Volume 169 Issue 10

Reducing indigenous mortality in Australia: lessons from other countries Ian T Ring and David Firman Mortality rates from all causes in Maori in New Zealand and Native Americans have fallen substantially since the early 1970s. Comparable mortality rates for Australian Aboriginals and Torres Strait Islanders in 1990-1994 were at or above the rates observed 20 years ago in Maori and Native Americans, being 1.9 times the rate in Maori, 2.4 times the rate in Native Americans, and 3.2 times the rate for all Australians. Circulatory diseases, respiratory diseases, injuries and endocrine diseases (mostly diabetes) are responsible for almost 70% of these excess deaths. Mortality rate trends in indigenous populations in other countries suggest the feasibility of substantial and rapid reductions in mortality rates of Australia's indigenous people. MJA 1998; 169: 528-533 For editorial comment, see Mooney et al Introduction - Methods - Results - Discussion - References - Authors' details - - More articles on Aboriginal health - ©MJA1998 Introduction The poor health of Australian Aboriginals and Torres Strait Islanders is well known. Since the 1970s, indigenous infant mortality rates have been declining, but life expectancy has not changed because of continued high adult mortality rates,1 due largely to high death rates from chronic diseases in middle age.2 This pattern contrasts with that of the indigenous people of Canada, the United States and New Zealand, where marked improvements in health have occurred.3-5 While the health status of Australians as a whole continues to improve, the all-cause death rate for Aboriginal women is unchanged and the rate among men has decreased only slightly.6 As a result, the gap between the death rates for the Aboriginal population and the total Australian population has widened.1,7 Relatively few causes account for most of the mortality rate difference between indigenous Australians and all Australians. We report trends in mortality from these causes of death in indigenous people in Australia, New Zealand (NZ), and the United States (US). Methods Australian data Over the past 10 years, death registration of Aboriginal and Torres Strait Islander people has reached an acceptable level of completeness (90% or more) in two States only -- Western Australia (WA) and the Northern Territory (NT); we have confined our analysis of indigenous death rates to figures from these two States. The accuracy of Aboriginal and Torres Strait Islander censuses has been investigated.8,9 Experimental, adjusted counts have been calculated by the Australian Bureau of Statistics (ABS) for 1986-199110 and for 199411 at the State level. Population counts of indigenous people in the 1996 Census were greater in every State than expected from the 1991 Census and adjusted counts, indicating that more people identified themselves as Aboriginal or Torres Strait Islander than in previous censuses. The 1985-1996 indigenous population counts we used for WA and the NT were based on ABS experimental counts, adjusted for the 1996 Census. In WA, adjusted 1996 population counts were greater than predictions based on experimental counts for earlier years. Consequently, ABS population counts for WA for 1985-1995 were adjusted upwards so that they were compatible with 1996 figures. In the NT, adjusted 1996 counts were consistent with predictions, and ABS experimental counts and predictions were used. Annual total numbers of deaths for all Australia and for WA and the NT, and corresponding populations, were obtained from the ABS for 1979-1996. ICD-9 coding to four digits was used for coding cause of death.12 US and NZ data Numbers of deaths by age, sex and year of registration for Native Americans (including Alaskan natives) living on or near reservations were provided by the United States Indian Health Service for 1972-1992. Population counts were based on US census data, with interpolation between census years. Annual numbers of deaths for Maori for 1974-1994 were obtained from the NZ Health Information Service, and corresponding population estimates were based on census data from Statistics NZ. Excess mortality For a given cause, excess mortality was defined as the difference between the observed number of deaths for 1992-1995 for indigenous people in WA and the NT and the expected number of deaths for that cause calculated from death rates for the WA and NT (indigenous and non-indigenous) populations for the same period. Excess deaths for a given cause were expressed as a percentage by dividing the number of excess deaths for that cause by the number of excess deaths from all causes. Standardised mortality rates The World Standard