in the world. Infertility rates among married couples in African countries range from 15% to 30%, compared with reported rates of 5 – 10% in developed countries (Okonofua, 2003). There is now conclusive evidence that much of the infertility in Africa is attributable to infections that produce irreversible reproductive tract damage in men and women (Okonofua, 2003). Recently, it has also been shown that also endometriosis may contribute

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as well to infertility in African countries, even though its true prevalence is underestimated (Kyama et al., 2007a). Apart from the share size of the problem, it is also now well known that infertility in African countries has severe negative consequences for women’s reproductive health. Owing to the high cultural premium placed on childbearing in many African countries, infertility often poses serious social problems for couples (Okonofua, 2003). Normally, women are more severely affected than men, even when the infertility is due to a male factor, often leading to divorce, social ostracization and sometimes physical abuse of women. Consequently, there is now a growing body of scientific opinion that suggests that addressing infertility could be one way to empower women in Africa and improve their sexual and reproductive health (Okonofua, 2003). The aim of this paper is to provide a review about the Institute of Primate Research (IPR), Nairobi, Kenya (www.ipr.or.ke), a

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WHO collaborating center, to describe reproductive research in endometriosis and assisted reproduction carried out at IPR during the last 18 years, and to discuss how this reproductive research at IPR can be a platform for the development of clinical infertility services in Nairobi. IPR, Nairobi, Kenya: a WHO collaborating center The IPR was started in 1960 by L. Leakey at Tigoni, a primate holding facility in the neighborhood of Nairobi, to support research in primate behavior as a model for the study of human evolution. In 1983, IPR was relocated to the indigenous Ololua forest (500 acres of land) in then Nairobi suburb of Karen, 20 min drive from the center of Nairobi and 40 min drive from Nairobi Jomo Kenyatta International Airport. The IPR is part of National Museums of Kenya (NMK) and is therefore a Kenya Government Institute. Over the last 25 years, the IPR has gradually transformed into a Biomedical Research Institute with major research programs in reproductive biology and health, tropical and infectious diseases, and ecology and conservation biology. The mandate of IPR is to support investigator-initiated biomedical research in non-human primates as preclinical models for important human diseases (including preclinical testing of new drugs, vaccines and diagnostics), and to generate scientific knowledge on the behavior and ecology of non-human primates as a basis for their conservation in the context of biodiversity. At a global level, research capacity building of the IPR in Nairobi, Kenya, or in other poor resource countries could and should be seen as relevant effort in the context of North– South collaboration with the ultimate goal to develop international research centers of excellence in these countries (D’Hooghe et al., 2008). The IPR is led by the IPR Director and is supervised by Secretary-General of the NMK, who represents NMK and IPR at the Board of the NMK. The IPR International Advisory Board (IAB) has been established in 2007 by IPR and NMK to advice IPR on its policy with respect to research, grant applications, international collaboration and research opportunities for Ph.D. students and for post-doctoral fellows both in Kenya and abroad. Furthermore, the IPR IAB is expected to advice IPR on how it can achieve institutional sustainability by, for example, assisting with the development of institutional grants that can be used to improve laboratory and animal facilities and acquire equipment. The IPR IAB includes 12 international experts who have an established reputation in the areas of reproduction, infectious diseases and ecology/ conservation and a WHO observer, and meets at least once a year in Nairobi. The total staff at IPR (status 2007) consists of 120 employees including 35 scientists at Ph.D. or M.Sc. levels, 5 veterinarians, lab technicians and supporting staff. The Department of Animal Resources is responsible for animal welfare, colony management, non-human primate medicine and surgery, quarantine, histopathology and diagnostics. The Department of Finance and Administration takes care of Human Resources, Physical Operations, Accounts, Information Technology, Library and Supplies. Research projects are reviewed by the

Institutional Review Board with respect to both ethical issues and animal welfare. Non-human primates kept at IPR included mostly baboons (mostly Olive baboons, a minority of Yellow baboons) captured from the wild, and some vervet monkeys. The program of ecology/conservation is aimed at the study of Colobus monkeys and De Brazza monkeys, an endangered species in the Tana River Natural Primate Reserve and in Kakamega Forest, respectively. The program of infectious diseases has developed both baboon and vervet monkeys as models for the study (immunology, preclinical vaccine and/or drug development) of schistosomiasis, leishmaniasis, malaria and SIV.

Reproductive research at IPR: the advantages of the baboon model The use of the baboons as preclinical research models in reproductive research is supported by the Kenyan government as one of the methods to mobilize national resources in order to improve human reproductive health. The baboon is a unique preclinical model for research in human reproduction for various reasons, as reviewed before (D’Hooghe, 1997, 2008; Kyama et al., 2007b). Reproductive anatomy, endocrinology and physiology is similar in baboons and in humans The baboon is comparable to women with respect to cycle length (33 + 2 days); duration of menstruation (3 + 1 days); time interval between LH peak and menstruation (17 + 1 days); maximum serum estradiol level attained per cycle (245 + 30 pg/ml) and maximum serum progesterone level attained per cycle (11.5 + 2 ng/ml) (Stevens, 1997). The baboon pregnancy lasts 6 months. Baboon placentation is in some ways comparable with and in other ways different from placentation in women and in rhesus monkeys (Pijnenborg et al., 1996). Non-invasive cycle monitoring based on perineal changes In baboons, but not in rhesus monkeys or in cynomolgus monkeys, is it possible to perform non-invasive perineal skin monitoring to determine the phase of the menstrual cycle in baboons. Perineal inflation and deflation correspond with follicular and luteal phase, respectively, whereas ovulation occurs 2 days before perineal deflation (Stevens, 1997). This perineal monitoring is performed by trained animal attendants at the IPR on a daily basis, and this allows the detailed follow-up of individual baboons over a long period of time (D’Hooghe et al., 2008). Continuous breeding Baboons have continuous breeding in captivity (Birrell et al., 1996), in contrast to the seasonal breeding observed in rhesus monkeys (Zondervan et al., 2002). This advantage allows investigators to carry out fertility throughout the year and saves costs (D’Hooghe et al., 2008). 103

