Department of Reproductive Health and Research, including UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction annual technical report

Publication date: 2002

Department of Reproductive Health and Research including UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction Annual Technical Report 2002 World Health Organization Department of Reproductive Health and Research Family and Community Health A n n u al Tech n ical R ep ort 2002 1 WHO Library Cataloguing-in-Publication Data World Health Organization. Dept. of Reproductive Health and Research. Department of Reproductive Health and Research, including UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction annual technical report : 2002. 1.Reproductive medicine 2.Reproduction 3.Family planing 4.Contraception 5.Research I.UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction II.Title. ISBN 92 4 159075 0 (NLM classification: WP 630) © World Health Organization 2003 All rights reserved. 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A n n u al Tech n ical R ep ort 2002 1 Contents Executive summary. 3 Section 1 – Promoting family planning. 19 Users’ perspectives in the context of reproductive health . 20 Development of improved and new methods of fertility regulation. 28 Safety and effectiveness of existing methods of fertility regulation. 54 Norms and guidelines for use of methods of fertility regulation. 67 Section 2 – Making pregnancy safer. 73 Generating new evidence for maternal and perinatal health. 74 Implementation of evidence-based programmes. 85 Section 3 – Controlling sexually transmitted and reproductive tract infections. 99 Section 4 – Preventing unsafe abortion. 123 Section 5 – Promoting sexual and reproductive health of adolescents. 137 Section 6 – Gender and reproductive rights in reproductive health. 151 Section 7 – Technical cooperation with countries. 161 Overview of activities—interregional activities and collaboration with regional offices. 162 The WHO Regions of Africa and the Eastern Mediterranean. 165 The WHO Region of the Americas. 180 The WHO Regions of South-East Asia and the Western Pacific. 188 Central and Eastern Europe, including the Newly Independent States and Central Asian Republics. 194 Policy and programmatic issues. 198 Section 8 – Implementing best practices. 207 Section 9 – Monitoring and evaluation. 221 Section 10 – Communication, advocacy and information. 227 Section 11 – Clinical trials and informatics support. 233 Appendix 1 – Staff of the Department, December 2002. 237 A n n u al T ec h n ic al R ep or t 2 00 2 2 A n n u al Tech n ical R ep ort 2002 3 A n n u al T ec h n ic al R ep or t 2 00 2 2 A n n u al Tech n ical R ep ort 2002 3 Executive summary A n n u al T ec h n ic al R ep or t 2 00 2 Annual Technical Report 2002 4 A n n u al Tech n ical R ep ort 2002 Executive summary 5 Executive summary THE DEPARTMENT The Department of Reproductive Health and Research (RHR—referred to in this document as “the Department”) sees its mission as helping people to lead healthy sexual and reproductive lives. In pursuit of this mission the Depart- ment endeavours to strengthen the capacity of countries to enable people to promote and protect their own health and that of their partners as it relates to sexuality and reproduc- tion and to have access to and receive quality reproductive health services when needed. The Department of Reproductive Health and Research was created in November 1998 by joining the UNDP/UNFPA/ WHO/World Bank Special Programme of Research, Devel- opment and Research Training in Human Reproduction (HRP—referred to in this document as “the Programme”) and the former WHO Division of Reproductive Health (Technical Support) (RHT). The purpose of bringing these two entities together was to facilitate integration of research and pro- gramme development in reproductive health within WHO. UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP) The Programme was established in 1972 by WHO. In 1988, the United Nations Development Programme (UNDP), the United Nations Population Fund (UNFPA), and The World Bank joined WHO as the Programme’s cosponsors. The four cosponsoring agencies, together with the major finan- cial contributors and other interested parties, make up the Programme’s governing body, the Policy and Coordination Committee (PCC), which sets policy, assesses progress, and reviews and approves the Programme’s budget and programme of work. Broad strategic advice on the Pro- gramme’s work is provided by the Scientific and Technical Advisory Group (STAG) (Annex 1). (In 1999, STAG assumed the responsibility for reviewing, and advising on, the work of the whole Department.) The Scientific and Ethical Review Group (SERG) Panel (Annex 2) reviews all projects involving human subjects and research in animals and contributes to ethical debate on matters relating to reproductive health. The Toxicology Panel (Annex 3) is a complementary review body to the SERG Panel. It provides expertise in the evaluation of pharmacokinetic, metabolic, endocrinological, toxicological, teratogenicity, carcinogenicity and mutagenicity studies of drugs or devices developed or studied by the Programme or referred to it for advice. In addition, the Programme has several specialist panels that advise on detailed research strategies. PROMOTING FAMILY PLANNING Research on users’ perspectives Research on users’ perspectives provides scientifically sound information on the needs and preferences of women and men for reproductive health technologies and serv- ices. This information is central to informed policy-making and programmes, and for designing services which better address the needs of users and of potential users. Research findings also provide the basis for developing appropriate evidence-based norms and tools and improving existing, or developing new, reproductive health technologies. In 2002, a workshop with country investigators was held in Nairobi, Kenya, to review and plan further work on a study A n n u al T ec h n ic al R ep or t 2 00 2 Annual Technical Report 2002 4 A n n u al Tech n ical R ep ort 2002 Executive summary 5 on pregnancy prevention in the era of HIV/AIDS in Kenya, South Africa, Uganda, United Republic of Tanzania, Zambia and Zimbabwe. Findings from Kenya were presented at the XIV International AIDS Conference, held in July 2002 in Bar- celona, Spain. Collaboration continued with scientists from the University of London School of Hygiene and Tropical Medicine, London, United Kingdom, on analysis of data from the Demographic and Health Surveys (DHS) on contracep- tive choice and discontinuation and switching of methods. Work was also undertaken to estimate the extent of child- lessness and primary or secondary infertility using DHS data for 495 000 women from 47 developing countries. Three new projects were launched under the research initiative on qual- ity of care. Selected highlights •• A study in Kenya showed that communities perceived HIV/AIDS to be a serious problem. Paradoxically, how- ever, the majority of sexually active individuals believed their own risk of HIV to be low or non-existent. Individu- als surveyed recommended condom use to prevent the spread of HIV in the community, but the vast majority engaged in risky sexual behaviours, including not using condoms. •• A policy brief was produced based on findings from a study in China. It highlighted the need to provide repro- ductive health information and services to young female migrants. The policy brief was translated into Chinese and disseminated widely. •• Research on users’ perspectives resulted in 12 pub- lications in national or international journals, provid- ing evidence for developing informed policies and programmes. Research on the development of new methods for fertility regulation The key objective of the Programme’s research on the devel- opment of methods of fertility regulation is to broaden the choice of methods for users and potential users, by improv- ing existing approaches and technologies, and by developing entirely new ones. The Programme has successfully collabo- rated with other funding partners and, in several cases, with the private sector in identifying research and development needs and in designing and executing relevant research in this area. The Programme’s portfolio includes work on meth- ods for women and men and ranges from basic research designed to identify novel and innovative approaches, to clinical trials of improved and new methods in a variety of settings; behavioural and acceptability research is also con- ducted, as appropriate. Selected highlights •• At the end of 2002, a Phase II study of a combined androgen and progestogen regimen for male hormonal contraception was completed in Indonesia. The definitive results of this study demonstrated that depot-medroxy- progesterone acetate, when used in conjunction with testosterone undecanoate, was an effective and long- acting suppressor of spermatogenesis. •• Investigations of the efficacy of low-dose mifepristone as an emergency contraceptive demonstrated that in Chinese women a 10 mg dose of the antiprogestogen was just as effective as a 25 mg dose; the pregnancy rate following either treatment regimen was 1.1%. •• Preliminary data from studies in monkeys suggested that levonorgestrel will disturb ovulation if given prior to ovulation, but that it seemed to have no effect on preg- nancy rates if ovulation had already occurred. These data imply that the primary action of levonorgestrel as an emergency contraceptive is through suppression of ovulation. •• A series of pre-clinical studies on the development of an immunocontraceptive method for women showed that a prototype human chorionic gonadotrophin (hCG) immu- nogen appeared to be safe, highly immunopotent and stable. An application has been submitted to the regula- tory authorities in Sweden to carry out a Phase I clinical trial with this matrix formulation. •• Microspheres appear to be a successful alternative delivery system for a chimeric peptide containing hCG beta subunit for immunocontraception. Recent tests demonstrated that this delivery system could be manipu- lated to produce a high level of immunogenicity with minimal irritation at the injection site. •• A study to evaluate two possible treatments for the irregular vaginal bleeding patterns in Norplant users demonstrated that neither Vitamin E nor low-dose aspi- rin provided significant relief from this troublesome side- effect. •• The collaborative initiative between the Programme and The Rockefeller Foundation for basic research in implan- tation has completed its fourth year. New data obtained on structural and functional changes that occur at the site and time of implantation have been reviewed, and each centre will concentrate efforts on its most promising lead in the upcoming fifth and final year of the initiative. •• The Phase III trial of testosterone undecanoate alone as a male contraceptive was progressing according to schedule in China. This study marks the first-ever Phase III trial of a male hormonal contraceptive method. A n n u al T ec h n ic al R ep or t 2 00 2 Annual Technical Report 2002 6 A n n u al Tech n ical R ep ort 2002 Executive summary 7 Research on safety and effectiveness of contraceptives The overall objectives of research in the area of safety and efficacy of existing methods of fertility regulation are (i) to assess evidence on the safety and effectiveness of different methods of contraception among women and men with par- ticular emphasis on developing countries, and (ii) to address priority unanswered questions on existing methods of fertility regulation when used in developing countries. Selected highlights •• Research continued on the safety and effectiveness of the levonorgestrel-releasing intrauterine device and on the long-term safety and effectiveness of the TCu380A intrauterine device. •• A multicountry study was launched on the comparative clinical performance of two second-generation implant- able progestogen-only contraceptive methods, Implanon and Jadelle. •• A review on the association between cervical cancer and long-term use of combined oral contraceptives was in progress. •• Research was under way (including a review of available evidence) to assess the safety and practicality of reuse of the female condom. • Recent research has found that among women with per- sistent human papilloma virus infection, those who have used hormonal contraceptives for longer than five years are at a higher risk of developing cervical cancer com- pared with non-users. In order to put these new results in a public health perspective, a consultation was con- vened in March 2002, which recommended no changes in contraceptive prescribing practice or use since the number of cervical cancers that might result from the use of hormonal methods is likely to be very small. •• A study was started on the contraceptive effectiveness of the female condom compared with the male condom. This study is being assessed in volunteers from family planning clinics in China, Nigeria, Panama and South Africa. A total of 500 women electing to use the female condom as their method of fertility regulation will be enrolled, together with a similar number of male condom users. Promoting family planning norms and tools The overall objective of this area of work is to create evi- dence-based and consensus-driven guidance to support the provision of high-quality family planning services globally. Selected highlights •• The document Selected practice recommendations for contraceptive use—a guide for policy-makers, family planning programme managers and the scientific com- munity—was published. Whereas the previously pub- lished document Improving access to quality care in family planning: medical eligibility criteria for contracep- tive use addresses who can safely and effectively use contraceptive methods, Selected practice recommenda- tions for contraceptive use address how contraceptive methods can be used safely and effectively. The docu- ment includes guidance on common clinical issues, such as what a woman should do if she forgets to take one or more of her oral contraceptive pills. •• Initial field-testing was under way of the Decision-making tool for family planning clients and providers—an inter- active tool derived from and supported by the Improv- ing access to quality care in family planning: medical eligibility criteria for contraceptive use and the Selected practice recommendations for contraceptive use. This decision-making tool is designed for use during the client–provider family planning encounter to help both the client and the provider in choosing the most appro- priate method of family planning, including dual protec- tion for those at risk of both pregnancy and HIV/sexually transmitted infections. •• Initial planning was done to develop a handbook for family planning providers, which is intended to provide detailed information to providers on the provision of high-quality family planning services. •• A system was developed for ensuring that family plan- ning guidance is created, and maintained, on the basis of the best available evidence. This system includes a continuous and comprehensive process of identifying, critically appraising, and synthesizing new evidence as it becomes available. MAKING PREGNANCY SAFER The Making Pregnancy Safer (MPR) initiative represents WHO’s contribution to the global safe motherhood move- ment. It strives to contribute to the attainment of the United Nations Millennium Declaration targets, which include the reduction of the maternal mortality ratio by three-quarters, between 1990 and 2015, and the reduction by two-thirds of under-five mortality by 2015 through a reduction in the number of newborn deaths. The work of the Department in this area consists of: (i) conducting research to map effective interventions and to improve the quality of services (see Generating new evi- dence for maternal and perinatal health); and (ii) providing normative guidance and technical support to countries for A n n u al T ec h n ic al R ep or t 2 00 2 Annual Technical Report 2002 6 A n n u al Tech n ical R ep ort 2002 Executive summary 7 the development, implementation and evaluation of cost- effective interventions to reduce maternal and newborn mor- bidity and mortality (see Implementation of evidence-based programmes). Generating new evidence for maternal and perinatal health The objective of research in this area is to find ways of reducing maternal and perinatal morbidity and mortality by: (i) evaluating promising biomedical and public health inter- ventions; (ii) conducting systematic reviews; (iii) improving the understanding of sociocultural and economic factors that influence maternal health (e.g. studies of cost-effectiveness and quality of care); (iv) reviewing methodological issues; (v) conducting follow-up studies of the populations included in maternal and newborn research (e.g. long-term follow-up studies of babies); and (vi) mapping the magnitude of mater- nal ill-health. During 2002, the main reports of several trials were pub- lished: the evaluation of a new model for routine antenatal care, the effectiveness of oxytocin in the prevention of postpartum haemorrhage, the treatment of pre-eclampsia with magnesium sulfate, and the strategy for the reduction of unnecessary caesarean sections. Additional publications reported findings on women’s and providers’ perception of care, and the economic evaluation of interventions tested in these trials. A new project, entitled “From Research to Practice”, was initiated to facilitate the implementation of the new WHO antenatal care model and of the prevention of postpartum haemorrhage. Implementation of the new model of antenatal care was under way in Argentina, Brazil, Chile, Cuba, Ethiopia, Haiti, Italy, Oman, Pakistan, Spain, Syrian Arab Republic, Thailand and Zambia. Selected highlights •• The calcium supplementation trial for the prevention of pre-eclampsia, which was started at the beginning of 2002 and which involved over 6500 women, was near- ing completion. •• The results of the so-called “MAGPIE” trial that evalu- ated the effect of magnesium sulfate for the prevention of eclampsia among 10 141 women, showed that the use of the compound could more than halve the risk of eclampsia. This trial is expected to lead to a major change in practice. •• In order to document the magnitude of maternal ill-health in developing countries a systematic review of epidemio- logical data, that became available between 1997 and 2002, was being conducted. This unique systematic review will be completed during 2003. •• A new comprehensive collaborative research and ser- vice project entitled “Global Programme to Conquer Pre-eclampsia–Eclampsia” was launched. The initial phase of this project includes the preparation of system- atic reviews on screening for pre-eclampsia, promising etiological and pathophysiological hypotheses to be tested in future research, and treatment recommenda- tions, including recommendations to treat impaired fetal growth. Implementation of evidence-based programmes The foci of this area of work are: (i) development of a strat- egy for global action on skilled care for pregnant women; (ii) documentation of current knowledge and experience regard- ing the relationship between maternal and neonatal health and poverty; and (iii) development of a concept and strategy paper for working with individuals, families and communities for improved maternal and neonatal health. Cost–effective- ness studies are also being conducted and are expected to guide recommendations for maternal and neonatal health interventions. Selected highlights—development of tools and guidelines •• The different tools for the Integrated Management of Pregnancy and Childbirth (IMPAC) were being used in countries through worldwide distribution of the manual entitled Managing complications in pregnancy and child- birth: a guide for midwives and doctors and its transla- tion into several languages including Bahasa Indonesia, French, Laotian, Russian and Spanish. The Arabic and Chinese translations of this guide are expected to be completed in 2003. The following tools were in press: Managing newborn problems: a guide for doctors, nurses and midwives and Pregnancy, childbirth and newborn care: a guide for essential practice. Plans were under way for the adaptation and utilization of these guides in several countries. •• Other clinical and programme tools/guidelines that were being finalized for publication included (provisional titles): Standards for maternal and newborn care; Handbook for communicating and counselling for pregnancy, childbirth and newborn care; and Kangaroo mother care: a practi- cal guide. A manual on surgical obstetrics care for use at the district level was in the field-testing phase. •• A set of education tools/guidelines were also under preparation: the revised WHO midwifery education mod- ules and the Strengthening midwifery toolkit. An educa- tion and training strategy was being developed with the WHO Department of Child and Adolescent Health and Development for improving health practitioners’ perfor- mance. •• Several management tools were either under prepa- ration (Making pregnancy safer planning guide and Beyond the numbers: a tool for reviewing maternal deaths and complications), or were at the field-test- A n n u al T ec h n ic al R ep or t 2 00 2 Annual Technical Report 2002 8 A n n u al Tech n ical R ep ort 2002 Executive summary 9 ing stage (Making pregnancy safer workshop planning manual; the Health and human rights assessment tool for maternal and neonatal health; and Making pregnancy safer—essential health technology package). Selected highlights—technical support to countries •• The Department continued to help countries: (i) to strengthen their political commitment to, and strategies for, maternal and neonatal health in national health and development plans; and (ii) to review/establish national as well as regional policies and strategies in order to ensure that issues related to maternal and neonatal health are adequately addressed. •• In the area of programme development and implementa- tion, the Department contributed to the strengthening of existing maternal and neonatal health programmes in an increasing number of countries. •• Specific areas that received substantial support in 2002 included: improving provider skills in order to enhance the quality of care; introducing and adapting IMPAC norms and tools into national standards and protocols; improving reporting of maternal mortality and severe morbidity to assess provider performance and improve quality of care. •• The Department collaborated with various partners in establishing or revitalising Making Pregnancy Safer/ Safe Motherhood ministerial committees, taskforces or partners’ coordination committees at national level. •• Web pages related to the Making Pregnancy Safer initia- tive were updated and expanded and an edition of the Safe motherhood newsletter that focused on the topic of skilled attendants was published. CONTROLLING SEXUALLY TRANSMITTED AND REPRODUCTIVE TRACT INFECTIONS The key objectives of the Department in the area of sexually transmitted infections (STIs) and reproductive tract infections (RTIs) are: (i) to increase the availability of high-quality, cul- ture- and gender-sensitive and non-stigmatizing services for the prevention, care and management of STIs and RTIs and their complications; (ii) to broaden the range of safe, effective and affordable methods to prevent and manage STIs and RTIs and mother-to-child transmission (MTCT) of HIV and STIs; and (iii) to contribute to the strengthening of national health system capacity to deliver these services. Selected highlights •• Work was under way to develop a comprehensive package of guidelines and tools designed to assist programme managers to plan and implement effective and appropriate interventions to prevent, control and manage STIs and RTIs. The package includes: an STI/ RTI programme guidance tool; STI/RTI management in reproductive health care settings: a guide for essential practice; Guidelines for the management of sexually transmitted infections and a set of training