Population 196013 was used for directly standardising death rates. We used Poisson regression to fit trend lines to time series of annual mortality rates, and calculated percentage change over time in annual standardised death rates from smoothed, trend-curve estimates rather than observed values. Results All-cause mortality rates Figure 1 shows annual all-cause mortality rates and fitted trend lines for Australian indigenous people, Maori, Native Americans and all Australians. The mortality rate from all causes for indigenous people in WA and the NT fell by 9% between 1985 and 1996. Over the same period, the all-cause rate for all Australians fell by 26%. The indigenous rate was 2.5 times the all-Australian rate in 1985 and three times the rate in 1996. The "hump" in the mortality rates for Australian indigenous people could represent a real increase to the 1990s followed by a decrease, but is more likely to be an artifact due perhaps to changing rates of registration of indigenous deaths. Death rates for NZ and US indigenous people fell relatively rapidly in the 1970s and more slowly thereafter. Between 1974 and 1984 mortality rates in Maori fell 32%, and a further 19% between 1984 and 1994. Mortality rates in Native Americans fell 17% between 1973 and 1982 from levels some 30% lower than those for Maori, and a further 11% between 1982 and 1992. Current mortality rates in Australian indigenous people are comparable with rates in Maori in the early 1970s. By 1990-1994, the average Australian indigenous all-cause mortality rate was 1.9 times the Maori rate, 2.4 times the US indigenous rate and 3.15 times the all-Australian rate. Main causes of excess mortality in Aboriginals and Torres Strait Islanders The ICD-9 coding system groups all causes of death into 17 broad categories. Four groups of conditions accounted for almost 70% of the total excess deaths in the Aboriginal and Torres Strait Islander population of WA and the NT during the five-year period 1992-1996. Circulatory conditions accounted for over a quarter (26%) of all excess deaths, with ischaemic heart disease, cerebrovascular disease and hypertension accounting for most of the circulatory disease excess; the injury and poisoning group, principally transport accidents, homicide and suicide, accounted for 15%, and respiratory conditions, including chronic obstructive airway disease and pneumonia, accounted for 16%; endocrine conditions, largely diabetes, caused a further 10% of excess deaths. International comparisons of mortality trends for the major causes of excess mortality Trends in annual standardised mortality rates for the four main causes of excess deaths in indigenous Australians are presented in Figure 2. (Data shown are for Australian indigenous people [1985-1996], Maori [1974-1994], Native Americans [1974-1992], and all Australians [1979-1996].) Circulatory disease: Current mortality rates for circulatory diseases in Aboriginals and Torres Strait Islanders were 50% higher than corresponding rates for Maori (the next-highest), and 2.5 times the all-Australian rate (Table, below). In the early 1970s, these mortality rates in Maori were above current Australian indigenous rates, but fell rapidly over the ensuing 20 years. Circulatory disease mortality rates in Native Americans have been lower than those in the other groups for the entire period, while the all-Australian mortality rates have held an intermediate course. Mortality rates from ischaemic heart disease in Maori fell in 1974 from above contemporary Australian indigenous rates to a third below by 1990-1994. By 1990-1994, mortality rates from cerebrovascular disease in Maori, after being equivalent in 1974, were down to less than half the corresponding Australian indigenous rates. Respiratory diseases: Mortality trends in respiratory system diseases were generally similar to those of the circulatory system, with Maori rates being initially very high (at the level of current Aboriginal and Torres Strait Islander rates) and then falling rapidly to levels not greatly exceeding current all-Australian levels. The overall reductions in rates of diseases of the respiratory system in Maori have been due largely to reductions in asthma and pneumonia deaths, which accounted for most respiratory system deaths in 1990-1994. In Australian indigenous people, other chronic obstructive pulmonary diseases and pneumonia accounted for a similar proportion of respiratory disease deaths in the same period. Injury and poisoning: The pattern here has been somewhat similar, although the relative positions of Native Americans and Maori are reversed. Death rates in Native Americans and Alaskan Natives were one and a half times