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Baboon size and strength Adult female baboons are stronger and larger (8 – 15 kg) than adult female rhesus monkeys (4 – 11 kg) or cynomolgus monkeys (3 – 7 kg) (Einspanier and Gore, 2005; Hunnell et al., 2007). This advantage allows repetitive blood sampling, repetitive laparoscopies (every 2 – 3 days) and complex experimental surgery (D’Hooghe et al., 1996a). Spontaneous peritoneal fluid Baboons, but not rhesus monkeys or cynomolgus monkeys, do have spontaneous presence of peritoneal fluid (PF) in sufficient amounts ( 2 ml after ovulation) to be used for research. This is important since the peritoneal cavity and PF are key players in the pathogenesis of endometriosis (D’Hooghe et al., 1991). Cross-reactivity between baboons and humans Owing to closely shared genetic similarities between baboons and humans, cross-reactive human steroid assays, antibodies or PCR primers can be used in baboons in the context of research in endometriosis or other reproductive disorders (D’Hooghe et al., 1996b, 1999, 2001a,b,c, 2008; Fazleabas et al., 2003; Overbergh et al., 2005; Kyama et al., 2007c). Vaginal transcervical uterine access In baboons, but not in rhesus monkeys or in cynomolgus monkeys, it is possible to have relatively easy vaginal transcervical access to the uterine cavity allowing endometrial biopsy, embryo transfer, preimplantation embryo flushing and hysteroscopy (D’Hooghe et al., 1996c, 2004; Chai et al., 2007; Nyachieo et al., 2007). If routine uterine access via a vaginal speculum is difficult, combined abdominal – cervical manipulation (the Chai technique) allows transvaginal uterine access in nearly all cases (Chai et al., 2007; D’Hooghe et al., 2008). Alternatively, endometrial biopsy is also possible by transabdominal insertion of a Novak curette through the uterine fundus under direct laparoscopic control (Nyachieo et al., 2007; D’Hooghe et al., 2008). Development of the baboon model for research in endometriosis at IPR Since 1990, the baboon model for endometriosis has been developed at the IPR, a WHO collaborating center in Nairobi, Kenya, where research in NHP reproductive disorders can be done at an affordable cost while maintaining high ethical standards (D’Hooghe et al., 2008). Baboons do have spontaneous retrograde menstruation (D’Hooghe et al., 1996d), display human-like minimal to severe spontaneous endometriosis (D’Hooghe et al., 1991; Cornillie et al., 1992; Coe et al., 1998; Dick et al., 2003), offer an in vivo culture model for endometrial – peritoneal interaction and develop induced endometriosis within 25 days after intrapelvic injection of menstrual endometrium (D’Hooghe et al., 1995). The baboon model also allows the study of the spontaneous evolution of both spontaneous and induced endometriosis by serial laparoscopies with detailed and repeated quantitative pelvic assessment of endometriosis, according to the classification system of the American Fertility Society/American 104

Society of Reproductive Medicine which has been adapted for use in the baboon (D’Hooghe et al., 1995, 2006; Falconer et al., 2006; Lebovic et al., 2007). The baboon model has been used to test new drugs for treatment or prevention of endometriosis (Barrier et al., 2004; D’Hooghe et al., 2006; Falconer et al., 2006; Lebovic et al., 2007) and is important to test general and reproductive safety of new antiendometriosis drugs (D’Hooghe et al., 2006, 2008; Falconer et al., 2006). The baboon model has also been developed for standardized and controlled fertility studies while controlling for the presence of endometriosis (laparoscopy assessment), ovulation (monitoring of the perineal cycle), for sexual activity (observation of timed intercourse with male baboon and post-coital test) (D’Hooghe et al., 1994, 1996e) and for male factors (males of proven fertility with a normal sperm analysis) (Amboka and Mwethera, 2003). Endometriosis-associated subfertility has been observed in baboons with mild, moderate or severe endometriosis (spontaneous and induced), possibly related to an increased incidence and recurrence of the Luteinized Ruptured Follicle Syndrome, in the absence of ovarian endometriotic cysts (D’Hooghe et al., 1996c, 1997). Development of the baboon model for assisted reproduction at IPR The need for non-human primate models is increasing due to ethical constraints of reproductive research in humans and to increased public awareness about the safety of new developments in assisted reproductive technology. All biomedical issues related to conception and early human life are bound to be scrutinized and analyzed critically, not only by physicians or scientists, but also by ethicists, sociologists, politicians and the media. In contrast, it is generally accepted in biomedicine and by the public opinion that new diagnostic or therapeutic methods in reproductive medicine should be safe and efficient before application in humans (Schatten, 2002; Winston and Hardy, 2002). There is concern about the efficiency and the safety for nearly all new reproductive technologies that are being developed or already applied in humans, especially regarding genomic imprinting and premature exposure of gametes and embryos to potentially damaging growth factors from in vitro culture media. The health of children born after these techniques and their impact on future generations is of course very important. These concerns are related to intracytoplasmatic injection of immature or abnormal sperm, spermatogonial stem cell transplantation, in vitro oogenesis and maturation, embryogenesis after cryopreservation and thawing of immature and mature oocytes, development of new culture media for long-term culture and their effect on embryo quality, clinical application of embryonic stem cells, therapeutic cloning, the efficacy of new cryopreservation techniques, etc. The practice of cytoplasmic transfer for the treatment of ‘infertility related to cytoplasmatic dysfunction in older women’ has been introduced in clinical practice without significant tests regarding safety and efficiency (Barritt et al., 2001). This assessment of safety and efficiency is difficult since human reproduction is a unique biological process, fundamentally different from reproduction in rats,

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mice, rabbits or even pigs, goats or cattle. Only non-human primates like the great apes (chimpanzees, gorilla, urang-utans), baboons and rhesus monkeys are in most aspects similar to humans in terms of reproductive anatomy and physiology. In fact, it is not surprising that some reproductive diseases, like endometriosis, only occur in non-human primates and not in other animals (D’Hooghe, 1997). Only in rhesus monkeys, procedures for ovarian stimulation, oocyte aspiration, IVF, intracytoplasmic sperm injection (ICSI), embryo culture and embryonic stem cell derivation have been well established (Thomson et al., 1995; Stouffer and Zelinski-Wooten, 2004). However, most rhesus monkeys are committed to research in infectious diseases (Sauermann, 2001; Bavister, 2004), which increasingly limits their availability for reproductive research. Although great apes such as the chimpanzee and gorilla are phylogenetically closer to humans (1.5% genome difference), as well as in terms of reproductive anatomy and physiology, they are endangered species and therefore not widely used as experimental animal models for reproduction (D’Hooghe, 1997; Taylor et al., 2002). The baboon offers an attractive alternative, as it is not an endangered species but an agricultural pest in many Sub-Saharan African countries. Therefore, it is ethically acceptable to consider the baboon as a research model for human assisted reproduction studies, since this is a medically and ethically important process that cannot be studied in a clinically meaningful way in other animal models (D’Hooghe et al., 2004). The baboon has also been validated for intrauterine research (Chai et al., 2007). Results achieved so far at IPR have shown that this baboon model is useful for assisted reproductive studies. Indeed, various ovarian stimulation procedures have been tested and optimized, gamete procedures established and in vitro fertilization (IVF) procedure optimized (D’Hooghe et al., 2004; Nyachieo et al., 2008). Both classical in vitro fertilization and ICSI have been evaluated and are being used (Nyachieo et al., 2008). We view that the availability of this model may assist in addressing the raised concerns in human assisted reproduction and infertility issues. This research provides the basis for the study of embryo development, uterine implantation after in vivo and in vitro fertilization, test the safety and efficacy of currently introduced cryopreservation techniques as well as the study of embryonic stem cell development in baboons and generation of genetically identical baboons by morula splitting (Liebermann et al., 2003; Bavister, 2004). Development of the baboon model for heterosexual transmission of SIV at IPR At present, several research teams at IPR have started to develop the baboon model for heterosexual transmission of SIV and related viruses. This model could be very important to evaluate several local vaginal microbicides in their capacity to prevent this heterosexual transmission. Cost and ethics As per 1 November 2007, the cost for baboon research at the IPR is $450 for purchase, $3 per diem and $60 per hour of

