Contraceptive Safety

Susan Holck, M.D.
Medical Officer, Special Programme of Research,
Development and Research Training in Human Reproduction,
World Health Organization
Geneva, Switzerland

It is estimated that over 400 million women in developing countries are using some form of "modern contraception." Although the patterns of contraceptive use vary widely around the world, the choice of a method of contraception - and the potential health effects - is an issue which touches most women at some time or another in their lives. It is clear that, overall, the effects of using effective contraception have been overwhelmingly positive for women's health, mainly through the direct effect of preventing pregnancy and the morbidity and mortality associated with pregnancy. But women are also concerned about the non-contraceptive health effects of individual methods of contraception. Increasingly, the choice is not whether or not to use an effective method of contraception, but rather which method carries the best combination of acceptability, efficacy, and balance of positive and negative side effects, for a given woman or couple. Thus, the relevant comparison is among available methods of contraception, rather than between any given method of contraception and the alternative of no contraception.

Although issues such as ease of use, cost, and convenience play an important role for women in selecting a method of contraception, concern about health effects is also a major issue for women in both developed and developing countries. In my presentation today I plan to review broadly what research has been conducted on side effects of contraceptives, how the research priorities have evolved over time, for both developed and developing countries, to what extent women's concerns have been taken into account, and to what extent women have been involved in setting the research priorities. Finally, I will make some suggestions as to what is needed in the immediate future so as to avoid the pitfalls of the past, and to ensure that the health concerns of women in developing countries are adequately addressed when undertaking research on contraceptive safety.

Virtually all of what we know about the major non-contraceptive health effects of contraceptives comes from research undertaken in North America and Western Europe. The landmark studies demonstrating an increased risk of cardiovascular disease among women using the pill, the protective effect of pills against cancer of the ovary and endometrium, the risk of serious pelvic inflammatory disease among women using IUDs and the impaired fertility that follows - all of these studies were conducted in a few developed countries. There were a number of reasons for this geographical concentration of research: in part, it reflected the rapidly growing popularity of "modern contraceptives" in the western, developed world; in part, it stemmed from the fact that expertise in conducting such studies was at that time very much concentrated in these countries. Perhaps it also reflected a cultural norm of questioning potential side effects of drugs routinely used; improved health in general allowed for more concern about side effects of drugs such as contraceptives.

In fact, systematic studies to assess the long-term safety of both oral contraceptives and IUDs were not begun immediately after these contraceptives were introduced. In general, the first reports of the major adverse effects of oral contraceptives came from spontaneous adverse drug reporting systems; subsequently, specific studies were initiated to confirm these reports. Since the first sporadic reports of adverse effects of oral contraceptives, an enormous amount of research has been conducted on specific health effects of oral contraceptives. The story is a similar one for IUDs. However, as I mentioned earlier, the vast majority of this research has been conducted in a few developed countries.

More recently, both hormonal contraceptives and IUDs have become widely used in many developing countries. Expanding population and family planning programmes have received a great deal of attention in a number of developing countries, as part of the general economic and social development process, and as part of an attempt to slow down the rate of population growth. A new interest in research on contraceptives accompanied this development. Initially the main interest was primarily in factors that affected acceptability of specific contraceptives and/or continuation rates. Put simplistically, the main goal was to get as many couples (women) using effective contraception for as long as possible.

This is not to say that there was no interest in the potential adverse health effects of these contraceptives, but this issue was not of high priority for research probably, in part, because it was generally assumed that the studies from developed countries had already addressed these issues. In addition, in the face of massive health problems in these countries, potential adverse health effects of contraceptives understandably received relatively little attention.

Over the past 10 to 15 years or so, the orientation of the research in both developed and developing countries has shifted. In western developed countries, research on contraceptive safety shifted towards "fine-tuning" the findings of the earlier studies. Are there subgroups of women using oral contraceptives who are at an increased risk of developing breast cancer? What role did specific micro-organisms play in the relationship between IUD use and pelvic inflammatory disease (PID)? Issues of acceptability of various contraceptives were also addressed to a limited extent - were menstrual patterns altered following tubal ligation? Which specific estrogen-progestogen combination in oral contraceptives minimized "breakthrough bleeding"?