the Australian indigenous injury and poisoning death rates in the early 1970s, but US rates have now fallen to below the current Australian level. For Aboriginals and Torres Strait Islanders in WA and the NT, there is little evidence of an overall decline (Figure 2). The decline in mortality rates from injury and poisoning in Native Americans has been driven particularly by changes in transport accidents, but also changes in homicide and suicide rates. For Australian indigenous people in WA and the NT, there appear to have been some relatively small recent falls in homicides and transport accident deaths, but there is some evidence that suicide rates are rising. Endocrine diseases: There has been no substantial improvement in mortality from endocrine diseases (largely diabetes). Death rates from diabetes in Maori fell in the 1970s, but have been rising slowly since the mid 1980s. Diabetes mortality rates in Native Americans have been rising slowly for 20 years. The rate for Australian indigenous people has also risen since the mid 1980s, but much more rapidly. In 1990-1994, the average mortality rate in Australian indigenous people for endocrine diseases was 2.4 times the Maori rate, 3.2 times the Native American rate and eight times the Australian rate (Figure 2). Discussion The health of Aboriginal and Torres Stait Islanders in WA and the NT is relatively poor compared with that of Maori and Native Americans, and has shown little, if any, improvement over the past 20 years. Although Australian mortality data cover only a 12-year period from 1985, there is no reason to believe that rates were much lower in the 10 years before 1985, and may have been somewhat higher. Several factors may influence the validity of comparisons among these three indigenous groups. A fundamental cause of non-random variation in annual mortality rates for indigenous groups is differences in factors influencing identification of a death as an indigenous death, and those determining whether people identify themselves as indigenous at census time. Special efforts to increase completeness in the 1996 Census resulted in a sharp rise in Australian indigenous population counts. However, similar improvements in ethnic identification on death certificates had not occurred by 1996. Indigenous population sizes over the 12 years studied were adjusted upwards to reflect the 1996 Census increase, which means that the Australian indigenous rates are likely to be lower than their true values. For all three indigenous groups, deaths were grouped by year of registration rather than year of death, so that they could be compared on a common basis. The extent of year-to-year variation in the proportion of deaths in a given year that were also registered in that year is unknown for Maori and Native Americans. Such variation would add a component of extra-Poisson variability to annual rate figures, but is unlikely to influence long term trends. The degree of late registration of Australian indigenous deaths is known to be relatively large compared with non-indigenous deaths and to vary from year to year. For this reason, apparent trends in Australian indigenous rates may be influenced to some degree by error in endpoint rate values. Different cause-of-death coding practices may have existed in the three comparison countries over time, leading to different apparent mortality rates for certain diseases. However, comparability of New Zealand and Australian non-indigenous rates suggests that there has been little difference between coding practices in these two countries over time. Furthermore, all-cause rates, not subject to coding variations, display the same patterns and differentials between ethnic groups observed for the separate causes of death. Although the three indigenous groups each have a different heritage and cultures, they share common experiences in their history. They are minority cultures in affluent nations dispossessed of their country and marginalised. However, Maori and Native Americans have made rapid gains in health and life expectancy over the past two decades. This progress is characterised by an initial rapid fall in death rates, followed by a more gradual decline as levels of the non-indigenous population are approached. Australian indigenous mortality shows little or no evidence of this pattern for any of the major causes of excess deaths. For some causes there is evidence of a recent decline, but no significant trend has yet been established. The health problems of Australia's indigenous people, and the circumstances responsible, are not unique. Why, then, has the health of Australia's indigenous people failed to match the improvement seen in other