Research in family planning [full issue]

THE MAGAZINE OF THE WORLD HEALTH ORGANIZATION • AUGUST-SEPTEMBER 1978 • USA $ 2 "Zrover2,23:4.4..!"' dal - .41%. 1 1. t<: I Cr ew social movements in the histo-W ry of mankind have affected medi-cine and health care as has the demand in the last two decades for family planning. This demand springs from a variety of motives. For some, it is based on the right of individ- uals or couples to determine when and how many children they will have. For others, it is justified on health grounds: too many pregnancies at too close inter- vals are bad for the health of mothers and children. Yet another argument for family planning stems from the recogni- tion by many countries that limiting population growth is an important fac- research in family planning by Alexander Kessler and Tabitha Standley Imixtiu) HEALTH TNE MAW. OF ,Int WORM NM.. AUGUS.1 , 51,f1MBER te,e, St Cover: Throughout history, the plan- ning of their family has been one of the main concerns of couples. ( Photo of Etruscan statue by Giraudon, Paris ©) One of the biggest problems facing devel- oping countries is to provide health care, including family planning, to the three-quarters of their population that live in villages. Research seeks to devise appropriate technology and services for this. ( Photo WHO/T. Marshall) for in their socio-economic development. This demand has led to authorities having to face the problem of how to provide family planning care for poten- tially all couples of reproductive age in their populations. Given that these cou- ples represent at least one-third of most populations, and that about ninety per cent of the world's population is in coun- tries where an attempt is being made to provide family planning care, it is easy to calculate that one is talking in terms of about 1,500 million people. Among these, there will be about ten per cent of couples with problems of infertility, that is 150 million people, who may be suffer- ing acute personal distress from the con- dition and who also have a claim to fami- ly planning care. Infertility is a medical problem. The approaches to its diagnosis and treat- ment are fundamentally similar to those for other pathological conditions. Birth control, however, is quite different. It in- volves mainly healthy people. Whereas in sickness it is the doctor who pre- scribes, in contraception it is the prefer- ences of the individual or couple that play the vital role. They have to make certain decisions. Should the responsibil- ity for protection against pregnancy lie with the man or woman? For either, a Contents Research in family planning by A. Kessler and T. Standley . 2 Family formation and health: the story of a study by V. Balderrama-Guzman 7 How safe is the pill? by R. Gray ........ 12 Plants to control fertility by D. D. Soejarto .... 16 Natural family planning by J. Spieler 20 Beyond the pill by E. Diczfalusy . 22 Family planning—where and how? by N. Fisek and R. Gray . 26 Infertility: a universal problem by M A Belsey 30 Self-reliance in research by N. Dusitsin and R. Grossman 34 News Page 38 „ ° Left: Birth control involves mainly healthy peo- ple. Whereas in sickness it is the doctor who prescribes, in contraception it is the prefer- ences of the couple that play the vital role. ( Photo Len Sirman ©) Above: Research in family planning requires many scientific disciplines and types of work: with animals, in the chemistry laboratory, in the hospital ward, at the outpatient clinic, and in the community. ( Photos WHO' E. Rice/Interfoto MTII Spoon- erIE. Rice) variety of methods needs to be available. Some women are prepared to make the effort to take a pill every day to avoid unwanted pregnancies; some prefer an intrauterine device, which provides near- ly as good protection against pregnancy and requires essentially no further action on their part once it has been inserted. Certain couples wish to avoid drugs and mechanical devices and instead rely on periodic abstinence from intercourse; others, if their family is complete, request an irreversible procedure such as tubectomy or vasectomy. Such prefer- ences are often culturally determined but also differ between individuals in the same community. Moreover, the ease with which a given fertility regulating method can be provided depends on the prevailing health service conditions, level of education, and other local factors. Contraception differs from most other forms of treatment also in other ways. For one thing, most methods interfere with normal body processes. These being reproductive processes, there is always a possibility of an effect on subsequent generations. Since it is practised by mil- lions of people, even though healthy, it can be anticipated that, owing to consti- tutional factors, the proportion of them that will have side-effects or more serious reactions will amount to quite a large number. Moreover, in most situations where people take drugs, they will do so only for the duration of their illness, and under medical supervision. In contrast, birth control measures may be used con- tinuously for years, even decades, and, since the users consider themselves heal- thy, with little or no supervision. Another problem health authorities have to face is that birth control methods will be wanted in areas where endemic parasitic disease or malnutrition may be prevalent. All users, therefore, may not be healthy. What methods would be most suitable, which contra-indicated? Maybe the greatest problem for au- thorities, besides a technology that is still far from adequate, is how to get the ser- vices to the population, particularly in the rural areas of developing countries. These services comprise many activities, for instance providing the information required to allow people to choose the methods that suit them best. Given the sensitivity that surrounds matters concerning sex and reproduction, this is no simple matter. Many of the methods of fertility regulation require special knowledge and skills on the part of the service provider. It may be difficult to add yet another function to the already overburdened personnel. Family plan- ning has been recognized as an integral part of primary health care. The chal- lenge is how to make it, together with the other elements of essential health care, 5 research in family planning "universally accessible to individuals and families in the community by means acceptable to them, through their full participation and at a cost that the community and country can afford" (WHO/UNICEF definition of primary health care). Why research? Many of the problems listed above cannot be resolved simply by increasing inputs of services or funds. Research is needed to assess the safety, in different populations, of present methods of fertil- ity regulation; to devise appropriate ways of making them available; and to develop new methods that are safer, more effective, more acceptable, simpler to use and to provide, and of low cost. It is surprising that, in this day and age, questions such as the following are still unresolved : do hormonal contraceptives cause cancer? can intrauterine contraception lead to infection and sterility? can the time during the menstrual cycle during which a woman is fertile be accurately and simply identified by her? does the taking of other drugs affect the efficacy of the pill? what are the risks to subsequent preg- nancies from abortion used as a method of birth control? are any of the thousands of plants used for birth control in different parts of the world in fact effective and safe? what is the likelihood that sterilization in men or women will lead to physical or psychological disturbance? These are but a few questions, and they relate only to presently available technology. Many can also be raised on the psycho-social aspects of family plan- ning and the delivery of services, such as : what affects people's choice of birth control method, and continuation of use ? which are the best ways of informing the public about family planning? can traditional birth attendants be trained to provide modern methods of family planning? Besides the unresolved questions about the safety of current methods, many of them suffer from practical dis- advantages, and the number of methods is still very limited. From the point of view of personal convenience, a weekly, monthly or three-monthly pill might be very attractive to substantial parts of the population. Some women would appear to have greater faith in an injection which might be administered every 3, 6 or 12 months; the present injectable con- traceptives are few in number and still have major drawbacks. Rather than be- ing kept under continuous contracep- tion, other women might prefer, if it were available, taking a pill only after inter- course, or even only after they have noticed a missed period. For those couples who wish to avoid drugs and mechanical devices and who prefer to rely on periodic abstinence, a fool-proof technique to predict the onset or the fertile period would be of immeas- urable help. This would increase the effectiveness of these methods and decrease the period of enforced con- tinence. It is not only the women's libera- tion movements that are asking that men take a greater share in family planning. There is wide demand for pills and injec- tables for men who at present are limited to condoms, vasectomy and the more traditional methods of family planning. Where abortion is legal, authorities are asking for simpler techniques that do not require invasion of the uterus or hospi- talization. The increasing popularity of sterilization in many parts of the world and the fact that younger women are resorting to it is leading to a demand for reversible methods of sterilization. Last- ly, the popularity of immunization has led to requests for vaccines for birth con- trol, to be used by men or women. Regarding infertility, why is it still im- possible to diagnose, let alone treat, the causes of infertility in a substantial pro- portion of those affected? Some of these, and many other ques- tions, are raised in this issue of World Health and illustrations given of the kinds of research which should give an answer to them. How much research? The need for research in this field has been brought out repeatedly and force- fully in the past decade. What is amaz- ing, however, is how small the total world input is in research on the biomed- ical and service aspects of fertility regula- tion : government allocations for this field represent only about one per cent of their expenditures on health research. Moreover, industry's investment in research on fertility control is rapidly disappearing because of its increasing complexity and costliness. These may be some of the reasons why reproduction, as a field of scientific en- deavour, occupies one of the least privil- eged places in biology, medicine and pub- lic health. It suffers from an acute short- age of manpower and of facilities. This is true everywhere and particularly in the developing countries. As a result, WHO was asked by its Member States to intensify and interna- tionalize research in this field and to strengthen national capabilities for such research. The WHO Special Programme of Research, Development and Research Training in Human Reproduction involv- ed in 1977 scientists from 69 countries, of which 45 are developing countries. The research is essentially collaborative, with scientists from different institutions and countries planning and conducting the re- search together. It also involves many disciplines, such as reproductive biology; obstetrics and gynaecology; organic, polymer, phyto- and biochemistry; pharmacology; toxicology; veterinary sciences; endocrinology; bioengineering; immunology; epidemiology; sociology; psychology; anthropology; statistics; operations research; and health eco- nomics. A major effort in the WHO Pro- gramme, in cooperation with national authorities, goes into building up self- reliance in developing countries for research on fertility regulation through the strengthening of their institutions and through a research training effort that is now the largest in the field. The aim is to develop resources for national family planning programmes to carry out research, adapt technology, interpret advances made elsewhere, and permit the full contribution to the field of scientists from developing countries. This institu- tion-strengthening involves much more than technical and financial inputs by WHO: it is a "learning by doing" process in which the developing countries' institu- tions are actively participating in and contributing to the international research effort. This programme of research is practi- cally entirely supported by voluntary contributions of governments to WHO. The response of scientists to join in this international collaborative effort has been extremely positive, reflecting the in- tellectual challenges of the field and its immediate social relevance. ■ 6 FAMILY FORMATION AND HEALTH: the story of a study by Virginia Balderrama-Guzman i everal studies have indicated that the health of the family, especially of mothers and children, may be affected by patterns of family formation, par- ticularly the age of mothers at pregnancy, the intervals between the births of children, and the total number of children. Most of these studies have been conducted in Europe and the USA. Their results have shown the harmful effects of pregnancy at too young or too old an age, or at too close intervals, and of large family size. These findings have formed the basis for what is known as "the health rationale for family planning". Health authorities in developing countries asked to what extent these relationships prevailed in their eco- nomically less privileged communities. For this reason, WHO organized a nine-country collaborative study, in which institutions in Colombia, Egypt, India, Iran, Lebanon, Pakistan, Philippines, Syria and Turkey par- ticipated. Besides examining the interaction between family formation and the health of the family the study addressed itself to a number of other questions such as whether high child loss in the early stages of a woman's B reproductive life leads to higher subsequent fertility. These photographs illustrate the different stages in the study, as it was carried out in the Institute of Public Health, University of the Philippines, Manila. The detailed methods and results of the study in the Philip- pines, together with those from four other countries, are described in the wHo publication "Family formation patterns and health" (1976). Two study areas were selected, one urban, one rural. The rural study area shown is about 50 kms from Manila. General orientation on the purpose of the study and careful de- scription of the methods to be used are an essential part of any study involving a large research team. The purpose of the study and its logistics are presented to the C Mayor before the research project is started. 