In developing countries, during this same time period, the assumption that the results from the United States - and the United Kingdom - based studies were directly applicable to the entire world, began to be questioned. Governments and family planning programmes in developing countries became increasingly concerned about potential adverse health effects of the contraceptives they were promoting, and that were now being widely used. Women's status and educational level increased in many developing countries, and women themselves became more vocal in their concerns about the safety of the contraceptives they and their friends were using. It began to be recognized that studies needed to be conducted in developing countries in order to assess the safety of contraceptives for Third World women. As a result, several large-scale multinational studies were initiated primarily by WHO's Special Programme of Research, Development and Research Training in Human Reproduction, on a number of safety issues, including IUD use and PID, hormonal contraceptives and cancer, and oral contraceptives and cardiovascular disease. These studies deliberately included developing country centres from different areas of the world. More recently, research on contraceptive safety and on behavioral and social factors affecting use of fertility regulation, has received high priority within the research and development component of WHO's Special Programme.

A major problem has emerged in this process. We really have not determined which side effects of contraceptives are applicable to women throughout the world, and which are not. This is of critical importance, since it has major implications for the scope of research that is still needed in developing countries. As an example, we know that oral contraceptive use lowers the risk of ovarian cancer among women in the United States and the United Kingdom. Can we assume that oral contraceptive use has the same effects on the risk of ovarian cancer among women in Kenya or in India? Or do we have to repeat studies of oral contraceptives and ovarian cancer virtually in every area of the world? Aside from issues of feasibility, this would be a very costly exercise. On the other hand, it is not wise to assume that all results on contraceptive safety from a few developed countries are directly applicable to all parts of the world. While there is a general acceptance that research on contraceptive safety must be undertaken in developing countries, more thought is needed as to which issues are of highest priority, given what we know from developed countries, and given the resources available. It will not be possible to replicate all studies of contraceptive safety in all areas of the world.

There are also issues of contraceptive safety, which are relevant only to some developing countries, and which would not have been addressed in developed countries. Examples include the safety of hormonal contraceptives for women infected with schistosomiasis, potential interactions between hormonal contraceptives and anti-malaria medication, and the effects of oral contraceptives on iron-deficiency anemia or vitamin deficiencies.

Further complicating the situation are those issues which are known to be culturally specific. Although amenorrhea may occur equally frequently among women in Pakistan using the implantable contraceptive, NORPLANT,® as compared to women in Sweden, the attitudes and reactions of the women to the amenorrhea may be dramatically different - which is ultimately what matters.

All of this leads to another relevant question: who determines what the research priorities are? Are the priorities set for research on contraceptive safety in developing countries truly relevant to and of high priority for developing countries, given other health problems in these settings? And are they truly high priority vis-a-vìs women's health? To what extent are women involved in the setting of research priorities in developing countries?

There are no simple answers to these questions. There is no single group of people that determines research priorities on contraceptive safety issues for the world. A wide variety of individuals, groups, governmental institutions, and international bodies play a role. The more powerful among these individuals and institutions obviously carry more weight and have more influence. Within WHO's Special Programme of Research in Human Reproduction, which has the specific mandate within WHO to undertake research on contraceptive safety, it is encouraging that there is a deliberate effort to include both men and women on the main decision-making committees. Thus, both those contributing resources and those receiving financial support are represented on the highest level, for example, the Policy and Coordination Committee. At the more technical scientific review level, experts from around the world, including the developing world, participate in the decision-making process, as members of the Scientific and Technical Advisory Group, and as members of steering committees.

At least until recently, women have not generally been extensively involved in the global decision-making, especially at the highest levels, even though virtually all of the research implications directly concern women's health. The lack of involvement of women is especially marked in countries where feminism has so far had little impact and where women's status remains low. In general, these are also countries where women's health has received insufficient attention.

There has also been little systematic involvement of feminist groups or of consumer groups speaking on behalf of women, even in countries where feminist groups are well-established as an important voice for women's health concerns. Feminist groups have generally not been asked to participate in the decision-making process, and have thus too often remained uninformed about the rationale behind decisions taken regarding research priorities ťand also uninformed about the results of the research as well. One result of this has been a regrettable schism between policy makers and even researchers on the one hand, and women's groups on the other. The situation has not maximized the likelihood that women's concerns will be taken into account.