surgery, as is listed on the IPR website at www.ipr.ke. The cost for a proof of concept randomized controlled trial in order to test a new drug in the prevention of endometriosis in 15 baboons during 3 months can be estimated to be ,$100.000 (D’Hooghe et al., 2008). Baboons are not an endangered species but represent a threat to agriculture in Sub-Saharan Africa and are often killed by local farmers. Baboon research at IPR has the advantage that the baboons live in their natural habitat, usually in group cages that allow them to maintain their social structure as much as possible. Baboons, like other NHPS, are the only clinically relevant animal models in endometriosis research that allow the study of cause – effect relationships, since they are the only species with spontaneous or induced endometriosis similar to the disease in women. In the view of the wide phylogenetic gap between rodents and humans, and the fact that the baboon model is well established, it can even be argued that it is unethical to test a new endometriosis drug in women before safety and efficiency for this drug have been established in baboons (D’Hooghe et al., 2008). However, it is very important that any baboon research carried out at the IPR in Nairobi, Kenya, meets the highest possible standards with respect to scientific excellence and animal welfare. Therefore, it can be recommended to seek double ethical approval for reproductive research studies in baboons both from the Ethical Commission at the IPR and from the Ethical Commission of the institution where the scientific collaborator is working (D’Hooghe et al., 2008). How can the scientific expertise in reproductive research at IPR be translated into the establishment of high-quality and affordable infertility services for the Kenyan people? On the basis of the information presented above, it is clear that IPR represents a Kenyan Institute with established expertise in research in reproduction. The Kenyan National Center for Research in Reproduction (NCRR) includes not only IPR but also the Department of Obstetrics and Gynecology at Nairobi University/Kenyatta National Hospital and the Department of Animal Physiology at the Department of Veterinary Sciences at Nairobi University. This NCRR could represent the platform to translate the reproductive research capacity present at IPR to the provision of high-quality and affordable clinical infertility services in a poor resource setting. This is important since there are no infertility services available in the public sector in Kenya. At least one private center is active in the Nairobi area, but treatment costs are high and Kenya has not yet put in place systems of quality control and/or accreditation for centers of reproductive medicine. Most Kenyans with infertility, who can afford it, travel to South Africa or to the EU for treatment. Over the last few years, the authors of this paper have taken several initiatives to develop clinical infertility services in Nairobi. These contacts have included: informal contacts with Kenya gynecologists (Kenyatta National Hospital, Nairobi Hospital and Aga Khan Hospital), a site visit/ meeting with the Director of Kenyan Medical Research Institute (KEMRI) followed by a written action plan involving 105

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a Leuven – KEMRI collaboration, and current plans to organize an Infertility Workshop in collaboration with the International Federation of Fertility Societies (IFFS) in Nairobi in the near future. The following challenges/questions will have to be addressed in the future: (i) identification of enthusiastic young gynecologists interested in offering high-quality/low-cost infertility services including assisted reproductive technology (ART); (ii) set-up ART as part of a center/network of reproductive medicine offering all diagnostic/treatment options; (iii) how to develop a win – win situation for both gynecologists and patients in and alliance between private and public sector. There is little doubt that, in order to be successful, the development of high-quality, low-cost infertility services in Nairobi will require a good business plan with respect to personnel training; quality assurance, protocols, SOPs; communication; work planning; electronic systems for records and data management (computer compatible from the start); data evaluation; . . . as has been proposed in another paper of this Monograph (Cooke, 2008).

Funding We thank Serono International, Flemish FWO (Fonds voor Wetenschappelijk Onderzoek/Foundation for Scientific Research) and Leuven University for funding reproductive health research projects at the Institute of Primate Research (IPR) through Prof. Thomas D’Hooghe who is FWO Fundamental Clinical Investigator (1998–2008) and holds the Serono Chair for Reproductive Medicine at Leuven University, Belgium.