7 D. The project director meets with lead- ers of the community on a Sunday morn- ing at the home of the President of the Women's Club. What the study involves (household survey, interviews, medical examinations, intelligence tests) is carefully explained and the collabora- tion of the community leaders enlisted. This too is essential to the smooth oper- ation of a project. Over 4,000 women under the age of 45 were interviewed in their homes. Women were asked about their back- ground, their pregnancies; illnesses in the family during the past month ; child deaths in the past ; what they thought to be the ideal family size; what they knew and did about birth control; and how im- provement in their children's survival would affect their practice of family planning. At the home interview, record cards were made out for each woman and for her children under the age of five. She was given an appointment for herself and the children for physical examina- tions at the health centre. Transport was provided to the mothers and children from the rural areas to go to the health centre. This enabled nearly 7,000 per- sons to have physical and laboratory ex- aminations. • et One of the difficulties encountered in the rural areas was the reluctance of many women to submit to a gynaecolog- ical examination, even when carried out by a woman health worker. Neverthe- less, three-quarters of the women had a gynaecological examination. All the 3,746 children under age five who were examined were seen by the same paediatrician. The examination focussed on physical abnormalities and diseases, nutritional diseases, history of illness, and use of medical services in the pre- ceding month. G. A complete physical examination was carried out on each woman. Blood pressure was measured after 15 to 20 minutes of rest. Blood samples were taken for haematological examinations. J. Height and weight were measured by two anthropometrists, and the laborato- ry investigations (haemoglobin level and stool examinations for parasites) were conducted by three technicians. K. Intelligence tests were given to the older children (aged 8 to 14) of the women in the study. In all, 1,300 rural and 900 urban children were tested, us- ing a method which is supposedly appli- cable in all cultures. Although it worked well in the Philippines, it gave rise to dif- ficulties in some of the other collaborat- ing centres. L. The study included an assessment of the family's dietary intake. The dietician stayed in the house from early morning until late evening. All foods were weighed and converted into units of nutrients using the Food Composition Table of the Philippines. some findings There was a clear relationship between pregnancy wastage (stillbirths and abortions) and maternal age in both the rural and urban areas. It was slightly higher in the earlier age groups than in the twenties, remained at the same level until the end of that decade, and rose steeply after the age of 30. The mortality of the children of urban women was highest when the mothers were under 20 or over 35. For the rural woman, mortality of offspring was highest in the youngest women. In both the rural and urban areas, child mortality declined as there was a longer in- terval between births. The harmful effect of short pregnancy intervals came out, however, more clearly in the results of other collabo- rating centres. Haemoglobin, height, weight and intelli- gence quotient were proportionately lower in the children from larger families. The women who had had the largest number of pregnancies had the largest num- ber of gynaecological disorders, even allow- ing for age. Women who had lost children in early reproductive life ended up, not with smaller, but with larger numbers of children. They would thus seem to have over-compensated for anticipated child loss. This emphasizes the close relation between levels of infant mortality and the practice of family plan- ning. Laboratory measurements included haemoglobin, serum protein and vitamin determinations, and urine and stool examinations. Fears had to be dispelled that the blood was being sold to hospitals or used for witch- craft. The study uncovered a considerable amount of sick- ness among the mothers and children. This was treated without charge. 0. Editing and coding of questionnaires and other data collection forms, subsequent transfer of data to punch cards and verification were done by the statistical team. M how safe is the pill? Millions of women throughout the world find the Pill effective and acceptable ; the overwhelming majority experience no ill-health as a result by Ron Gray fr he use of hormones for con- traceptive purposes is a relatively recent medical advance. Only in the 1950s did researchers discover that two types of hormones, called estro- gens and progestogens, could in combi- nation act as a highly •effective con- traceptive. These substances are the con- stituents of combined oral contracep- tives, commonly called "the pill", which first became available for general use in the United States in 1960. The pill was rapidly adopted in many other countries, and the growth in popularity of this drug has been such that, according to present estimates, more than 80 million women around the world are currently using the pill. This is a unique situation in modern medical science, since never before have such a large number of healthy young women taken potent hormonal drugs over long periods. Not suprisingly, the situation has caused some concern to the authorities responsible for drug safety in many countries; and not unnaturally, women who are actually taking these drugs, or who have used the pill in the past, are legitimately concerned that it may affect their health. The evaluation of drug safety is ex- tremely complex, and although there are certain health risks associated with the use of the pill, it is important to place them in a proper perspective. They must be balanced against the potential hazards associated with the unwanted pregnan- cies that might have occurred if the wom- en had not been using the pill, or against the risk associated with other forms of contraception or abortion. This weighing of risks, which is still the subject of study and debate, is a difficult matter of statis- tical and medical judgment. Many drugs lead to so-called "side-ef- fects" which, though troublesome, are not life-threatening medical conditions. With the pill, many women experience relatively minor side-effects such as nausea, weight-gain, changes in mood, problems with their complexion, and so on. These may respond to medical treat- ment, or may be so unacceptable that some women stop using the pill. But it is very difficult to measure the impact of such side-effects on health. Most of the questions of safety to be considered here deal with much more serious medical complications. Many of the short-term complications that occur during or shortly after starting to use the drug are associated with the heart, blood vessels or blood pressure (the cardiovascular system), or changes in the body chemistry. Numerous studies have assessed the potential risks associat- ed with these short-term complications, and these will be described later. However, there may be longer-term problems which may result from either very prolonged pill taking, or which do not occur until many years after a wom- an has stopped taking it. The pill has only been widely available for 18 years, and few women have individually ex- perienced both prolonged use of the drug and the intensive medical follow-up required for proper evaluation of any long-term effects. Therefore existing evi- dence can only be applied to a relatively limited life-span, and it is not possible to predict problems that may arise in the future. Before considering the medical evi- dence for health risks associated with the pill, it is necessary to describe some of the safety screening that is undertaken prior to the release of drugs for general use. In many countries, the drug regula- tory authorities lay down stringent rules for testing drugs, both in animals and in carefully controlled studies on humans, before such drugs are released for use on a wider scale. Over the years, the require- ments for drug testing have become more and more rigorous. The pill was intro- duced before the present stringent stan- dards for drug safety screening were adopted, but over the years the various brands in current use have undergone ex- tremely careful and continuing testing. Despite the careful testing, there are still many relatively uncommon compli- cations which cannot be detected until the drug has been used on a very large scale. For example, if an illness usually affects one person per thousand per year, and the drug increases the risk of this ill- ness fivefold, to five cases per thousand, it is highly unlikely that the association between the drug and this illness will be found until it has come on to the general market. In addition, many complications could not have been accurately predicted from the screening and testing of drugs in animals or in clinical trials. One difficulty about research on drug safety is that drugs seldom cause ill health in the absence of other predispos- ing factors; they usually interact with other conditions to cause disease. This means that only a certain minority of women in a population may be at serious risk of complications and, equally, it may be very difficult to generalize the results obtained from research in one Risks of pill use, smoking and childbirth Women in the United Kingdom who both smoke and take the pill run a much higher risk of death than women who do not smoke and/or do not take the pill. However, the risks of pill-taking must be balanced against the risks of unwanted pregnancies. In Britain, deaths due to childbirth are very few, but in countries such as Mexico or Bangladesh childbirth is much more hazar- dous. It must be remembered, however, that virtually no information is at present vailable on adverse effects of the pill in developing countries. 12 UNITED KINGDOM 1 1.1 kb,_ Deaths due to pregnancy in different countries Pill use among non- smokers 13.8 Smoking without pill use 8.9 No pill use and no smoking 3 90_ 80_ z w 60_ 0 O O O 0 50_ cc Lu 0 cf) I < H 0 4 _ 0 30_ 20_ 10_ 70_ 100 Dr Gregory Pincus (1903-1967) of the USA, "Father of the Pill". (Foto Italia, Milan ©) Pill use plus smoking 39.5 Deaths in UK due to circulatory diseases associated with pill use and smoking BANGLADESH 93.5 MEXICO country to another, if the background risk factors differ considerably. One of the most serious problems en- countered with the pill is that the estro- gen component tends to increase blood clotting. But it was not until the pill had been in general use for eight years that researchers in Oxford first showed an as- sociation between the use of oral con- traceptives and an increased risk of blood clots (thrombo-embolic disease) affecting the veins of the leg, lung and brain. Subsequent research both in the United Kingdom and the United States has confirmed these findings, and has also shown that the use of oral con- traceptives is associated with an in- creased risk of heart attacks (myocardial infarction) and of high blood pressure (hypertension). This catalogue of cardio- vascular conditions linked with the pill is daunting, and to it can be added other illnesses such as an increased risk of gall bladder disease, migraine and diabetes. Balanced against these increased risks are the pill's protective effects. For in- stance, benign tumours of the breast and ovary, severe menstrual disorders and rheumatoid arthritis all tend to be less common among users of oral contracep- tives. We also have to consider the risks of illness associated with other forms of contraception, pregnancy or abortion. With so many competing alternatives of risk and benefits, it is very difficult to draw up a final balance sheet for the pill, particularly since some illnesses such as heart attacks or strokes are far more serious than others such as migraine or menstrual disturbances. In the end, the relative hazards of oral contraceptives must depend upon the deaths which can be attributed to their use. It has taken almost two decades to arrive at scientifically based estimates of the excess risk of death (mortality) asso- ciated with the pill. These studies have mainly been conducted in Britain, and the results may be summarized with a few statistics. Non-pilltaking British women aged 15 to 49 years have an over- all death rate from cardiovascular dis- eases of about 5.5 per 100,000 per year. By comparison, the death rate among oral contraceptive users who do not smoke is estimated to be about 13.8 per 100,000 per year, and among those pill users who do smoke, the death rate is thought to be around 39.5 per 100,000 per year. The risk of death increases mar- kedly among women over the age of 35, especially if they are also smokers, and Women receiving their supply of contraceptive pills at an Egyptian family planning clinic. ( Photo WHO/M. Jacot) have used the pill for long periods of time. These statistics are, of necessity, an over-simplification of the position, but there is now no reasonable doubt that, in industrialized societies, the pill leads to an excess of deaths from cardiovascular disease. However, two mitigating con- siderations must be borne in mind. First- ly, some of the current evidence applies to brands which contained very high doses of estrogen and are now no longer in widespread use. The new lower-dose formulations are likely to have a reduced health risk. Secondly, although adverse effects of the pill are severe and should not be dismissed lightly, the conditions causing death are relatively uncommon. The medical journal Lancet which pub- lished recent studies on pill-associated mortality commented : "Little in this week's Lancet is going to dismay the many women who regard oral contracep- tives as a blessing which carries a minute risk of premature death. The doctors 14 rtninpitullii THE ORAL PILL dinth IfIBUwaanl NOVEMBER 51,711 ;111 ■ 1, suw, MOM THE unamiluth MENSTRUATION .L WOO MR 9 %116'4' FM MX .