modules for the management of sexually transmitted infections. •• The Department held a technical consultation involving academic institutions and the private sector to assess the increasing threat of the herpes simplex virus becom- ing a major driving force for HIV transmission. The con- sultation also reviewed the launch of new collaborative work within WHO and with external partners, which aims to accelerate the implementation of research and other strategies to prevent and control genital herpes infec- tion, thus diminishing its impact on HIV transmission. •• A protocol was finalized to study the impact of highly active antiretroviral therapies (HAART) on mother-to- child transmission (MTCT) of HIV and maternal health. This research will address key issues of acceptability, safety and effectiveness of HAART in MTCT prevention and the impact of a triple-combination antiretroviral pro- phylactic regimen on the rate of MTCT. •• As part of ongoing efforts to develop microbicides to fight STIs/HIV, the Department, in collaboration with CONRAD, is conducting a three-centre randomized double-blind Phase I study of the safety and acceptabil- ity of a 6% cellulose sulfate gel compared with placebo among healthy women volunteers in India, Nigeria and Uganda. •• Work was in progress to develop an updated global STI strategy that reflects recent national, regional and global evidence and experience in STI control and its impact on the HIV epidemic. The new strategy is expected to facilitate the dissemination, adaptation and adoption of the recommended policies and strategies for STI pre- vention, care and control. PREVENTING UNSAFE ABORTION The two main objectives of the Department’s work in this area are prevention of unsafe abortion and its consequences and assessment of the safety of current abortion procedures. To achieve these objectives, the work plan focuses on gen- erating scientifically sound evidence for providers and policy- makers in order to enable them to make informed decisions on implementing best practices and resource allocation. Projects include documentation of global and regional preva- lence rates of unsafe abortion and associated morbidity and mortality, social science research to understand better the pathways to safe and unsafe abortion, clinical trials to evalu- ate medical abortion techniques, the development of guide- lines for safe abortion, and technical support on request to countries on issues related to abortion care. A n n u al T ec h n ic al R ep or t 2 00 2 Annual Technical Report 2002 8 A n n u al Tech n ical R ep ort 2002 Executive summary 9 Selected highlights •• A document entitled Safe abortion: technical and policy guidance for health systems was completed in 2002 and sent to print. Over the next year, the document will be translated into French, Russian and Spanish, and pos- sibly Portuguese and Romanian. •• As part of the Department’s commitment to maintaining up-to-date information on unsafe abortion, new global and regional estimates of unsafe abortion were made available in 2002. The Department’s work on estimating unsafe abortion provided inputs to WHO’s work on the Global Burden of Disease 2000. •• A national conference was supported in Bucharest, Romania, in April 2002 to disseminate the findings of the 2001 Strategic Assessment on abortion in Romania. The conference included a wide range of stakeholders from across the country, who formulated a new policy requir- ing all obstetrics/gynaecology departments in the country to provide safe, high-quality abortion services, including post-abortion contraception, at an affordable price set by the Romanian Ministry of Health and Family. •• Results from a study on the pharmacokinetics of sub- lingual administration of misoprostol suggest great potential for the sublingual route to be developed into a method of medical abortion. PROMOTING SEXUAL AND REPRODUCTIVE HEALTH OF ADOLESCENTS The objective of the Department’s work on adolescent sexual and reproductive health is to generate evidence for the pro- motion of healthy sexual development and maturation and strengthening the capacity of adolescents to have equitable and responsible relationships. Activities primarily focus on supporting research and developing the evidence base on the sexual and reproductive health situation and needs of adolescents in developing countries. Related to this work are activities intended to strengthen national capacity for research in this area and dissemination of findings. Selected highlights •• Analysis of Demographic and Health Survey (DHS) data for never-married young women in Colombia and Peru showed that over the course of the 1990s, an increas- ing percentage of younger women were sexually active. While use of contraceptives, especially condoms, had increased, there had been an even greater rise in sexual activity and an increasing percentage of young, never- married women had experienced unintended pregnancy and abortion. •• Research undertaken to generate global estimates for unsafe abortion found that nearly 40% of all unsafe abor- tions occur among women aged 15–24 years. Overall, 7.3 million unsafe abortions were estimated to take place each year in this age group. •• A total of 43 studies were being supported under the social science research initiative on adolescent sexual and reproductive health; 41 were ongoing, with two new studies being initiated in 2002. Thirty-six papers report- ing on evidence accumulated through this initiative were published in national and international journals and in the proceedings of two international conferences, held in Bangkok (Thailand) and Kunming (China). •• Various research capacity strengthening activities continued for the network of investigators engaged in research on adolescents, including assistance in devel- oping papers for presentation at conferences and for submission to journals. •• Core instruments developed for the study of adoles- cent sexual risk behaviours (focus-group discussion guidelines, in-depth interview guides and a survey ques- tionnaire) and an annotated bibliography of relevant materials were provided to a large number of research- ers working in this area. These instruments and a related bibliography were also published on the Department’s web site. •• Research was under way to investigate: the extent to which hormonal contraception depresses peak bone mass achieved among adolescents, thus placing them at greater risk of osteoporosis in later life; factors under- lying reports of unusually high levels of lower genital tract infection among pre-adolescents in Mongolia; and the reproductive health needs of young migrants in the Greater Mekong region. GENDER AND REPRODUCTIVE RIGHTS IN REPRODUCTIVE HEALTH The Department’s objectives in this area are: to develop and evaluate strategies and mechanisms for promoting gender equality and human rights in reproductive health research, programming and technical support; to support countries to ensure that reproductive health programmes and policies respect, protect and fulfil human rights and promote gender equity and equality; and to ensure that the promotion of gender equity and equality and human rights principles are integrated into the Department’s work. Selected highlights •• The Department published the CD-ROM version of a document entitled Transforming health systems: gender and rights in reproductive health—a three-week training curriculum in gender and rights in reproductive health for health managers—and made arrangements for transla- tion of the English document into Chinese and Spanish. A n n u al T ec h n ic al R ep or t 2 00 2 Annual Technical Report 2002 10 A n n u al Tech n ical R ep ort 2002 Executive summary 11 •• A three-day training of trainers workshop was conducted on the rights module from the above curriculum in order to provide additional training to the five regional centres (in Argentina, Australia, China, Kenya and South Africa) that are already running the full course. The aim was to train experienced trainers in running a two- to three-day module on human rights and reproductive health within their region. •• The Department provided to United Nations Treaty Bodies sexual and reproductive health data for a number of countries that were required to report to the Treaty Bodies in 2002 about their adherence to various rights-related international treaties. The main purpose of the United Nations treaty monitoring system is to encourage governments to comply more fully with their legally-binding obligations to respect, protect, and fulfil the human rights enshrined in the various treaties. The Department’s concern is to ensure that key sexual and reproductive problems, such as maternal mortality, are included in the monitoring of States’ efforts to protect the rights of their citizens. •• The Department is developing a tool to help govern- ments to become more accountable for their interna- tional commitments—among others, to international human rights treaties, conventions and consensus document targets—to promote and protect their citizens’ rights to maternal and neonatal health care. A study was commissioned to validate the internal consistency of this tool. •• A Technical Consultation on Sexual Health was held, which resulted in the formulation of new definitions of sex, sexuality, sexual health and sexual rights for the field. • Two reviews were commissioned on Integration of sexual health into reproductive health services: needs, evidence and implications (Royal Tropical Institute of the Netherlands, Amsterdam, Netherlands), and Searching for sex: a systematic literature review of international research related to sexuality and sexual behaviour (La Trobe University, Melbourne, Australia). TECHNICAL COOPERATION WITH COUNTRIES The main objective of the Department in its technical coop- eration with countries is to assist countries to enhance their capacity to develop and implement national and regional research and programme activities aimed at improving reproductive health. Specifically, the aims are: (i) to assist developing countries with the identification of areas where research is required to address reproductive health needs; (ii) to support national planning and programming including the introduction of reproductive health technologies and the adaptation and application of practice guidelines essential for improving reproductive health; (iii) to provide assistance to developing countries to strengthen their capacity to under- take research, and to disseminate and apply results of repro- ductive health research; and (iv) to collaborate with countries in the monitoring of effects of policies and initiatives related to health sector reforms in reproductive health programmes and outcomes. Overview •• Nineteen Long-term Institutional Development (LID) grants and eight Resource Maintenance Grants (RMGs) were awarded to the network of collaborating research institutions. Research Training Grants (RTGs) were also awarded to 27 scientists from these institutions, most of whom received their training within their respective regions. • With support from HRP and from national and interna- tional sources, up to 204 research projects were ongoing in the above institutions in 2002, and findings from a total of 730 research articles were published and/or dissemi- nated through presentations during the year. The WHO Regions of Africa and the Eastern Mediterranean The main objective of the Department in the WHO Regions of Africa and the Eastern Mediterranean is to build and develop the research capacity of institutions in order to enhance their potential to implement reproductive health research relevant to national and regional needs, and to facilitate their partici- pation in the global research effort. In 2001–2002, the Department collaborated with 37 institu- tions or research groups in 24 countries of the two regions. Six institutions in these countries received Long-term Institutional Development (LID) grants and three received Resource Maintenance Grants (RMGs), while 17 were awarded small grants for library support and the purchase of consumable laboratory supplies. Three centres were partici- pating in regional research projects. Selected highlights •• A call for proposals on sociocultural aspects of female genital mutilation (FGM) yielded many concept propos- als; several of these were selected for further develop- ment. •• In 2001 (most recent year for which complete data are available), 72 studies were carried out by the nine cen- tres receiving LID grants or RMGs. Of these projects, 13% received financial support from the Programme, while 51% received support from other international agencies. The highest number of projects concerned maternal health, followed by family planning and HIV/ AIDS. A n n u al T ec h n ic al R ep or t 2 00 2 Annual Technical Report 2002 10 A n n u al Tech n ical R ep ort 2002 Executive summary 11 •• The nine centres receiving a LID grant or RMG pub- lished 57 papers in national and international journals, and staff of these centres served in 53 different advisory roles at national, regional and international levels. •• Ten staff members from these nine centres attended courses outside their home countries and six research- ers received a Research Training Grant (RTG). •• Workshops and short courses were organized on sev- eral themes: research methodology, semenology, and ethical issues in reproductive health research. The WHO Region of the Americas The Department collaborated with eight institutions in the Region of the Americas which are implementing a large number of research projects on topics relevant to regional and national reproductive health problems. Ongoing projects supported by Long-term Institutional Development (LID) grants include basic science work in the area of male fer- tility, an assessment to identify priority interventions that would improve access to and quality of family planning and of maternal and neonatal health care, and social science research in the area of male involvement in reproductive health. Selected highlights •• During 2001 (most recent year for which complete data are available), from the overall number of 106 projects, four were implemented with support from the Programme’s capacity building grants, 51 with support from national sources (48%), 21 (20%) were supported by the specific work areas of the Department, and 30 (28%) were funded by international agencies other than WHO. •• Ten staff from regional centres underwent training out- side their home countries and the eight centres receiving research capacity strengthening support trained in turn 112 professionals and technical staff from other local institutions. Thirty-one fellows participated in formal courses and 653 attended short, group-learning activi- ties, such as seminars and workshops organized by the centres. •• During 2001, a total number of 143 research articles (128 original papers and 15 review articles) were pub- lished and 34 books and book chapters were authored by staff from the centres receiving research capacity strengthening support. •• In an effort to enhance the dissemination and utilization of research findings, two national workshops—attended by researchers, policy-makers and other stakeholders—were organized in Argentina and in Peru to disseminate research findings and discuss the policy implications for programmes and services. A regional workshop was convened in coordina- tion with the FRONTIERS Program of the Population Council to bring together researchers and policy-makers to discuss barriers and facilitators to the process of utilization of research findings. •• Steps were taken to strenghten the coordination with the WHO Regional Office for the Americas: during 2002, eight joint missions were undertaken to participate in site visits or in meetings held in various countries of the region. The WHO Regions of South-East Asia and Western Pacific The primary strategic objectives of the Department in supporting developing countries in the WHO Regions of South-East Asia and the Western Pacific are to assist the countries of the regions: (i) to identify their needs in national reproductive health policies and programmes for improving reproductive health, and in areas where research is required to address these needs; (ii) to build their own capacity to plan, implement, monitor and evaluate such programmes and policies and to participate in national, regional and global research in accordance with the highest scientific and ethical standards; (iii) to disseminate and apply the results of repro- ductive health research and to adopt, adapt and implement new updated norms, standards, tools and approaches; and (iv) to develop appropriate strategic approaches to improv- ing the quality of reproductive health services. Through such support, the countries will ultimately develop and sustain their ability to address a broad range of reproductive health research and service-related areas, and to establish and strengthen an enabling national reproductive health research system and research culture. Continued development of rel- evant skills for enhancing national leadership, priority-set- ting, advocacy, communication, networking, negotiation, use of research results and partnerships is an integral part of the process. Selected highlights •• The Programme continued to provide institution-based support in nine countries through award of seven Long- term Institutional Development (LID) grants and four Resource Maintenance Grants (RMGs). •• Three new Research Training Grants (RTGs) were awarded to scientists from China (2) and Mongolia (1), one of whom will be trained within the region. •• Two regional joint research programmes involving most of the recipients of LID grants were in the process of being implemented. A n n u al T ec h n ic al R ep or t 2 00 2 Annual Technical Report 2002 12 A n n u al Tech n ical R ep ort 2002 Executive summary 13 The WHO Region of Europe, including Central and Eastern Europe, the Newly Independent States and Central Asian Republics The main objectives of the Department in the WHO Euro- pean Region are: (i) to strengthen national capacity in repro- ductive health research, with a particular focus on providing training opportunities for scientists in the countries of Cen- tral and Eastern Europe, the Newly Independent States and Central Asian Republics; and (ii) to assist the WHO Regional Office for Europe (EURO) in providing technical support to countries to implement their programmes in reproductive health. Selected highlights •• The second meeting of the European Regional Advisory Panel (RAP), was held at The Netherlands School of Public Health, Utrecht, Netherlands, on 29–30 May 2002. •• The Programme continued to provide support to the former participants in the first WHO/FRONTIERS course on operations research to help them to implement their research proposals. •• Continued technical support was provided for coun- try adoption and adaptation of WHO evidence-based policies and standards for maternal and newborn care. Clinical guidelines on evidence-based medicine and appropriate use of technologies were issued, targeting specific categories of health care providers and were used in Kazakhstan, Republic of Moldova, Turkmeni- stan, and Uzbekistan. •• Support was provided to a retrospective study that is reviewing some examples of interventions that had an influence on the reduction of maternal mortality in Europe. The report on this study will be available in 2003. •• Preparatory steps were undertaken for the second WHO/FRONTIERS course on operations research to be held at the Kazakhstan School of Public Health, Almaty, Kazakhstan, in April 2003, for Russian-speaking scien- tists. •• Technical support was provided to the postgraduate course on reproductive medicine and reproductive biology, organized annually by the WHO Collaborating Centre, University of Geneva, Geneva, Switzerland. Policy and programme issues The Department’s objectives in this area are to review, develop and test methodologies to assist countries in the planning and implementation of reproductive health services. Central to this work are the testing, refinement and promo- tion of the Strategic Approach1 to improving the quality of care of reproductive health services. Selected highlights •• Dissemination of the Strategic Approach in 2002 included the implementation of regional training work- shops in Africa and Asia. A field guide for implementing strategic assessments was published, as was as a docu- ment providing an overview of the Strategic Approach and summarizing experiences with its implementation in 18 countries. •• The Strategic Approach continued to be adapted for strategic planning in a range of areas of reproductive health: for example, in Bolivia, the approach was used to address issues related to cervical cancer screening and treatment; and in Yunnan, China, an assessment was made of comprehensive, integrated reproductive health services, with emphasis on access and utilization of services by the poor. In Romania and Viet Nam, inter- ventions recommended in prior assessments of issues related to abortion are currently being tested. •• Stage II activities were ongoing in China, Ethiopia, Myanmar and Viet Nam. Scaling-up of tested interven- tions was under way in Stage III activities in Bolivia, Brazil, Viet Nam and Zambia. •• An initiative examining the impact of health sector reforms on reproductive health services and outcomes began with development and implementation by the World Bank Institute of a course on this topic for Departmental, regional office and country office staff. The Department also collaborated with the South African Women’s Health Project on their “Sexual rights and reforms” project, con- ducting regional and global literature reviews of existing knowledge concerning the relationships between health reforms and reproductive health. MONITORING AND EVALUATION Monitoring and evaluation activities aim: (i) to map maternal and newborn morbidities and mortality in a comprehensive and systematic manner; and (ii) to develop tools to facilitate 1The Strategic Approach is a three-stage process to assist national- level decision-making to improve the quality of care of reproductive health service. Stage I strategic assessments examine users’ needs and perspectives, the available technologies and services, and the capacity of the service delivery system, so as to determine appro- priate strategies for improving the quality of care. Stage II involves action research to design and test optimal models for introducing or re-introducing technologies or services. Stage III uses research results and lessons learned in Stage II for policy and programme development and the scaling-up of activities. A n n u al T ec h n ic al R ep or t 2 00 2 Annual Technical Report 2002 12 A n n u al Tech n ical R ep ort 2002 Executive summary 13 the collection and distribution of data on indicators to monitor progress towards the achievement of the Millennium Devel- opment Goals (MDGs) for improving maternal health. Selected highlights •• Substantial progress was made in the systematic review of epidemiological evidence on maternal morbid condi- tions and mortality. The methodological challenges of summarizing data from observational studies have been discussed within a methodology working group. Over 9000 published and unpublished reports from 1997 were evaluated for possible inclusion in the review, and data were extracted from 417 that fulfilled the inclusion crite- ria. It is expected that for the entire period 1997–2002, evaluation of around 60 000 reports will result in the inclusion of approximately 3000 articles in this unique systematic review, which will be completed in mid-2003. This is the first ever systematic attempt to map the situ- ation of a group of medical conditions with data. •• The global, regional and subregional estimates of the proportions of births attended by a skilled health worker were updated and published on the Department’s web site. •• A systematic review to estimate the prevalence, asso- ciated factors and consequences of genital organ pro- lapse was initiated, and the first draft was completed. •• An analysis of