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D’Hooghe TM, Bambra CS, Cornillie FJ, Isahakia M, Koninckx PR. Prevalence and laparoscopic appearance of spontaneous endometriosis in the baboon (Papio anubis, Papio cynocephalus). Biol Reprod 1991;45:411–416. D’Hooghe TM, Bambra CS, Koninckx PR. Cycle fecundity in baboons of proven fertility with minimal endometriosis. Gynecol Obstet Invest 1994;37:63 –65. D’Hooghe TM, Bambra CS, Raeymaekers SCM, De Jonge I, Lauweryns JM, Koninckx PR. Intrapelvic injection of menstrual endometrium causes endometriosis in baboons (Papio cynocephalus and Papio anubis). Am J Obstet Gynecol 1995;173:125– 134. D’Hooghe TM, Bambra CS, Raeymaekers BM, Koninckx PR. Disappearance of the ovulation stigma in baboons (Papio anubis, Papio cynocephalus) as determined by serial laparoscopies during the luteal phase. Fertil Steril 1996a;65:1219– 1223. D’Hooghe TM, Bambra CS, Hill JA, Koninckx PR. Effect on endometriosis and the menstrual cycle on white blood cell subpopulations in the peripheral blood and peritoneal of baboons. Hum Reprod 1996b;11:1736–1740. D’Hooghe TM, Bambra CS, Raeymaekers BM, Koninckx PR. Increased incidence and recurrence of recent corpus luteum without ovulation stigma (Luteinized Unruptured Follicle-Syndrome?) in baboons (Papio anubis, Papio cynocephalus) with endometriosis. J Soc Gynecol Investig 1996c;3:140–144. D’Hooghe TM, Bambra CS, Raeymaekers BM, Koninckx PR. Increased prevalence and recurrence of retrograde menstruation in baboons with spontaneous endometriosis. Hum Reprod 1996d;11:2022–2025. D’Hooghe TM, Bambra CS, Raeymaekers BM, Riday AM, Suleman MA, Koninckx PR. The cycle pregnancy rate is normal in baboons with stage I endometriosis but decreased in primates with stage II and stage III-IV disease. Fertil Steril 1996e;66:809–813. D’Hooghe TM, Bambra CS, Raeymaekers BM, Hill JA. Pelvic inflammation induced by diagnostic laparoscopy in baboons. Fertil Steril 1999;72:1134– 1141. D’Hooghe TM, Pudney J, Alves L, Peixe K, Hill JA. Immunobiology of the female reproductive tract in the baboon. Am J Primatol 2001a;53:47– 54. (Impact factor: 1.647). D’Hooghe TM, Ling Xiao, Koninckx PR, Hill JA. Cytokine profile in peripheral blood and peritoneal fluid of women with deep and superficial endometriosis. Arch Gynecol Obstet 2001b;265:40– 44. D’Hooghe TM, Bambra CS, Ling Xiao, Hill JA. The effect of menstruation and intrapelvic injection of endometrium on peritoneal fluid parameters in the baboon. Am J Obstet Gynecol 2001c;184:917– 925. (Impact factor: 3.083). D’Hooghe TM, Spiessens C, Chai DC, Mwethera PG, Makokha AO, Mwenda JM. Ovarian stimulation, oocyte aspiration, in vitro fertilization and embryo transfer in the baboon (Papio anubis): a pilot project at the Institute of Primate Research, Nairobi, Kenya. Gynecol Obstet Invest 2004;57:23–26. D’Hooghe TM, Nugent NP, Cuneo S, Chai DC, Deer F, Debrock S, Kyama CM, Mihalyi A, Mwenda JM. Recombinant human TNFRSF1A (r-hTBP1) inhibits the development of endometriosis in baboons: a prospective, randomized, placebo- and drug-controlled study. Biol Reprod 2006; 74:131– 136. D’Hooghe TM, Kyama CK, Mihalyi AM, Chai D, Falconer H, Mwenda JM. The baboon model for translational research in endometriosis. Reprod Sci 2008. Dick EJ, Hubbard GB, Martin LJ, Leland MM. Record review of baboons with histologically confirmed endometriosis in a large established colony. J Med Primatol 2003;32:39– 47. Einspanier A, Gore MA. Reproduction: definition of a primate model of female fertility. In: Wolfe-Coote S (ed). The Laboratory Primate, Part II: Use of Primate Model in Research. Elsevier books, 2005,105– 117. Falconer H, Mwenda JM, Chai DC, Wagner C, Song XY, Mihalyi A, Simsa P, Kyama C, Cornillie FJ, Bergqvist A et al. Treatment with anti-TNF monoclonal antibody (c5N) reduces the extent of induced endometriosis in the baboon. Hum Reprod 2006;21:1856–1862. Fazleabas AT, Brudney A, Chai D, Langoi D, Bulun SE. Steroid receptor and aromatase expression in baboon endometriotic lesions. Fertil Steril 2003;80:820–827. Hunnell NA, Rockcastle NJ, McCormick KN, Sinko LK, Sullivan EL, Cameron JL. Physical activity of adult female rhesus monkeys (Macaca mulatta) across the menstrual cycle. Am J Physiol Endocrinol Metab 2007;292:E1520– E1525. Kyama CM, Mwenda JM, Machoki J, Mihalyi A, Simsa P, Chai DC, D’Hooghe TM. Endometriosis in African women. Women’s Health 2007a;3:629–635. Kyama CM, Mihalyi A, Chai D, Simsa P, Mwenda JM, D’Hooghe TM. Baboon model for the study of endometriosis. Women’s Health 2007b;3:637– 646.

Primate research: basis for infertility services? Kyama CM, Overbergh L, Mihalyi A, Cuneo S, Chai D, Debrock S, Mwenda JM, Mathieu C, Nugent NP, D’Hooghe TM. Effect of recombinant human Tumor Necrosis Factor Binding Protein -1 (r-hTBP-1) and GnRH antagonist on mRNA expression of inflammatory cytokines, adhesion and growth factors in endometrium and endometriosis tissues from baboons. Fertil Steril 2007c. Lebovic DI, Mwenda JM, Chai DC, Mueller MD, Santi A, Fisseha S, D’Hooghe T. PPAR-gamma receptor ligand induces regression of endometrial explants in baboons: A prospective, randomized, placebo- and drug-controlled study. Fertil Steril 2007. Liebermann J, Dietl J, Vanderzwalmen P, Tucker MJ. Recent developments in human oocyte, embryo and blastocyst vitrification: where are we now? Reprod Biomed Online 2003;7:623–633. Nyachieo A, Chai DC, Deprest J, Mwenda JM, D’Hooghe TM. The baboon as a research model for the study of endometrial biology, uterine receptivity and embryo implantation. Gynecol Obstet Invest 2007;64:149– 155. Nyachieo A, Spiessens C, Chai DC, Mwenda JM, D’Hooghe TM. Menstrual cycle synchronization, ovarian stimulation and in vitro fertilization in olive baboons (Papio anubis): a prospective randomized study. Fertil Steril 2008; March 5 (Epub ahead of print). Okonofua F. New reproductive technologies and infertility treatment in Africa. Afr J Reprod Health 2003;7:7–8. Overbergh L, Kyama CM, Valckx D, Debrock S, Mwenda JM, Mathieu C, D’Hooghe T. Validation of real time RT-PCR assays for mRNA quantification in baboons. Cytokine 2005;31:454– 458.