*(:)* 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 how safe is the pill? whose task it is to interpret this news will have to say the danger now appears to be greater than it once seemed, but it is still, in the absence of other risk factors, very small indeed for younger women." However, both the Lancet editorial and the British committee for the Safety of Medicines emphasized the very marked increase in risk among pill users over the age of 35 who smoke, are overweight or have diseases such as diabetes. Almost all the studies in the associa- tion between pill use and cardiovascular disease have been undertaken in indus- trialized countries where women fre- quently have characteristics which place them at high risk of cardiovascular ill- nesses. They often have weight problems, they take relatively little physical exercise and many smoke cigarettes. In most developing countries, this is not the case and the cardiovascular hazards may be substantially lower. In addition, the high risk of death associated with childbirth in most non-industrialized countries may more than offset any pill-related ill health. However, further research is required. and WHO is undertaking an active pro- gramme to evaluate pill safety, especially in developing countries. For example, studies are being conducted on its effects on types of heart disease, such as rheu- matic fever, which are common in the developing world. The possible interac- tion between the drug and various infec- tions or parasitic diseases is also under investigation, as is the pill's possible in- fluence upon vitamins in societies where poor nutrition is prevalent. It is well known that many tumours occurring in women are related to the natural production of hormones within the body. So it is important to assess the significance of external hormones such as the pill in relation to such tumours. A great deal of research has been done on laboratory animals such as the rat, mouse, monkeys and dog. Over- whelmingly, most of this work has sug- gested that the drugs used in the pill today have no propensity to cause tumour development in animals. In humans, the situation is extremely complex, because it often takes a long time for tumours to develop and we have not had long experience with the pill. Furthermore tumours occur relatively infrequently during the reproductive ages when women use it, and we have in- sufficient information on the effects of prior pill use on tumour development among older post-menopausal women, in whom such tumours occur with great- er frequency. In 1977 WHO convened a meeting of in- ternational experts to consider these diff- icult questions, and the Organization is currently embarking upon an extensive research programme to evaluate the risks that might be associated with the pill and other hormonal contraceptives. The ex- perts concluded that pill use for more than two years reduced the risk of benign tumours or "lumps" in the breast, and this protective effect appears to be asso- ciated with the progestogen component. However, the evidence available thus far suggested neither an adverse nor benefi- cial effect on the risk of breast cancer. After a very careful and extensive review of a large amount of scientific evidence, the group of experts felt that there may Malaysian poster explaining the use of the pill. ( Photo WHOIUNFPAI D. Roger) be "an increased risk of early forms of cancer of the cervix (the lower part of the womb) among women who have used the pill for a long period of time, and who have other' characteristics, such as an early age of first sexual activity, which predispose to this disease". There is evidence of a marked increase in the risk of certain benign liver tumours among women who used it over long periods, but such tumours are ex- ceptionally rare among women under 45 (in the United States the disease occurs at a rate of five cases per million per year). The chances of a pill user develop- ing the disease is estimated to be three per 1 .00,000 per year for women un- der .30. The risk among older women may be substantially higher but cannot at present be estimated. What are the possible effects on the health of children whose mothers have recently used the pill, accidentally took it during pregnancy or used it while breast- feeding? A number of studies have assessed the effect of the pill on subsequent pregnan- cies, and most suggest it may delay the next conception for about two months but has no harmful effects. But this is a difficult area of research and the possibil- ity of rare adverse effects cannot be ruled out at present. The effects of accidental pill use during pregnancy are also sub judice. There is some evidence of a higher risk of abnormalities resulting in miscar- riages or, very rarely, in live-born infants with heart defects, but the research find- ings are inconclusive. In many societies prolonged breast- feeding is of vital importance to the health of infants, and there is evidence that the pill can decrease the amount of breast-milk. Some national authorities have advised women either not to use it while breast-feeding, or only to use it once lactation is well-established. The hormones contained in the pill have been shown to enter the breast-milk and to be absorbed by the breast-fed infant, but the actual amount is very small and no adverse effects have been demonstrated. WHO is collaborating with several coun- tries in examining the effects of the pill both on breast-milk and on the health of breast-fed infants. Clearly the question "How safe is the pill?" does not lend itself to any simple answers. Despite the actual and potential health risks, many millions of women throughout the world find it an effective and acceptable method of fertility con- trol, and the overwhelming majority ex- perience no ill-health as a result. Increas- ingly, however, research is identifying particular sub-groups at special risk, such as women over 35 who smoke. It would, with the evidence available, seem prudent for these women to use other methods. For the larger number of young women who do not have such ad- ditional risk factors, the pill would seem to be a safe and reliable contraceptive. There probably will never be a final and all-embracing answer to the ques- tion. The answer will vary, depending upon the health of the individual woman and the general health problems or health services in different countries. In the final analysis, it will be for each wom- an and her health care adviser to decide whether to go on using the pill, in the light of current medical knowledge. ■ 15 plants to control fertility Six centres around the world are collaborating with WHO in the search for acceptable, safe and inexpensive fertility regulating agents which derive from plants by Djaja D. Soejarto Ai! esa is a Jivaros Indian in Amazo- nia who was married as a child to a man she hated. After several years with him and bearing one child, Tesa sought the advice of several older women in the tribe. They gave her a plant root and described its use—one dose and Tesa would be infertile. Tesa followed their directions and had no more children. Eventually her husband left her for another woman, one who could give him the sons he wanted. Tesa later remarried, and once satis- fied that this marriage was a good one, decided to have another child. The wom- en of her tribe also knew how to promote fertility, if desired. The root of another plant, when chopped up and swallowed would make a woman fertile again. It did so for Tesa. She and her second husband now have four children of their own. For many couples in developed coun- tries, fertility regulation is next to fool- proof. The birth control pill is readily available and considered safer and equal- ly effective as Tesa's root. On the other hand, in most developing countries, modern contraceptive devices and medi- cations are simply not readily available. When made available, these modern con- traceptives are often too expensive, too complicated to use effectively, or may not be readily accepted by the people. While fertility regulation may be prac- tised routinely by certain isolated indige- nous cultures (many explorers have reported low, constant birth rates main- tained in certain societies), this fertility- infertility information is not shared openly with the rest of the world. But why is it that modern science has not been able to discover a natural, effec- tive, fertility regulating substance, that can be taken by women to prevent conception, can enhance fertility or regu- late the female reproductive cycle, or can be taken orally to control the reproduc- tive process in men? The plant kingdom is a virtual treasure- house of potential drugs, having pro- vided mankind with useful agents to cure or allay its ills from earliest times. In fact, the use of synthetic or purified compounds as drugs is relatively recent, since crude extracts of plants and animals have had to satisfy human requirements for centu- ries. The entire health care system of 800 to 900 million individuals in the People's Republic of China is based on the use of the best of Traditional Chinese Medicine and Western Medicine, and this lead is being increasingly followed in the deve- loping countries of the world. Tradi- tional Chinese Medicine actually com- prises about 15 per cent the practice of acupuncture and 85 per cent the use of plant, animal, and mineral materials. The fact that such large numbers of people still depend on plants as drugs, together with evidence that such plants have useful biological effects, should in- dicate their potential value as sources of fertility regulating agents. Although no plant has yet been shown by contempo- rary scientific standards to exert such effects in humans, there is sufficient wealth of peripheral evidence to warrant an organized major effort in this area. However, it is often claimed that the evidence in support of such activity in plants is unimpressive, consisting mainly of varying accounts in folklore. In addi- tion, a reasonably large body of scientific literature exists about extracts of plants which have been studied either in vitro or in vivo in a variety of model systems and/or animals. The practical signifi- cance of these reports is difficult to ass- ess. The conditions of the experiment are often inadequately described or the control data inadequately reported. The experimental design may not necessarily relate to the effect described in folklore, and there is often reason to believe that the plant being evaluated may not have been correctly identified. Furthermore, a great deal of publicity has been given in the past to such plant- derived agents as the oestrogenic isofla- vones, steroids and so forth which, though predictably of little practical value in human fertility regulation, may be of economic significance because they impair animal fertility, especially that of livestock. Scores of powerful uterine stimulant compounds have been isolated from plants, with the implication that these compounds might prove useful in fertility regulation. These have mostly been studied only in vitro, and it may be that a reassessment of this type of agent, using additional test models, could prove of value. The only plant principles that have been found useful in humans for condi- tions related to fertility regulation are the alkaloids sparteine and pachycarpine. But while these have been used as aids in the delivery of the foetus at term, and to prevent post-partum haemorrhage, they cannot be used to regulate fertility in a practical way, and are not effective in in- ducing abortion in the early stages of pregnancy. Perhaps the most intriguing of the agents found in plants, and one which has been studied extensively in humans, is m-xylohydroquinone, a simple aro- matic compound first isolated in 1952 from the common garden pea, Pisum Samples of plants that are being investigated. Right: Diospyros tricolor Hiern. A coastal shrub from tropical West Africa, whose root is used by certain communities in Ghana to regu- late fertility. Far right: Moringa oleifera Lam. A plant of tropical Asia, widely used in native medicine to provoke abortion and to diminish the secretion of milk. ( Photos WHO/D. Soejarto) 16

sativum L. Initial interest in the pea plant is said to have been at least partly based on the belief in a cause-and-effect rela- tionship between the fact that peas con- stitute the major protein staple of the diet in Tibet, and that the population there has remained essentially static for the past 200 years. This agent is reported to have anti-fertility activity in several species of laboratory animals, and dur- ing the late 1950s it was extensively eva- luated in women subjects in India. But it was abandoned when it proved to be only about 60 per cent effective in pre- venting conception. In retrospect, however, might it not be that m-xylohy- droquinone was insufficiently studied in the light of what is now known about ex- perimental design, patient non-compli- ance, and other testing modalities? A thorough re-evaluation of this intriguing substance derived from peas might prove worthwhile. Although no useful and safe fertility regulating agent has been found in plants, the varied types and the volume of data still keep tempting us, as a cookie- jar tempts little children. They know what should be in the jar and what the reward will be if it contains what they ex- pect, but they are often reluctant to remove the lid for fear of finding the jar empty, or of being punished for violating traditional taboos. Given the proper planning, guidance, personnel, financial support, and recognition of the problems to be overcome, the right. kind of re- search programme may yet be successful. The most useful information is likely to evolve from plants which grow in the Third World, since in most developing countries, the use of traditional medicine is widely accepted and trusted. The dis- covery of effective agents from the flora of these countries will eventually prove economically beneficial, while the neces- Left: This is the entire plant, Moringa oleifera Lam., whose flower appears on the previous page. For purposes of identification, all vouch- er specimens that accompany plant samples must have flowers and/or fruits. Above : With localhelp in the village of Botia- , nor ; Ghana, Dr Soejarto presses herbarium specimens as vouchers of the plant samples collected in the WHO Programme. ( Photos WHO/D. Soejarto) nary development of scientific personnel and expertise will enhance their overall research capabilities. If a programme to discover effective fertility regulating agents is properly organized, only those plants which yield substances with few side-effects and with action mechanisms that differ from currently available sub- stances need be developed. It might be said that, in the 15th centu- ry, folklore was science; today the same 18 plants to control fertility folklore may or may not be science. On the other hand, what is considered science today could suffer the same fate in the 25th century. In order to establish the validity of folklore claims about her- bal preparations as fertility regulating agents, all information has to be seen in its proper perspective, and the credibility of such information has to be studied from every possible point of view. This is often difficult, even impossible, yet virtu- ally every drug obtained from plants would have remained undiscovered if someone had not carried out such an analysis. For example, a recipe taken from the Ebers Papyrus of 1550 BC says : "In or- der to cause that a woman should cease to conceive for one year, two years, or three years, use tips of acacia; triturate with a measure of honey, moisten lint therewith and place in her vulva." Should we accept at its full value that "tips of acacia", when placed in the vul- va, will prevent