levels, trends and differentials of ante- natal care in developing countries using data from the Demographic Health Surveys (DHS), the Multiple Indi- cator Cluster Surveys (MICS) and the Pan Arab Proj- ect for Child Development (PAPCHILD) surveys from 1990–2001 was completed. •• A database of reproductive health indicators to provide up-to-date information at the national, regional and global levels of the 17 reproductive health indicators short-listed for global monitoring was under develop- ment and will be published on the Department’s web site in early 2003. IMPLEMENTING BEST PRACTICES The Department is the leading institution in the efforts to map best reproductive health practices and to develop a strategic approach that helps developing country health profession- als to capture, adapt according to their needs and apply best practices. The activities of the Department in this area include primary research, research synthesis, dissemination and capacity strengthening in evidence-based decision- making worldwide. Selected highlights •• The randomized controlled trial of an active dissemina- tion strategy for evidence-based reproductive health information using The WHO Reproductive Health Library (RHL) was ongoing in 40 hospitals in Mexico and Thai- land. The intervention has been completed and data col- lection on clinical outcome was under way. A qualitative research component evaluating the experiences of staff was being developed. •• Eight new Cochrane reviews and three Cochrane review protocols were published. Nine systematic reviews were updated. Six systematic reviews were under way. •• Subscriptions to RHL exceeded 12 000 in 2002 and a total of 29 000 copies in English and Spanish were dis- tributed. Work was progressing on the Chinese transla- tion of RHL, which is expected to be published in 2003. •• RHL editors and scientists from partner institutions con- ducted more than 100 RHL presentations or workshops worldwide. •• The training initiative developed jointly with the WHO Regional Office for Africa and the South African Cochrane Centre was pilot-tested and the first workshop was held in South Africa. Implementing Best Practices (IBP) Initiative The Department is leading the development of a programme to support the adaptation and application of best practices, known as the Implementing Best Practices (IBP) Initiative. This collaborative partnership aims to use innovative strategies to support the transfer of knowledge, harmonize approaches and reduce duplication of efforts at country level in order to help health care professionals access and apply the latest research and best practices in reproductive health. Selected highlights •• All 17 partners have agreed to sign a Memorandum of Understanding to form the Implementing Best Practice Consortium. The Department will act as the Secretariat for the first two years of operation. •• The IBP Initiative continued to attract more members in 2002, including two country-based nongovernmental organizations. •• In collaboration with the WHO Regional Office for the Eastern Mediterranean Region the IBP Initiative was introduced to seven country teams from Egypt, Jordan, Lebanon, Pakistan, Palestine, Turkey and Yemen at a meeting held in Cairo, Egypt, in 2002. The country teams A n n u al T ec h n ic al R ep or t 2 00 2 Annual Technical Report 2002 14 A n n u al Tech n ical R ep ort 2002 Executive summary 15 have initiated action to implement the plans they agreed to during this meeting and IBP partners are providing a programme of supportive follow-up. COMMUNICATION, ADVOCACY AND DISSEMINATION OF INFORMATION Through this area of work, the Department seeks to facilitate access to reproductive health knowledge within and outside the Department. Selected highlights •• A total of 23 information products were issued. •• The Department’s annual technical report for 2001 and two biennial reports for 2000–2001 were published in electronic format on an elegantly designed, interactive CD-ROM. •• Issue No. 5 of The WHO Reproductive Health Library was issued and widely distributed. •• The Department’s web site continued to grow and, in December 2002, housed some 3300 pages. •• In a workshop in Mumbai, India, 20 scientists were trained in how to write good scientific research articles. •• Twenty senior faculty members of a collaborating insti- tute in India were trained in teaching scientific writing. •• Twenty-two physicians were trained in communication skills in a workshop in Malaysia. CLINICAL TRIALS AND INFORMATICS SUPPORT This area of work relates to the provision of statistical and data-processing support for all multicentre and some single- centre research projects undertaken by the Programme. It also provides support to research capability strengthening in the formulation and execution of institution strengthening policies in biostatistics and data processing. Informatics sup- port is also provided to the administration and management area of the Department. Selected highlights •• Statistical data and entry support was provided to 68 single and multicentre projects. •• Work continued on the editing of Standard Operating Procedures drafted for implementation of the WHO Good Clinical Practice guidelines in all of the Programme’s research activities. •• Work was ongoing on methodological research on statis- tical issues related to cluster randomization trials and on the meta-analysis of observational studies. • The statistical and data-processing capabilities of selected collaborating institutions were strengthened. A n n u al T ec h n ic al R ep or t 2 00 2 Annual Technical Report 2002 14 A n n u al Tech n ical R ep ort 2002 Executive summary 15 Annex 1 SCIENTIFIC AND TECHNICAL ADVISORY GROUP IN 2002 Members Lawrence Adeokun, Association for Reproductive and Family Health, Ibadan, Nigeria Yagob Y. Al-Mazrou, Assistant Deputy Minister, Ministry of Health, Riyadh, Saudi Arabia Robert W. Blum, University of Minnesota, Minneapolis, MN, USA John Cleland, London School of Hygiene and Tropical Medicine, University of London, London, United Kingdom Jock Findlay, Prince Henry’s Institute of Medical Research, Clayton, Australia (Chairman) Catherine Hankins, McGill University AIDS Center, Montreal, Canada Barbara Hulka, University of North Carolina, Chapel Hill, NC, USA (Vice-chairperson) Angela Kamara, Regional Prevention of Maternal Mortality Programme, Accra, Ghana Hoda Rashad, The American University in Cairo, Cairo, Egypt Reijo Vihko, The Academy of Finland, Helsinki, Finland Xiao Shaobo, State Family Planning Commission, Beijing, China Developing countries Countries in transition Developed countries Totals Number % of total Number % of total Number % of total Members 5 45 6 55 11 Women 2 18 2 18 4 from: AFRO 2 18 2 AMRO 3 27 3 EMRO 2 18 2 EURO 2 18 2 SEARO WPRO 1 9 1 9 2 A n n u al T ec h n ic al R ep or t 2 00 2 Annual Technical Report 2002 16 A n n u al Tech n ical R ep ort 2002 Executive summary 17 Annex 2 SCIENTIFIC AND ETHICAL REVIEW GROUP PANEL IN 2002 Gordon Ada, John Curtin School of Medical Research, Canberra, Australia Abdul-Aziz Al Meshari, King Saud University, Riyadh, Saudi Arabia Karen Beattie, EngenderHealth, New York, NY, USA Chai Podhisita, Institute for Population and Social Research, Nakorn Prathom, Thailand Jean Cohen, Paris, France Rebecca Cook, University of Toronto, Toronto, Canada Ian Diamond, University of Southampton, Southampton, United Kingdom Dwip Kitayaporn, Mahidol University, Bangkok, Thailand Murdoch Elder, Biggar, Lanarkshire, United Kingdom Andrea Genazzani, Institute of Obstetrics and Gynaecology, Modena, Italy Ron Gray, Johns Hopkins University, Baltimore, MD, USA Kerstin Hagenfeldt, Karolinska Hospital, Stockholm, Sweden (Chairwoman) Tim Hargreave, Western General Hospital, Edinburgh, United Kingdom Korrie de Koning, Royal Tropical Institute, Amsterdam, the Netherlands Fernando Larrea, National Institute of Nutrition, Mexico City, Mexico Ruth Macklin, Albert Einstein College of Medicine, Bronx, NY, USA Manee Piya-Anant, Siriraj Hospital, Bangkok, Thailand Oscar Mateo de Acosta, National Institute of Endocrinology, Havana, Cuba Marvellous Mhloyi, Population Studies Center, Harare, Zimbabwe Yuji Murata, Osaka University Medical School, Osaka, Japan Ngeow Yun Fong, University of Malaya, Kuala Lumpur, Malaysia Charles Ngwena, Centre for Health Systems Research and Development, University of the Free State, Bloemfontein, South Africa Edith Pantelides, Population Studies Centre, Buenos Aires, Argentina Kazuo Satoh, Nihon University School of Medicine, Tokyo, Japan Jack Sciarra, Northwestern University Medical School, Chicago, IL, USA Carmel Shalev, The Gertner Institute for Health Policy, Tel Hashomer, Israel Carlos Simon, Institute of Infertility, Valencia University, Valencia, Spain Sonia Tabacova, National Centre of Hygiene, Ecology and Nutrition, Sofia, Bulgaria Godfrey B. Tangwa, University of Yaoundé I, Yaoundé, Cameroon Zhao Baige, State Family Planning Commission, Beijing, China Developing countries Countries in transition Developed countries Totals Number % of total Number % of total Number % of total Members 13 43 1 3 16 53 30 Women 6 20 1 3 5 17 12 from: AFRO 3 10 3 AMRO 3 10 5 17 8 EMRO 1 3 1 EURO 1 3 1 3 8 27 10 SEARO 3 10 3 WPRO 2 7 3 10 5 A n n u al T ec h n ic al R ep or t 2 00 2 Annual Technical Report 2002 16 A n n u al Tech n ical R ep ort 2002 Executive summary 17 Annex 3 TOXICOLOGY PANEL IN 2002 Colin L. Berry, The London Hospital Medical College, London, United Kingdom Ranjit R. Chaudhury, National Institute of Immunology, New Delhi, India Ralph Heywood, The Larches, The Lanes, Huntingdon, United Kingdom Alex Jordan, Division of Reproductive and Urologic Drug Products, Food and Drug Administration, Rockville, MD, USA Shirley Price, University of Surrey, Guildford, United Kingdom Sonia Tabacova, National Centre of Hygiene, Ecology and Nutrition, Sofia, Bulgaria Developing countries Countries in transition Developed countries Totals Number % of total Number % of total Number % of total Members 1 17 1 17 4 67 6 Women 1 17 1 17 2 from: AFRO AMRO 1 17 1 EMRO EURO 1 17 3 50 4 SEARO 1 17 1 WPRO A n n u al T ec h n ic al R ep or t 2 00 2 Annual Technical Report 2002 18 A n n u al Tech n ical R ep ort 2002 19 A n n u al T ec h n ic al R ep or t 2 00 2 Annual Technical Report 2002 18 A n n u al Tech n ical R ep ort 2002 19 Section 1 Promoting family planning A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 20 A n n u al Tech n ical R ep ort 2002 Users’ perspectives in the context of reproductive health 21 Users’ perspectives in the context of reproductive health I.H. Shah and I.K. Warriner INTRODUCTION As part of the global effort to achieve improved levels of reproductive health through informed policies, programmes and services, understanding men’s and women’s reproduc- tive health needs and preferences as well as the constraints to the use of services has become increasingly important. The perspectives and needs of users are shaped by their interactions with providers, the available reproductive health services and supplies, and their assessment of the dual risks of unwanted pregnancy and sexually transmitted infections (STIs). Their reproductive health behaviour, including con- traceptive practice, and the acceptability of various methods, are also influenced by the quality of the care they receive, their perceptions and attitudes and the sociocultural context of these services. The primary objective of the Department’s work in this area is to understand better men’s and women’s behaviours and perspectives as users or potential users of reproductive health services and emerging or currently available fertility regulating methods. The second objective is to understand the constraints and sociocultural contexts that influence users’ practices, behaviours and perspectives. The third objective is to address neglected aspects of quality of care that have an important bearing on the access to and use of reproductive health services. Findings on users’ perspec- tives provide policy-makers and programme managers with evidence-based recommendations for improving care. The findings also indicate the acceptability of reproductive health services and technologies for both users and potential users while identifying the unmet needs of clients. The Depart- ment’s work also covers selected issues related to infertility, which is an integral, but often neglected, aspect of reproduc- tive health. RESEARCH ACTIVITIES Specific objectives of research Research on users’ perspectives aims to understand better men’s and women’s reproductive health decision-making, and their needs for and perspectives on reproductive health technologies and services. Projects focus on various aspects of users’ perspectives, some of which are supported under a social science research initiative on quality of care. Progress Family planning in the era of HIV/AIDS In a pioneering attempt to assess the interactions between family planning and risk behaviour related to HIV/AIDS, a multicountry research project has been ongoing in six east- ern and southern African countries where the HIV epidemic is most severe: Kenya, South Africa, Uganda, United Republic of Tanzania, Zambia and Zimbabwe. The project is designed to address three main objectives: (i) to determine the per- spectives of sexually active individuals on the dual risks of STIs (including HIV/AIDS) and unintended pregnancy; (ii) to develop strategies that sexually active individuals would con- sider appropriate, practical and effective in coping with these risks; and (iii) to explore opportunities for and constraints to behavioural change. An analysis workshop with country investigators was held in Nairobi, Kenya, on 3–8 March 2002, jointly sponsored by the African Population and Health Research Centre, Nairobi, Kenya. The main objectives of the workshop were: (i) to review results from the study; (ii) to plan and initiate further analysis and write-up; and (iii) to develop plans for dissemi- nation and further work. A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 20 A n n u al Tech n ical R ep ort 2002 Users’ perspectives in the context of reproductive health 21 The workshop consisted of a series of focused discussions, individual presentations, and individual work with investiga- tors and resource persons. Discussions focused on issues associated with the questionnaire, defining concepts from items measured in the questionnaire, and addressing ways to integrate findings from the qualitative data into overall find- ings. Drafts of research papers were developed, based on interpretations of preliminary findings and their programmatic implications. Investigators submitted papers to an upcoming International Union for the Scientific Study of Population (IUSSP) conference, Taking Stock of the Condom in the Era of HIV/AIDS, to be held in Gaborone, Botswana, in July 2003. Findings from the Kenyan component of the study were presented at the XIV International AIDS Conference held in Barcelona, Spain, in July 2002. The data were collected during 1998–2000 from sexually active individuals in Nakuru district, Kenya. Four male and eight female focus group dis- cussions (FGDs), were conducted, and a household survey consisting of a structured questionnaire was administered to couples comprising 1422 male and female respondents in total (743 men and 679 women; the partners of 64 men could not be interviewed). In-depth interviews were held with 40 survey respondents selected for their high risk behaviours. Findings confirm that HIV/AIDS is perceived as a very seri- ous community problem. “It is a big problem because almost every month we bury someone who died of AIDS. That means that AIDS cases have really increased in this area” (male, rural). “HIV/AIDS is a very serious problem in this area. You are aware that there are many soldiers here as well as women who are not married. In such a situation, there is no control over sex, and this results in the high spread of AIDS” (male, married, rural). Nonetheless, participants in the study felt their own risk of contracting HIV to be low. Figure 1.1 presents data on study participants’ own assessment of their risk of contracting HIV/ AIDS. Less than 10% felt that their risk was high and approxi- mately 40% of sexually active individuals felt that they were at no risk of contracting the disease. Although the majority of participants were aware that condom use prevents the spread of HIV/AIDS, condom use was low. Only one in three who had casual sexual partners reported using the condom. The study concluded that HIV/AIDS is perceived to be highly prevalent and to be a serious problem in the study commu- nity. Paradoxically, personal risk of HIV is perceived to be low or non-existent. Individuals recommend condom use to prevent HIV in the community but nevertheless engage in risky sexual behaviour without using condoms themselves. Condom use in long-term relationships is perceived to imply a lack of mutual trust. Improving family planning services to reduce unwanted pregnancies Findings from a Chinese study on ways to provide better family planning services in order to improve contraceptive use-effectiveness, and to reduce unwanted pregnancies and induced abortion, were made available in 2002. The back- ground to the study is as follows. In 1993, the Chinese State Family Planning Commission initiated an “informed choice” programme to upgrade quality of care and respond to users’ needs and demands. In 1995, the Jiangsu Family Planning Figure 1.1. Perceived level of personal risk of HIV infection among respondents in Kenya, by sex P er ce nt ag e of re sp on de nt s Male Female Total High Medium Low None 50 40 30 20 10 0 10 10 44 36 6 14 34 46 8 11 40 41 A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 22 A n n u al Tech n ical R ep ort 2002 Users’ perspectives in the context of reproductive health 23 Commission conducted a pilot intervention to improve and integrate family planning services with reproductive health care for clients. Four villages in Jiangsu Province were selected to receive the intervention and four comparable vil- lages were selected as controls. About 1000 eligible women in each of the intervention villages and control villages were interviewed in 1993. A follow-up survey was conducted in 1998. As part of the project, providers were given intensive training in examinations, conducting regular follow-ups and in reproductive health knowledge. Service settings and equip- ment were upgraded and facilities were equipped with televi- sions, videotapes, handbooks, computers, etc. Clients were provided with tools for informed decision-making, were given information about the proper use of contraceptives, and were provided with a greater choice of modern methods. Findings demonstrated that, compared to the control villages, women in the intervention villages had a higher percentage of IUD use (78% vs. 65%), and more women shifted from tra- ditional to more effective methods during the experiment. A higher percentage of women chose their contraceptive meth- ods by informed choice compared to the control group (19% vs. 2%) and there was a higher continuation rate of contra- ceptive use over 60 months (75% vs. 61%). Furthermore, a much lower percentage of women in the intervention group who already had one child had an induced abortion (11% vs. 22%) as a result of lower contraceptive failure and unwanted pregnancy during the experiment. The same model for improving quality of services could be duplicated in other areas. The paper was presented at the Sixth Asia-Pacific Social Sciences and Medicine Conference (APSSAM), in Kunming, China, on 14–18 October 2002. Understanding women’s status and condom use Findings from a study on “Culture, Gender, Sexual Behav- iours and STI/AIDS” conducted in central and west Cam- eroon among 1679 men and women aged 15–49 years will be published in the next issue of International Family Planning Perspectives. The study compared sexual risk behaviours from two very different ethnic groups, the Beti, where relatively permissive sexual norms prevail in society, and the Bamileke, where more conservative mores prevail. Multivariate logistic regression models were used to analyse the effects of women’s, men’s, and couples’ education levels on condom use initiated by women, and the effects of inter- spousal communication on condom use. In both populations, analyses demonstrate that the probability of condom use increases with men’s and women’s educational levels. Other factors significantly associated with greater condom use among women include: a smaller age gap between women and their partners; increased frequency of discussion about sexual matters; and increased women’s decision-making power within couples. Interestingly, pregnancy prevention was reported as the most common (72%–82%) reason for the use of the condom by both men and women in the two ethnic groups. In spite of the major differences in sexual norms and cultural mores, attitudes toward condom use and sexual behaviours in the two ethnic groups were broadly similar. These and other findings on the relationship between women’s status and condom use are noted as being critically important for the development of effective AIDS prevention programmes, irrespective of the ethnicity of the population. Improving knowledge of STIs and condom use Further findings from a study on sexual behaviour and condom use in China became available in 2002. The study examined the effectiveness of a video-based reproductive health education intervention in increasing knowledge of STIs and condom use, and in improving attitudes towards condom use among 2266 male STI clients attending a large STI clinic in Shanghai from May to December 1998. Study participants were randomly assigned to one of three groups: (i) regular treatment (control group); (ii) regular treatment and video viewing; and (iii) regular treatment, video view- ing, and participating in a discussion group facilitated by a physician. Data on knowledge of STIs and attitudes toward condom use were collected at baseline and at 2 to 3 weeks following the intervention. Results showed a very significant relationship between higher scores and participating in either the video group or the video and discussion group. The findings indicate that video-based interventions have a significant impact on clients’ knowledge of STIs and favourable attitudes toward condom use. Video viewing is an inexpensive, feasible and practical approach to education about STIs and condom use, and shows promise for integration into different STI clinic settings. Social science research initiative on quality of care In 2000, a research initiative on quality of care was launched, focusing on supporting research that seeks to assess the quality of reproductive health services from the perspec- tives of clients, potential clients, providers, and/or objective standards of care. Additionally, the initiative sought propos- als designed to assess the effects of improved service quality on intermediate outcomes (e.g. provider behaviour, client knowledge, client satisfaction, or client behaviour with regard to the continuation of contraceptive use). Research that explores quality of care in such relatively under-studied areas of reproductive health as maternal health, providers’ perspectives, abortion or STI treatment, was especially encouraged. Ongoing studies include: (i) the quality of maternal care in Turkey; (ii) provider perspectives on family planning quality of care in Egypt, Peru, and Uganda; (iii) barriers to con- traceptive access in Mali and Senegal; and (iv) improving quality of care in STI clinics in Shanghai, China. Results are expected in 2003–2004. A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 22 A n n u al Tech n ical R ep ort 2002 Users’ perspectives in the context of reproductive health 23 New projects initiated during the year Quality of care One new project on quality of care was approved from 13 submissions that were reviewed during 2002. A number of variables affect the quality of reproductive health services. The main objective of this newly approved Argentinian study is to evaluate the quality of family planning care in