countries? Kunitz14 identified several aspects of Australian postcolonial indigenous experience which he felt contributed to the lack of improvement in health. He argues that Aboriginal affairs have traditionally been first a colonial then a State responsibility; and that there has been constant tension between State interests, particularly relating to land and management of the indigenous population. Furthermore, an official policy of assimilation maintained over many decades discouraged the creation of specialised indigenous health programs. In more recent times, competition for federal health funding by State and non-State bodies has meant that efforts to improve indigenous health have lacked coordination. Another factor, he suggests, is a lack of a sense of a single identity in many present-day indigenous communities, which were created artificially by gathering together people from many different tribal groups. The Treaty of Waitangi has been central to the relationship between Maori and other New Zealanders, and in the United States treaties established some status for Native Americans in their relationships with the "invading" Europeans, although these treaties were often abused. It is therefore difficult to entirely discount the suggestion that the absence of a treaty is a factor in the relative lack of progress in improving Australian indigenous health. Treaties, no matter how loosely worded, have appeared to play a significant and useful role in the development of health services, and in social and economic issues, for the indigenous people of New Zealand, the United States and Canada. Syme15 has hypothesised that the sense of control that people have over their lives and the sense of hope that this creates are important determinants of health status. He links both of these factors to disadvantage. It is arguable that colonial paternalism, an official policy of assimilation, and a lack of formal recognition through treaties have together acted to create and reinforce a sense of powerlessness in Australian indigenous people which is relatively less in other indigenous groups. It may well be that these intangible factors are adversely affecting indigenous health in Australia. The experience of other indigenous people around the world generates considerable confidence that effective action in Australia will produce substantial changes in indigenous health. Progress is needed in five key areas: infrastructure (land, housing, water supply, education, income, etc), self-determination of health services, access to a network of community-controlled primary healthcare services delivering effective health services for priority issues, an adequate level of resources, and a skilled workforce.16 Future success requires much greater progress within each of these five areas than has occurred in the past. A greater sense of control may only come from a wider acceptance and recognition of a valued role for Australian indigenous people in Australian society. References Kunitz SJ, Streatfield R, Santow G. Health of populations in northern Queensland Aboriginal communities: change and continuity. Hum Biol 1994; 66: 917-943. Veroni M, Gracey M, Rouse I. Patterns of mortality in Western Australian Aboriginals, 1983-1989. Int J Epidemiol 1994; 23: 73-81. Hogg RS. Indigenous mortality: placing Australian Aboriginal mortality within a broader context. Soc Sci Med 1992; 35: 335-346. Ring I. The Elkington Oration. Inequalities in health, the challenge for the nineties. Brisbane: Queensland Health, 1993. Runciman C, Ring I. The health of indigenous people in Queensland, some background information. Brisbane: Queensland Health, 1994. Australian Bureau of Statistics/ Australian Institute of Health and Welfare. The health and welfare of Australia's Aboriginal and Torres Strait Islander peoples. Canberra: ABS/AIHW, 1997 (Catalogue No. 4704.0.) Australian Institute of Health and Welfare. Australia's Health 1996. Canberra: AGPS, 1996. Australian Bureau of Statistics. Estimates of the Aboriginal population: review of data sources. Canberra: ABS, 1993. (Demography working paper: 93/2.) Gray A, Tetfaghiorghis H. Aboriginal population prospects. J Aust Popul Assoc 1993; 10: 81-99. Australian Bureau of Statistics. Experimental estimates of Aboriginal and Torres Strait Islander population (June 1986 to June 1991). Canberra: ABS, 1994. (Catalogue No. 3230.) Australian Bureau of Statistics. National Aboriginal and Torres Strait Islander Survey 1994. Detailed findings. Canberra: ABS, 1995. (Catalogue No. 4190.0.) The Australian version of the International Classification of diseases, 9th revision, clinical modification (ICD-9-CM). 