a woman conceiving for periods up to three years? Let us first ex- amine the basic chemistry of acacia. The tips of the acacia shrub exude gum ara- bic, a polymeric carbohydrate material. Under fermentation, the carbohydrate liberates lactic acid anhydride, which dis- solves readily in water to form lactic acid. Lactic acid is known to be spermi- cidal. So this ancient prescription might have been effective if used on a regular basis. However, the implication is that it was used once only, and that a long period of sterility resulted. Should all the information gleaned from such a pre- scription be discounted, simply because the implication seems unreasonable? Nomenclature presents another prob- lem. One of the oldest known herbals, that of Culpeper from about 1650 AD, frequently mentions plants which, when used in a specific manner, manage to "bring down a woman's courses". Is it unreasonable to believe that the action of this plant extract is to induce menstrua- tion, and that it might thus act as an ef- fective means of fertility regulation? Similarly, might we not be on solid ground when we find mention made of a plant taken by men to control excessive sperm production, and interpret this as having an application in male fertility control? Ruta graveolens is documented in the older folklore literature as having been used to produce abortion in Argentina, China, Mexico and the Philippines. Sure- ly the reporting of an identical use for a plant in these geographically distant areas increases the credibility of this in- formation? The amount of available information relating to traditional applications of plants for fertility regulation is almost in- exhaustible. It stems from ancient her- bals, field observations by botanists, physicians and travellers, the pharmaco- poeias of various countries, systems of indigenous medicine, such as Ayurvedic Medicine in India, and many other sources. But there is no systematic man- ner in which all this information can be gathered with confidence. Nevertheless we have managed to organize data on more than 3,000 species of plants to date, and some of this information must surely be valid. To date we have found that about 120 different countries have tradi- tionally used such plants in one way or another. After two years of intensive planning, the Task Force on Indigenous Plants for Fertility Regulation at wHo initiated a collaborative effort involving scientists and institutions located in Brazil, Hong Kong, the Republic of Korea, Sri Lanka, United Kingdom and USA. The function of these centres is to establish whether or not the alleged traditional uses for plants as fertility regulating agents can be con- firmed in the laboratory, and to isolate and identify the active principles. The selection of the plants is based on com- puter analysis. A major problem was to determine where, in a given geographic area, each plant could be collected in sufficient quantity to satisfy the requirements of the programme. Timing is of impor- tance, since in most instances a plant should be collected when it is in a flower- ing or fruiting condition, in order to as- sure adequate identification. At least one of the reference specimens is deposited in a major herbarium of the country of ori- gin. Next, each plant has to be carefully dried, packed, and shipped to the as- signed centre for further studies. Arr- angements must be made for appro- priate export and import permits, and to ensure that the plant samples are free from insects and other pests. Detailed records are made by the WHO consultant botanist, who works in close collabora- tion with expert colleagues in each coun- try where the plant collections are made. When the plant samples arrive at each centre, one or more extracts are prepared from each plant, using the same methods of preparation as in the folklore refer- ences. Each plant is then tested in an in vitro or in vivo system that is appropriate to validate what is claimed for it. The protocols used by each centre are identi- cal and control measures have been in- corporated so that all biological testing can be reproduced in any one of the centres. For in vitro testing, a protocol was established in which the plant extract is introduced into a container containing a strip of rat uterine muscle. If the uterine muscle contracts, this is preliminary evidence that a useful uterine stimulant might be present in this extract. The next step is to add a series of chemical substances to the uterine prep- aration that are known to prevent the contracting effects of uterine stimulants. If the uterine muscle does not contract when the plant extract is subsequently added, this indicates that a potentially useful uterine stimulant is absent. The plant extract is then administered to rabbits that are 29 days pregnant. If the rabbit aborts, we consider this as reas- onably good evidence to continue work- ing on the plant. However, built into the operating procedures is a stipulation that no chemical work can be carried out on a plant until an additional centre also tests the same plant and finds it to be active. For various reasons, one laboratory can produce a given biological effect in ani- mals while another cannot reproduce this result. Only then will the chemists begin the tedious and arduous task of isolating the active principle or princi- ples. Many more tests will follow before, eventually, large-scale human studies will be carried out to establish efficacy, side-effects and safety. Parallel with the study of an active compound from dis- covery to human testing, there will be a need to isolate large quantities of the compound and/or to develop syntheses if this seems practical. It is too early yet to determine whether or not the unique approaches being fol- lowed by WHO in the search for effective, safe and inexpensive fertility regulating agents from plants will be productive. That the programme is innovative means that there are bound to be a certain an- ticipated number of "blind alleys" and frustrations. The untapped potential of these efforts, however, serves only to in- fuse enthusiasm into those associated with the WHO programme. ■ 19 Bladder Vas deferens Urethra Spermatozoon Penis Testis Scrotum Seminal vesicle Prostate 1. Male reproductive system Uterus Ovary Developing OVUM Cervical mucus— thick, sticky, opaque Endometrium Cervix Vagina Fallopian tube Hymen 3. Preovulatory infertile phase Endometrial lining thickest Cervix—firm, closed PRO-GESTERONE Corpus luteum Cervical mucus—very thick 5. Postovulatory infertile phase EDVARY ESTROGEN PROGESTERONE Endometrial lining thickening Fallopian tube ItiPtiiiNtil" Ovary Cervix—soft, open ESTROGEN Follicle Cervical crypt Cervical mucus—watery, clear, like raw egg-white 4. Fertile phase BRAIN Pituitary stimulates inhibits (feedback) 7. Regulation of hormones natural family planning by Jeff Spieler he so-called natural family planning (NFP) methods ap- peal to people who wish to use the pattern of fertile and infertile phases of the menstrual cycle to regulate their fertility, or who do not wish to use drugs or devices either because they are concerned about their side-effects or for reli- gious or other reasons. NFP has not been shown, in gene- ral use, to be very reliable for limiting births, although it does appear to be useful as an aid for spacing or achiev- ing pregnancy. The successful prac- tice of NFP depends greatly upon the quality of the instruction provided and the degree of understanding and motivation of the user. For this reason, a number of interested groups and governments have requested WHO to undertake research aimed at evaluat- ing and improving the educational component of NFP. In order to meet this request, the Special Programme of Research in Human Reproduction—with the as- sistance of WHO's Education Com- munications Systems unit and the WHO Collaborating Centre for Edu- cational . Technology, London—has developed educational materials that could form the core of a standardized curriculum for teaching NFP. The materials are intended for use by non-physicians ranging from nur- ses to lay members of a community who are interested in becoming NFP instructors. A research project aimed at evaluating these materials and Designed by the British Life Assur- ance Trust, WHO Collaborating Centre for Educational Technology, London. 20 Ovary Bladder Urethra Liter Endometrium Cervix Clitoris Vulva Labia Minora Labia Majora Fallopian tube Hymen Vagina Anus 2. Female reproductive system OVULATION HIGH TEMPERATURE LOW TEMPERATURE N O I lsv 'M zl IS N 6. Basal body temperature Lining Cervix modifying them to make them more culturally acceptable is at present being undertaken in Colombia, Kenya, the Republic of Korea, the Philippines, Canada and the United Kingdom. Some understanding of reproduc- tive biology is considered essential as a foundation for learning NFP. Many people learning about the structure and function of the human body for the first time may feel inhibited and timid about looking at anatomical diagrams and discussing the various parts of the male and female repro- ductive system (figures 1 and 2). However, it is stressed in the educa- tional materials that learning about the body is necessary for teaching and learning about NFP. In NFP a woman is taught to iden- tify the fertile and infertile phases of the menstrual cycle by observing changes in the body which occur around the time of ovulation. Figures 3, 4 and 5 are used for teaching about the menstrual cycle and demonstrate the progressive changes occurring in the ovary, endometrium and cervix during the different phases of the menstrual cycle. One method of NFP, the Billings ovulation method, is based on obser- vation by the woman of a sequence of changes in the quality and quantity of cervical mucus. Cervical mucus is the fluid produced by the cervix which appears as a normal vaginal discharge. The cervical mucus chan- ges from a thick, sticky, opaque fluid to a thin and watery, stretchy clear fluid around the time of ovulation. Women can be taught to identify the infertile and fertile days of the men- strual cycle by paying attention to the sensation produced by the mucus and its appearance. The measurement of basal body temperature is an integral part of certain methods of NFP, e.g. the sympto-thermal methods. Figure 6 is used to diagrammatically explain why the basal temperature of the body increases after ovulation. Of course, a greater level of under- standing and knowledge is required to teach NFP than to practise it. Fi- gures 7 and 8 are used to illustrate for teachers of NFP how the hormones of the pituitary gland affect the ovary and uterus, and the changes that oc- cur in the ovarian cycle, respectively. In addition to basic reproductive biology the educational materials contain modules on the ovulation method, the sympto-thermal method and the psycho-sexual and behav- ioural aspects of NFP. The purpose of the research con- ducted by WHO in this area is to de- termine what is the minimal essential information required to properly teach and effectively practise NFP. ■ 21 L n these days of extremely rapid tech-nological progress, it may seem hard to understand why the development of new birth control technology is still such a slow process. The explanation is that drug development in general is a slow process. In addition, fertility regu- lating agents and methods are intended for use by millions and millions of heal- thy subjects over prolonged periods of time. Therefore their use must be safe and without any long-term health hazards. To prove safety is a time- and money- consuming enterprise. It takes generally some 10 to 15 years (and an expenditure of as many million dollars) before a scientific discovery can be translated into a widely available fertility regulating agent. Few people seem to realize the practical consequence of this, namely that a new method discovered today can- not be available for general use before the 1990s ! Why should it take such a terribly long time, when the need is so great? Some years ago, C. Djerassi indicated the time sequence of the most important steps that would be involved in develop- ing a "male pill". He assumed that it was already known what type of chemical agents were effective; but it was not known whether the agents available were the best possible ones. So it would be necessary to prepare a number of related compounds (analogues) and to assess their efficacy in laboratory animals. Af- ter selection of the "favoured com- pound", its properties and metabolic effects would be carefully evaluated in a variety of animal experiments. Then the synthetic method would have to be "scaled up" to obtain large enough quantities for toxicological studies in dif- ferent animals, including subhuman pri- mates. Djerassi divided the clinical assess- ment into three phases. Phase I would represent the first time a human being was exposed to the new drug; it would be given to only very few subjects (say 8 to 10) for a very short time, and the ef- fects would be monitored very carefully. In Phase II, more subjects (up to 50 or so) are studied; therefore more toxico- logical information is needed before these studies can be initiated. At this stage one attempts to find a suitable dose and formulation, which will be tested in Phase III, studies involving several hun- dred subjects. Before phase III, the life- time toxicological studies in two animal species must be initiated. If everything goes well, the Phase III studies are fol- lowed by large-scale field trials. From the start of the studies to their successful end it was estimated to take from 150 to 250 months, that is, as long as 20 years! The developmental costs in- volved could be around a million dollars a year. Clearly the immediate needs of deve- loping countries in terms of new birth control technologies may not always represent an economically justifiable project for a pharmaceutical company. Therefore there is a need to involve pub- lic sector agencies such as wHo. It also follows that any major effort to develop a whole variety of new fertility regulating agents, which are safer and more conve- nient than presently existing ones, must represent a sustained long-term commit- ment, over decades, in order to have a reasonable chance of success. Viewed against this background, which are the major lines of research today that may result in new and im- proved methods tomorrow, that is, in the late 80s and early 90s? Oral contraceptives: It is estimated that today more than 80 million women in more than 150 countries are using oral contraceptives. During more than 20 years of experience, the doses of com- bined (estrogen-progestogen) oral con- traceptives have been reduced gradually and many formulations have been elimi- nated. It is rather unlikely that the pre- sently used doses could be reduced fur- ther, but there is still room for improve- ment in selecting the optimal estro- gen : progestogen ratio. It can be expect- ed that by