three hospitals in Buenos Aires by comparing, among other factors, the experiences of both Argentinian and foreign women. Specific objectives include: (i) defining users’ expec- tations and evaluations of reproductive health services; (ii) assessing the quality of care using the Quick Investigation of Quality (QIQ) method; and (iii) developing new indicators of quality of care as appropriate. The study will use several methodologies. In-depth interviews and structured interviews using the QIQ method will be conducted with 90 clients, 30 per facility, half of whom are migrants. Fifteen providers, including doctors, nurses, and administrative personnel, will also be interviewed. In addition, non-participant observation of the three study sites will be conducted to assess facility conditions, adequacy of supplies, etc. Social science policy briefs and dissemination of findings The series of Social science research policy briefs, launched in 1999 by the Programme, continued in 2002. The briefs are intended to highlight the policy relevance and programmatic impact of social science research and to build the analytical capacity and technical writing skills of in-country investiga- tors through extensive collaboration during the development of these publications. A brief on the reproductive health information and service needs of young female migrants in China was produced in 2002. The brief is based on a study that investigated the knowledge, attitude, and practice of young female migrants to five large Chinese cities (Reproductive Health Matters, 2001, 9:118–127). The methodology was entirely qualita- tive: 22 focus group discussions and 58 in-depth interviews were conducted with young migrant women. In addition, key informant interviews were conducted with 16 health providers and personnel from floating-population management offices. Major findings suggest that premarital sex is no longer taboo in the study population and that norms and behaviours are changing; nonetheless, self-reporting of premarital sexual experience is relatively uncommon. Knowledge about con- traceptives among female migrants is low, as is method use. Consequently, unwanted pregnancy and induced abortion are not uncommon among the sexually active. Policy recom- mendations include the need to make reproductive health information and services in urban areas accessible to young migrant workers. Registration offices could provide young migrants with information about family planning methods and services, and employers of migrants could distribute pamphlets produced by the local government family planning and health departments. Finally, urban family planning work- ers could visit workplaces where large numbers of migrants are employed to offer reproductive health information and services. Infertility and childlessness in developing countries In collaboration with Opinion Research Cooperation (ORC) Macro, work has been undertaken on a comparative report on “Infecundity, infertility and childlessness in less developed countries”. Demographic and Health Surveys data from nationally representative surveys conducted in 1995–2000 in 47 developing countries were analysed. Data were collected from 495 000 women between the ages of 15 and 49 years. Topics covered in the analyses included the level of child- lessness, primary involuntary infertility, self-reported infecun- dity, secondary involuntary infertility, secondary infecundity, and differentials and trends in childlessness and infertility. Overall, 2.5% of couples in the developing world, excluding China, were estimated to experience primary involuntary infertility. Important regional, socioeconomic, and demo- graphic differentials were noted. Results were presented at the Second Global Conference on Infertility in the Third Mil- lennium: Implications for the Individual, Family and Society, held in Prague, Czech Republic, on 16–17 November 2002. The report is expected to be issued by mid-2003. Future work plans In the coming years, the work on users’ perspectives will focus on four major activities. First, the results from the mul- ticountry study on “Pregnancy prevention in the era of HIV/ STIs” will be summarized and disseminated. Country papers from the study will be presented at the upcoming IUSSP con- ference, Taking Stock of the Condom in the Era of HIV/AIDS, to be held in Gaborone, Botswana, in July 2003. A report with comparative results and policy implications will be completed for publication and dissemination. Second, in collaboration with staff of the University of London School of Hygiene and Tropical Medicine, London, United Kingdom, a compendium will be developed to provide com- parative information on contraceptive use, continuation and switching in developing countries. This compendium will also provide information on such key aspects as unmet need, unwanted fertility, postpartum contraceptive protection, and antecedents of sterilization. Third, research proposals on quality of care and on users’ perspectives on reproductive health services and technolo- gies will continue to be considered for support. Fourth, a comparative report on involuntary childlessness and infertility in developing countries will be completed and published. A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 24 A n n u al Tech n ical R ep ort 2002 Users’ perspectives in the context of reproductive health 25 TECHNICAL COOPERATION WITH COUNTRIES Technical cooperation with countries in 2002 primarily con- cerned the research workshop held in Nairobi, described above. Technical assistance was also provided to the State Family Planning Commission of China and its affiliate institu- tions on the implementation of the Quality of Care project, including activities on informed choice. As part of the team visiting Uzbekistan, the Secretariat participated in discus- sions on gaps in research and capacity building needs in that country. Missions were also undertaken to China, Thailand and Turkey to respond to requests for technical assistance in social science research on users’ perspectives. A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 24 A n n u al Tech n ical R ep ort 2002 Users’ perspectives in the context of reproductive health 25 Annex 1 SPECIALIST PANEL FOR SOCIAL SCIENCE AND OPERATIONS RESEARCH ON REPRODUCTIVE HEALTH Members Kofi Awusabo-Asare, University of Cape Coast, Cape Coast, Ghana (Co-chairman) Mario Bronfman, National Institute for Public Health, Cuernavaca, Mexico Aykut Turkiz Gokgol, Willows Foundation, Istanbul, Turkey Gu Baochang, China Family Planning Association, Beijing, China Veronica Kaune, John Snow Inc./Mothercare/Bolivia, La Paz, Bolivia Mike Koenig, Johns Hopkins University, Baltimore, MD, USA (Co-chairman) Akim Jasper Mturi, University of Natal, Durban, South Africa Leela Visaria, Institute of Economic Growth, New Delhi, India Bencha Yoddumnern-Attig, Mahidol University, Nakhon Pathom, Thailand Developing countries Countries in transition Developed countries Totals Number % of total Number % of total Number % of total Members 8 89 1 11 9 Women 4 44 4 from: AFRO 2 22 2 AMRO 2 22 1 11 3 EMRO EURO 1 11 1 SEARO 2 22 2 WPRO 1 11 1 Collaborating agency scientists John Casterline, Population Council, New York, NY, USA Ondina Fachel Leal, Ford Foundation, Rio de Janeiro, Brazil Sarah Harbison, Agency for International Development, Washington, DC, USA Vasantha Kandiah, United Nations Population Division, New York, NY, USA Suman Mehta, United Nations Population Fund, New York, NY, USA John Townsend, Population Council, Washington, DC, USA A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 26 A n n u al Tech n ical R ep ort 2002 Users’ perspectives in the context of reproductive health 27 Annex 2 SCIENTISTS IN 2002 Principal investigators Shamina Ali, Maternity and Child Welfare Association of Pakistan, Lahore, Pakistan Evasius Bauni, African Population Policy Research Centre, Nairobi, Kenya Aysen Bulut, University of Istanbul, Istanbul, Turkey Şanda Cali, Marmara University, Istanbul, Turkey Fatimata Diallo, Cellule de Recherche en Santé de la Reproduction au Mali, Bamako, Mali Thierno Dieng, Centre de Formation et de Recherche en Santé de la Reproduction, Dakar, Senegal Graciela Dominguez, Centro de Estudios de Poblacion, Buenos Aires, Argentina Maria Garate, Branoe SA, Lima, Peru Pimonpan Isarabhadki, Mahidol University, Salaya, Nakhon Pathom, Thailand Magdalena Kleincsek, Education para el Mejoramiento de la Calidad de Vida, Santiago, Chile Liu Yun-rong, National Research Institute for Family Planning, Beijing, China Sarah Loza, Social Planning, Analysis and Administration Consultants, Cairo, Egypt Pranitha Maharaj, University of Natal, Durban, South Africa Osegbemi Makanjuola, University of Jos, Jos, Nigeria Amir Mehryar, Institute for Research in Planning and Development, Tehran, Islamic Republic of Iran Farid Midhet, The Asia Foundation, Islamabad, Pakistan Janet Molzan Turan, University of Istanbul, Istanbul, Turkey Frank Mugisha, Institute of Public Health, Kampala, Uganda William Muhwava, Union for African Population Studies, Dakar, Senegal Andrew Mushingeh, University of Zambia, Lusaka, Zambia Peter Mwarogo, Development Communications Support Programme, Nairobi, Kenya Marilyn Nations, Tropical Institute of Applied Social Medicine, Fortaleza, Brazil Stella Neema, Makerere Institute of Social Research, Kampala, Uganda Somchai Niruthisard, Chulalongkorn Hospital, Bangkok, Thailand Silvina Ramos, Centro de Estudios de Estado y Sociedad, Buenos Aires, Argentina Helen Rees, University of Witwatersrand, Bertsham, South Africa Peter Riwa, Healthscope Tanzania Ltd., Dar es Salaam, United Republic of Tanzania Mburano Rwenge, Institut de Formation et de Recherche Démographique, Yaounde, Cameroon Alejandro Villa, Centro de Estudios de Estado y Sociedad, Buenos Aires, Argentina Wei Yuan, Shanghai Institute of Planned Parenthood Research, Shanghai, China Wu Junqing, Shanghai Institute of Planned Parenthood Research, Shanghai, China Zhao Peng-Fei, Shanghai Institute of Planned Parenthood Research, Shanghai, China Developing countries Countries in transition Developed countries Totals Number % of total Number % of total Number % of total Scientists 32 100 32 Women 15 47 15 from: AFRO 13 40 13 AMRO 6 19 6 EMRO 4 13 4 EURO 3 9 3 SEARO 2 6 2 WPRO 4 13 4 A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 26 A n n u al Tech n ical R ep ort 2002 Users’ perspectives in the context of reproductive health 27 Annex 3 PUBLICATIONS IN 2002 Ali MM, Cleland JG, Shah IH. Neglected HIV intervention: condom use within marriage (forthcoming). Fang K, Li X, Hang Y. The effectiveness of reproductive health education intervention on increasing knowledge about sexually transmitted diseases and condom use and improving attitude towards condom application among male patients with sexually transmitted diseases in Shanghai. Journal of Reproductive Medicine, 2002, 11(2):84–90. Ganapathy S, Matthews Z, Ramakrishna J, Mahendra S, Kilaru A. Sociocultural determinants of maternal health in rural south India. In: Koenig M, Jejeebhoy S, eds. Reproductive health in India: new evidence (forthcoming). Guo YN, Davin D, Ng EML, Chan K, Shah I. Dynamics of contraceptive desire among Shanghai couples and their determi- nants. In: Zhang K, ed. Proceedings of the 6th Asia-Pacific Social Science Conference (APSSAM 2002). Kunming, Institute of Health Sciences (forthcoming). Kilaru A, Matthews Z, Mahendra S, Ramakrishna J, Ganapathy S. ‘She has a tender body’: Postpartum care and care-seeking in rural south India. In: Unnithan M, ed. Anthropology, reproduction and health policy (forthcoming). Li Y, Chen CHC, Yue H, Sun Z, Stupp PW, Wu Y, Shah I. The effect of improved quality of family planning services on reduc- tion in the rate of induced abortion in six years follow-up. In: Zhang K, ed. Proceedings of the 6th Asia-Pacific Social Science Conference (APSSAM 2002). Kunming, Institute of Health Sciences (forthcoming). Liu Y. Role of Chinese men in reproductive health. In: Zhang K, ed. Proceedings of the 6th Asia-Pacific Social Science Confer- ence (APSSAM 2002). Kunming, Institute of Health Sciences (forthcoming). Ramakrishna J. Ganapahty S, Matthews Z, Mahendra S, Kilaru A. Health, illness and care in the obstetric period: a prospec- tive study of women in rural Karnataka. Bangkok, United Nations Economic and Social Commission for Asia and the Pacific (ESCAP), 2002. Rwenge M. Women’s status and condom use in Cameroon (Centre and West Provinces). International Family Planning Per- spectives (forthcoming). Szulik D, Ramos S, Gogna M, Romero M, Petracci M. La responsabilidad de los médicos ante las políticas públicas sobre anti- concepción y aborto. Serie seminarios “Salud y Publíca” CEDES. Buenos Aires, Argentina, Seminario VI, septiembre 2002. Xiao Y, Sanders S, Wu Shizhong, Luo L. The effect of women’s employment on breast-feeding in urban areas of Sichuan. Zhang K, ed. Proceedings of the 6th Asia-Pacific Social Science Conference (APSSAM 2002). Kunming, Institute of Health Sciences (forthcoming). A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 28 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 29 Development of improved and new methods of fertility regulation C. d’Arcangues, P.D. Griffin, H. von Hertzen, M. Mbizvo, E. Vayena, K.M. Vogelsong INTRODUCTION In 2001, the United Nations Population Division reported that approximately 648 million couples worldwide regularly used a method of family planning. Because use does not neces- sarily mean acceptance, this statistic offers only a glimpse of the behaviours that determine a couple’s decision to use a method of fertility regulation. Nearly one-half of users of a reversible method discontinue use within a year, for a variety of reasons including health concerns and the occurrence of an unplanned pregnancy. On the other hand, at least 120 million couples do not use any method of family planning, despite expressing a desire to space or limit the number of their children. Obstacles to the use of contraceptive methods include ambivalence towards modern contraception, espe- cially because of the fear of side-effects, and lack of access to high-quality services. Experts have determined that the availability of improved or totally new methods of family planning could lead to a significant public health benefit and could meet the needs and demands of millions of men, women, and families. The Programme’s research on improved and new methods for fertility regulation provides one of the several interconnect- ing building blocks required for the delivery of quality family planning services. The Programme has pursued high-priority leads for new methods and approaches that are easier to use and simplify service delivery, that are associated with fewer and less severe side-effects, and that respond to the needs of various users, including men. The Programme’s goals link this work to the introduction of methods, and sub- sequent large-scale trials of their safety and efficacy. Users’ perspectives are gathered during the product development, introduction and routine service provision phases; together with clinical trial data, this information provides a basis for the development of norms, guidelines and other tools for provid- ers and for family planning acceptors. RESEARCH ACTIVITIES Emergency contraception Specific objectives of research For the past ten years, the Programme has been in the fore- front of research on new technologies for emergency con- traception. The aim is to improve further the safety, efficacy, acceptability, and ease of service delivery of methods for this indication. After demonstrating the superiority of levonorg- estrel (LNG) over the regimen of combined oral contracep- tives, the aim was to simplify further the LNG regimen and to compare it to low-dose mifepristone. The efficacy and safety of the copper-IUD and gestrinone are being assessed as alternative methods of emergency contraception. Progress Levonorgestrel Previous research by the Programme has demonstrated that a single 10 mg dose of mifepristone and two 0.75 mg doses of LNG taken 12 hours apart are effective for emergency contraception. A new three-arm, randomized study inves- tigated the efficacy and side-effects of these two methods, compared with a single 1.5 mg dose of LNG, when given up to 120 hours after unprotected intercourse. A total of 4136 women were enrolled at 15 family planning clinics in Asia and Europe. Of 4071 women with known outcome, pregnancy rates did not differ among treatment groups and were 1.6 % in women given mifepristone, 1.5 % in women assigned single-dose LNG, and 1.8 % in women assigned two-dose LNG (see Table 1.1). Side-effects were mild and did not differ greatly between the groups; most women menstruated within two days of the expected date. The results of this ran- A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 28 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 29 domized, double-blind multinational study were published in The Lancet in December 2002. Women and providers can benefit immediately from these new findings, since the now widely accepted LNG-only regimen will become even easier to use in a single dose. Guidelines for emergency contracep- tion need to be modified accordingly. A double-blind, multicentre study carried out in collabora- tion with investigators in Hong Kong Special Administrative Region of China compared the effectiveness of two regi- mens, one with a 12-hour interval between the two doses of LNG and one with a 24-hour interval. The study included over 2000 women; results will be available by mid-2003. LNG is also being studied in a seven-centre study in Nigeria. The efficacy and side-effects of a one-dose regimen of 1.5 mg will be compared to a two-dose regimen of 0.75 mg taken twice, with a 24-hour interval between doses. This study will include a total of 3150 women and is expected to be com- pleted by the end of 2003. An additional aim of this study is to develop the capacity of the centres to carry out research according to Good Clinical Practice (GCP) standards. Mifepristone Based on the above and previous results, mifepristone does not seem to have any advantages over LNG, in terms of effectiveness or side-effects. In addition to more frequent delays in menses, women in the mifepristone group also had a high pregnancy risk after treatment. The research conducted to date suggests that, from the service delivery point of view, mifepristone may be a less feasible and less acceptable method. To test further the low-dose mifepristone regimen for emer- gency contraception, the Programme collaborated with Chi- nese investigators in a three-year initiative funded by The Rockefeller Foundation. Two large multicentre trials were carried out during this initiative. The first trial, a randomized, double-blind study, compared the effectiveness and side-effects of 10 mg and 25 mg doses of mifepristone among 3052 women in 10 centres. The results of the study indicated that the two doses are equally effective, with a crude pregnancy rate of 1.1%. The treat- ments led to very few, if any, reported side-effects. Women treated after 48 hours following unprotected sex had a risk of pregnancy 2.3 times higher than women treated within 48 hours (relative risk = 2.3; 95% confidence interval 1.2 to 4.5; p=0.02). The results were published in December 2002 in the journal Human Reproduction. The second trial is a prospective study of the efficacy and side-effects of 10 mg mifepristone among nearly 5000 women in 30 centres. The results are being analysed and should be available in early 2003. Gestrinone Gestrinone is registered and used in more than 40 coun- tries for the treatment of endometriosis. In addition to its antigonadotrophic activity, the compound also has some antiprogestogenic activity. It is anticipated that, owing to its fairly long duration of action, one dose of gestrinone might be sufficient for effective emergency contraception. A randomized, double-blind study is continuing in China to compare 10 mg of gestrinone with 10 mg of mifepristone for emergency contraception when administered up to 120 hours after unprotected intercourse. The study will include 1200 women. Recruitment has been slower than anticipated because emergency contraception is now widely available in China and women do not necessarily come to family plan- ning clinics when they need it. Mechanism of action studies Several studies are being undertaken by the Programme’s collaborating centres to investigate possible mechanisms of action of emergency contraceptives. A study in Santiago, Chile, is looking at the effects of LNG in the Cebus apella monkey. Preliminary results suggest that, if administration takes place before ovulation, ovulation is disturbed; however, the progestogen seems to have no effect on pregnancy rates if it is administered after ovulation has occurred. Another study in Chile examined the effects of a single 1.5 mg dose of LNG on follicular growth and ovulation in the human. The pharmacokinetics as well as the levels of the steroid in endometrial tissue were examined after oral and vaginal administration. The results should be available in early 2003. Table 1.1. Efficacy of mifepristone and two regimens of levonorgestrel as emergency contraceptives Group Women Observed pregnancies Rate Mifepristone 10 mg 1359 21 1.55 % LNG 1.5 mg x 1 1356 20 1.47 % LNG 0.75 mg x 2 1356 24 1.77 % A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 30 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 31 Six-monthly, non-steroidal, injectable immunocontraceptive for women Specific objectives of research The development of a totally new method of contraception, based on a controlled and time-limited immune response to reproduction-specific molecules, has been the subject of extensive investigation supported by a number of interna- tional and national agencies for several decades. The research being supported by the Programme in this area is the development of an immunocontraceptive based on, and directed against, hCG. The objective of this work is to develop a long-acting, non-hormonal method of contra- ception that could provide perhaps as much as six months of protection following a single injection and which would be free of the endocrine and other metabolic disturbances often experienced with long-acting steroid hormone preparations currently on the market and under investigation. Progress An application was submitted to the regulatory authorities in Sweden in May 2002 to carry out a Phase I clinical trial with the current formulation of the hCG immunocontraceptive. A manufacturer meeting the required regulatory requirements has been identified and preparation of the clinical trial sup- plies is awaiting the availability of funds. The initiation of the second stage of the preclinical safety studies, to run in parallel with the first stage of the Phase I clinical trial, is also awaiting the availability of funds. In 2002, the development work on this project was mainly concerned with supporting the forthcoming Phase I clinical trial in Sweden, as described below. Dose–response studies Several doses of the new matrix delivery system for the hCG immunogen were tested in rabbits, with each dose adminis- tered twice at an interval of 24 weeks. All doses elicited puta- tively protective levels of antibodies by four weeks which, at higher doses, were sustained for 24 weeks. Tissue reactions were considered to be within clinically acceptable limits. Adequate antibody levels were also elicited when the dose of the booster injection was half that of the initial injection, with the added advantage that the frequency and severity of the tissue reactions were reduced. These studies are continuing in order to identify the optimal dose regimen. Stability testing The immunopotency of the matrix formulation was tested using freshly prepared particles, and particles stored at 4°C for 12 months and for more than 24 months. The antibody profiles elicited by these three batches of materials were nearly identical. Additional testing of material stored for two years is in progress. Studies for improving manufacturing procedures Preparing materials for the