Pijnenborg R, D’Hooghe T, Vercruysse L, Bambra C. Evaluation of trophoblast invasion in placental bed biopsies of the baboon, with immunohistochemical localization of cytokeratin, fibronectin and laminin. J Med Primatol 1996;25:272– 281. Sauermann U. Making the animal model for AIDS research more precise: the impact of major histocompatibility complex (MHC) genes on pathogenesis and disease progression in SIV-infected monkeys. Curr Mol Med 2001;1:515–522. Schatten GP. Safeguarding ART. Nat Cell Biol 2002;4(Suppl):S19– S22. Stevens VC. Some reproductive studies in the baboon. Hum Reprod Update 1997;3:533–540. Stouffer RL, Zelinski-Wooten BM. Overriding follicle selection in controlled ovarian stimulation protocols: quality vs quantity. Reprod Biol Endocrinol 2004;2:32. Taylor RN, Lundeen SG, Giudice LC. Emerging role of genomics in endometriosis research. Fertil Steril 2002;78:694–698. Thomson JA, Kalishman J, Golos TG, Durning M, Harris CP, Becker RA, Hearn JP. Isolation of a primate embryonic stem cell line. Proc Natl Acad Sci USA 1995;92:7844–7848. Winston RM, Hardy K. Are we ignoring potential dangers of in vitro fertilization and related treatments? Nat Cell Biol 2002;Suppl:S14–S18. Zondervan K, Cardon L, Desrosiers R et al. The genetic epidemiology of spontaneous endometriosis in the rhesus monkey). Ann NY Acad Sci 2002;955:233–238.

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Patients’ voice Rita Sembuya Namusisi* Joyce Fertility Support Centre Uganda (JFSCU), 32 Windsor Crescent off Babiiha Avenue, Next Athina Club, PO Box 28095, Kampala, Uganda *

Correspondence address. Tel: þ256-41-345-366/þ256-774-100-873; E-mail: joycefertility@hotmail.com/sembuyar@yahoo.com

International declarations have already endorsed the importance of a family. Different international organizations recognized the right of everyone to enjoy the benefits of scientific progress and its applications, and the right of everyone to enjoy the highest standard of physical and mental health. In African Traditional Society, if a woman does not give birth, she is considered as if she has not existed. Her family line internally disowns her in that she does not participate in practices that promote continuity. A woman or a man who fails to go through the biological process of reproducing offspring loses a complete life and her/his community regards her or him as incomplete. When Rachael failed to get children, she said unto her husband Jacob, ‘Give me children or else, I die’. In case of developing countries, specifically sub-Saharan Africa, the situation is exacerbated by the already existing burden on the health of the population. The priority focuses on what is regarded as catastrophic; Malaria, HIV/AIDS, maternal mortality and infant mortality are the major concerns for the country’s budgets. In the existing health systems, there exist no drive for documentation or any demand for studies leading to the plan of action for the management of infertility. Most of the researches are directed towards fertility and population, mainly investigating demographic indications on reducing and maintaining of population. Reproductive programs in developing countries have channeled their focus to HIV/AIDS, malaria and family planning, neglecting infertility completely. The World Health Organization (WHO) also published many reports on Assisted Reproduction and Infertility, however, no actions have been undertaken. Subsequently, the need for organized institutions for patients comes into existence with the different countries coming on board. The key issues are affordability, accessibility and quality. The target groups are governments, medical community, industry, media and the general society. Although 108

identification of the problem is most important in sub-Saharan Africa, there is almost no documentation on infertility prevalence. There is a significant need for a research to profile the real prevalence of infertility in developing countries and an action plan adopted in the health structure of countries, i.e. coordinating all stakeholders. Patient organizations in developing countries have emerged to address the above problems. Five-patient organizations were founded between 1996 and 2006 in Uganda, Kenya, Zimbabwe, Israel and Argentina. The main objectives were the following: (i) Building partnerships with reproductive programs, health providers, other non-profit organizations, politicians, traditional healers and religious leaders. (ii) Addressing gender based violence, domestic based violence, financial insecurity on the side of women, and cultural barriers. (iii) Supporting education to public including medical practitioners, scientists and politicians to understand patients’ roles and perspectives. (iv) Increasing awareness in the media to inform communities about infertility. Challenging issues are the findings that infertility is a neglected disease, the high costs of treatment and insurance companies not interested, restrictive laws that make ART difficult to be accessible and governments’ budgeting in developing countries which eludes important views of the communities. Some churches also strongly oppose ART. Patients’ organizations opened infertility awareness that was not addressed in any of the reproductive health programs of countries. Independent views of patients are voiced through their organizations. Patients organizations are patient led, they are not affiliated to any hospitals hence their ability to voice independent views. The long-term goals are self-sustainability, to establish centers of excellence for education, counseling and research, to obtain fair-legislative laws on ART to allow accessibility and to

Patientsâ&#x20AC;&#x2122; voice

develop networks taking into account the problem of language barriers with respect for cultures of different communities To conclude, as patients advocates we need to start with documentation of prevalence as a tool to lobby for the funding of infertility treatment as one of our reproductive rights. The role of the patients in the management of infertility comes as an important call for all stakeholders in healthcare delivery of countries. The key targets for patientsâ&#x20AC;&#x2122; voices are the governments, the medical and scientific community, the media and the public. Between 1980s and 2000, patients organized critical masses of advocate groups to address the problem of infertility and insert their voices in public policy and management of infertility. The present challenges in the health delivery systems of developing countries are the structure from top-down criteria,

which creates major gaps between the providers and the final beneficiaries of the services. There is a strong need to incorporate patientsâ&#x20AC;&#x2122; views and perspectives in discussions and major decisions in all matters pertaining to healthcare service for infertility.

Acknowledgements We would like to acknowledge the following people in the contribution of this article: Prof. Willem Ombelet-Editorial, Genk University Belgium; Sandra K Dill AM-Supervisor, International Consumer Support for Infertility. Patient leaders: Ofra Balaban, Chen Fertility Patient Association Israel; Evelyn Madziba, The Fertility Network of Zimbabwe; Sarah Muthanje Ndwiga, Hope Fertility Support Centre Kenya; Estela Chardon, Concebir Argentina.

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Human Reproduction 2008

IVF in developing countries: an artist’s view Koen Vanmechelen1 Gestelstraat 13, 3670 Meeuwen-Gruitrode, Belgium 1