the late 80s, this will be estab- lished in different populations and that the usefulness of the so-called "paper pill" and the effect of the presently used pills on lactation will probably also be evaluated. A very important aspect, the possible effect of the pill in women who are malnourished or suffer from various parasitic diseases, is now under careful study; it is likely therefore that by the 1980s the indications and contra-indica- tions for the use of the pill in many deve loping countries will be well established. By that time, some of the true and beyond the pill Translating a new discovery into a widely available fertility regulating agent may take almost 20 years and can cost as much as one million dollars a year! by Egon Diczfalusy 22 Interpreting results. Dr E. Diczfalusy, Direc- tor of the WHO Collaborating Centre for Research and Training in Human Reproduc- tion at the Karolinska Institute and Hospital, Stockholm, discusses results with colleagues and trainees. ( Photo Lennart Nelson, Stockholm ©) alleged adverse effects of the long-term use of oral contraceptives on sugar, fat, protein, vitamin and mineral metabol- ism and on cardiovascular and thrombo- embolic diseases in different populations will have been carefully evaluated, and more information will be available on any possible association of oral contra- ceptives with benign and malignant tumours. Will it be possible to replace the daily pill with a once-a-week or once-a-month formulation, or with a new type of "post- coital" pill? The answer is not yet known today, but probably will be by the end of the next decade. The large doses of estrogens used in several countries and the various "visit- ing pills" tested in the People's Republic of China represent the first generation of "post-coital pills"; for the time being the administered doses are rather high, so that the use of these pills disrupts the menstrual cycle. There are, however, sev- eral compounds with promising post- coital antifertility activity in baboons; if their toxicological evaluation is favour- able, one or several of these agents may be ready for large-scale use within a decade. Long-acting injectables: There is a great demand from family planning pro- grammes for safe and "trouble-free" long-acting contraceptives. This is one area in which pharmaceutical companies show little interest, and the number of available injectable preparations is ex- tremely limited. WHO's Special Pro- gramme of Research, Development and Research Training in Human Reproduc- tion is testing some 150 compounds un- der its major synthetic and screening programme. One or several of these should reach the stage of clinical testing within a few years. A new approach is the development of biodegradable delivery systems which are slowly broken down by normal body processes as the contraceptive steroid is released at an even rate. It is hoped that a constant release may reduce the undesir- able side-effects of long-acting con- traceptives, especially the menstrual cycle irregularities. There is a major demand too for monthly injectables, which might produce fewer bleeding ir- regularities than the three- to six-month- ly formulations. It appears to be a realis- tic prediction that one or several such preparations may be available to WHO's Member States before the end of the next decade. Clinical trials on the safety and effica- cy of long-acting injectables conducted by the Special Programme's Collaborat- ing Centres for Clinical Research repre- sent an important development. The comparative assessment of two or more injectables by ten or more Centres pro- vides a new approach to the proper eval- uation of fertility regulating agents. One study involved scientists from Bahia (Brazil), Alexandria (Egypt), Bombay (India), Chandigarh (India), Ibadan (Nigeria), Utrecht (Netherlands), Lima (Peru), Manila (Philippines), Bangkok (Thailand) and Ljubljana (Yugoslavia). Scientists from Alexandria, Ibadan, Mexico, Singapore and Stockholm col- laborated in another. Intra-uterine devices: Whereas the 1960s witnessed major developments in the field of conventional intra-uterine devices, the 1970s were characterized by the development of medicated devices, such as those releasing copper or proges- terone into the uterine cavity. An impor- tant advantage of the devices releasing progesterone over those releasing copper is that their use decreases the menstrual blood loss, whereas the latter increases it. This is of great importance in develop- ing countries where women are frequent- ly suffering from anaemia. What can be expected to happen in the 1980s and 1990s? Some of the present pro- blems associated with the use of intra- uterine devices, such as increased men- strual blood loss, intermenstrual bleeding, pain, expulsion, pelvic inflammation and an increased risk of ectopic pregnancies may be eliminated or reduced during the next decade. Intermenstrual bleeding represents a particularly important prob- lem. WHO's Special Programme also aims at developing so-called "post-placental" devices, to be inserted immediately fol- lowing the delivery of the placenta, which would adapt in shape and size to conform with the gradual decrease in ut- erine size following delivery. Vaginal rings: A new vaginal ring, developed by WHO, releases a constant amount of contraceptive steroid over 100 days. The major advantage is that it of- fers lengthy protection, like a long-acting injectable, but the contraceptive effect can be stopped simply by removing it. Another advantage is that it can easily be inserted and removed by the woman, af- ter simple instruction. The first genera- tion of such rings could be made avail- able for the public sector within four to five years. Determination of the fertile period: Why should WHO invest time, energy and funds to find out when ovulation exactly takes place? Because it is a practical proposition of great importance. The fer- tilizable life span of the freshly shed human ovum is only a few hours, and if fertilization does not take place, ovula- tion is followed by a period of "physio- 23 DEVELOPMENT OF A BIRTH CONTROL PILL FOR MEN The development of birth control drugs is a highly complicated and lengthy process. The requirements are even more stringent than for other drugs, since they are to be taken by healthy people, possibly for long periods of time. This diagram shows the steps in developing a birth control drug, in this case one to be used by men. At any one of these steps, unfavourable results may mean that research on that product has to be discounted. Question and answer Example Time 1 Q: Which step in the production of sperm in the testis can be interfered with ? A: Research in animals on male reproductive biology NAB r __ --------- --..... 10 ----------'■----'------•'1% Cannot be estimated 2 Q: What chemical substances might do this? ? A: Synthetize chemical compounds AIL A_IL..0.. moti® fiiiiVritotr mil fig AL iiii i .77_ g 4 years 3 Q: Which of the compounds is most effective in stopping sperm production ? A: Laboratory and mating studies in animals C s i 2 years . 4111.11 111 4 Q Does the selected compound cause any harm ? A: Pharmacological and toxicological studies in animals 2 ears cn D Lo 0 O-o c t Pril L.... 411..1 Hillialtilr malEMM, \\--.. _ \\'' \•,,,,, 5 Q: How do we produce enough of the drug for further testing ? A: Set up pilot plant processes C n3 4 1 1 to 2 years • — cn Efl Eli El El 6 Q: Will the drug be toxic to humans? A: Make studies very cautiously in five to ten volunteers in a hospital setting - • UV 2 years 7 Q: What arc: he longer-term effects of the drug ? A: Look in animals for possible toxic effects, cancer, malformations in offspring 2 years ...„.0.. -.. A° 8 0: Will the drug stop sperm production in men and will it cause side effects ? A: Study cautiously in 50 men and monitor for pregnancies in wives m■ it • 0 • . 0 i 3 years • .,.. 1 1 ° 9 If successful, expand study to 500 to 2,000 men \ P I • OTWAyik " k :O. , j 'h V; ' . • . A "■fik ' ' 4 11 4' k 4 years cn O 0 0 10 Simultaneously, start long-term animal studies for safety C r— co -0 — c (1:5 7years E — a) cn _c -i--, 11 Q How can we produce the drug for millions of users, living in different climates and conditions ? A: Study the stability of the drug, packaging and so forth, and ensure large-scale production c5 ,-- Z 3 years \\-,-\ ----- — — -"- \\"\\` `N WEE1831110353tEEBEEIEBEBEillai --, l 12 0: How do we obtain the drug regulatory authority's agreement to marketing this birth control pill for men ? A: Submit all animal and human data resulting from the studies - __L \%-t4,. -° 1 year Total: About 20 years --1'.-1 beyond the pill logical infertility" lasting for some two weeks. This is the scientific basis of the so-called "safe period" on which mil- lions of couples around the world rely as the only method of fertility regulation. However, the efficacy of the various methods based on this principle is rather low, because sperm deposited in the female reproductive tract may maintain its fertilizing ability for several days, and because there is a great variation from cycle to cycle in the time of the onset of ovulation. The Special Programme is therefore engaged in developmental studies to enable women to determine, with the aid of simple "do-it-yourself" kits, objectively and precisely the fertile and infertile phases of each menstrual cycle. It is easy to see that such methods—if they become available— could be used both to improve fertility and to prevent it. Non-surgical methods for the termina- tion of pregnancy: An increasing number of countries are including termination of pregnancy among the methods provided by their family planning programmes. Because of the shortage in manpower and facilities, the availability of a safe non-surgical method would be of signifi- cant assistance to many developing countries. A major advance in this field was the introduction of a group of naturally occ- urring substances, prostaglandins, for termination of pregnancy. The adminis- tration of prostaglandins induces rhyth- mic contractions of the uterus, with the expulsion of the products of conception as a consequence, and it is established that the natural prostaglandins are effec- tive and safe agents for the interruption of second trimester gestation. However, because they have a very short "half- life", i.e. they are rapidly converted by the organism into inactive metabolic products, they have to be administered either by continuous intravenous infu- sion, or by the "intra-amniotic route" directly into the fluid surrounding the foetus. Recently, powerful prostaglandin ana- logues have been synthesized with a much longer "half-life" than the natural compounds. This opened the way for development of a successful out-patient self-administered (vaginal) method for the termination of early pregnancy. It can be predicted that, in the early to mid- 1980s, prostaglandin analogues will be available which are stable in vaginal sup- positories and can be self-administered during the first eight to nine weeks of pregnancy. It can also be anticipated that within three to five years "prostaglandin pills" will be available to be taken orally. Another promising development is the identification of several very potent "uterotonic" principles of plant origin which induce uterine contractions simi- lar to those produced by prostaglandins. An example is the Mexican plant "Zoa- patle" (Montanoa tomentosa). Decoc- tions of this have been used by Mexican women for centuries to induce "men- strual bleeding". It can be predicted that during the next decade a variety of safe and effective agents will be developed or perfected, and will be suitable for self-ad- ministration. Male methods: There is much heated discussion on why men are not sharing the burden of birth control with women, and the objective scientific explanations of why it is difficult to develop methods to be used by men can hardly be heard for the loud accusations of "male chau- vinism". In fact, presently available male methods are restricted to surgical steril- ization, condoms and periodic ab- stinence. Why is it so complicated to develop a "male pill" ? First, because the process leading to the formation of mature sperm is a continuous and com- plex one taking more than two months. This makes it difficult to interfere with a specific portion of it, and requires pro- longed and uninterrupted administration of the fertility regulating agent. Second- ly, because the suppression of sperm for- mation necessitates the use of considera- bly higher steroid doses than the inhibi- tion of ovulation, with a higher risk of untoward side-effects. Thirdly, because suppression of sperm formation also decreases libido, unless suitable doses of testosterone are simultaneously ad- ministered. This is therefore a difficult area of research, requiring a long-lasting com- mitment. But promising results have al- ready been obtained, for instance the use of injectable contraceptive steroids com- bined with testosterone derivatives, and the use of anti-androgens as fertility regulating agents. The most promising lead consists, however, of a new class of compounds, special "halogenated" sug- ars, which do not inhibit sperm produc- tion, but interfere with their metabolism and thus maturation. If the long-term safety of these compounds is equally favourable, the first "male pill" might be a reality by the end of the next decade. Immunological methods: An antifertili- ty vaccine would offer major advantages, since it could be manufactured on a large scale at low cost, could be administered by non-physicians and would have a long-lasting effect. However, there are many potential problems to overcome, such as possible adverse reactions (various auto-immune reactions), and variation in the duration of antifertility effect and its reversibility. Obviously, the vaccine must be absolutely specific, so that no body constituents whatsoever can react with the antiserum formed in the organism against the vaccine. The most advanced line of research uses syn- thetic fragments of a placental hormone, chorionic gonadotrophin. Another difficulty is the selection of a suitable animal model to test the efficacy of this vaccine, since similar placental hormones are only formed by a few sub- human primates, such as the gorilla, the chimpanzee and the baboon. The first two are endangered species, and their use in the required numbers could not be jus- tified. The baboon is the second-best model, and intensive studies have been in progress under the WHO Programme for several years. This is another area of research where the probability of suc- cess cannot be accurately predicted, but with a great potential pay-off. If progress continues to be favourable, the first gen- eration of antifertility vaccine might become available by the end of the next decade. * * * In the National Anthropological Museum in Mexico City, a mural por- trays how each generation of human be- ings has