2nd edition. Sydney: National Coding Centre (NCC), 1996. Waterhouse J, Muir C, Correa P, Powell J, editors. Cancer incidence in five continents. Vol III. Lyon: International Agency for Research on Cancer, 1976. (IARC Scientific Publications No. 15) Kunitz SJ. Disease and social diversity: the European impact on the health of non-Europeans. New York: Oxford University Press, 1994. Syme SL. Individual vs. community interventions in public health practice: Some thoughts about a new approach. Health Promotion Matters (Vic Health) July 1997; (2): 2-12. Ring I. An open letter to the President of the Public Health Association. Aust J Public Health 1995: 19: 228-230. (Received 8 Apr, accepted 22 Sep 1998) Authors' details School of Public Health and Tropical Medicine, James Cook University, Townsville, QLD. Ian T Ring, MB BS, MPH, MSc, Professor; and Head. Health Information Centre, Queensland Health, Brisbane, QLD. David Firman, MMath, Statistician. Reprints: Professor T Ring, School of Public Health and Tropical Medicine, James Cook University, Townsville, QLD 4811. E-mail: ian.ringATjcu.edu.au - Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

Ian T Ring · David Firman

For Debate Polycystic ovary syndrome: a new direction in treatment Warren Kidson MJA 1998; 169: 537-540 Abstract - Introduction - Insulin resistance in the polycystic ovary syndrome - Polycystic ovaries and the "metabolic syndrome" - Diabetes therapies in the polycystic ovary syndrome - Managing polycystic ovary syndrome - Conclusion - References - Authors' details - - More articles on Endocrinology Abstract Polycystic ovary syndrome is a diagnosis made in 5%-10% of women between late adolescence and the menopause. Patients may present with oligomenorrhoea or amenorrhoea, anovulation or infertility, hirsutism or acne. Women with the syndrome have at least seven times the risk of myocardial infarction and ischaemic heart disease of other women, and by the age of 40 years up to 40% will have type 2 diabetes or impaired glucose tolerance. Polycystic ovary syndrome is associated with insulin resistance, with consequent hyperinsulinaemia and (frequently) hyperlipidaemia and obesity. Recent research has shown that the application of diabetes management techniques aimed at reducing insulin resistance and hyperinsulinaemia (such as weight reduction and the administration of oral hypoglycaemic agents) can not only reverse testosterone and luteinising hormone abnormalities and infertility, but can also improve glucose, insulin and lipid profiles. The management of polycystic ovary syndrome should now include patient education and attention to diabetes and cardiovascular risk factors such as hyperlipidaemia, obesity, physical exercise, glucose intolerance, hypertension and cigarette smoking. Introduction The finding of polycystic ovaries on ultrasound is not an unusual one, occurring in 21% of premenopausal women in population surveys.1 Polycystic ovaries are due to incomplete follicular development or to failure of ovulation, and are therefore often seen in women with bulimia, recovery from anorexia nervosa, conditions of increased adrenal androgen production and hyperprolactinaemia.2 In early to mid adolescence, the ultrasound finding of polycystic ovaries is common and not regarded as abnormal, presumably because of the high prevalence of non-ovulatory cycles at this age. Polycystic ovary syndrome, which affects 5% to 10% of premenopausal women,3,4 is one of the most common endocrinopathies of women. It consists of at least two of the following features: polycystic ovaries, hyperandrogenism and anovulation (see Box 1). The classic therapy for symptoms of hyperandrogenism (such as hirsutism and acne) was to suppress ovarian testosterone production with an oral oestrogen/progestogen contraceptive, often with the addition of the antiandrogenic progestogen cyproterone acetate. Infertility and anovulation are usually treated with clomiphene citrate, gonadotropins or laparoscopically applied physical therapies to the ovaries, such as laser or diathermy.12-14 Open wedge resection of ovaries is rarely used because of the risk of obstructive infertility from adhesions. Insulin resistance in the polycystic ovary syndrome In a study of women with polycystic ovary syndrome performed 18 years ago, most were found to be hyperinsulinaemic and to have a glucose metabolism that was resistant to the stimulatory effects of insulin.15The insulin resistance in type 2 diabetes and polycystic ovary syndrome occurs mainly in muscles,16 but also in the liver in obese women with polycystic ovary syndrome.11 Insulin resistance is aggravated by physical inactivity, upper abdominal obesity, hyperandrogenism, pregnancy, the ageing