forthcoming clinical trial has required weighing very small quantities of the matrix particles for the individual doses. To make the weighing easier and more accurate, larger amounts of particles with a reduced loading of immunogens, or the addition of “blank” particles to keep the immunogen dose constant, have been tested. The expected level of antibody was elicited by these materi- als but the tissue reactions were greater than those of the standard preparation. Testing of chimeric peptides in microspheres During the past two years, studies have been conducted to test the immunogenicity and safety of chimeric immunogen peptides, containing B-cell epitopes of hCG beta subunit and at least one T-cell epitope from tetanus toxoid or measles protein, formulated in polylactide/glycolide microspheres and administered in phosphate buffered saline. This approach requires the preparation of separate microspheres contain- ing adjuvant and the mixing of the two before use. The incor- poration of an inorganic salt into the same microspheres as the immunogens might be an alternative to the adjuvant in that this formulation elicits high levels of antibodies that are sustained for several months from a single injection with minimal tissue reaction at the injection site. New projects initiated during the year Testing an improved formulation for manufacture The method currently used to manufacture the hCG immuno- contraceptive involves weighing doses of dry particles into sterile syringes and mixing them with the emulsion vehicle (containing the adjuvant compound) immediately prior to injection. The weighing of small amounts of particles is diffi- cult and would not be practical for large-scale manufacturing. Mixing at the time of injection could introduce errors in the mixing procedure or improper dosing. During the past year, tests have been conducted on the immunogenicity of a fully formulated preparation stored at 4°C for periods of up to 270 days. A test of material stored for 360 days is in progress. The data obtained so far indicate that this preparation is equally immunogenic in rabbits after storage at this temperature for up to 9 months. In addition, no change in the physical appearance of the formulation was noted. These data suggest that it may be possible to prepare a stable preformulated version of the hCG immunocontra- ceptive which could be developed and provided in a “ready to use” form. A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 30 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 31 Injectable hormonal contraceptives Specific objectives of research A number of long-acting injectable esters of LNG were pre- pared in a chemical synthesis programme conducted by the National Institute of Child Health and Human Development (NICHD) of the United States National Institutes of Health (NIH) and the Programme, in the late 1970s and early 1980s. One of these, LNG butanoate (LNG-B), is being investigated as a possible improved alternative to depot-medroxypro- gesterone acetate (DMPA), which could be used for female and/or male contraception. Progress Levonorgestrel butanoate Discussions have taken place with collaborating agencies and industry in connection with the preparation of supplies of LNG-B for use in pharmacokinetic and pharmacodynamic studies and for comparative efficacy studies with DMPA. Suitable sites have been identified for the bulk manufacture and processing of the steroid. The terms and conditions under which the production of clinical trial supplies will be prepared are under discussion. Combined vaginal ring Specific objectives of research Acceptability studies show that women need long-acting methods of contraception that do not require daily inter- ventions and that are under the user’s control. The vaginal ring meets these needs. It has several positive attributes: most steroid hormones are absorbed efficiently through the vaginal wall and can be released from a Silastic ring; the ring can be easily inserted and replaced by the woman herself; it can be worn continuously for a number of weeks; its use is not coitally related; it provides a constant rate of drug release resulting in a steady plasma level of the minimum dose required for contraception; metabolic side-effects are reduced by avoiding the first-pass effect through the liver; and upon removal, fertility rapidly returns. The Programme has discontinued its development of a levonorgestrel-releas- ing vaginal ring and is planning to support the Population Council’s efforts to develop a combined contraceptive vagi- nal ring. Progress The Population Council will launch a Phase III clinical trial of a combined contraceptive vaginal ring that releases 150 μg of nestorone and 15 μg of ethinyl estradiol daily over the course of a year. The initiation of the trial has been delayed owing to the need to establish analytical methods for inproc- ess quality control and quality assurance assessments for large-scale manufacture. The trial is scheduled to begin in 2004; the Programme is planning to provide support to two clinical research centres. Basic research on implantation Specific objectives of research An anti-implantation or menses-inducing agent is an attrac- tive approach to fertility regulation since it would need to be taken only on one occasion in any menstrual cycle, and then only on an as-needed basis or as a backup method—for example, in the case of condom breakage. Such a method would be free of the logistical problems and side-effects associated with many existing methods of family planning and, because of its infrequent use, should be relatively inex- pensive. A collaborative initiative in the area of basic research in implantation was established in 1998 between The Rockefel- ler Foundation and the Programme, with financial support being provided by The Rockefeller Foundation and technical oversight being provided by the Programme. The primary objective is to identify promising leads for development, in eventual collaboration with industry, of novel anti-implantation or menses-inducing agents which would be woman-controlled, effective, safe and acceptable in their mode of administration and their mechanism of action. The continuing focus of the research is on: (i) the implanta- tion window in the primate, at the endometrial level; (ii) the development and demise of the primate corpus luteum; and (iii) preimplantation embryo–uterus–corpus luteum interac- tions. The work is being carried out in a network of six cen- tres in Australia, China, Germany, India, the United Kingdom and the USA. Progress During the past year, further information has been obtained on the complicated and interactive structural and functional changes that occur in the monkey corpus luteum and in the mouse, monkey and human uterus at the site and time of implantation. These changes include both increased and decreased production of specific molecules, the proliferation of blood vessels, and the controlled destruction of certain cell types. New projects initiated during the year Further studies have been carried out to investigate the spatial and temporal expression of genes and their products in the pregnant and non-pregnant uterus and in the corpus luteum. Further evidence of an antifertility effect was obtained when antibodies raised against angiogenic factors were administered to monkeys at a fixed and predetermined time A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 32 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 33 post ovulation. Future studies are planned, involving larger numbers of animals, higher doses of antibodies and a variety of treatment regimens, to further investigate their antifertility potential. Studies are continuing in all six centres with an emphasis to be placed during this final year of the initiative on the most promising leads in each location. Basic research on endometrial bleeding Specific objectives of research A large proportion of the more than 20 million women using progestogen-only methods of contraception endure the irregularities in vaginal bleeding that these methods induce. This has significant implications for their sexual lives and impacts on the sociocultural, economic and, for some, religious dimensions of their lives. Few options are available to women to prevent or alleviate this problem. As a result, counselling is the main assistance that women who experience bleeding irregularities can expect from providers. Clearly, there is a need to understand better the mechanisms of menstruation and of irregular bleeding, and how these are affected by contraceptive steroids, particularly progestogens, in order to formulate appropriate treatments and to develop new methods free of these side-effects. Progress A double-blind, randomized, placebo-controlled clinical trial was conducted to test the effect of vitamin E as an antioxidant, and of low-dose aspirin as an anti-inflamma- tory agent, alone and in combination, on Norplant-induced prolonged bleeding. Participating centres were located in Beijing (China), Jakarta (Indonesia), Santiago (Chile), Santo Domingo (Dominican Republic) and Tunis (Tunisia). Treat- ment with vitamin E had no beneficial effect on bleeding patterns in the study population. Although treatment with low-dose aspirin often led to a more rapid cessation of pro- longed bleeding episodes, significant differences were rarely observed. A systematic review of the evidence for the efficacy of vari- ous therapies in the treatment or prevention of progestogen- induced irregular endometrial bleeding is being supported by the Programme, through the Fertility Regulation Group of the Cochrane Collaboration. The protocol for the review was published in the Cochrane Library Issue 1, 2002, available on CD-ROM and online. The review is ongoing and should be completed in early 2003. A basic science project, “Studies on the Role of Progestogens in Endometrial Breakthrough Bleeding”, was initiated in 2002. It was designed to provide insight into the cellular and molecular mechanisms that underlie progestogen-induced breakthrough bleeding. In the first year of this three-year project, it has been found that progesterone receptors are expressed by human myometrial microvascular endothelial cells in culture, but no changes in cellular gene expression resulted from ligand stimulation of these receptors. Chem- okines stimulate the migration and activation of leukocytes, which are important mediators of endometrial breakdown. Additional data from the study have demonstrated that the specific chemokine, fractalkine, is found in uterine luminal and glandular epithelial cells and in decidualized stromal cells, with maximal production occurring in the secretory phase in cycling women. In endometria of women using DMPA or Mirena (the levonorgestrel-releasing IUD), frac- talkine was strongly expressed in the decidualized stroma; uterine tissue from women using Norplant exhibited lower- than-normal levels of this chemokine. Fractalkine may there- fore contribute to the endometrial fragility seen in women using these methods. Preliminary evidence using a mouse model of menstruation indicates that doxycycline, a broad- spectrum matrix metalloproteinase inhibitor, does not alter the integrity of blood vessels when given from day 5 to day 16 of decidualization, as induced by chronic progesterone exposure. Male hormonal contraception—clinical and social science research Specific objectives of research The family planning community is becoming increasingly aware of the need for, and public-health benefits of, male participation. The Programme has taken a leadership role in the development of male contraceptives, as a step toward the goal of increased shared responsibility in this area. A research agenda in male contraceptive development must identify and exploit the leads that are feasible and show the most promise, such as a hormonal method that suppresses spermatogenesis and produces temporary infertility. The Programme’s clinical trials are complemented by acceptabil- ity and behavioural research. Progress Androgen alone A Phase III study of the safety and contraceptive efficacy of the injectable androgen, testosterone undecanoate (TU), was initiated in late 2001. This four-year trial will evaluate the effects of a monthly injection of 500 mg TU on the fertility of 1000 men, from 10 centres in China. Volunteers receive monthly injections of TU (1000 mg in the first injection and 500 mg thereafter) and are followed for sperm suppression during the first 6 months (Suppression phase). If sperm con- centrations are suppressed to £ 1 million/ml, the volunteers continue to receive monthly injections and are followed for contraceptive efficacy for 24 months (Efficacy phase). If sperm concentrations are not adequately suppressed, the volunteer is discontinued from the study; all men who discon- tinue early for any reason are followed until their sperm con- centrations return to levels generally considered to be fertile A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 32 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 33 (20 million/ml or more). The study is progressing accord- ing to schedule, though no preliminary data are available yet (Table 1.2). Table 1.2. Current status of 1040 volunteers enrolled in Phase III trial of TU alone as a male contraceptive Study Phase Number of Volunteers Suppression (first 6 months) 175 Efficacy (24 months) 681 Early discontinuation: Lost to follow-up 45 Change in contraceptive method 35 Inadequate response 34 Missed injection 31 Other 39 Total 1040 Androgen/progestogen combinations This year saw the completion of a Phase II trial to evalu- ate the suppression of spermatogenesis resulting from the administration of an androgen/progestogen combination, TU + DMPA, to Indonesian men. The study compared the efficacy of the administration of 500 mg TU at 6 week inter- vals with that of the same regimen of TU combined with 250 mg DMPA administered at 12 week intervals. The combined regimen was more effective than TU alone and suppressed sperm counts to a level of infertility in all study participants. The duration of sperm suppression was longer than antici- pated; all volunteers were followed until their sperm concen- trations recovered to fertile levels. In order to simplify the injection regimen, lengthen the interval between injections, and determine the lowest effective doses of both TU and DMPA, the study will be revised and expanded when a new formulation of TU is available. The initiation of a multicentre Phase IIb trial of TU combined with the progestogen norethisterone enanthate (NET-EN) was again delayed due to the non-availability of the study compounds. The protocol has been finalized and negotia- tions with the manufacturer are ongoing. The study would be funded and conducted in collaboration with CONRAD. Behavioural and social science research In conjunction with the clinical trial of the TU + DMPA regi- men in Indonesia, a study to assess users’ perspectives and acceptability of the study compounds was completed. The study participants and their wives generally found the regi- mens to be acceptable. Reasons for participating included the opportunity to have a health check and the desire to relieve partners of the responsibility for family planning. Many men did report short-lived pain at the injection site and increased sexual activity and energy levels during the study. The Programme is supporting a study to pilot test instru- ments to assess the acceptability of, and mood or behav- ioural changes following, the administration of the TU + NET-EN regimen as a potential contraceptive in Italian men. Instruments have been developed and validated; preliminary evidence indicates that sexual behaviour and mood are not altered as a result of the hormonal administration. Data col- lection will be completed in early 2003. New projects initiated during the year A protocol to evaluate the pharmacokinetics and pharmaco- dynamics of a novel formulation of TU is under development. The Xianju Pharmaceutical Corporation, Zhejiang, China, has developed a high-concentration preparation of the steroid; this will allow the injection volume to be halved and should reduce pain at the injection site and improve accept- ability. A study of the pharmacokinetics of this formulation in monkeys is under review; the clinical trial will begin once the monkey study is completed (expected to be in 2003). Basic science leads toward the development of novel approaches to male fertility regulation Specific objectives of research As a complement to the clinical research related to regulation of male fertility, the Programme supports innovative, goal- oriented basic research on male physiology related to sper- matogenesis and spermiogenesis. Potential research targets include the identification, characterization and manipulation of developmental events such as acrosome and flagellar formation; the expression and function of sperm-specific pro- teins; and specific intracellular pathways or events required for sperm function. Investigators are required to focus on the unique aspects of their research with implications for male contraceptive development. Progress In 1998/99 and 2000/01, the Programme issued calls for proposals for basic science activities targeted toward the identification of a novel male contraceptive approach. The following activities were approved through a competitive peer-review process and are currently ongoing. Delivery of antibodies to the male reproductive ducts to achieve immunocontraception This study seeks to determine whether a sufficient titre of antibody can be delivered to the lumen of the male reproduc- tive ducts to saturate a target antigen, in order to achieve immunocontraception. Results indicate that Immunoglobu- lin G and Immunoglobulin A do enter the rete testes and prostatic fluids of the mouse and rat. The investigators are A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 34 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 35 currently using a preparation of sperm surface antigen to immunize male mice and to prepare antibodies that will be used to assess whether sufficient antibody enters the male reproductive ducts to saturate these antigens. Investigation of the possible presence of the C proges- terone isoform at the level of the human sperm plasma membrane In order to characterize and clone a sperm membrane progesterone receptor, the investigators have extracted ribonucleic acid (RNA) from selected human spermatozoa and have performed reverse transcriptase polymerase chain reaction (RT-PCR) on these samples using oligoprimers designed from different regions of the human progesterone receptor RNA sequence. Since it seems that a deoxyribo- nucleic acid (DNA) transcript corresponding to the specific membrane progesterone receptor is not present in human sperm, post-transcriptional or post-translational modifica- tions of the genomic receptor may occur. The study is now investigating the novelty of the receptor protein. Anti-spermatogenic effects of luteinizing and thyroid hormones Data from this pilot study indicate that, in three-month-old Sprague Dawley rats, thyroxin, administered continuously by means of a subcutaneous pump, exerts an anti-sperma- togenic effect. Studies are ongoing to determine the optimal doses of the two peptide hormones, with respect to arresting spermatogenesis and maintaining androgen concentrations. The prostasome as a potential new target for fertility regulation in men Work in the first year of this study has demonstrated that, of 116 infertile men with anti-sperm antibodies, 97% have antibodies against prostasomes. This suggests that prosta- somes are a major target for anti-sperm antibodies. Eighty- five per cent of these men had antibodies to proteins of 70–75 kDa; 80% reacted with a protein of 50–55 kDa. These two potential immunogens may therefore be candidates as antifertility targets. Work is ongoing to identify the proteins and genes of interest. Human sperm mitogen-activated protein kinase cas- cades and their role in sperm functions Natural and potential sperm ligands are being used to investigate the presence and role of a series of kinases in ligand-stimulated human sperm function in this study. Initial results have demonstrated localization of kinases and their upstream regulators in human sperm. Inhibitors of these enzymes seem to alter sperm motility and ligand-induced stimulation of the sperm acrosome reaction in vitro. A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 34 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 35 Annex 1a RESEARCH GROUP ON POST-OVULATORY METHODS FOR FERTILITY REGULATION IN 2002 Members György Bartfai, Albert Szent-György Medical University, Szeged, Hungary Cheng Linan, Shanghai Institute of Family Planning Technical Instruction, Shanghai, China Luigi Devoto, University of Chile, Santiago, Chile Kristina Gemzell-Danielsson, Karolinska Hospital, Stockholm, Sweden Ho Pak Chung, University of Hong Kong, Hong Kong Special Administrative Region of China (Chairman) Jayasree Sengupta, All India Institute of Medical Sciences, New Delhi, India Developing countries Countries in transition Developed countries Totals Number % of total Number % of total Number % of total Members 4 67 1 17 1 17 6 Women 2 33 1 17 3 from: AFRO AMRO 1 17 1 EMRO EURO 1 17 1 17 2 SEARO 1 17 1 WPRO 2 33 2 A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 36 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 37 Annex 1b RESEARCH GROUP ON IMMUNOCONTRACEPTIVES IN 2002 Members John Beale, Cranbrook, Kent, United Kingdom Marc Bygdeman, Karolinska Hospital, Stockholm, Sweden Richard Elton, Tuscon, AZ, USA Warren Jones, Flinders Medical Centre, Adelaide, Australia (Chairman) Rob Loblay, Clinical Immunology Research Centre, Sydney, Australia Viveca Odlind, University Hospital, Uppsala, Sweden Susan Pierce, Northwestern University, Evanston, IL, USA Faye Schrater, Smith College, Project on Women and Social Change, Northampton, MA, USA Shobha Sehgal, Postgraduate Institute of Medical Education and Research, Chandigarh, India Gennadi Sukhikh, International Institute of Biological Medicine, Moscow, Russian Federation Developing countries Countries in transition Developed countries Totals Number % of total Number % of total Number % of total Members 1 10 1 10 8 80 10 Women 1 10 3 30 4 from: AFRO AMRO 3 30 3 EMRO EURO 1 10 3 30 4 SEARO 1 10 1 WPRO 2 20 2 Collaborating agency scientist Doug Colvard, CONRAD, Arlington, VA, USA A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 36 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 37 Annex 1c RESEARCH GROUP ON METHODS FOR THE REGULATION OF MALE FERTILITY IN 2002 Members Richard Anderson, MRC Human Reproductive Sciences Unit, Edinburgh, United Kingdom Kiagus Arsyad, Sriwijaya University, Palembang, Indonesia Hermann Behre, Martin-Luther-University, Halle, Germany William Bremner, University of Washington, Seattle, WA, USA Gu Yi-Qun, National Research Institute for Family Planning, Beijing, China Ilpo Huhtaniemi, University of Turku, Turku, Finland Robert McLachlan, Prince Henry’s Institute of Medical Research, Victoria, Australia Cristina Meriggiola, University of Bologna, Bologna, Italy Nukman Moeloek, University of Indonesia, Jakarta, Indonesia Christina Wang, Harbor-University of California at Los Angeles Medical Center, Torrance, CA, USA (Chairwoman) Frederick Wu, University of Manchester, Manchester, United Kingdom Developing countries Countries in transition Developed countries Totals Number % of total Number % of total Number % of total Members 3 27 8 73 11 Women 2 18 2 from: AFRO AMRO 2 18 2 EMRO EURO 5 45 5 SEARO 2 18 2 WPRO 1 9 1 9 2 Subcommittee for the review of male basic science research Stella Campo, Endocrinology Research Centre (CEDIE), Buenos Aires, Argentina Patricia Cuasnicu, Institute of Biology and Experimental Medicine, Buenos Aires, Argentina Anton Grootegoed, Erasmus University Rotterdam, Rotterdam, Netherlands David Hamilton, University of Minneapolis Medical School, Minneapolis, MN, USA Norman Hecht, University of Pennsylvania, Philadelphia, PA, USA Ilpo Huhtaniemi, University of Turku, Turku, Finland (Chairman) Collaborating agency scientists Mark Barone, EngenderHealth, New York, NY, USA Douglas Colvard, CONRAD, Arlington, VA, USA Henry Gabelnick, CONRAD, Arlington, VA, USA Robert Spirtas, National Institute of Child Health and Human Development, Bethesda, MD, USA Judy Manning, United States Agency for International Development, Washington, DC, USA Elof Johansson, Population Council, New York, NY, USA A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 38 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 39 Annex 1d WHO/ROCKEFELLER FOUNDATION INITIATIVE ON IMPLANTATION RESEARCH IN 2002 Members Ruben Gonzalez, Boston Biomedical Research Institute, Watertown, MA, USA Michael Harper, The Consortium for Industrial Collaboration in Contraceptive Research (CICCR), Arlington, VA, USA Hideharu Kanzaki, Kansai Medical University, Osaka, Japan Stephen Killick, The Princess Royal Hospital, Hull, United Kingdom John White, Hammersmith Hospital, London, United Kingdom Developing countries Countries in transition Developed countries Totals Number % of total Number % of total Number % of total Members 5 100 5 Women from: AFRO AMRO 2 40 2 EMRO EURO 2 40 2 SEARO WPRO 1 20 1 Collaborating agency scientists Mahmoud Fathalla, The Rockefeller Foundation, Assiut, Egypt Evelyn Majidi, The Rockefeller Foundation, New York, NY, USA A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 38 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 39 Annex 2a RESEARCH GROUP ON POST-OVULATORY METHODS FOR FERTILITY REGULATION Scientists in 2002 Principal investigators Oyunbileg Amindavaa, State Research Centre on Human Reproduction and Maternal and Child Health, Ulaanbaatar, Mongolia Dan Apter, The Family Federation of Finland, Helsinki, Finland David Baird, University of Edinburgh, Edinburgh, United Kingdom György Bártfai, Albert Szent-György Medical University, Szeged, Hungary Cheng Li-cun, Shanghai Changning Obstetrics and Gynaecology Hospital, Shanghai, China Cheng Linan, Shanghai Institute of Family Planning Technical Instruction, Shanghai, China Cheng Wei-yu, Tianjin Municipal Research Institute for Family Planning, Tianjin, China Horacio Croxatto, Chilean Institute of Reproductive Medicine, Santiago, Chile Olukayode Dada, Ogun State University Teaching Hospital, Sagamu, Nigeria Dai Jiejie, Medical Primate Research Centre of China, Kunming, China Luigi Devoto, University of Chile, Santiago, Chile Ding Ju-hong, Jiangsu Family Planning Research Institute, Nanjing, China Robert Garfield, University of Texas Medical Branch, Galveston, TX, USA Kristina Gemzell-Danielsson, Karolinska Hospital, Stockholm, Sweden Archil Khomassuridze, Zhordania Institute of Human Reproduction, Tbilisi, Georgia Rosemary Kirkman, University Hospital of South Manchester, Manchester, United Kingdom Laszlo Kovacs, Albert Szent-Györgyi Medical University, Szeged, Hungary Frank Lüdicke, University of Geneva, Geneva, Switzerland Lena Marions, Karolinska Institute, Stockholm, Sweden Suneeta Mittal, All India Institute of Medical Sciences, New Delhi, India Ernest Ng, University of Hong Kong, Hong Kong Special Administrative Region of China Cora Ngai, University of Hong Kong, Hong Kong Special Administrative Region of China Maria Elena Ortiz, Catholic University of Chile, Santiago, Chile Alenka Pretnar-Darovec, University Medical Centre, Ljubljana, Slovenia Shi Shao-Qing, University of Texas Medical Branch, Galveston, TX, USA Song Si, Shanghai Institute of Planned Parenthood Research, Shanghai, China Wang Jie-dong, National Research Institute for Family Planning, Beijing, China Wu Shang-chun, National Research Institute for Family Planning, Beijing, China Developing countries Countries in transition Developed countries Totals Number % of total Number % of total Number % of total Scientists 16 57 4 14 8 29 28 Women 10 36 1 4 3 11 18 from: AFRO 1 4 1 AMRO 3 11 2 7 5 EMRO EURO 4 14 6 22 10 SEARO 1 4 1 WPRO 11 40 11 A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 40 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 41 Annex 2a (continued) Developing countries Countries in transition Developed countries Totals Number % of total Number % of total Number % of total Scientists 9 75 4 33 12 Women 6 50 2 17 8 from: AFRO AMRO EMRO EURO 3 25 3 SEARO 1 8 1 WPRO 8 67 8 Other scientists Bao Gui-xia, Shanghai Changning Obstetrics and Gynaecology Hospital, Shanghai, China Mark Bygdeman, Karolinksa Institute, Stockholm, Sweden Maria Condrea, University of Geneva, Geneva, Switzerland Fang Pei-ying, Wuxi Maternal and Child Health Hospital, Wuxi, China Oskari Heikinheimo, Helsinki University Central Hospital, Helsinki, Finland Ho Pak Chung, University of Hong Kong, Hong Kong Special Administrative Region of China Sunesh Kumar, All India Institute of Medical Sciences, New Delhi, India Wang Yi-fang, Wuxi Maternal and Child Health Hospital, Wuxi, China Wei Fei-ying, Shanghai Changning Obstetrics and Gynaecology Hospital, Shanghai, China Wu Er-ruo, National Research Institute for Family Planning, Beijing, China Xiao Bilian, National Research Institute for Family Planning, Beijing, China Zhu Peng-di, National Research Institute for Family Planning, Beijing, China A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 40 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 41 Annex 2b RESEARCH GROUP ON LONG-ACTING SYSTEMIC AGENTS FOR FERTILITY REGULATION Scientists in 2002 Principal investigators Hany Abdel-Aleem, Assiut University, Assiut, Egypt Rim Ben Aissa, Research Centre for Human Reproduction, Tunis, Tunisia Vivian Brache, PROFAMILIA, Santo Domingo, Dominican Republic Gu Sujuan, Beijing Municipal Research Institute for Family Planning, Beijing, China Rebecca Massai, Chilean Institute of Reproductive Medicine (ICMER), Santiago, Chile Peter Rogers, Monash Medical Centre, Clayton, Australia Lois Salamonsen, Prince Henry’s Institute of Medical Research, Clayton, Australia Sri Bekti Subakir, University of Indonesia, Jakarta, Indonesia Developing countries Countries in transition Developed countries Totals Number % of total Number % of total Number % of total Scientists 6 75 2 25 8 Women 5 62 1 12 6 from: AFRO AMRO 2 25 2 EMRO 2 25 2 EURO SEARO 1 12 1 WPRO 1 12 2 25 3 Other scientists Frank Alvarez, PROFAMILIA, Santo Domingo, Dominican Republic Melissa Brasted, Prince Henry’s Institute of Medical Research, Clayton, Australia Horacio Croxatto, Chilean Institute of Reproductive Medicine (ICMER), Santiago, Chile Rebecca Jones, Prince Henry’s Institute of Medical Research, Clayton, Australia Hayet Mansour, Research Centre for Human Reproduction, Tunis, Tunisia Marion Marsh, Prince Henry’s Institute of Medical Research, Clayton, Australia Developing countries Countries in transition Developed countries Totals Number % of total Number % of total Number % of total Scientists 3 50 3 50 6 Women 1 17 3 50 4 from: AFRO AMRO 2 33 2 EMRO 1 17 1 EURO SEARO WPRO 3 50 3 A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 42 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 43 Annex 2c RESEARCH GROUP ON IMMUNOCONTRACEPTIVES Scientists in 2002 Principal investigators Richard Ascione, Aphton Corporation, Woodland, CA, USA James Hampton, Peninsula Laboratories, San Carlos, CA, USA Vernon Stevens, Ohio State University, Columbus, OH, USA Developing countries Countries in transition Developed countries Totals Number % of total Number % of total Number % of total Scientists 3 100 3 Women from: AFRO AMRO 3 100 3 EMRO EURO SEARO WPRO Other scientists Faz Chowdury, Aphton Corporation, Loughborough, United Kingdom Theo de Roij, Aphton Corporation, Tervuren, Belgium Peter Fagan, Quintiles Pharmaceutical Services, Edinburgh, United Kingdom Frederick Frye, Comparative Medical, Surgical and Pathology Consultation, Davis, CA, USA Stephen Grimes, Aphton Corporation, Woodland, CA, USA Susan Hagan, Aphton Corporation, Loughborough, United Kingdom Pravin Kaumaya, Ohio State University, Columbus, OH, USA Dov Michaeli, Aphton Corporation, Woodland, CA, USA John Powell, Ohio State University, Columbus, OH, USA Peter Rees, Huntingdon Life Sciences, Huntingdon, United Kingdom Peter White, Nova Laboratories Limited, Leicester, United Kingdom Developing countries Countries in transition Developed countries Totals Number % of total Number % of total Number % of total Scientists 11 100 11 Women 1 9 1 from: AFRO AMRO 5 45 5 EMRO EURO 6 55 6 SEARO WPRO A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 42 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 43 Annex 2d RESEARCH GROUP ON METHODS FOR THE REGULATION OF MALE FERTILITY Scientists in 2002 Principal investigators Kiagus Arsyad, Sriwijaya University, Palembang, Indonesia Gianni Forti, University of Florence, Florence, Italy Gu Yi-Qun, National Research Institute for Family Planning, Beijing, China Chandindrami Handagama, University of Tennessee, Knoxville, TN, USA Russell Jones, The University of Newcastle, New South Wales, Australia Maria Cristina Meriggiola, University of Bologna, Bologna, Italy Nukman Moeloek, University of Indonesia, Jakarta, Indonesia Zvi Naor, Tel-Aviv University, Ramat Aviv, Israel Ove Nilsson, Uppsala University, Uppsala, Sweden Anthony Tan, University of Indonesia, Jakarta, Indonesia Developing countries Countries in transition Developed countries Totals Number % of total Number % of total Number % of total Scientists 5 50 5 50 10 Women 2 20 2 from: AFRO AMRO 1 10 1 EMRO EURO 1 10 3 30 4 SEARO 3 30 3 WPRO 1 10 1 10 2 Other scientists Elisabetta Baldi, University of Florence, Florence, Italy Hermann Behre, International Society of Andrology, Halle, Germany Richard Blye, National Institute of Child Health and Human Development, Bethesda, MD, USA Cheng Li-Fa, Henan Family Planning Research Institute, Henan, China Antonietta Costantino, S. Orsola Hospital, Bologna, Italy Patricia Cuasnicu, Institute of Biology and Experimental Medicine, Buenos Aires, Argentina Gustavo Doncel, CONRAD, Norfolk, VA, USA Ralph Heywood, Huntingdon Life Sciences, Huntingdon, United Kingdom Li Han-Min, Birth-Control Institution, Guizhou, China Liang Xiaowei, National Research Institute for Family Planning, Beijing, China Lin Peng, Yunnan Family Planning Research Institute, Yunnan, China Michaela Luconi, University of Florence, Florence, Italy Sabrina Ritchie, American Society of Andrology, Walnut Creek, MN, USA Song Shu-Xiu, Hebei Family Planning Research Institute, Hebei, China Tong Jian-Sun, Jiangsu Family Planning Institute, Jiangsu, China Gerhard van der Horst, University of the Western Cape, Bellville, South Africa Donald Waller, College of Pharmacy, Chicago, IL, USA Ronald Weiss, University of Ottawa, Ottawa, Ontario, Canada Wen Ren-Qian, Family Planning Research Institute, Guandong, China Xiao Hong, Asian Journal of Andrology, Shanghai, China Yao Kang-Shou, Zhejiang Institute of Planned Parenthood Research, Zhejiang, China A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 44 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 45 Kathryn Yount, Emory University, Atlanta, GA, USA Yu Guobin, Anhui Family Planning Institute, Anhui, China Zhao Heng, National Research Institute for Family Planning, Beijing, China Annex 2d (continued) Developing countries Countries in transition Developed countries Totals Number % of total Number % of total Number % of total Scientists 13 54 11 46 24 Women 2 8 5 21 7 from: AFRO 1 4 1 AMRO 1 4 6 25 7 EMRO EURO 5 21 5 SEARO WPRO 11 46 11 A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 44 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 45 Annex 2e RESEARCH GROUP ON NATURAL REGULATION OF FERTILITY Scientists in 2002 Stan Becker, Johns Hopkins University, Baltimore, MD, USA Shakuntala Bhatnagar, National Institute of Health and Family Welfare, New Delhi, India Len Blackwell, Massey University, Palmerston North, New Zealand James Brown, Royal Women’s Hospital, Melbourne, Australia Hernan Delgado, Institute of Nutrition of Central America and Panama, Guatemala City, Guatemala Kathy Kennedy, Denver, CO, USA Pablo Lavin, University of Chile, Santiago, Chile Nicholas Mascie-Taylor, University of Cambridge, Cambridge, United Kingdom Cui Nian, Sichuan Family Planning Research Institute, Chengdu, China Chandrika Subasinghe, The Family Planning Association of Sri Lanka, Colombo, Sri Lanka Kamani Tennekoon, University of Colombo, Colombo, Sri Lanka Developing countries Countries in transition Developed countries Totals Number % of total Number % of total Number % of total Scientists 6 55 5 45 11 Women 4 36 1 9 6 from: AFRO AMRO 2 18 2 18 4 EMRO EURO 1 9 1 SEARO 3 27 3 WPRO 1 9 2 18 3 A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 46 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 47 Annex 2f WHO/ROCKEFELLER FOUNDATION INITIATIVE ON IMPLANTATION RESEARCH Scientists in 2002 Principal investigators Peter Kaufmann, University of Aachen, Aachen, Germany Liu Yi-Xun, State Key Laboratory of Reproductive Biology, Institute of Zoology, Beijing, China Lois Salamonsen, Prince Henry’s Institute of Medical Research, Clayton, Australia Jayasree Sengupta, All India Institute of Medical Sciences, New Delhi, India Stephen Smith, The Rosie Maternity Hospital, Cambridge, United Kingdom Richard Stouffer, Oregon Regional Primate Research Center, Beaverton, OR, USA Developing countries Countries in transition Developed countries Totals Number % of total Number % of total Number % of total Scientists 2 33 4 67 6 Women 1 17 1 17 2 from: AFRO AMRO 1 17 1 EMRO EURO 2 33 2 SEARO 1 17 1 WPRO 1 17 1 17 2 A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 46 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 47 Annex 3a RESEARCH GROUP ON POST-OVULATORY METHODS FOR FERTILITY REGULATION Publications in 2002 Brown A, Cheng L, Lin S, Baird DT. Daily low-dose mifepristone has contraceptive potential by suppressing ovulation and menstruation: a double-blind randomized control trial of 2 and 5 mg per day for 120 days. Journal of Clinical Endocrinology and Metabolism, 2002, 87:63–70. Trussell J, Ellertson C, von Hertzen H, Bigrigg A, Webb A, Evans M, Ferden S, Leadbetter C. Estimating the effectiveness of emergency contraceptive pills. Contraception, 2003, 67:259–265. UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduc- tion. Task Force on Post-ovulatory Methods of Fertility Regulation. Low dose mifepristone and two regimens of levonorgestrel for emergency contraception: a WHO multicentre randomised trial. The Lancet, 2002, 360:1803–1810. Xiao BL, von Hertzen H, Zhao H, Piaggio G. A randomised double blind comparison of two single doses of mifepristone for emergency contraception. Human Reproduction, 2002, 12:3084–3089. A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 48 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 49 Annex 3b RESEARCH GROUP ON LONG-ACTING SYSTEMIC AGENTS FOR FERTILITY REGULATION Publications in 2002 Long-acting methods of fertility regulation Brache V, Faundes A, Alvarez F, Cochon L. Nonmenstrual adverse events during use of implantable contraceptives for women: data from clinical trials. Contraception, 2002, 65:63–74. Cekan SZ. A dedicated External Quality Assessment system for immunoassays of reproductive hormones. Accreditation Qual- ity Assurances, 2002, 7:73–76. Chikamata DM, Miller S. Health services at the clinic level and implantable contraceptives for women. Contraception, 2002, 65:97–106. Croxatto H. Progestin implants for female contraception. Contraception, 2002, 65:15–19. Croxatto H. Mechanisms that explain the contraceptive action of progestin implants for women. Contraception, 2002, 65: 21–27. Curtis KM. Safety of implantable contraceptives for women: data from observational studies. Contraception, 2002, 65:85–96. d’Arcangues C, Vogelsong K. Recent advances in family planning methods. Archives of Ibadan Medicine, 2002, 3:6–9. Diaz S. Contraceptive implants and lactation. Contraception, 2002, 65:39–46. Dorflinger L. Metabolic effects of implantable steroid contraceptives for women. Contraception, 2002, 65:47–62. Glasier A. Implantable contraceptives for women: effectiveness, discontinuation rates, return of fertility and outcome of preg- nancies. Contraception, 2002, 65:27–37. Hickey M, d’Arcangues C. Vaginal bleeding disturbances and implantable contraceptives. Contraception, 2002, 65:75–84. Jordan A. Toxicology of progestogens of implantable contraceptives for women. Contraception, 2002, 65:3–8. Meirik O, Fraser IS, d’Arcangues C for the WHO Consultation on Implantable Contraceptives for Women. Implantable contra- ceptives for women. Human Reproduction Update, 2003, 9(1):1–11. Ortayli N. Users’ perspectives on implantable contraceptives for women. Contraception, 2002, 65:107–111. Petta CA, Hays M, Brache V, Massai R, Yang H, Alvarez-Sanchez F et al. Delayed first injection of the once-a-month inject- able contraceptive containing 25 mg of medroxyprogesterone acetate and 5 mg of E2-cypionate: effects on cervical mucus. Contraception, 2001, 64:363–368. Shastri P. Toxicology of polymers of implantable contraceptives for women. Contraception, 2002, 65:9–13. Sivin I, Moo-Young A. Recent developments in contraceptive implants at the Population Council. Contraception, 2002, 65: 113–119. Basic research on endometrial bleeding Gargett C, Rogers PAW. Human endometrial angiogenesis. Reviews in Reproduction, 2001, 121:181–186. Gargett C, Weston G, Rogers PAW. Mechanisms and regulation of endometrial angiogenesis. Reproductive Medicine Review, 2002, 10:45–61. A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 48 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 49 Salamonsen LA, Zhang J, Brasted M. Leukocyte networks and human endometrial remodelling. Journal of Reproductive Immu- nology, 2002, 57:95–108. Salamonsen LA, Zhang J, Vincent AJ. New insights into the mechanisms underlying menstruation and abnormal uterine bleeding. In: Maruo T, Barlow D, Mardon H, eds. Proceedings of Kobe Institute symposium “Cell and molecular biology of endometrium in health and disease”. Osaka, SOEISHA, 2002:171–183. Vincent AJ, Zhang J, Ostor A, Rogers PAW, Affandi B, Kovacs G, Salamonsen LA. Decreased tissue inhibitor of metallo- proteinase in the endometrium of women using depot medroxyprogesterone acetate: a role for altered endometrial matrix metalloproteinase/tissue inhibitor of metalloproteinase balance in the pathogenesis of abnormal uterine bleeding? Human Reproduction, 2002, 17(5):1189–1198. Weston G, Lederman F, Vollenhoven B, Rogers PAW. Progesterone effects on uterine vasculature: an in vitro model. IFFS 17th World Congress, Melbourne, Australia, 25–30 November 2001:55. Weston GC, Rogers PAW. Endometrial angiogenesis. In: Smith S, ed. Best Practice and Research Clinical Obstetrics and Gynaecology (part of the Bailliere’s Best Practice and Research Series). Harcourt Publishers, 2000, 14(6):919–936 (ISSN 1521-6934 ). Annex 3b (continued) A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 50 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 51 Annex 3c RESEARCH GROUP ON METHODS FOR THE REGULATION OF MALE FERTILITY Publications in 2002 Ellerman DA, Busso D, Cohen DJ, Morgenfeld MM, De Ros VG, Cuasnicú P. Epididymal protein DE and sperm-egg interaction. In Epididymis III, Third International Conference on the Epididymis, Charlottesville, VA, USA, May 29–June 1, 2002, Abstract S13. Gu YQ, Zhang GY. Androgens alone for hormonal male contraception. In: Qian SZ, Handelsman DJ, Waites GMH, eds. Pro- ceedings and programme of the first Asia-Pacific forum on andrology. Asian Journal of Andrology, 2002, 4(Supplement):32–33, Abstract S8-1. Luconi M, Bonaccorsi L, Forti G, Baldi E. Nongenomic progesterone receptors in human spermatozoa. Journal of Andrology, 2002, March/April Supplement Program and Abstracts of 27th Annual Meeting, April 24–27, 2002, Seattle, Washington. Luconi M, Bonaccorsi L, Bini L, Liberatori S, Pallini V, Forti G, Baldi E. Characterization of membrane nongenomic receptors for progesterone in human spermatozoa. Steroids, 2002, 67:505–509. Moeloek N, Pujianto DA, Agustin R, Arsyad KM, Waluyo P, Prihyugiarto Y, Mbizvo MT. Achieving azoospermia by injections of testosterone undecanoate alone or combined with depot medroxyprogesterone acetate in Indonesian men (Jakarta center study). In: Robaire B, Chemes H, Morales CR, eds. Andrology in the 21st century. Proceedings of the VIIth International Con- gress of Andrology. New Jersey, Medimond Publishing Company Inc., 2001:545–550. O’Connor DB, Archer J, Hair WM, Wu FCW. Exogenous testosterone, aggression, and mood in eugonadal and hypogonadal men. Physiology and Behavior, 2002, 75:557–566. A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 50 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 51 Annex 3d RESEARCH GROUP ON NATURAL REGULATION OF FERTILITY Publications in 2002 Bhatnagar S for the WHO Task Force on Methods for the Natural Regulation of Fertility. Infant feeding paterns and lactational amenorrhoea in New Delhi. International Journal of Public Health (submitted). Blackwell LF, Brown JB, Vigil P, Gross B, Sufi S, d’Arcangues C. Home definition of the potentially fertile and infertile phases of the human ovulatory cycle by the home Ovarian Monitor, Part I. Correlation of results obtained by the ovarian monitor and those obtained by radioimmunoassay. Steroids (in press). Blackwell LF, Brown JB. Hormonal monitoring of ovarian activity using the Ovarian Monitor, Part II. Characteristics of the normal menstrual cycle (submitted). Blackwell LF, Brown JB, d’Arcangues C, Van Look PFA, Vigil P, Perez A, Gross B. Hormonal monitoring of ovarian activity using the Ovarian Monitor, Part III. Multicentre study of the hormonal definition of the fertile days of the cycle by home hormonal moni- toring for natural family planning. A comparison with the basal body temperature and cervical mucus symptoms (submitted). Cui N for the WHO Task Force on Methods for the Natural Regulation of Fertility. The impact of breastfeeding pattern on the duration of lactational amenorrhoea in Chengdu, China. Reproduction and Contraception, 2002, 13:98–109. Dada OA, Akesode FA, Olanrewaju DM, Olowu OA, Sule-Odu O, Fakoya TA, Oluwole FA, Odunlami BV for the WHO Task Force on Methods for the Natural Regulation of Fertility. Infant feeding and lactational amenorrhea in Sagamu, Nigeria. African Journal of Reproductive Health, 2002, 6:39–50. Gross A, Burger H for the WHO Task Force on Methods for the Natural Regulation of Fertility. Breastfeeding patterns and return to fertility in Australian women. Australian and New Zealand Journal of Obstetrics and Gynaecology, 2002, 42:148–154. Tennekoon KH. Maternal prolactin concentrations and lactation in the early postpartum period in women with lactational amen- orrhoea. Ceylon Medical Journal, 2001, 46:6–10. WHO Working Group on the Growth Reference Protocol and the WHO Task Force on Methods for the Natural Regulation of Fertility. Growth of healthy infants and the timing, type, and frequency of complementary foods. American Journal of Clinical Nutrition, 2002, 76:620–627. A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 52 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 53 Annex 3e WHO/ROCKEFELLER FOUNDATION INITIATIVE ON IMPLANTATION RESEARCH Publications in 2002 Borges M, Bose P, Frank HG, Kaufmann P, Pötgens AJG. Differential syncytial fusion behavior, measured by a two-colour fluorescence fusion assay of choriocarcinoma cell lines expressing the genes for syncytin and its putative receptor RDR (sub- mitted). Borthwick, JM, Charnock-Jones DS, Tom BD, Hull ML, Tierney R, Phillips SC, Smith SK. Determination of the transcript profile of human endometrium. Molecular Human Reproduction, 2003, 9:19–33. Chen XL, Gao HJ, Wei P, Song XX, Liu YX. Expression of transforming growth factor-beta and its receptor type-2 and their regulation by IFN gamma in the pregnant corpus luteum of rhesus monkey. Acta Pharmacologica Sinica (in press). Chen XL, Gao HJ, Wei P, Zhang ZH, Liu YX. Expression of Fas/FasL and BcL-2/Bax and their relationship to apoptosis in rat corpus luteum. Science in China (in press). Gao F, Fu GQ, Ma J, Peng W, Feng Q, Hu ZY, Liu YX. Expression of MMP-2, TIMP-1, -3 mRNAs in mouse placenta. Acta Zoologica Sinica, 2002, 48:227–232. Gao F, Pong W, Chen XL, Hu ZY, Liu YX. Apoptosis