Correspondence address. E-mail: koen.vanmechelen@skynet.be

Participation or aloofness? The introduction of IVF in the developing countries is faced with a lot of fundamental objections. Development aid is often doubted. To what extent are the humane reasons, the basis for IVF in Africa, mainly a translation of the western needs and interests? How big are the economic motives? Is it reasonable to put my foot on to this slippery slope of the north – south relations? An artist mostly uses motives which move freely in relationship to the pure ethical, scientific or economic discourse. Why should I join this new development? My participation only makes sense if this project disposes of a dynamism that is essential in my work. In my opinion, art should be individual, up-to-date and universal. Moreover, those three constructive components do not find themselves in a static connection but ask for a new appraisal in each creation. Can I find any dynamism in this current issue? The dynamism of crossbreeding When exporting a western technology to developing countries, ‘environmental factors’ obviously play an important role. These factors are also determinant in the ‘Cosmopolitan Chicken Project’ (The Cosmopolitan Chicken project includes the worldwide experimental project with which Koen Vanmechelen hopes to develop a super-hybrid chicken. Crossbreeds clearly play an essential role in Vanmechelen’s work, not only in chickens but also in materials and disciplines. Topical themes such as genetic manipulation, cloning, globalization and multiculturalness are found throughout his work. He likes to describe his work in Hegelian terms: thesis, antithesis and synthesis. The chicken and the egg are a metaphor for the human race and art.). Crossbreeding always means welcoming external, partly unverifiable influences. Indeed, the artist steers the breeding process but the power of moment and place counts to the same extent. In this way, an intersection of several factors is created in the objective and biological reality of chickens and the subjective motive and situation of the artist and the audience. The concrete and mental reality harmonizes with one another, creating something that is materialistic as well as immaterial: a chicken that is called art. This duality creates contrasts that differ according to the generation of chickens. Each new breeding place puts a different light upon the relation between local and global, fertile and infertile, 110

science and nature. Each chicken tells its own story, looking forward and backward, respecting its relative independence. It is a fascinating dynamism allocating me as an artist, an active as well as responding role. In the issue of ‘developing countries and infertility’ I hoped to find back that epistemological, double, fundamental attitude of creating and waiting with renewed attention for the individual of the chicken, the current issue of crossbreeding and the universal (philosophy) of the project. Art chicken—art man My participation in the experts’ meeting about IVF in the developing countries fits in with the breeding project I have started up in Arusha. It was not developing aid but the typical, unfamiliar patterns and principles of the Cosmopolitan Chicken Project that took me to Tanzania. It appeared to be rather difficult to find local partners to build up the cages and to maintain the chickens. Do they really need a chicken which, due to manipulation of the natural copulation, is considered as art. What is the attitude of the Tanzanian towards a crossbreed art chicken that may not be eaten? Extremes can be very useful; therefore, we transfer the previous question to the IVF debate: what is the attitude of the developing countries towards an expensive test-tube baby? This matter also includes a radical confrontation of the local and the global, the infertile and the fertile, science and nature. Economic, cultural, anthropological as well as ethical themes are discussed. Is the African mother able to pay for an IVF treatment? Are there enough possibilities to educate the child? Are there no other priorities like situations that urgently demand financial support? Will only the rich people benefit from the technique? Do we have to make the unaffordable affordable? Wouldn’t it be better to promote prevention with reference to different sexual partners and sexually transmitted diseases and badly carried out abortions rather than fertilize infertility? IVF means interfering in a high-technological way in a basic fact of nature, namely reproduction. Because of interference in the natural coupling, we could get the impression that an art man is born. Because of religion masturbation is forbidden or should be taught in some regions. In Congo parents disown their children, for evangelists call them wizards. Can we, as an outsider, make what is unheard, heard?

IVF in developing countries

Extremes are useful Making the unaffordable affordable, the infertile fertile and what is unheard heard. . .. IVF in developing countries creates dualities in life which makes us feel the daggers drawn. The contrasts are so sharp that they almost neutralize. Reproductive medicine as well as development aid create an extreme outcome of the scientific-technological and capitalistic development of the West. We can probably make use of the extremes by examining their meanings. Extreme limits expand our consciousness, provided we deal with them in a suitable reflexive way. Therefore when a technique is globalized not only the local customs and possibilities should be taken into consideration. ‘The ongoing dialogue of technoculture often takes its more interesting turns in areas outside the developed west’ (Hess, 1994). The total project should fit in the specific context and therefore the local is the ideal test for the global. Infertility is frequently prevalent in regions of high fertility. This contradiction leads to comprehension of the causes and treatment of infertility to finally reach a greater knowledge of the ‘healthy’ condition. Eventually, the reaction of a community—in which belief and superstition are important—can clarify our ethical approach to IVF. IVF is an outstanding example of technoculture and thus a product of the thinking, non-natural human being who pushes his belief away in favor of science. Especially with reference to reproductive medicine, this division of belief and science leads to ethical problems. How can we declare moratoriums if things are not restricted by ‘natural’ borders such as belief or religion. Because of the loss of belief, economic motives push away the ethical considerations. Sometimes it is difficult to find out the essential motivation. The comparison between the way how the Third World and the Western World deal with IVF, can lead to a new ethical and epistemological dialogue. Conclusion The impact of external environmental factors leads to unexpected views on the personal project, or throws light upon

the ‘common’ or ‘healthy’ departing situation in an unusual way. On the other hand, our positive effort influences a process in which all parties are involved. That principle is daily experienced in the ‘Cosmopolitan Chicken Project’ and for me it is a gift. In relationship with a complicated theme as IVF in developing countries, that seems too simple (utopian) or even utilitarian. Does the Third World have to give us a more subtle view? This criticism is appropriate but not complete. It might be that only an artist can evoke such sensitivity. It is a sensitivity of the mutual influence resulting in an intellectual willingness to permanent evaluation. When two extremes meet, an unbelievable density of potential arises at the section of both lines. That is a potential we have to handle thoughtfully and with care. My contribution to this important project on ‘Developing countries and infertility’ may consist of a series of numbered and signed reproductions of a painting. Each work can be sold at the price of one IVF or 3 to 4 IUI treatments. Each individual fertilization combines the story of an infertile woman with the owner of a piece of art. This will draw the attention to the individual welfare of an infertile family and in the meantime it emphasizes the topical subject of IVF, against a stubborn mentality and against medical and material motives. To those involved, this may result in an attitude of cautious sincerity in relation to the individual, the variable, the other. The original meaning of the word ‘religion’ is to observe carefully and to honor what is totally different (from the human being). This ‘religious’ reflection should be added to the ethical, juridical and economic motives of the IVF debate. Because of its place on the crossroad of social motives, this is pre-eminently the approach of the artist.

Reference Hess D. Parallel universe: anthropology in the world of technoscience. Anthropol Today 1994;10:16 –18.

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Message from the French Ministry of Foreign Affairs Bernard Kouchner Minister of Foreign Affairs, France

The worldâ&#x20AC;&#x2122;s population is increasing tremendously. By the year 2000, it was over 6 billion, contradicting previous prognosis. At the same time, 60 â&#x20AC;&#x201C; 80 million couples are involuntarily childless. The growth of general population cannot compensate the requirements of the each individual infertile couple. Sterility is a dramatic situation on the personal level; in some ethnic groups, it can be explained as a supreme punishment and may lead to the exclusion of the couple from the family and the Society, subsequent depression and even suicide. This is especially traumatic for the females, for whom maternity can be the vital demand. All sorts of psychological problems frequently bring couple to the conflicts and even divorce, also known to be suffered more severely by women, for whom to find a new partner can be far more difficult than for the men. Reproductive medicine, management of infertility, has always been one of the main concerns of the Society. ART has brought new horizons for the infertile couples, which nowadays is widely used in many countries. But should it be reserved only for the rich countries or it is possible to create, adopt and propose new treatment modalities without decreasing the medical level of the programme for everyone?