process and by medications such as thiazide diuretics, corticosteroids and certain hormonal steroid preparations. Insulin resistance in polycystic ovary syndrome is not due primarily to obesity (as lean women with polycystic ovary syndrome are insulin resistant) or to hyperandrogenism17 (as androgen blockade reduces insulin resistance by only 10%-15%).18 Insulin resistance leads to hyperinsulinaemia as pancreatic insulin secretion rises to maintain normoglycaemia. Hyperinsulinaemia can then stimulate lipid storage, altered lipoprotein and cholesterol metabolism and (possibly) altered steroid hormone metabolism. Hyperinsulinaemia increases ovarian androgen production19 by stimulating an ovarian enzyme complex cytochrome P450c17α, either directly and/or by stimulating pituitary luteinising hormone secretion. The accurate measurement of insulin resistance is an expensive, labour-intensive research technique. The easiest, but least sensitive, measure of insulin resistance is fasting serum insulin, with values between 10 and 14 mU/L (72-100 pmol/L) indicating mild insulin resistance and values above 14 mU/L indicating moderate or severe insulin resistance. As fasting serum insulin values lie in the least sensitive range of the immunoassay curve, fasting serum insulin is more accurate if a mean of three specimens taken over 10 minutes is used. The insulin assay should have no cross-reactivity with proinsulin. Insulin resistance can also be assessed by the serum insulin response to an oral glucose load during an oral glucose tolerance test, peak serum insulin levels above 100 mU/L (718 pmol/L) being highly suggestive of insulin resistance. As most women with polycystic ovary syndrome should have a glucose tolerance test, serum insulin can be measured on three fasting specimens, as well as at one and two hours, so that both parameters of insulin resistance can be assessed. Various measures of insulin resistance in polycystic ovary syndrome have recently been studied, and the ratio of fasting insulin (mU/L) to fasting glucose (mmol/L) has been found to be a simple and accurate indicator of insulin resistance (sensitivity 95%, specificity 84%, positive predictive value 87% and negative predictive value 94%) at values above 4mU/mmol.20 Polycystic ovaries and the "metabolic syndrome" Over the past decade, studies have shown that women with polycystic ovary syndrome have a high prevalence of hyperlipidaemia,5-7 hypertension,8 and progression to type 2 diabetes mellitus,11 similar to the features of the so-called "metabolic syndrome" or "syndrome X". Of greatest concern is an estimate that the relative risk of myocardial infarction in women with polycystic ovary syndrome is 7.4 times that of other women.9 An ovarian ultrasound study found that 46% of women undergoing coronary angiography for ischaemic heart disease before the age of 60 years had polycystic ovaries and that the degree of coronary narrowing was greater than in the remaining 54%.10 Assuming a prevalence rate of polycystic ovary syndrome of 10%, I calculate the relative risk of premature ischaemic heart disease in polycystic ovary syndrome in this study was 7.7. Diabetes therapies in the polycystic ovary syndrome The growing body of evidence linking polycystic ovary syndrome to an inherited resistance to insulin action, aggravated by lifestyle problems such as obesity, poor diet and physical inactivity (such as happens with type 2 diabetes mellitus), has led to trials of diabetic therapies in patients with the polycystic ovary syndrome. Many studies, not all referenced in this article, have demonstrated that the lifestyle measures of diet and weight reduction can not only lower insulin levels and reduce hyperlipidaemia, but can lower androgen and luteinising hormone levels, restore regular menstruation and ovulation and hence improve fertility.21-23 Regular physical exercise is often recommended,24 but has been poorly studied and documented, despite its apparent efficacy. Four trials (two controlled and two uncontrolled) of metformin, a diabetes medication that reduces insulin resistance, have demonstrated a fall in serum androgens, luteinising hormone and weight and an improvement in fertility and fibrinolysis in both obese and lean women with polycystic ovary syndrome.19,25-27 Two studies have shown no improvement with metformin.28,29 The women in the first of these two studies were Turkish, which may have influenced the result as it is known that many intracellular enzyme defects can lead to insulin resistance and that the nature of insulin resistance can vary between racial groups. In the second negative study, the diet of the subjects was modified to prevent weight loss during