contributed towards improving the quality of life of subsequent genera- tions. Perhaps, when the history of the 20th century is written, its last third will be characterized as the period in which mission-oriented research, organized on a truly global basis, provided mankind with a great variety of safe and efficient methods of fertility regulation to suit the great diversity of requirements. The road ahead of us is a straight, but very long and difficult one; yet it is paved, not only with problems and unforeseen complica- tions, but also with a series of highly sti- mulating challenges and great potential rewards. ■ 25 family planning—where and how? by Nusret Fisek and Ron Gray te he administrators who organize and plan family planning pro-grammes are often faced with diff-icult problems and decisions. For instance, what contraceptives are ap- propriate for a given cultural setting? Or, given the characteristics of the fertility- regulating methods and the limited health resources available, how can the administrator design effective service structures or use the most appropriate staff so as to provide comprehensive and continuing family planning care to all who wish to practise fertility control? In many cases, common sense and the sound judgment of an experienced admi- nistrator will provide sufficient guidance. However, there are frequently situations where research is needed to resolve important questions or to provide the information necessary for programme planning. The type of service research required will vary according to the problem to be solved. For instance, a health adminis- trator may wish to evaluate a pro- gramme, or to demonstrate the efficacy of a new service strategy, by undertaking a pilot project. To a certain extent, this kind of research is essentially a com- ponent of good programme manage- ment, and largely entails the monitoring of services. On the other hand, the national authorities may contemplate a major innovation in their programme strategy which would require rigorous controlled research to evaluate its effica- cy and safety. The broad spectrum of ser- vice research activities which lie between these two extremes can best be illustrated by a series of case studies. Use of non-physicians The acute shortage of doctors in many developing countries has led to consider- able emphasis being placed on greater use of non-physicians in providing health and family planning care. With family planning, an extra problem presents it- self in that many women seeking family planning services are reluctant to be ex- amined by men. However, women pre- dominate among other categories of health personnel such as nurses or mid- wives and, because of this, they are often culturally more acceptable to potential family planning users. An important place exists, therefore, for female non-physicians in the provi- sion of family planning care, but there is a need both to define their role more clearly and to win for them the support of the medical authorities and physi- cians. Service research can help to achieve these objectives by demonstrat- ing that, with proper training, non-physi- cians can acquire complex new clinical skills, and that their performance can be comparable to or even better than that of physicians. WHO has collaborated with national authorities in undertaking a number of studies along these lines in several different countries. One study was designed to evaluate the provision of intra-uterine devices (tum) by non-physicians in the Republic of Korea, the Philippines and Turkey. Training manuals and procedures were designed, and special checklists incorpo- rating instructions were devised to assist the non-physicians with patient care. The performance of the nurses and midwives after their training ends is being compared with that of physicians, under realistic field conditions which vary from urban settings in cities such as Seoul or Manila, to rural areas of the Philippines or Tur- key. In Turkey the study is taking place in the Cubuk district, a mountainous area of the Anatolian plateau north of Ankara. The people here live in small scattered villages and, because of the dif- ficult terrain and the harsh winters, health and family planning services have to be supplied at village level by auxiliary nurse/midwives. The Institute of Com- munity Medicine of the Hacettepe University is one of the centres collabo- rating in the WHO studies, and specialists from the Institute have organized and supervised the field work in this district. During their training course the aux- iliary nurse/midwives proved that they could correctly diagnose medical prob- lems in 89 per cent of all cases, while the problems of mis-diagnosis diminished as they gained experience until, after 20 cases had been examined, no further er- rors were made. The auxiliary nurse/ midwives were found to be just as competent as the physicians both in terms of correctly inserting the IUD, and in referring problem cases to a specialist. But, because the midwives lived in the villages, they could provide far better fol- low-up and continuity of patient care than could the physicians, who only periodically visited the area. This was particularly important when, during the cold winters, the villages were cut off by the heavy snows. Studies in Cubuk and other rural areas of Turkey have shown that if the aux- iliary nurse/midwife provides face-to- face education to both the women and their husbands, the couple's motivation to use family planning is much better than when such education is provided to the women alone. As a result of these studies, the Ministry of Health is em- barking upon a large-scale training pro- gramme for the rural auxiliary nurse/ midwives. Progress reports from the studies in the Philippines and Korea are showing In many countries, women seeking family planning care prefer to be advised and ex- amined by nurses or midwives, rather than by male physicians. (Photo WHO/M. Jacot) 26

similar results : namely that, with proper training, nurses or midwives can provide high quality family planning care, com- parable to, if not superior to that given by doctors. Choice of methods A programme administrator also has to plan the most appropriate combina- tion of contraceptives for a programme, and this is a subjeCt that may require research. The problem is even more com- plex when an administrator wishes to in- troduce a new type of contraceptive into a programme. He has to determine whether the new method is potentially acceptable to the population, how heavy the demand for the method is likely to be, and whether the new method will at- tract additional couples into the pro- gramme or merely induce individuals to change from one method to another. Studies in a number of countries in- cluding India, the Republic of Korea, the Philippines, Thailand and Turkey are providing interesting multi-national com- parisons of the patterns of choice and the cultural reasons for preferring different contraceptive methods. Women were told of the advantages and disadvantages of the pill, intra-uterine device and an injec- table contraceptive. In rural areas of Thailand and Turkey, there appears to be a preference for the injectable method, whereas in urban cen- tres in these countries, women tend to choose other forms of contraception. The rural women frequently state that convenience is the major reason underly- ing their choice of an injectable con- traceptive. In urban areas of Korea and India, the women markedly favoured the pill and IUD, and there was no appreci- able demand for an injectable contracep- tive. By contrast, in Manila, women who recently had delivered a child expressed a strong preference for the injection, since they believed this to be more satisfactory than the pill as a method of contracep- tion while breast-feeding their babies. Servicesettingsforfamily planning A family planning programme must provide not only the most appropriate methods of contraception, but also the most acceptable and convenient service for the "consumer". It is important therefore to assess which services women find most suitable, what type of service personnel they prefer, and what com- plaints or reservations they may have 28 fancily planning where and how? The performance of nurses and midwives in providing family planning care compares favourably with that of physicians in studies conducted under realistic field conditions in countries as far apart as the Republic of Korea and Turkey. Left : A nurse in the Philippines demonstrates an intra-uterine device to a group of young women attending a family planning clinic. ( Photo WHO/ P. Almasy) Right : A more informal "consultation" on birth con- trol methods, this time in the open air in a small Turkish village. ( Photo WHO IC. Erkal ) about existing services. It has been men- tioned that in rural Turkey village wom- en strongly resist gynaecological exami- nations by male physicians, and since there are few female physicians available, the burden of family planning care must fall upon the auxiliary midwives. Anoth- er study in urban Bangkok indicated that working mothers only used contracep- tion for relatively short periods of time, and made insufficient use of clinic ser- vices. This suggested a need to ex- periment with ways of delivering family planning care to the women's place of work. A current study in the Philippines is investigating the best way of bringing family planning to rural populations. One approach is to train the midwives at- tached to the network of rural health units to provide comprehensive family planning care. Another is to compare the impact of this approach with the distri- bution by lay workers of pills and con- doms, a system operated completely in- dependently from the health services. * * * Research into family planning services is often complex and time-consuming, and results of this work are sometimes less "scientifically" conclusive than in other fields of research. The results of service studies are nonetheless important and, in particular, their significance often lies in a broader, less clearly visible polit- ical sphere. They often have an impact on the views and policies of the medical profession or of service officials who, because of their influence over the whole programme strategy, can amplify the outcome of limited research projects by applying the results on a national scale. The problems facing the delivery of health and family planning care are by and large specific to individual countries or programmes. Thus the planning and execution of service research must, of necessity, be the responsibility of admi- nistrators and investigators in each coun- try. However, there are problems such as the shortage of doctors which face all health services, and there is a world med- ical community whose policies and opi- nions shape the internal strategies of in- dividual countries. It is WHO's role to re- spond to requests from national authori- ties for collaboration on specific research projects, and to help bring together health planners and health personnel from many countries, so as to share the global experience in service research and thus attain the goal of "health for all by the year 2000". ■ 29 infertility: a universal problem There is still a need to know what are the major causes of infertility in the developed countries, while the role of research in the developing world has yet another dimension by Mark A. Belsey L nvoluntary infertility is a worldwide problem, although the frequency, the causes and the implications for both the couple and the health ser- vices vary from area to area. Among couples in developed coun- tries, childlessness may range from 5 to 15 per cent. However, it is unknown to what extent voluntary infertility contrib- utes to this rate. Among developing countries where voluntary infertility is rare, the corresponding rates vary even more widely, and in some areas, the levels may be so high as to constitute a major social and economic problem as well as a priority problem for the health services. In some areas of the Cameroons, Gabon, Zaire and Sudan as many as 40 per cent of married women finish their reproductive years without ever having borne a child. In the developed countries, medical consultations for infertility are time-con- suming and costly. In the past, though more difficult recently, the option in cases of unsuccessful therapy has been for the couple to adopt a child. In the developing countries, particularly those where the prevalence has reached high levels, the facilities for diagnosis and therapy are lacking, and the social stigma of barren- ness is so deep-seated that this is asso- ciated with high levels of marital in- stability and divorce. In some developing countries, fully one-third of the consulta- tions at the family planning clinics are for infertility. Research into the prevalence, causes and possible therapies for infertility is of concern to developed and developing countries. For those countries where in- fertility rates are particularly high, it is reasonable to assume that some prevent- able cause underlies the excessively high rates. Ignorance and psychological factors appear to account for a substantial pro- portion of what is perceived by couples as infertility. The timing and frequency of intercourse with respect to conception are often not understood by even presu- mably well-educated couples. For exam- ple, the chance of conceiving within six GLOSSARY PRIMARY INFERTILITY: The woman has never conceived, despite cohabitation and exposure to pregnancy for a period of two years. SECONDARY INFERTILITY: The woman has previously conceived, but is subsequently unable to con- ceive. PREGNANCY WASTAGE: The woman is able to conceive, but unable to produce a live birth. months if intercourse occurs only once a week is 32 per cent. If less than once a week, the chance of conception is only 17 per cent. Once couples seek medical at- tention, at least in developed countries, between 25 and 40 per cent of the couples conceive during the course of diagnostic examinations before any therapeutic in- tervention has taken place. A problem of the couple Infertility is a problem of the couple. In developed countries, causes attribut- able to the man have been estimated to occur in from 20 to 40 per cent of cou- ples. In the man, sperm production may be interfered with so that no sperm are produced (azoospermia) or the numbers produced are few (oligospermia) or defective (immature, poor motility). Factors known to interfere with sperm production include failure of the testicles to descend into the scrotum, high envi- ronmental heat exposure, exposures to certain chemicals, varicocoele of the scrotum, pituitary failures or other endo- crine disorders and certain genetic or chromosomal abnormalities. In addi- tion, several infectious agents are known either to affect the testicle or to result in blockage or altered passage of the sperm in the vas deferens. Thus, mumps infec- tion acquired after puberty may result in permanent testicular damage. Tuberculosis, leprosy and syphilis may also affect the testicles, while gonorrhoea or other infections may produce thicken- ing and blockage to the passage of sperm through the epididymis and vas deferens. Recent evidence suggests that filariasis in certain areas of Africa may produce azoospermia or oligospermia secondary to damage to the testes. In a significant but unknown proportion of men, the cause of infertility, even azoospermia, remains obscure and unknown. Although far more is known about in- fertility in the woman, there are still A young couple seek a doctor's advice: why are they unable to have a baby? (Photo WHO/P. Almasy) 30