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We can use different ways of stimulation, increase the use of mild stimulation, thus diminishing the cost of the procedures, but also the rate of possible complications. Undoubtedly, this will be very interesting for the countries with big experience in ART. To avoid hyperstimulation syndrome, diminish births of twins and triplets is not a complete clinical demand of reproductive medicine today. We should also think about increasing neonatal health, diminishing prenatal and maternal mortality and morbidity. We should choose the time of the pregnancy when it is not naturally possible and give opportunity for the protected delivery. The aim of the Congress is not only to make an impact for the infertility treatment success, but also for the achievement of the safe pregnancy, delivery and maternity. Certainly, private system should exist and support maternal service. Nevertheless, public system is responsible for covering these urgent demands of the Society. Friends are ready to be involved via different ways. But also different significant societies and authorities such as WHO and Governmental Institutions would participate, supplying medical care and supporting educational process with a possibility to exchange doctors, willing to follow this programme. France is concerned by this field and the French Ministry of Foreign Affairs will do his best to participate actively in it.

doi:10.1093/humrep/den173

Human Reproduction 2008

Message from the government of Uganda Alhajm Tezikuba Sajjabi Senior Presidential Advisor The Republic of Uganda

Infertility is a major challenge in Uganda with an estimated 5 000 000 people facing infertility, mainly handled by the private centers in urban areas. This means that the patients in the rural centers do not have access to treatment. The World Health Organization (WHO) Report of 2002 puts the prevalence of infertility to be the most concentrated in Sub-Saharan Africa. Of all couples attempting a pregnancy, in any given year, approximately 10â&#x20AC;&#x201C;15% fail and require serious medical help. Whereas Malaria, HIV etc. are considered top priority, apparently the policy makers have not been provided with the right facts and information regarding the devastating effects of infertility on the emotional and social wellbeing of the population. In my preparation, I invited health practitioners in Uganda from both public and private health facilities to provide updates on prevalence of infertility to help me in putting my case. They were not able to provide any data from Uganda. This is my first challenge as a government voice. However, they have cooperated and came up with the suggestions and recommendations on which we can be able to build. Management of infertility is included in the national policy guidelines and service standards for sexual and reproductive health and rights, but unfortunately the policy guidelines and objectives are not yet integrated in existing sexual and reproductive health services at all levels. Where gynecological clinics exist, which is mainly at referral centers, they are poorly facilitated and there are no specific facilities for infertile patients. There is no national program for the management of infertility. This puts our country to poor access to the management of infertility. Levels of technology are still low, i.e. equipments, laboratory support, technical trained staff, drugs and medication. There are two private centers that provide advanced assisted conception at a price only affordable by very few (,10%) of infertile couples. The key issues to address in Africa are (i) training, (ii) staffing, (iii) establishing specialized centers and integrating services in already established health units at all levels and (iv) providing affordable or free services. The most important recommendations of our government will include the development of the prevention of infertility as a public health issue, gender awareness, making assisted reproduction techniques affordable and accessible to many. Supporting the vital role of education and information, to

develop statistical data to guide policy and creating ethical guidelines on religious and moral issues. International organizations and the pharmaceutical industry should work together with governments and relevant institutions to document data on infertility. These data will inform the governments about the magnitude of the problem. The WHO and the European Society for Human Reproduction and Embryology can guide healthcare systems of developing countries. It is time to break the silence, to get information about the disease in Africa. Patient organizations such as Joyce Fertility Support Centre Uganda are mobilizing couples and advising them to seek partnership with health providers, government and the media advocating for Advanced Reproductive Technology as a treatment. Low cost IVF might be an answer to this long time of suffering. In order to be well coordinated, countries should build corresponding structures to roll out the project, such as community sensitization, healthcare providers networking, ethical guidelines and government coordinating. Uganda government policy has decentralized services at District levels. In the Ministry of Health strategic planning, we have health centers from Village, Parish, sub-county up to District. All these institutions will have to document infertility cases. The Joyce Fertility Support Center Uganda will be invited to work with the government in documenting the infertility prevalence in the country. When infertility is handled, it is evident that many diseases will be managed including safe obstetrical care. We also plan to continue emphasizing prevention of diseases that cause infertility. These will run concurrently with HIV/AIDS prevention. Fertility treatment is rather expensive in the world and more threatening in the developing world where resources are scarce; priority is often given to the more obvious life-threatening diseases. Thus leaving fertility treatment on the back burner, yet infertility is a silent killer both emotionally and socially. Our aim is to create awareness and empower and sensitize the population regarding fertility issues with the help of patientsâ&#x20AC;&#x2122; organizations. I am looking forward to a future proposal which improve the health of communities faced by infertility and I am also calling for a united front by all forces in this Arusha meeting to uphold to the objectives which will lead to important goals of this meeting to become a reality.

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Acknowledgement Dr. Mbisirikire Kitamirike J. (M.MED M.U), Senior Consultant â&#x20AC;&#x201C; Obs/Gynae. Rubaga Hospital (Uganda). Dr. Pius Okong. M.Med, PhD, Senior Consultant Obstetrician and Gynecologist, San Raphael

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of St. Francis Hospital Nsambya (Uganda). Dr. Prakash A. Patel MD. (Obs/Gyn); Diploma in Endoscopy (Germany), Specialist Gynecologist, Laparoscopic Surgeon. Joyce Fertility Support Centre Uganda, National Association of Patient Support for infertility.

doi:10.1093/humrep/den149

Human Reproduction 2008

Message from the European Commission: the role of the developed countries, a political issue Sonia Languille Economic Affairs, European Commission Delegation, Tanzania E-mail: sonia.languille@ec.europa.eu