occurs in early stage of pregnancy. Contraception, 2002, 64:193–200. Gao F, Pong W, Chen XL, Zhang ZH, Liu YX. Relationship between uterine expression of matrix metalloproteinases and their inhibitors and endometrial receptivity. Science in China (Series C), 2002, 45:406–411. Hastings JM, Licence DR, Burton GJ, Charnock-Jones DS, Smith SK. Soluble vascular endothelial growth factor receptor 1 inhibits edema and epithelial proliferation induced by 17-estradiol in the mouse uterus. Endocrinology, 2003, 144:326–334. Hazzard TM, Rohan RM, Molskness TA, Fanton JW, d’Amato RJ, Stouffer RL. Injection of antiangiogenic agents into the macaque preovulatory follicle. Endocrine Reviews, 2002, 17:199–206. Hazzard TM, Xu FH, Stouffer RL. Injection of soluble vascular endothelial growth factor receptor 1 into the preovulatory follicle disrupts ovulation and subsequent luteal function in Rhesus monkeys. Biology of Reproduction, 2002, 67:1305–1312. Martoglio-Schofield A-MM, Miskin JW, Smith SK, MacKay DJC. A decomposition model to track gene expression signatures: preview on observer-independent classification of ovarian cancer. Bioinformatics, 2002, 18:1617–1624. Nie GY, Hampton AL, Fu GQ, Liu YX, Findlay JK, Salamonsen LA. A potential molecular mechanism for regulating pre-mRNA splicing of implantation related genes through unique uterine expression of splicing factor SC35 in women and rhesus mon- keys. Reproduction, 2002, 124:209–217. Nie GY, Hampton YA, Li Y, Findlay JK, Salamonsen LA. Identification and cloning of two isoforms of human HtrA3, characteri- sation of its genomic structure and comparison of its tissue distribution with HtrA1 and HtrA2. Biochemical Journal, 2003, 371: 39–48. Nie GY, Li Y, Minoura H, Findlay JK, Salamonsen LA. Specific and transient up-regulation of proprotein convertase 6 (PC6) at the site of embryo implantation and identification of a unique transcript in mouse uterus during early pregnancy. Biology of Reproduction, 2003, 68:439–447. Nie GY, Li Y. Minoura H, Batten L, Ooi GT, Findlay JK, Salamonsen LA. A novel serine protease of the mammalian HtrA family is up-regulated in mouse uterus coinciding with placentation. Molecular Human Reproduction, 2003, 9:1–11. Pötgens AJG, Schmitz U, Bose P, Versmold A, Kaufmann P, Frank HG. Mechanisms of syncytial fusion: an overview. Placenta, 2002, 23:S107–S113. A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 52 A n n u al Tech n ical R ep ort 2002 Development of improved and new methods of fertility regulation 53 Salamonsen LA, Dimitriadis E, Jones RL, Nie GY. Complex regulation of decidualization: a role for cytokines and proteases. Trophoblast Research (in press). Salamonsen LA, Nie GY, Findlay JK. Newly identified endometrial genes of importance for implantation. Journal of Reproduc- tive Immunology, 2002, 53:215–225. Salamonsen LA, Nie GY. Proteases at the endometrial-trophoblast interface: their roles in implantation. Reviews in Endocrine and Metabolic Disorder, 2002, 3:133–143. Sengupta J, Dhawan L, Lalitkumar PGL, Ghosh D. A multiparametric study of the action of mifepristone used in emergency contraception using the rhesus monkey as a primate model. Contraception (in press). Sengupta J, Ghosh D. Blastocyst–endometrium interaction at implantation in the rhesus monkey. Journal of Reproductive Immunology, 2002, 53:227–239. Sengupta J, Ghosh D. Experimental models for human implantation. In: Acosta AA, ed.12th World Congress on In Vitro Fertil- ization and Molecular Reproduction. Monduzzi Editore, S.p.A, International Publications Division, 2002:69–77. Sengupta J, Ghosh D. Experimental models for human implantation. Indian Journal of Physiology and Pharmacology, 2003, 47(1):10–26. Wei P, Zhang ZH, Chen XL, Liu YX. Expression and function of AA98, a newly found vascular endothelial cell related factor, in the maternal-embryonic boundary of rhesus monkey implantation site. Chinese Science Bulletin (in press). Annex 3e (continued) A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 54 A n n u al Tech n ical R ep ort 2002 Safety and effectiveness of existing methods of fertility regulation 55 Safety and effectiveness of existing methods of fertility regulation T.M.M. Farley and J. Schmidt INTRODUCTION Most of the information on the safety and clinical perform- ance of methods of fertility regulation is generated in developed countries and it is not necessarily appropriate to extrapolate to developing countries. The health and social situations are very different and there may be different inter- actions with endemic conditions. To address these issues, the Programme carries out research on the safety and effec- tiveness of existing methods of fertility regulation by review- ing the existing evidence and building the evidence base on the safety and performance of fertility regulating methods in developing countries. Clinical trials leading to product reg- istration are conducted under ideal conditions with carefully screened and monitored volunteers. These may not reflect what happens when the products are made available to a wider population of users, and observational epidemiologi- cal methods must be used to study safety and effectiveness under actual conditions of use. The evidence forms the basis for the development and promotion of norms, guidelines and training materials for the use of different methods of fertil- ity regulation and for the development of high-quality family planning services. Progress in those areas is summarized in other chapters in the section on Promoting family planning. Objectives The overall objectives of the work on the safety and effec- tiveness of existing methods of fertility regulation are: (i) to collect evidence on the safety and effectiveness of differ- ent methods of contraception among women and men in developing countries; and (ii) to address priority unanswered questions on existing methods of fertility regulation when used in developing countries. RESEARCH ACTIVITIES Progress Breast cancer and breastfeeding The Programme supported The Collaborative Group on Hormo- nal Factors in Breast Cancer in compiling individual patient data from epidemiological studies of breast cancer. The database includes more than 50 000 cases of breast cancer and almost 100 000 women without the disease. The relationships between breast cancer and hormonal contraception, hor- mone replacement therapy and family history have been investigated. A new analysis addressed the impact of breast- feeding and its duration on breast cancer risk. Data on 50 302 women with breast cancer and 96 973 controls from 47 studies in 30 countries were used. Women with breast cancer had, on average, fewer births than con- trols (2·2 vs. 2·6). Furthermore, fewer parous women with cancer than parous controls had ever breastfed (71% vs. 79%), and their average lifetime duration of breastfeed- ing was shorter (9·8 vs. 15·6 months). The relative risk of breast cancer decreased by 4·3% (95% confidence interval 2·9–5·8; p<0·0001) for every 12 months of breastfeeding. There was a decrease of 7·0% (5·0–9·0; p<0·0001) for each birth. The size of the decline in the rela- tive risk of breast cancer associated with breastfeeding did not differ significantly for women in developed and develop- ing countries, and did not vary significantly by age, meno- pausal status, ethnic origin, the number of births a woman had, nor her age when her first child was born. A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 54 A n n u al Tech n ical R ep ort 2002 Safety and effectiveness of existing methods of fertility regulation 55 It was estimated that the cumulative incidence of breast cancer in developed countries would be reduced by more than half, from 6·3 to 2·7 per 100 women by age 70, if women had the average number of births and lifetime duration of breastfeeding that had been prevalent in developing coun- tries until recently. Breastfeeding could account for almost two-thirds of this estimated reduction in breast cancer inci- dence. The lack of or short lifetime duration of breastfeed- ing typical of women in developed countries makes a major contribution to the high incidence of breast cancer in these countries. Bone mineral density and progestogen-only contraception Worldwide, over 20 million women are estimated to be currently using progestogen-only contraceptives, including injectables, implants, vaginal rings, the levonorgestrel- releasing intrauterine device and oral preparations. Con- cerns have been raised that progestogen-only preparations can decrease bone mineral density and thus increase sub- sequent risk of osteoporotic fracture. It is unclear whether any decrease noted with current use of progestogen-only contraception is transient or persists. Investigators at the Reproductive Health Research Unit, Durban, South Africa, are conducting a prospective study of the impact of progestogen-only contraception among women in the age ranges 15–19 years and 42–49 years. The younger age group covers the period of maximal bone mass acquisition, and any decrease caused by progestogen- only contraception may affect the peak bone mass achieved. In the older age group, a transient decrease in bone mass with progestogen-only contraception may result in a woman starting her menopause-related decline in bone mass from a lower level. The study has completed recruitment of at least 100 women in each of eight subgroups: depot-medroxyprogesterone acetate (DMPA), norethisterone enanthate (NET-EN), combined oral contraceptive (OC), and non-hormonal method users in each of the two age groups. Most young women in South Africa are given the two-monthly injectable NET-EN, so it was difficult to identify young DMPA users. All women are being followed at six monthly intervals up to five years. Among the younger women, body weight increased by about 2% over one year in all groups, with a greater increase among the combined OC users. There was a slight decline in bone mineral density among the OC users and an increase among the other groups. However, the differences were not significant after adjustment for difference in body weight. Interpretation of these data is difficult since there are large ethnic differences in the composi- tion of the hormonal method user groups. Long-term safety and effectiveness of copper intrauterine devices Up to 240 million women worldwide use intrauterine devices (IUDs) as their preferred method of family planning. IUDs have the advantage of being long-acting and relatively easy to remove, with a rapid return of fertility upon removal. The demonstration of their long-term safety and efficacy is an important aspect of the work of the Programme. The long-term follow-up of cohorts of women using the copper-releasing TCu 380A device continued. In the period Figure 1.2. Cumulative intrauterine and ectopic pregnancy rates by device (interim data, cut off July 2002) Intrauterine ML 375 Intrauterine TCu380A Ectopic ML 375 Ectopic TCu380A R at e (% ) Time since insertion (years) A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 56 A n n u al Tech n ical R ep ort 2002 Safety and effectiveness of existing methods of fertility regulation 57 1989 to 1998 a total of 5953 women had this device inserted as part of Programme-sponsored randomized trials compar- ing the safety and effectiveness of different devices. The majority of the insertions took place in the period 1990–1991. The first large cohort of users completed 10 years of use at the end of 2001, and over 500 are expected to have com- pleted 12 years of use by the end of 2002. The Programme will continue to follow users up to 15 years from insertion, thus providing unique information on long-term contraceptive safety and efficacy of this device. Previous data from the Pro- gramme’s research have been used to progressively extend the approved life span of the device from the initial three to ten years. It is anticipated that the 12 and 15 year data will be used to extend the approved life span even further. The randomized comparative study of the TCu 380A and the Multiload (ML) 375 copper-releasing device started in the early 1990s, and the interim 10-year results are shown in Table 1.3 Both devices are highly effective in prevent- ing pregnancy and have similar overall continuation rates, although the intrauterine pregnancy rate with the TCu 380A is about half the rate of the ML 375 device at all times since insertion (Figure 1.2). There were few ectopic pregnancies, none of which occurred beyond the fifth year of use. Just over half (54%) the women taking part in the trial are in China. These women had an overall continuation rate of 55 per 100 after 10 years of use compared with only 15 per 100 among women from the other countries (Table 1.4). The pregnancy rates with both devices were higher among women in China than in the other countries, consistent with observations from previous multinational research on IUDs conducted by the Programme. Clinical performance of the levonorgestrel-releasing intrauterine device The clinical performance of the 20 µg/day levonorgestrel (LNG)-releasing IUD (Mirena) compared with the TCu 380A device is being assessed in a multicentre study involving a total of 3815 insertions. The interim results six years after insertion are presented in Table 1.5. The pregnancy rate for the LNG device is significantly lower than for the TCu 380A, but there is a high rate of device removal for menstrual related reasons, in particular amenorrhoea, with the LNG- releasing device. The overall continuation rate at six years was 42.7 per 100 women for the LNG device and 68.5 per 100 women for the TCu 380A. HIV and steroid contraception To assess the impact of different contraceptive methods on the clinical course of human immunodeficiency virus (HIV) infection, the Programme is sponsoring a multicentre study in Brazil, Kenya, Thailand and Zimbabwe. Women with HIV infection are invited to participate in an observational cohort study with six-monthly follow-up visits for four years. Study endpoints include HIV disease progression, the incidence of opportunistic infections, and changes in CD4+ cell counts. These will be analysed according to the contraceptive meth- ods used. By November 2002, 372 women had been enrolled in Bang- kok (Thailand), Harare (Zimbabwe) and Nairobi (Kenya). Recruitment to the study was not possible in Brazil since few patients had CD4+ counts of at least 500 cells/mm3 and antiretroviral therapy (ART) is available nationally for Table 1.3. Cumulative net probabilities (standard error) of discontinuation and continuation rates per 100 women at 10 years of use (interim data, cut off July 2002) TCu 380A Multiload 375 P-value Total pregnancy 3.4 (0.5) 5.3 (0.7) 0.029 - Ectopic pregnancy 0.8 (0.3) 0.1 (0.1) 0.011 - Intrauterine pregnancy 2.7 (0.5) 5.2 (0.7) 0.002 Expulsions 11.2 (1.0) 14.8 (1.2) 0.023 Total medical removals 29.9 (1.4) 28.9 (1.5) 0.80 - Pelvic inflammatory disease 0.4 (0.2) 0.5 (0.2) 0.82 Loss to follow-up 12.7 (1.0) 12.2 (1.1) 0.72 Continuation rate 40.1 (1.3) 37.4 (1.3) 0.14 Woman–years 10,164 10,014 Number of women completing interval 291 271 A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 56 A n n u al Tech n ical R ep ort 2002 Safety and effectiveness of existing methods of fertility regulation 57 all patients. The majority of women enrolled use hormonal contraception (primarily DMPA in Nairobi and combined OCs in Harare). Non-hormonal methods are used by 25% of the study cohort. Recruitment will continue to the end of 2003. The rates of CD4 decline are much steeper in Bangkok and Harare than in Nairobi (Figure 1.3), possibly reflecting the impact of different HIV subtypes. As a result of increasing access to sustainable ART in the study sites, the protocol is being modified to introduce ART in a structured way to women in the cohort as they become eligible for therapy. This will permit a preliminary assessment of differences in clinical response to ART by type of hormonal contraception. HIV and vaginal epithelium Progestogen-only contraception has been associated with increased susceptibility to HIV infection. In a study in Umeå, Sweden, to assess the impact of different contraceptive methods on the vaginal epithelium, vaginal biopsies were taken from 15 women using combined OCs, DMPA or Norplant, and from 15 women not using hormonal contra- ception. The vaginal epithelium was thicker in all hormonal contraceptive user groups compared with controls and exhibited a distended hyperplastic superficial layer. The fre- quency of intraepithelial vaginal leukocytes was increased in DMPA users compared with controls; a marginal comparitive increase was seen in the Norplant users, and no increase in combined OC users. This difference may reflect a higher frequency of subclinical infections in DMPA users, or behav- ioural differences between women using the different meth- ods. Full results are expected in 2003. New projects initiated during the year Randomized trial of two implantable contraceptives for women The first paper on a progestogen-releasing contraceptive implant was published in 1969. The first implant, Norplant, was approved in 1983 by the Finnish drug regulatory author- ity. Norplant is now registered in over 60 countries, and an estimated 11 million women worldwide have used the method. Several newer implant systems releasing differ- ent synthetic progestogens have been developed or are under development. Because of the increasing importance of implantable contraceptives for women, the Programme convened an expert consultation on these methods in May 2001. The background papers prepared for this consultation were published in 2002, in the journal Contraception (see page 48). The most extensive data on safety and effectiveness cover the six-capsule levonorgestrel-releasing Norplant device. There have been reports of difficult and time-consuming Table 1.4. Cumulative net probabilities (standard error) of discontinuation and continuation rates per 100 women at ten years of use (interim data, cut off July 2002) Chinese centres Non-Chinese centres TCu 380A ML 375 TCu 380A ML 375 Total pregnancy 4.0 (0.7) 6.7 (0.9) 2. 1 (0.6) 2.1 (0.6) - Ectopic pregnancy 0.9 (0.4) 0.1 (0.1) 0.3 (0.2) - - Intrauterine pregnancy 3.1 (0.5) 6.6 (0.9) 1.8 (0.6) 2.1 (0.6) Expulsions 11.4 (1.2) 16.3 (1.4) 9.9 (1.8) 9.8 (1.6) Total medical removals 20.1 (1.5) 17.5 (1.6) 52.0 (3.3) 53.8 (3.3) - Pelvic inflammatory disease - - 1.6 (1.2) 1.6 (0.8) Loss to follow-up 5.9 (0.9) 6.8 (1.1) 25.9 (2.7) 21.8 (2.6) Continuation rate 57.5 (1.7) 52.8 (1.8) 14.9 (1.6) 15.2 (1.6) Woman–years 6780 6672 3365 3343 Number of women completing interval 238 214 53 57 A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 58 A n n u al Tech n ical R ep ort 2002 Safety and effectiveness of existing methods of fertility regulation 59 removals. Implants with fewer units have been developed, including the two-rod 5-year levonorgestrel-releasing Jadelle and the 3-year single-rod etonogestrel-releasing Implanon. While Jadelle has been compared with Norplant in a moder- ately sized multinational study, and Implanon with Norplant in a single-country study, there have been no formal compari- sons between the two newer devices. The Programme is implementing a multinational randomized comparative trial of Jadelle and Implanon to determine dif- ferences in clinical performance and contraceptive efficacy. Primary endpoints include pregnancy rates, incidence of adverse effects, method acceptability and continuation rates. A total of 2000 women will be enrolled and randomly assigned to use one of the two implants. While non-repro- ductive system complaints such as headache, dizziness, skin alterations and mood changes are commonly associ- ated with progestogen-only implants, their interpretation is difficult. Therefore, in addition to the implant users, an age- matched cohort of 1000 women who use the TCu 380A IUD will be enrolled in parallel with the randomized study. These women will provide data on the incidence of non-reproduc- tive system complaints in users of a non-hormonal method in order to place the observations from the implant users in context. Ten sites in nine countries are participating: Australia, Brazil, Chile, China (Beijing and Shanghai), Dominican Republic, Hungary, Thailand, Turkey and Zimbabwe. Preparations for the trial are almost complete and recruitment will start in early 2003 and last up to one year. Final results on the key study end- points three years after insertion will be available in early 2007. Structural integrity of female condoms The high cost of the female condom limits its widespread use. Reuse has been reported by women unable to afford or access an adequate supply of female condoms. WHO convened a consultation in January 2002 to review data on the safety and practicality of reuse (see also page 60) during which the question of the impact of different potential lubricants on the structural integrity of the female condom was raised. There is limited choice of lubricants available to female condom users. In studies conducted to date, corn oil has been used to relubricate the condoms but it is not known whether this or other potential lubricants have any deleteri- ous effect on the condoms. A study was undertaken to screen a wide range of potential lubricants, including two often used as sexual lubricants (Vaseline and Baby Oil), eleven com- monly available household oils (sunflower, olive, corn, coco- nut, rape seed, palm, grape seed, mustard, groundnut), two fats (lard and shortening) and Canestan Cream (a vaginal antifungal ointment). Sections of polyurethane film were cut from a single roll and soaked for four days with each lubricant. No samples showed any deterioration in tensile strength compared with controls. The only exception was Canestan Cream, which resulted in a 10% drop in tensile strength, most probably caused by one of the excipients. This decrease is unlikely to affect adversely the female condom in normal use. Table 1.5. Cumulative net probabilities of discontinuation (standard error) per 100 women at six years of use (interim data, cut off August 2002) TCu 380A 20 µg LNG device P-value Total pregnancy 2.0 (0.4) 0.5 (0.2) 0.001 - Ectopic pregnancy 0.1 (0.1) - 0.002 - Intrauterine pregnancy 1.8 (0.4) 0.5 (0.2) 0.162 Expulsions 8.3 (0.8) 7.6 (0.8) 0.52 Pelvic inflammatory disease 0.1 (0.1) 0.3 (0.1) 0.29 Menstrual reasons 11.0 (0.9) 35.8 (1.4) < 0.001 - Amenorrhoea 0.5 (0.3) 23.5 (1.3) < 0.001 - Reduced bleeding 3.1 (0.5) 10.9 (1.0) < 0.001 - Increased bleeding 7.2 (0.7) 5.4 (0.7) 0.085 Total device-related removals 25.6 (1.2) 47.8 (1.3) < 0.001 Loss to follow-up 7.7 (0.7) 5.5. (0.7) 0.029 Woman–years 7334 6308 Number completing interval 580 464 A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 58 A n n u al Tech n ical R ep ort 2002 Safety and effectiveness of existing methods of fertility regulation 59 Figure 1.3. Decline in CD4+ cell counts (cells/mL) by centre Given the wide range of oils tested it is highly probable that any vegetable oil will be compatible with the female condom and further testing is unnecessary. Of greater concern is the potential for certain lubricants to adversely affect the vagina or penis during intercourse. NORMS AND TOOLS Specifi c objectives and targets Work on the development and dissemination of norms and tools is reported in the chapter on Norms and guidelines for use of methods of fertility regulation, but specifi c activities undertaken under the umbrella of the work on safety and effectiveness of contraceptive methods are reported here. The relationship between hormonal contraceptives and cervical cancer, and the safety of female condom reuse are reviewed. New norms and tools developed Cervical cancer and steroid hormone contraception The question of whether the use of OCs is causally asso- ciated with an increased risk of cervical cancer has been highly controversial. A WHO scientifi c group concluded in 1990, as part of a comprehensive review of hormonal con- traception and cancer, that use of OC for more than 5 years was associated with a modest (1.3- to 1.8-fold) increase in the risk of cervical cancer. However, it was unclear whether that risk refl ected a biological relationship or was