infertility : a universal problem Left: In certain areas of Africa the social impact and personal tragedy of infertility can be felt in the quiet villages where children's voices are rarely heard, as among this tribe in the Sou- thern Sudan. ( Photo WHO; !II. Belsey) Right: This Indian woman has been fortunate to es- cape the social stigma of primary infertility. But the risk of secondary Mfertility, a conse- quence ofpost-partum infection, may still deny her and her family the second child they desire. (Photo WHO; J. Marshall) great gaps in our knowledge, so that in a significant proportion of women, despite extensive and sophisticated efforts, the cause of infertility remains obsure. The congenital abnormalities of the repro- ductive tract and chromosomal abnor- malities are generally considered as rare causes of infertility. More common are the endocrine causes, such as deficient production of certain hormones (FSH and LH) by the pituitary gland; excessive production by the pituitary of the hor- mone stimulating breast-milk produc- tion, prolactin; deficient progesterone production by the ovary; and other less specific and less well understood hor- monal mechanisms. Infections in the woman's genital tract are a major underlying cause of infertili- ty. Tubal obstruction accounts for up to 70 per cent of the cases of infertility seen in Kenya and Nigeria. In the individual woman, it is difficult to establish whether obstruction is a consequence of gonorr- hoea, post-partum or post-abortal sepsis or some other infection. To establish the underlying cause of tubal obstruction requires epidemiological investigation. In the developed countries, there is still a need to know what are the major causes of infertility, what is the most ef- fective sequence of investigation to reach a diagnosis, what is the validity of the in- creasing number of diagnostic tests and, for the specific diagnosed conditions, what should be the sequence of therapeutic efforts. The costs incurred by the health services and the frustrated ex- pectations of the couple warrant the development of well-defined, scientifical- ly sound and efficient diagnostic and therapeutic procedures. The role of research The role of research in the developing world has yet another dimension, par- ticularly where infertility constitutes a major health problem. In these coun- tries, infections are more likely to play a major role in the high rates of infertility, possibly in association with dietary fac- tors. Establishment of the actual infec- tious etiology or process of infertility would enable preventive programmes to be developed. However, three and possibly more major infectious processes may be con- tributing to infertility in areas of Africa, where the control programmes for each differ quite markedly. These include the sequelae of filariasis, post-partum or post-abortal sepsis and the sequelae of gonorrhoea. If in fact nutritional defi- ciencies also contribute to the problem, then the solutions become more complex and difficult to implement. A chronic in- fection such as filariasis affecting the male and possibly the female, possibly acquired before or during puberty, may result in high levels of primary infertility. Tubal or pelvic infection acquired either post-partum or post-abortal may be a consequence of poor delivery practices and may be manifested by high levels of secondary infertility. Gonorrhoea, and possibly other sexually transmitted dis- eases, depending on the sexual and mari- tal practices, may result in either primary or secondary infertility with either or both the man and woman affected. Establishing the pattern of etiology would affect whether primary emphasis is placed on endemic disease control, such as filariasis; on improvement in delivery practices and asepsis; or on con- trol programmes for sexually transmitted diseases. With such widely divergent op- tions for infertility prevention, research plays a critical role in countries with lim- ited resources and competing priorities for health service development. ■ 33 self-reliance in research The injectable contraceptive proved far more popular than the IUD or the Pill for rural Thai women, yet was less popular among women attending urban clinics by Nikorn Dusitsin and Richard Grossman it! he Chulalongkorn Hospital in Bangkok first made family plan- ning services available when it opened an IUD clinic in 1965 un- der the auspices of the Thai Red Cross Society. That was five years before fami- ly planning was adopted as a national policy by the Thai Government, and al- most immediately the demand for ser- vices was very high. Although only word-of-mouth dissemination of infor- mation was available at the time, the clinic soon became one of the busiest fam- ily planning clinics of its kind in the world. In response to the increasing demand for services outside of Bangkok, mobile IUD services were instituted. By 1968, new arrivals at the Chulalongkorn Hospital clinic were able to choose the daily pill or a three-monthly injectable contraceptive as alternatives to the intra- uterine device. Despite the obvious popularity of these contraceptive methods and the generally low frequency of problems related to their use, some politicians and health professionals criticized the pro- gramme and questioned the appropriate- ness of various contraceptive methods for the Thai people. As is generally the case, negative rumours about the methods, whether based on fact or not, spread rapidly and caused some setbacks in the programme. In fact the planners had thought from the start that research should be under- taken into the safety, efficacy and accep- tability of contraceptive methods in Thais. Previous research work had been almost exclusively undertaken in devel- oped countries and it was clear that the many cultural, health and nutritional, environmental and genetic differences within the Thai population could have a bearing on the usefulness of contracep- tives and on the relevance of particular methods to local field conditions. In 1971, Chualalongkorn Hospital Medical School asked for collabora- tion in WHO's programme of research in human reproduction which had, as one of its major aims, the streng- thening of national resources for research in this field. Extensive discus- sions resulted in the WHO Research Team on Clinical Evaluation of Fertility Regu- lating Agents starting work at the Chula- longkorn Hospital Medical School in 1972. A close relationship was estab- lished with the Thai National Family Planning Programme (NFPP), and this en- sured from the outset that research work performed by the team would be relevant and in direct support of the national pro- gramme. The Thai researchers in the group came from many of the clinical and basic science departments of the Faculty of Medicine—among them the Depart- ments of Obstetrics and Gynaecology, Preventive and Social Medicine, Pedia- trics, Radiology, Urology, Pharmacolo- gy and Pathology. Other investigators belonged to the Faculties of Science, Pharmacy, Political Science and Eco- nomics, the Institute of Population Studies and the family health sections of the Bangkok Metropolis Health Depart- ment and the Ministry of Public Health. Clinicians, biologists, pharmacolo- gists, endocrinologists, epidemiologists and biostatisticians working in the field of fertility regulation in other countries came to Bangkok and spent varying lengths of time as WHO staff or consul- tants working with counterpart Thai researchers to help strengthen the team's multidisciplinary research capabilities. There were a total of 22 such experts from seven countries in Europe and North America as well as Australia and India. Most of these multinational ex- perts also took part in training seminars or gave open lectures to large audiences of interested scientists. Existing facilities at the Hospital in support of the team's research activities expanded rapidly to include a laboratory for hormone testing by radio-immuno- assay procedures and another for clinical chemistry determinations. Automatic data-processing software and a data- processing section enabled investigators to play a more active role in processing and analysing their own data. An elec- tronic workshop with its own trained technicians ensured that all the equip- ment could be maintained in satisfactory working order, something which had previously been a major stumbling- block. Since 1972 the studies carried out have covered a wide range of relevant research problems. For example, two epidemio- logical studies suggested that the average Thai woman who is using the pill may be at much lower risk of developing throm- bo-embolism (blood clotting) than the average British woman. Such a finding not only has considerable significance for the Thai programme but has global scientific implications, which are now be- ing examined in other centres collaborat- ing with the WHO Special Programme of Research, Development and Research Training in Human Reproduction. Another study, requested by the The national family planning programme of Thailand carries out research in many dif- ferent settings. ( Photo WHO/ UN) 34

Ministry of Public Health, looked into the effects of the popular injectable con- traceptive, depot medroxyprogesterone acetate, in women who were infected with a liver fluke parasite. This parasite is highly prevalent in the thickly popula- ted north-east part of Thailand, and there were fears about using a contraceptive drug that is eliminated through the liver in women whose liver function might be impaired by these parasites. The results showed that there were no deleterious ef- fects on liver function in these women through 18 months of use of the con- traceptive. The effects of injectable and oral contraceptives on liver, carbohydrate fat, thyroid and adrenal functions have also been assessed through careful meta- bolic studies in Bangkok. Current studies are determining whether the average Thai woman, who is lighter in weight and different in build from the average American woman, for example, might experience less frequent side-effects (and yet still be protected from pregnancy) if given a lower dose than usual of various hormonal con- traceptives. The potential savings to the NFPP (which distributes the contracep- tives free of charge) would be consider- able if this could be demonstrated, while the generally low continuation rates of these methods could be expected to in- crease. In another field of research, a major trial with more than 2,000 partici- pants under realistic conditions in a rural area showed that the iuD currently recommended by the NFPP was as accep- table in the long run (two years) as two newer IUD designs, although the frequen- cy with which each device was acciden- tally expelled was lower for one of the newer types. The research group has also been as- sessing various programmatic and accep- tability aspects of family planning ser- vices and the methods offered. This is a very challenging but difficult field of research, which requires a dedicated team of clinical, epidemiological and socio-demographic investigators. They are trying to study the complex health and behavioural factors that go into the family planning acceptor's decision- making process—why he or she starts, continues and discontinues contracep- tion, and how these processes interact with all the factors involved in the deliv- ery of contraceptive services. The results can play a big part in resolving which types of contraceptives will be most appropriate for the people and how best to deliver them. A large study in Uthaithani Province, for example, demonstrated that the injec- table contraceptive was indeed a far more popular choice than the IUD or pill for rural Thai women, and that a high proportion of the women kept on using this method after one year. A similar study in Bangkok, on the other hand, is currently finding that the injectable con- traceptive is much less popular with peo- ple who attend at urban clinics. Finding such a difference in preferences between urban and rural acceptors is not surpris- ing, but it does reinforce the need for us- ing such knowledge in the efficient plan- ning of service delivery. Another major area of service research involves the use of non-physicians to provide clinical family planning. It is becoming more and more widely recog- nized that people with less than an MD 36 self-reliance in research Left: A health worker explains the importance of returning for check-ups in a rural study con- ducted by the Collaborating Centre . for Clinical Research at Chulalongkorn Hospital, Bang- kok. Upper right: Under careful supervision, the medical student ( left) is carrying out a vasectomy operation. These studies have shown that students can be rapidly trained to perform vasectomies and ob- tain results as satisfactory as their teachers. Lower right : Thai researchers at the WHO Collaborating Centre at Chulalongkorn Hospital come from many of the clinical, basic science and commu- nity medicine departments of the Faculty of Medicine. ( Photos WHO/N. Dusitsin) degree are quite capable of providing family planning methods and can thus help to fill the gap caused by the shortage of trained physicians, especially in rural areas. However, it is certainly important to demonstrate under scientifically con- trolled conditions that the training and performance of the non-physicians are satisfactory. The research group has been working with two categories of non-physicians. One study has already shown that medi- cal students can be rapidly trained to perform vasectomies and that they are able to obtain results as satisfactory as their teachers. The Government hopes that extending this training programme will help to meet the increasing demand for vasectomy services in rural areas by employing students during the summer as well as by rapidly increasing the num- ber of motivated and competent young physicians. In response to another request from the Ministry of Public Health, research work is currently under way on the train- ing and capability of theatre nurses to perform female sterilizations after the birth of one child. Again, in order to have a more realistic health setting than is the case at the University Hospital in Bangkok, this study is being performed at