The Arusha meeting has a broad scope: not only scientific but also economic and cultural issues are addressed, including, for example, the financial aspects of infertility treatment in the developing world, and the value of children in Africa. As citizens of developed countries trying to construct a viable working relationship with Africa, we have a duty to modulate our views and also to focus our objectives according to the specific context in which we work. This principle applies as strongly to development co-operation as it does to research in the field of reproductive biology and medicine. One of the jobs of your organization is to disseminate research findings in human reproduction and embryology to the general public, as well as to scientists, clinicians, politicians and policy makers. This means you have to break down the wall between the knowledge and power, and this is why the duty to educate and the duty to inform come through very strongly in the themes of this conference. These aspirations also bring with them an implied sense of people’s rights, both to have information and to make free and rational choices with that information. I will address these issues but also focus on the approach taken by the EU Member States and the Commission to health in their development policy and especially their efforts to increase the efficiency of aid delivery. When we discuss infertility, we often forget that it affects 10 –20% of couples in the world and that this rate in Africa may be as high as 20 – 30%. We know of course that factors that affect the prevalence of infertility include the sexually transmitted diseases and post-partum and post-abortal infections. Yet the causes of infertility are also related to poor sexual and reproductive health and to human rights, as well as low access to health services. Of course, prevention of infertility should be the primary goal of any strategy since curative treatment is often very expensive and of low effectiveness. This preventive strategy must involve the effective control of sexually transmitted diseases. This is why we consider that the access to comprehensive information, education, freedom of choice and access to family planning means and reproductive health services are essential. But prevention cannot stand alone without proper infertility surveillance and control systems. A lack of infertility data from

developing countries makes it difficult to implement treatment and care strategies. Again this is a question of information—if we are to assess the results, we need to know the starting point. We are not only talking about data, but about qualitative aspects as well. Infertility is not just a statistic. It is felt as one of the most serious health problems for adult women in developing countries. It can be a handicap that affects women’s role in the family and in society. Childless women often find themselves abandoned in destitute situations. In some cultures, a woman needs to prove her fecundity in order to marry, so many of the infertile women are marginalized by society and even their own families. These values are a challenge for us as they undermine efforts on gender equality. It is thus important that any efforts to address infertility gather different stakeholders whom operate in separate communities, such as the advocates for women’s rights, health scientists such as yourselves and last but not least administrators and health workers in public policy. An important way of coping with infertility is adoption. Some studies show that in Africa, more than half of childless couples live in households with adopted children. There is a tragic increase of orphans and vulnerable children in relation to the HIV/AIDS pandemic. By 2010, there will be .40 million orphans in Africa, 15% of all children. Many of them will be in a destitute situation and would recover their chances and hope in life and society through adoption into a loving family. This is a way to address two problems at the same time in a way which is accepted traditionally and that enhances social cohesion. Let me turn now to what the European Union (EU) can do. New strategies and policies have to be financed. Health needs and rights have to be owned by partner countries to be viable, because both governance and economic capacities are needed to be able to guarantee the access to basic care, including comprehensive sexual and reproductive health services. The starting point for the European Commission (EC) is the new European Consensus—our development framework. There are several references to the importance of sexual and reproductive health and rights in this document. In the European Consensus, it is also clearly set out that budget support or sector budget support is the preferred tool for future aid.

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Languille

Another issue that features strongly in the Consensus is the need for donors to coordinate better in order to make aid more effective than it has been. The challenge is enormous and urgent but we have great opportunities ahead of us, which I would like to remind ourselves today. EU Member States and the EC will continue to complement our country support to health with significant contribution to some global priorities. In this context, we will continue to confront poverty diseases, mainly through the contribution to the Global Fund. Let’s remember that HIV/ AIDS is one of the main causes of infertility and the HIV/ AIDS prevention strategies also have an effect in reduced Sexually Transmitted Infections and infertility. In this area, the Commission recently decided to frontload E300 millions as the contribution for the coming 3 years. We are also planning to support the global and especially African regional initiatives to tackle the crisis of human resources for health. But the main channel of the EC aid to social sectors will be through Budget Support. This is the ‘natural ally’ of the support to health: most of the costs related to the provision of equitable basic health care services are recurrent costs: salaries, medicines, information and management systems, the logistics of services. The best way to support our partner countries to plan equitable and pro-poor health strategies is through predictable budget support. This will allow countries to plan with at least 3 and preferably 6 years horizon, solid strategies with predictable funds. For instance, in Kenya, the many uncoordinated and ad hoc projects led to 22 different procurement channels of essential medicines with very limited efficiency. The EC’s budget support is closely linked to progress on health indicators: this is a strong incentive for both Ministries

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of Finance and Ministries of Health to better talk one another, plan pertinent strategies and progress in priority health areas. This requires quality dialogue, so as to understand the lack of progress and explore jointly timely corrective measures. One year after the adoption of the European Consensus, the EU’s focus is on delivering on its political and financial commitments. In fact, the year 2006 was our first credibility test. First, we have met our commitments regarding aid volumes: in 2006, EU ODA (Overseas Development Assistance) reached 0.42% of the gross national index (GNI), exceeding the initial target of 0.39%. Thus, the EU disbursed a record E48 billion in 2006 compared with E45 billion in 2005 (Commission Staff working document ‘Keeping Europe’s promises on Financing for Development’ 4 April 2007). Over the next few years the EU’s share of total ODA will increase even more with the commitment by Member States to reach the 0.7% GNI target by 2015. Collectively, the EU ODA allocated to health is 6.6% of the EU total ODA. With the gradual increase ODA committed by Member States, the present share of EU ODA to health could be increased and we could collectively progress on filing the financial gap on health. But beyond the quantitative aspects, we are committed to enhance the quality of EU aid with emphasis on efficiency, education and information. With less reliance on externally funded projects, except crucially in the area of innovation, national decision-makers need clear and reliable information on which to make their policy choices: nowhere is this more evident than in the area of reproductive rights.

doi:10.1093/humrep/den225

Human Reproduction 2008

Recommendations Arusha-meeting 2007

1. The ultimate aim is to establish low-cost fertility clinics in developing countries, with affordable, effective and safe diagnostic and therapeutic procedures. 2. Documentation of the problem of infertility in developing countries has to be organized. 3. Studies have to be performed on the health economics of infertility in developing countries. 4. Treatment of infertility should be integrated within settings of general health care where opportunities exist for contraception, health education, maternal and child care, as well as prevention and treatment of STIs and HIV (Reproductive and Sexual Health Care Centres).

5. The terminology â&#x20AC;&#x2DC;affordable ARTâ&#x20AC;&#x2122; has a relative meaning depending on the region of the world or within a health care setting. 6. The start of an ART project should be related to the obstetric capacities and educational level of the country. If no appropriate obstetric service is offered this should be the first goal of the reproductive health clinics in collaboration with the government. 7. The necessary instruments and laboratory material for infertility treatment should be robust, simple to use, easily replaced and standardized.

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