metformin therapy. A recent controlled trial was performed in the United States, Venezuela and Italy in which obese women with polycystic ovary syndrome were given either metformin or placebo.30 Women in both groups who had not ovulated by Day 35 were given clomiphene as additional medication. By Day 35, 34% of women taking metformin had ovulated, compared with only 4% of the placebo-treated women (P < 0.001). Within 18 days after the addition of clomiphene, 90% of the remaining women taking metformin ovulated, compared with 8% of the placebo-treated women (P < 0.001). In summary, within 53 days only 7% of women treated with metformin or metformin plus clomiphene had not ovulated, compared with 88% of women treated with clomiphene alone. Troglitazone, another diabetes medication, has been demonstrated to improve insulin sensitivity and to lower serum insulin, androgen and luteinising hormone levels without causing weight loss in two studies.31,32 A recent Lancet editorial on the use of insulin-sensitising agents in polycystic ovary syndrome concluded that "confirmation of the beneficial effects of metformin on hormonal and metabolic variables in women with polycystic ovary syndrome will have implications not only for the treatment of the common gynaecological presenting features, but also for the burden of vascular disease in women".33 Managing polycystic ovary syndrome Glucose tolerance testing and lipid measurements Most women with polycystic ovary syndrome should have an oral glucose tolerance test at diagnosis and at five-yearly intervals thereafter, and measurement of fasting lipids at diagnosis and at two- to three-yearly intervals. The exception would be a woman aged less than 20 who is not overweight and who does not have a family history of diabetes mellitus, gestational diabetes or large birth weight. A considerable number will be found to have impaired glucose tolerance or mild type 2 diabetes. The measurement of serum insulin in the fasting state and at one and two hours will detect most insulin-resistant women. The parents of the woman with polycystic ovary syndrome should also have glucose tolerance tests. Her siblings' glucose tolerance should be assessed if a parent is shown to be diabetic. Lifestyle changes Obesity should be treated with a structured diet and exercise program,34 with appropriate dietary modification for the woman with hyperlipidaemia. Simply telling a patient to "lose weight" or "eat less" is unlikely to result in a significant reduction in weight, judging from experience in the management of type 2 diabetes. Consultation with dietitians working in type 2 diabetes or commercial weight reduction programs may be useful in refractory obesity. Hyperlipidaemia persisting after dietary modification and weight reduction may require drug therapy. Cigarette smoking should be vigorously discouraged in all women with polycystic ovary syndrome as it will exacerbate the increased risk of atherosclerosis. Cigarette smoking has recently been shown to aggravate insulin resistance in type 2 diabetes mellitus.35 Attempts to reduce weight, increase exercise and stop smoking will fail if the woman with polycystic ovary syndrome is not educated about the long term adverse health implications of this condition. Too often these women are told only about the cosmetic nuisances of hirsutism or acne. Oral contraceptives Oral contraceptives reduce acne and hirsutism by inhibiting ovarian steroid production, including androgens, and by suppressing pituitary follicle stimulating hormone and luteinising hormone secretion. The effect is dependent on the oestrogen dose in the contraceptive. Oral contraceptives are also used to effect secretory change in the endometrium and reduce the suggested, but unproven, increased risk of endometrial carcinoma in polycystic ovary syndrome.36,37 Any therapy that results in regular ovulation, however, should reduce the risks of endometrial carcinoma. A recent uncontrolled study of 16 non-diabetic hyperandrogenic women treated with a combined oral contraceptive containing 150 µg of desogestrel and 30 µg of ethinyloestradiol demonstrated a significant deterioration in glucose tolerance over six months, with two women developing frank diabetes.38 This raises doubts about the short and long term safety of ovarian suppression in polycystic ovary syndrome with oral contraceptives. The effects of individual oral contraceptives on glucose tolerance will now need to be studied specifically in polycystic ovary syndrome before their use can be advocated. The use of a "triphasic" combined oral contraceptive should be avoided as the early cycle ethinyloestradiol dose is often too low to inhibit dominant