a Government Maternal and Child Health Centre in Khon Kaen, north-east Thailand. If the outcome is satisfactory (and preliminary results are very encou- raging), and if the Government then proceeds with its plan to have a greatly expanded training programme, it is an- ticipated that the demand for such ser- vices will be much more efficiently met than is at present possible while main- taining the high quality of the services. In 1977, the WHO Research Team changed its title to that of a WHO Colla- borating Centre for Clinical Research, which is jointly administered by the In- stitute of Health Research of Chulalong- korn University and the Department of Obstetrics and Gynaecology of the Faculty of Medicine, Chulalongkorn Hospital Medical School. The group continues to function as a multidiscipli- nary research group, for whom clinical research is only one of the areas of in- terest. The group has received recognition from the Ministry of Health which now routinely turns to it for advice, from the Ministry of Universities for its impact on academic research, and from the scientif- ic community at large. It has had favour- able responses to its numerous papers published in international journals and presented at various conferences, from the seminars and courses (both local and regional) it has held, and from the many scientists who have visited its facilities. Its members continue to strive for national self-reliance through a further building-up of facilities and by obtain- ing training fellowships for interested research workers. At the same time it hopes to maintain direct links with the international scientific community through continuing collaboration with and support from WHO. The group will continue to emphasize what it believes is its major role and its major asset—that of being a national research resource directly supporting, and able to rapidly respond to, the needs and requests of the Ministry of Public Health's national pro- gramme in family planning. ■ 37 ••• ••• •• • •• • ••• ••• •• • ••• ••• ••• ••• ••• ••• ••• ••• ••• Soo orpo 000 0000 0• •• • ••• ••• ••• ••• ••• ••• ••• ••• ••• ••• ••• ••• ••• ••• ••• ••• ••• ••• • •• ••• ••• ••• ••• ••• ••• •• • •• • ••• ••• ••• ••• ••• ••• ••• ••• 000 ••• ••• ••• Malaria : the biggest killer Malaria today menaces more people than any other disease in the world and the situation is getting worse, ac- cording to reports received by WHO. The number of cases has more than doubled in the last five years and many cases go unreported. The WHO Di- rector-General, Dr H. Mahler, reporting to the Thirty-first World Health Assembly on Photo VVH0/1=i da Silva Looking for malaria parasites in blood. the situation last May, esti- mated that one hundred and fifty million people suffer from malaria every year and, in Africa alone, one million children die annually from malaria before they reach the age of five. A variety of complex fac- tors make malaria control dif- ficult. Resistance of the mos- quito to insecticides has been reported in 62 countries of the 107 where the disease exists. To make matters wor- se, 20 countries have re- ported strains of the malaria parasite that have become resistance to the available medication, thus making it imperative to search for alter- natives. Finally, the soaring costs of petrol and insecti- cides mean that countries have to scrape the barrel to find resources to cover opera- tional costs. Besides, industry appears to have lost interest in devel- oping effective, cheaper and safer insecticides for public health use. The number of in- secticides offered to WHO for field testing has dropped to zero. This is because of tech- nical reasons and because industry prefers to develop these products for the more profitable market in agricul- ture. The lack of insecticides is a serious matter consider- ing that other methods, such as genetic control or use of larvicidal fish, are either still in the early stages of develop- ment or only partially effec- tive. The malaria situation is most critical in South-East Asia where it has become es- tablished at its former ende- mic level in large parts of Bangladesh, India and Sri Lanka. The situation in Africa remains unchanged and it is here that the largest number of fatalities occur. This is not the result of a setback since there has never been a large- scale anti-malaria programme in this part of the world. Nige- Cia, however, with WHO co- operation, is launching the first nationwide control pro- gramme. The European Region is alarmed about the recent epi- demic in Turkey which poses the threat of reintroduction of malaria into countries long free of the disease. In the Americas, 17 countries are forced to cope with the prob- lem of malaria. The situation is complicated both by resis- tance to insecticides and re- sistance of the malaria para- site to 4-aminoquinolines, the most commonly used anti-malaria drugs. However, eradication remains the ulti- mate goal of most countries there. WHO has outlined new tactics and strategy largely based on reducing mortality and preventing the disease from hampering socio-eco- nomic development. The world community is being mobilized and there is need for more funds to keep the disease under control.A WHO representative told the UN Disarmament Commission that it would take a minimum of 1,700 million dollars an- nually to bring malaria to the point of control where the disease would not be a public health hazard. Iran's cold chain system pays off An unbroken cold chain system to transport vaccines from central depots to remote rural areas has played an im- portant role in the success achieved by Iran in its immu- nization campaign against smallpox and six major dis- eases of childhood : diph- theria, pertussis (whooping cough), tetanus, measles, poliomyelitis and tubercu- losis. The six diseases are the targets of attack in the Ex- panded Programme for Im- munization in which WHO has been collaborating with a number of Member coun- tries. One of the problems posed by the programme is the difficulty of keeping the vaccines from spoiling in trop- ical climates in remote areas lacking refrigeration facilities. Photo WHO/D. Deriaz Children line up at a vaccination centre. In 1965, when Iran launch- ed its mass immunization campaign, it recorded 40,000 cases of whooping cough. In 1977 there were only 5,849 cases. Over the same period, measles declined from 120,000 cases to 14,000. Equally impressive reduc- tions were achieved in the other diseases. Tetanus cases fell from 744 to barely 4, diph- theria from 2,405 to 168 and polio from 609 to 197. Small- pox was eradicated in Iran six years ago. The vaccines responsible for these dramatic declines arrive in Teheran by air, are immediately transferred to a vehicle called "mobile cold store- , and are soon on their way to the provincial centres. Poliomyelitis and measles vaccines get special treat- ment. They are packed in dry ice and sent to their provincial destinations by air mail. Each provincial headquar- ters has two or three central cold stores with sufficient space to stock vaccines need- ed for the provincial immu- nization campaign over a per- iod of six months. When the vaccines are moved from the provincial headquarters to the districts they are stored in cold stores or refrigerators. At the rural health centres, the last point in the chain, the vaccines are stored before use in refrigera- tors run on kerosene oil. 2,810 "new" drugs introduced in 1977 A total of 2,810 "new" me- dicinal products were intro- duced in 1977 by the world's leading multi-national drug corporations, according to a study published by World Pharmaceutical Introduc- tions, a publication of the drug industry. Included in the study were 15 companies with head off- ices in four countries—the Federal Republic of Germany, France, Switzerland and USA —and subsidiaries or branch offices in various parts of the world. Of the total of "new" drugs, 1,466 or 52 per cent were introduced in Europe, 761 in Latin America, 486 in Asia, Africa and Australasia, and 97 in North America. Among the countries where the pro- ducts were introduced, the Federal Republic of Germany topped the list with 308 38 "new" products, followed by Switzerland (213), Brazil (197), Argentina (194), Italy (188), Japan (175), Mexico (151), and Spain (145). Antibiotics accounted for the largest number of the in- troductionsfollowed by drugs against cough and cold and against rheumatism. The proliferation of drugs presents problems to health authorities, particularly in the developing countries, with which WHO has been seri- ously concerned for some time. While genuinely new medicinal products may re- present a real advance in treat- ing a disease, most of the so-called "new" drugs flood- ing the markets year after year are variants of existing com- pounds under new brand names which must fight for a place in the sun through high- pressure salesmanship and costly publicity. That raises the price of the drugs, and de- veloping countries, lacking the means to judge their qual- ity and efficacy, are forced to waste their limited resources on products of marginal the- rapeutic value to their real health needs. The World Health Assem- bly at its meeting in May last expressed itself "deeply con- cerned by the high proportion of health budgets spent on pharmaceuticals by govern- ments, particularly develop- ing countries, thereby limiting the remaining funds available for the provision of adequate health care to the whole pop- ulation". As instructed by the Ass- embly, the WHO Secretariat is now engaged in preparing a comprehensive programme on essential drugs, some ele- ments of which are: identifi- cation of drugs and vaccines that are indispensable for pri- mary health care and control of widely prevalent diseases; cooperation with govern- ments in formulating national drug policies and setting up quality control systems with a view to ensuring access of the whole population to es- sential drugs at a cost the country can afford ; and de- velopment of a dialogue with the pharmaceutical industries to ensure their collaboration in meeting the needs of large underserved segments of the world's population. A crippling disease under coconut palms A connection between the flourishing coconut industry of rural Kerala in India, and the disfiguring, disabling dis- ease, filariasis, has been re- ported by a team of visiting WHO scientists. Coconut is the mainstay of the local economy. It is a source of food and edible oil as well as of fibre for high quality ropes and matting. As a part of the manufacturing process, the coir—coconut fibre—must be soaked in wa- ter. The numerous water ponds that dot the Kerala countryside serve the pur- pose very well. These ponds are covered with two species of water- plants—Pistia Sp. and Salvi- nia Sp., which are allowed to grow unchecked because they are believed to keep the water clean and prevent eva- poration in the burning sum- mer sun. The dried plants are also valued as manure for coconut plants. These weed-covered ponds provide an ideal breeding ground for the Mansonia mosquito, whose larvae se- cure their oxygen by attach- ing themselves to the water plants. This mosquito is the vector of the type of filariasis that afflicts Kerala—Brugian filariasis. A perfect example of an ecological set-up for the transmission of disease. It is an example also of the socio-economic problems that must be taken into ac- count in combating a disease. The drying or de-weeding of the ponds is sure to bring down the vector population, but it is unthinkable until an alternative source of water or economy can be found. The measure now being used by Kerala health author- ities against the vector is the treatment of the ponds with an insecticide that destroys the mosquito larvae. A num- ber of pilot studies have also been carried out on the treat- ment of filariasis sufferers with a compound known as DEC (diethylcarbamazine). The drug is only partially ef- fective. Brugian filariasis is caused by a nematode (thread worm) transmitted from person to Photo WHO/P. N. Sharma Woman at left is a victim of fila- person by the bite of the Man- sonia mosquito. The nemato- des develop in the human blood, and enter the lympha- tic system where the adult worms pair and produce forms known as microfilariae. The microfilariae circulate in the bloodstream, moving at night to the peripheral blood where the night-biting Mansonia is likely to pick them up. The microfilariae mature into infective larvae in the body of the mosquito. The mosquito deposits the worms in the blood of the person it bites next, thus adding an- other link in the chain of in- fection. The presence of the worms in the lymphatic zones of the body results in the typical de- formity of Brugian filariasis- elephantiasis of the lower limbs. According to a study car- ried out some years ago, the rate of Brugian filariasis in rural Kerala was estimated to be between 3.5 and 13.4 per cent of the population. In the next issue Mankind lives in perma- nent symbiosis with the animal kingdom. Some species are specially bred and reared as sources of food, as working animals or as pets. Other species are pests that may carry diseases to human hosts. World Health in October will look at "Animals and Man". Authors of the month Dr A. KESSLER is the Director of wito's Special Programme of Re- search, Development and Research Training in Human Reproduction, and Mrs T. STANDLEY is a Senior Scientist in the Programme. Dr V. BALDERRAMA-GUZMAN is Pro- fessor of Maternal and Child Health at the Institute of Public Health, Uni- versity of the Philippines, Manila. Dr R. GRAY is a Medical Officer in the Special Programme in Geneva. Dr D. D. SoEJAR.To is Associate Pro- fessor in the Department of Biology, University of Antioquia, Medellin, Colombia. Mr J. SPIELER is a Scientist in the Spe- cial Programme in Geneva. Professor E. DICZFALUSY is Director of the Reproductive Endocrinology Research Unit at the Karolinska In- stitute in Stockholm and of the WHO Collaborating Centre for Research and Training there. Dr N. FISEK is Professor of Commu- nity Medicine at Hacettepe Univer- sity, Ankara, Turkey. Dr M. BELSEY is a Medical Officer in the Special Programme in Geneva. Dr N. DUSITSIN is Deputy Director of the Institute of Health Science Re- search, Chulalongkorn University, and a senior member of the WHO Col- laborating Centre for Clinical Re- search there. Dr R. A. GROSSMAN is a Medical Offi- cer with the Special Programme in Bangkok. WORLD HEALTH ORDER FORM Please enter my subscription to "World Health" as follows: US$* Swir.* One year 12.50 25.— Two years 22.50 45.— Three years 30.— 60. One year: Two years: Three years: I enclose cheque/postal order in the amount of Name: Street: City: Country: * or equivalent in local currency. World Health, WHO, Avenue Appia, 1211 Geneva 27, Switzerland Ashanti fertility symbol. See page 30. (Photo WHO) P r i nt e d in S w itz er la n d Im p r i m er ie s R eu n ie s S .A . La u sa n ne