International organizations play an important role in determining research priorities for contraceptive safety in developing countries. These organizations have only recently realized the importance of involving women in decision-making and in establishing links with women's groups concerned primarily with women's health in developing countries. WHO's Human Reproduction Programme has made some important first steps recently. Women's consumer groups were formally involved in a Symposium on Safety Requirements for New Contraceptive Steroids, and a Symposium on the Assessment of the Safety and Efficacy of Vaccines to Regulate Fertility. Furthermore, an increasing number of women at higher levels within the Programme has fostered the development of informal links with women's groups, both within and outside of WHO. The Population Council has also sponsored meetings with the International Women's Health Coalition, on quality of care, for example.

My impression is that there persists among feminist groups a general dissatisfaction about the focus of research on contraceptive safety - that insufficient attention is being paid to health effects which may not be life-threatening, but which directly concern women. I also have the impression that there is insufficient understanding on the part of some feminist groups as to what research has been conducted and what it has shown. For example, I still hear allegations that women who use Depo Provera (DMPA) risk impaired fertility, when this has been clearly shown not to be the case. I believe much of this misinformation to be a direct result of the lack of communication between researchers and women's groups. As I have been told by numerous women who are concerned about women's health, but who are not trained as scientists, it is often very difficult to understand the technical scientific articles that describe the research findings, and the popular syntheses of the articles in the lay media are not always accurate. I am told that even for women trained as scientists, but in fields other than reproductive health, it is difficult to understand the relative merits of various studies and thus the overall conclusions that can be drawn. The discrepant findings from several studies on oral contraceptives and breast cancer is a good example of a case in which it is very difficult for someone not directly involved in discussions with experts in this subject, to know what, if any, conclusions to draw.

What can one conclude from all of this? What changes are needed so as to ensure that women's concerns about women's health are adequately taken into account, especially in developing countries, when decisions are made about research on contraceptive safety? How can direct links between decision-makers and women's groups be fostered in international and national settings?

I am not convinced that the priorities of the past have been all wrong. Tremendous progress has been made in identifying the major health effects of contraceptives such as oral contraceptives and IUDs. Issues such as the link between oral contraceptives and cancer and the risk of serious pelvic infection linked with IUDs are of major concern to women. There is rightly a growing recognition that these issues are of critical importance in developing countries, as well as developed ones. I have reviewed some of the reasons for the relatively slow development of research on contraceptive safety in developing countries. However, we still need to undertake research on issues directly relevant to developing countries, such as the safety of various contraceptives in the presence of diseases endemic in developing countries. We also need to identify those safety issues which have been studied in developed countries, but need further study in developing countries.

It is right, too, that research on major health effects has, in general, preceded research on side effects that are less serious from a direct health point of view. Side effects that are troublesome to women, or that influence women's decisions to change contraceptives, fade in comparison to the need to know, for example, that sequential pills (no longer used) increase the risk of endometrial cancer, a life-threatening condition.

Many developing countries are just beginning to set up mechanisms to determine research needs vis-a-vìs contraceptive safety. Many of the decisions are still being made largely by developed country donor agencies and by international organizations. Recognition is slowly growing among the decision making groups that women and women's groups concerned with women's health need to be involved. This recognition needs to be fostered. The advantages for both sides in establishing direct links need to be pointed out and emphasized. We need to identify the most constructive ways for women and feminist groups to be involved in decision-making about contraceptive research. Having specific mechanisms for collaboration would greatly enhance the likelihood of success. Finally, the initiative needs to come from both sides. Too often, both feminist groups, as well as national and international decision-making bodies, have been too distrustful of each other even to approach the other for information needed, to discuss concerns, or to explore possible collaboration.

I am optimistic. This mini-plenary session is an example of changes in the right direction. It is exciting to be able to discuss these issues in a forum such as this, which brings together policy makers, such as Dr. Barzelatto, and feminist groups such as IWHC. By fostering this momentum, we will do a better job of ensuring that women's health concerns are of high priority throughout the world.