attributable to other factors, such as differences in lifestyle between contraceptive method users, or patterns of sexually trans- mitted infections (STIs), particularly with human papilloma virus (HPV). New results published in early 2002 showed that among women who tested positive for HPV infection, those who had used hormonal contraceptives for between 5 and 9 years had a 2.8-fold increased risk of cervical cancer, while women who had used hormonal contraception for 10 or more years had a 4-fold increased risk. In order to put these new results in a public health perspective, and in the context of evidence from other research regarding the relationship between cervical cancer and hormonal contraception, the Programme convened a consultation in March 2002. Persistent infection with specifi c HPV types is now recog- nized to be the underlying cause of cervical cancer. However, since few women with HPV infection (a common, transient viral infection) ever develop cervical cancer, other factors such as smoking and high parity, are also considered impor- tant. Since 1990, studies have shown an increased risk of carcinoma in situ and invasive carcinoma in long-term users of combined OCs. The increased risk appears to be confi ned to women with persistent HPV infection and is thought to be about twice as high after long-term use (5 years or more) of combined OCs. The consultation recommended no changes in contraceptive prescribing practice or use. The number of cervical cancers that result from OC use is likely to be very small. All contra- ceptive methods, including OCs, carry health risks as well as benefi ts. For young, healthy women who do not smoke, the health benefi ts of OCs far exceed the risks. Many cases of cervical cancer are preventable through use of appropriate screening practices. Where screening services are available, OC users should use them in the same way as other women. However, in many settings screening services are not avail- able; pregnancy-associated morbidity and mortality risks are often high in such settings and combined OCs are one of the 700 500 300 Adm 6m 12m 18m Total Nairobi Harare Bangkok Time C D 4+ (c el ls /m L) A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 60 A n n u al Tech n ical R ep ort 2002 Safety and effectiveness of existing methods of fertility regulation 61 few contraceptive methods widely available. Furthermore, since parity is a risk factor for cervical cancer, use of OCs may reduce the risk of cervical cancer attributable to parity. The consultation concluded that women should not be denied use of OCs simply because they do not have access to cervi- cal cancer screening services. In such settings the risk asso- ciated with unwanted pregnancy would likely exceed the risk of cervical cancer for the majority of women. Female condom reuse The high cost of the female condom is a barrier to its wide- spread use. Reuse has been reported by women who cannot afford or have inadequate access to female condoms. The Programme has sponsored research on the practicality and safety of reuse practices in order to provide guidance to programme managers and potential users, and convened a consultation on reuse in June 2000. Following this consulta- tion, new research was initiated on whether female condoms could withstand repeated bleach disinfection, washing and drying, on the minimum bleach disinfection required to inactivate STIs, and on the impact on the vagina of reusing disinfected female condoms. The new data were reviewed at a second consultation in January 2002. The 2002 consultation revised and simplified the previous protocol on bleach disinfection, washing and drying, and rec- ommended that used female condoms be soaked for a period of 2–5 minutes in a bleach solution of 1:19 household bleach to water (0.25% sodium hypochlorite solution) before further handling. They also recommended that individual female condoms be used no more than five times. A final reuse pro- tocol was issued for adaptation to local conditions. This pro- tocol must be demonstrated to be understandable and safe to apply before female condom reuse can be recommended and promoted in different settings. In many contexts, reuse of the female condom could expose both the woman and her male partner to more risks, particularly if reuse undermined confidence in female condoms, and/or resulted in less use of male condoms or fresh female condoms. In some contexts, promoting reuse may result in more protected acts of inter- course, while in others a reuse protocol would be impossible to apply safely. Decisions about the utility and risks and benefits of introducing a female condom reuse protocol must ultimately be made at the country or local level. WHO issued a statement in July 20021 on the conclusions of the consultation and is developing guidelines on specific practical issues to be considered by programme managers who intend to evaluate the feasibility and applicability of female condom reuse in particular settings. 1WHO information update: considerations regarding reuse of the female condom. Available online at: http://www.who.int/reproductive- health/rtis/reuse.en.html A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 60 A n n u al Tech n ical R ep ort 2002 Safety and effectiveness of existing methods of fertility regulation 61 Annex 1 SPECIALIST PANEL FOR EPIDEMIOLOGICAL RESEARCH IN REPRODUCTIVE HEALTH Members Valerie Beral, Radcliffe Infirmary, Oxford, United Kingdom Michel Boulvain, Hôpital Universitaire de Genève, Geneva, Switzerland Tsungai Chipato, University of Zimbabwe, Harare, Zimbabwe Patricia Claeys, International Centre for Reproductive Health, Ghent, Belgium Maria del Carmen Craviotto, National Institute of Nutrition, Mexico City, Mexico Gao Ersheng, Shanghai Institute of Planned Parenthood Research, Shanghai, China Phil Hannaford, University of Aberdeen, Aberdeen, United Kingdom Carlo La Vecchia, Instituto di Ricerche Farmacologiche “Mario Negri”, Milan, Italy Olav Meirik, Instituto Chileno de Medicina Reproductiva, Santiago, Chile Megan Passey, Southern Cross Institute of Health Research, Lismore, Australia David Skegg, University of Otago, Dunedin, New Zealand (Chairman) Developing countries Countries in transition Developed countries Totals Number % of total Number % of total Number % of total Members 4 36 7 64 11 Women 1 9 3 27 4 from: AFRO 1 9 1 AMRO 2 18 2 EMRO EURO 5 45 5 SEARO WPRO 1 9 2 18 3 Collaborating agency scientists Ann Duerr, Centers for Disease Control and Prevention, Atlanta, GA, USA Silvia Franceschi, International Agency for Research on Cancer, Lyon, France Jennifer Smith, International Agency for Research on Cancer, Lyon, France Robert Spirtas, National Institute of Child Health and Human Development, Bethesda, MD, USA A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 62 A n n u al Tech n ical R ep ort 2002 Safety and effectiveness of existing methods of fertility regulation 63 Annex 2 SCIENTISTS IN 2002 Principal investigators Ahmed Abdennadher, Office National de la Famille et de la Population, Tunis, Tunisia Ayşe Akin, Hacettepe University School of Medicine, Ankara, Turkey Simon Alexaniants, Armenian Centre of Maternal and Child Health Protection, Yerevan, Armenia Eliana Amaral, Universidade Estadual de Campinas, Campinas, Brazil Amaury Andrade, Federal University of Juiz de Fora, Juiz de Fora, Brazil Luis Bahamondes, Universidade Estadual de Campinas, Campinas, Brazil György Bártfai, Albert Szent-Györgyi Medical University, Szeged, Hungary Istvan Batár, University Medical School of Debrecen, Debrecen, Hungary Mags Beksinska, Reproductive Health Research Unit, Durban, South Africa Vivian Brache, Profamilia, Santo Domingo, Dominican Republic Cao Xiaoming, Tianjin Municipal Research Institute for Family Planning, Tianjin, China Chen Zhu ping, Ren Ji Hospital, Shanghai, China Cheng Junling, International Peace Maternity and Child Health Hospital, Shanghai, China Cheng Yimin, National Research Institute of Family Planning, Beijing, China Craig Cohen, University of Nairobi Health Science Campus, Nairobi, Kenya Brian Cox, University of Otago, Dunedin, New Zealand Oluwakayode Dada, Centre for Research in Reproductive Health, Sagamu, Nigeria Reinprayoon Damrong, Chulalongkorn Hospital, Bangkok, Thailand Fan Hui-min, Beijing Obstetrics and Gynaecology Hospital, Beijing, China Anibal Faundes, Centre for Research and Control of Maternal and Infant Disease, Campinas, Brazil Glenda Fehler, National Reference Centre for Sexually Transmitted Diseases, Johannesburg, South Africa Feng Zhuan-chong, Shanghai Institute of Planned Parenthood Research, Shanghai, China Marie-Louise Hammarström, Umeå University, Umeå, Sweden Ho Jialiang, Family Planning Institute of Guangdong, Guangzhou, China Jian Li, Beijing Obstetrics & Gynaecology Hospital, Beijing, China Kang Hong, Xuan Wu Hospital, Beijing, China Jonathan Kasule, University of Zimbabwe, Harare, Zimbabwe Orawan Kiriwat, Siriraj Hospital, Bangkok, Thailand Laszlo Kovacs, Albert Szent- Györgyi Medical University, Szeged, Hungary Pablo Lavin, Hospital Ramon Barros Luco-Trudeau, Santiago, Chile Liu Xiaozhang, Family Planning Research Institute of Sichuan, Chengdu, China Luo Lin, Family Planning Research Institute of Sichuan, Chengdu, China Luo Shi-yuan, Family Planning Research Institute of Sichuan, Chengdu, China Elsebeth Lynge, Institute of Public Health, University of Copenhagen, Denmark Alexio Mashu, University of Zimbabwe School of Medicine, Harare, Zimbabwe Rebeca Massai, Instituto Chileno de Medicina Reproductiva, Santiago, Chile Christina Mwachari, Kenya Medical Research Institute, Nairobi, Kenya Peng Dunren, Tianjin Municipal Research Institute, Tianjin, China Ernesto Pizarro, Hospital José Joaquin Aguirre, Santiago, Chile Alenka Pretnar-Darovec, Gynaecological Clinic, Ljubljana, Slovenia Qian Shao-zhen, Jiangsu Family Health Institute, Nanjing, China Atisook Ronachai, Siriraj Family Health Research Centre, Bangkok, Thailand Eyra Ruiz, Centro de Investigación en Reproducción Humana, Panama, Panama Veronica Schiappacasse, Instituto Chileno de Medicina Reproductiva, Santiago, Chile Inga Sjöberg, Umeå University, Umeå, Sweden Jaisamrarn Unnop, Chulalongkorn University, Bangkok, Thailand Patricia Valdes, University of Frontera, Temuco, Chile Wei Yuying, Family Planning Research Institute, Tong-ji Medical University, Wuhan, China Edith Weisberg, Ashfield, New South Wales, Australia Wu Shangchun, National Research Institute for Family Planning, Beijing, China Wu Yu-ming, Peking Union Medical College, Beijing, China Yang Xiulan, International Peace Maternity and Child Health Hospital, Shanghai, China Yuan Wei, Shanghai Institute of Planned Parenthood Research, Shanghai, China Zhang Shaozhen, Xin Hua Hospital, Shanghai, China Zhao Yue Min, Tianjin Municipal Research Institute for Family Planning, Tianjin, China A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 62 A n n u al Tech n ical R ep ort 2002 Safety and effectiveness of existing methods of fertility regulation 63 Developing countries Countries in transition Developed countries Totals Number % of total Number % of total Number % of total Scientists 45 82 5 9 5 9 55 Women 21 38 1 2 4 7 26 from: AFRO 7 13 7 AMRO 11 20 11 EMRO 1 2 1 EURO 1 2 5 9 3 5 9 SEARO 4 7 4 WPRO 21 38 2 4 23 Annex 2 (continued) Other scientists Mohamed Ali, London School of Hygiene and Tropical Medicine, London, United Kingdom Tsedmaa Baatar, State Research Centre on Maternal and Child Health and Human Reproduction, Ulaanbaatar, Mongolia Ron Ballard, Centers for Disease Control and Prevention, Atlanta, GA, USA Emily Banks, Imperial Cancer Research Fund, Oxford, United Kingdom Queen Cebekhulu, Reproductive Health Research Unit, Durban, South Africa Limmie Chang, Imperial College of Science, Technology and Medicine, London, United Kingdom Chen Gui-ying, National Research Institute for Family Planning, Beijing, China Chen Xiao qin, Family Planning Research Institute of Sichuan, Chengdu, China Chen Yuan qing, Family Planning Research Institute of Sichuan, Chengdu, China Cui Nian, Family Planning Research Institute of Sichuan, Chengdu, China Karen Davis, University of Texas Medical Branch, Galveston, TX, USA Soledad Diaz, Chilean Institute of Reproductive Medicine, Santiago, Chile Berna Dilbaz, SSK Maternity Hospital, Kizilay-Ankara, Turkey Ding Ju-hong, Jiangsu Family Health Institute, Nanjing, China Ding Wan-hua, Jiangsu Family Health Institute, Nanjing, China Fan Guang-sheng, Peking Union Medical College, Beijing, China Fan Xin lin, Family Planning Research Institute of Sichuan, Chengdu, China Fang Hui lan, Tong-ji Medical University, Wuhan, China Fang Li Zhi, Family Planning Research Institute of Sichuan, Chengdu, China Gan Xian qin, International Peace Maternity and Child Health Hospital, Shanghai, China Gao Ya jie, Tianjin Municipal Research Institute for Family Planning, Tianjin, China John Gerofi, Enersol Pty Ltd., Annandale, NSW, Australia Han Li hui, Beijing Obstetrics and Gynaecology Hospital, Beijing, China Jiang Lin-lin, Ren Ji Hospital, Shanghai, China Sirimai Korakot, Siriraj Reproductive Health Research Centre, Mahidol University, Bangkok, Thailand Liu Zhong hua, Family Planning Research Institute of Sichuan, Chengdu, China Györgyi Meszaros, Albert Szent-Györgyi Medical Univerity, Szeged, Hungary Abdel Malek M’Hamdi, Ariana Centre for Human Reproductive Research, Tunis, Tunisia Ni Ming-hong, Ren-Ji Hospital, Shanghai, China Pan Xin-lan, Peking Union Medical College, Beijing, China Mojca Pirc, Gynaecological Clinic, Ljubljana, Slovenia Bill Potter, Stapleford Scientific Services, Cambridge, United Kingdom Neil Poulter, Imperial College School of Medicine, London, United Kingdom Mirjana Puksic, Gynaecological Clinic, Ljubljana, Slovenia Stane Pusenjak, Gynaecological Clinic, Ljubljana, Slovenia Erdenetungalag Radnaabazar, State Research Centre on Maternal and Child Health and Human Reproduction, Ulaanbaatar, Mongolia Primoz Res, Gynaecological Clinic, Ljubljana, Slovenia A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 64 A n n u al Tech n ical R ep ort 2002 Safety and effectiveness of existing methods of fertility regulation 65 James Schlesselman, Sylvester Comprehensive Cancer Center, Miami, FL, USA Alejandra Silva, University of Frontera, Temuco, Chile Song Li juan, Tianjin Municipal Research Institute, Tianjin, China Suvanichchati Sukanda, Siriraj Reproductive Health Research Centre, Mahidol University, Bangkok, Thailand Sun Hong-zhu, National Research Institute for Family Planning, Beijing, China Tao Jin-Zhang, Jiangsu Family Health Institute, Nanjing, China Walter Vitor da Fonseca, Institute of Woman and Child Health, Fortaleza, Brazil Gail Walker, Sylvester Comprehensive Cancer Center, Miami, FL, USA Wang Yue-bao, Shanghai Institute of Planned Parenthood Research, Shanghai, China Weng Li-Ju, Peking Union Medical College, Beijing, China Wong Hong, Xin Hua Hospital, Shanghai, China Wu Ming-hu, Beijing Obstetrics and Gynaecology Hospital, Beijing, China Wu Mu-zhen, Peking Union Medical College, Beijing, China Wu Shi Zhong, Sichuan Provincial Family Planning Research Institute, Chengdu, China Wu Yue-zhe, Shanghai Institute of Planned Parenthood Research, Shanghai, China Xiao Ling, Family Planning Research Institute of Sichuan, Chengdu, China Xie Li, Family Planning Research Institute of Sichuan, Chengdu, China Yang Bang yuan, International Peace Maternity and Child Health Hospital, Shanghai, China Yun Ming-ming, Jiangsu Family Health Institute, Nanjing, China Yun Ming rong, Family Planning Research Institute of Sichuan, Chengdu, China Zhang Wen hao, Tianjin Municipal Research Institute, Tianjin, China Zhao Dan ping, Tianjin Municipal Research Institute, Tianjin, China Zhu Xiao-ling, Beijing Obstetrics and Gynaecology Hospital, Beijing, China Zhuang Liu-qi, International Peace Maternity and Child Health Hospital, Shanghai, China Annex 2 (continued) Developing countries Countries in transition Developed countries Totals Number % of total Number % of total Number % of total Scientists 46 75 5 8 10 16 61 Women 30 49 2 3 4 7 36 from: AFRO 1 2 1 AMRO 3 5 4 7 7 EMRO 1 2 1 EURO 1 2 5 8 5 8 11 SEARO 2 3 2 WPRO 38 62 1 2 39 A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 64 A n n u al Tech n ical R ep ort 2002 Safety and effectiveness of existing methods of fertility regulation 65 Annex 3 PUBLICATIONS IN 2002 Castellsagué X, Bosch FX, Muñoz N, Meijer CJLM, Shah KV, de Sanjosé S et al. for the International Agency for Research on Cancer Multicenter Cervical Cancer Study Group. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. New England Journal of Medicine, 2002, 346:1105–1112. Chang CL, Marmot MG, Farley TMM, Poulter NR. The influence of economic development on the association between educa- tion and the risk of acute myocardial infarction and stroke. Journal of Clinical Epidemiology, 2002, 55:741–747. Chang CL, Shipley MJ, Marmot MG, Poulter NR. Can cardiovascular risk factors explain the association between education and cardiovascular disease in young women? Journal of Clinical Epidemiology, 2002, 55:749–755. Collaborative Group on Hormonal Factors in Breast Cancer. Alcohol, tobacco, and breast cancer: collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. British Journal of Cancer, 2002, 87:1234–1245. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and breastfeeding: collaborative reanalysis of indi- vidual data from 47 epidemiological studies in 30 countries, including 50,302 women with breast cancer and 96,973 women without the disease. The Lancet, 2002, 360:187–195. Cox B, Sneyd MJ, Paul C, Delahunt B, Skegg DCG. Vasectomy and risk of prostate cancer. Journal of the American Medical Association, 2002, 287:3110–3115. Donaghy M, Chang CL, Poulter N. Duration, frequency, recency and type of migraine and the risk of ischaemic stroke in women of childbearing age. Journal of Neurology, Neurosurgery & Psychiatry, 2003 (submitted). Farley TMM. Considerations regarding re-use of the female condom. Reproductive Health Matters, 2002, 10:182–186. Farley TMM, Potter W, Gerofi J, Pope M. Structural integrity of the polyurethane female condom after multiple cycles of dis- infection, washing, drying and re-lubrication. XIV International AIDS Conference, Barcelona, Spain, 7–12 July 2002. Abstract No. TuOrD1233. Meriggiola MC, Farley TMM, Mbizvo M. A review of androgen-progestin regimens for male contraception. Human Reproduc- tion, 2003 (in press). Moreno V, Bosch FX, Muñoz N, Meijer CJLM, Shah KV, Walboomers JMM, Herrero R, Franceschi S for the International Agency for Research on Cancer (IARC) Multicentric Cervical Cancer Study Group. Effect of oral contraceptives on risk of cer- vical cancer in women with human papillomavirus infection: the IARC multicentric case-control study. The Lancet, 2002, 359: 1085–1092. Muñoz N, Franceschi S, Bosetti C, Moreno V, Herrero R, Smith JS, Shah KV, Meijer CJLM, Bosch FX for the International Agency for Research on Cancer (IARC) Multicentric Cervical Cancer Study Group. Role of parity and human papillomavirus in cervical cancer: the IARC multicentric case-control study. The Lancet, 2002, 359:1093–1101. Pettifor AE, Beksinska ME, Rees HV, Mqoqi N, Dickson-Tetteh KE. The acceptability of reuse of the female condom among urban South African women. Journal of Urban Health, 2001, 78:647–657. Potter B, Gerofi J, Pope M, Farley TMM. Structural integrity of the polyurethane female condom after multiple cycles of disinfec- tion, washing, drying and re-lubrication. Contraception, 2003, 67:65–72. Thomas DB, Ray RM, Qin Q and the WHO Collaborative Study of Neoplasia and Steroid Contraceptives. Risk factors for progression of squamous cell cervical carcinoma in-situ to invasive cervical cancer: results from a multinational study. Cancer Causes and Control, 2002, 13:683–690. A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 66 A n n u al Tech n ical R ep ort 2002 Norms and guidelines for use of methods of fertility regulation 67 World Health Organization. Cervical cancer, oral contraceptives and parity. WHO Weekly Epidemiological Record, 2002, 77: 167–168. World Health Organization. The safety and feasibility of female condom reuse: report of a WHO Consultation. Geneva, World Health Organization, 2002 (available online at: http://www.who.int/reproductive-health/rtis/reuse.en.html#1). Annex 3 (continued) A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 66 A n n u al Tech n ical R ep ort 2002 Norms and guidelines for use of methods of fertility regulation 67 Norms and guidelines for use of methods of fertility regulation H.B. Peterson, K. Church, S. Johnson INTRODUCTION Family planning programmes are facing the challenge of finding better ways to deliver high-quality family planning services to the millions of people who would use family plan- ning if they had access to it. However, many family planning programmes have substantial progress to make in improving quality of care. The Department is contributing to these efforts by creating four cornerstones of evidence-based and con- sensus-driven guidance for family planning. This new series includes two guidelines—Improving access to quality care in family planning: medical eligibility criteria for contraceptive use (referred to as Medical eligibility criteria for contraceptive use) and Selected practice recommendations for contracep- tive use. There are also two tools—the Decision-making tool for family planning clients and providers and the Handbook for family planning providers. A system has also been cre- ated to ensure that this global family planning guidance is based on the best available evidence through a continuous, systematic process of identifying, critically appraising, and synthesizing new evidence as it becomes available. The creation of evidence-based guidelines and tools alone, while important, is insufficient to assure that family planning services are improved. The ultimate impact of the Depart- ment’s norms and tools will be contingent on the develop- ment of successful strategies for implementation. OVERALL OBJECTIVE The overall objective of the Department’s work in this area is to create evidence-based and consensus-driven guidance to support the provision of high-quality family planning services globally. This objective will be achieved by: •• establishing the context for norms and tools within a programme of research for promoting family planning; •• developing the four cornerstones of evidence-based guidance for promoting family planning; •• creating a system for developing guidelines based on the best available evidence and ensuring that they are kept up to date; •• developing an implementation strategy for and provid- ing support for countries adopting and adapting WHO’s family planning guidance. Establishing the context The context for developing norms and tools in family plan- ning is based on a framework that links the four major goals of the Department in family planning, namely: •• to develop new and improved methods of contraception (including methods for dual protection); •• to evaluate the safety and effectiveness of existing meth- ods; •• to assess the sociocultural and behavioural determi- nants of successful family planning; and •• to translate available evidence into guidelines that are used successfully at country level. The first three goals are supported by research programmes, and the fourth is based on the findings derived from these A n n u al T ec h n ic al R ep or t 2 00 2 Section 1 - Promoting family planning 68 A n n u al Tech n ical R ep ort 2002 Norms and guidelines for use of methods of fertility regulation 69 programmes and other relevant research. Thus, the findings from both social sciences research and safety and efficacy research feed directly into the evidence base for norms and tools. As new methods are developed and evaluated, safety and efficacy research as well as research on acceptability of these methods are included in the evidence base. Further- more, a feedback loop exists between the guidelines and the research priorities. Key gaps in evidence are identified as available evidence is appraised, synthesized and consid- ered for guidelines and some of t

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