follicle selection and hence follicular development,39 theoretically having the potential to increase, rather than reduce, the number of ovarian cysts. Androgen-blocking drugs Spironolactone and cyproterone acetate preparations are generally equally effective in the treatment of hirsutism and acne, with occasional patient differences in response. Spironolactone generally does not cause weight gain and slightly reduces insulin resistance,18 but can cause polymenorrhoea (which may respond to a reduction in dose from 100 mg daily to 50 mg). Serum potassium levels and renal function should be checked. Non-steroidal anti-inflammatory drugs can potentiate the effects of spironolactone on renal potassium retention. Ovulation is commonly restored by spironolactone therapy, an event which may or may not be desired by the patient. Cyproterone acetate not infrequently causes depression and, at a dose of 100 mg, weight gain,40 the latter aggravating insulin resistance. Cyproterone preparations are relatively expensive. Insulin-sensitising drugs Metformin is now being suggested as initial therapy for women with polycystic ovary syndrome whose condition does not respond to lifestyle measures, ahead of traditional hormonally active agents, for amelioration of hirsutism and for the restoration of regular menses and ovulation.41,42 The drug should be withdrawn after conception. My limited experience with metformin suggests that it is at least as effective as spironolactone or cyproterone in the treatment of hirsutism and acne. Further studies will undoubtedly define the indications for insulin-sensitising medications in polycystic ovary syndrome, but they are already indicated for women with established diabetes and may be useful for women with refractory obesity or hyperlipidaemia. Infertility Infertility in polycystic ovary syndrome is usually treated successfully by improving diet and exercise, weight reduction and spironolactone therapy. If these measures are not successful, conception can usually be achieved by one or more of clomiphene citrate, gonadotropins, gonadotropin-releasing hormone analogues, laparoscopically applied therapies to the ovaries and assisted reproductive techniques. Metformin therapy increases spontaneous ovulation and dramatically enhances the ovulatory response to clomiphene29 and will hopefully reduce the need for more expensive forms of ovulation induction. Pregnancy in polycystic ovary syndrome Women with polycystic ovary syndrome have recently been shown to have an increased prevalence of gestational diabetes or impaired glucose tolerance during pregnancy43,44 and should therefore have a glucose tolerance test early in pregnancy and again at 26 to 28 weeks. Conclusion Much epidemiological and basic endocrine research is yet required to answer questions about the proportion of women with type 2 diabetes who have had polycystic ovary syndrome and the role of other hormones such as androstenedione, dihydroepiandrosterone sulfate, oestrone, insulin-like growth factor and opioid receptors. However, we now have sufficient scientific information to recommend randomised controlled trials of new therapies that should not only make treatment of immediate problems more effective, but which should also reduce the long term prevalence of ischaemic heart disease and diabetes, with all of its attendant complications. Never before have we been able to identify such a large group of women at risk of diabetes and vascular disease at such an early age, when preventive measures are most effective. References Farquhar CM, Birdsall MA, Manning P, et al. The prevalence of polycystic ovaries on ultrasound scanning in a population of randomly selected women. Aust N Z J Obstet Gynaecol 1994; 34: 67-72. Isik AZ, Gulekli B, Zorlu CG, et al. Endocrinological and clinical analysis of hyperprolactinaemic patients with and without ultrasonically diagnosed polycystic ovarian changes. Gyn Obstet Invest 1997; 43: 183-185. Hull MGR. Epidemiology of infertility and polycystic ovarian disease: endocrinological and demographic studies. Gynecol Endocrinol 1987; 1: 235-245. Polson DW, Adams J, Wadsworth J, et al. Polycystic ovaries -- a common finding in normal women. Lancet 1988; 1: 870-872. Robinson S, Henderson AD, Gelding SV, et al. Dyslipidaemia is associated with insulin resistance in women with polycystic ovaries. Clin Endocrinol 1996; 44: 277-284. Birdsall MA, Farquhar CM. Polycystic ovaries in pre- and post-menopausal women. Clin Endocrinol 1996; 44: 269-276. Meirow D, Raz I, Yossepowitch O, et al. Dyslipidaemia in polycystic ovary syndrome: different groups, different aetiologies? Hum Reprod 1996; 11: 1848-1853. Wild RA. Obesity, lipids, cardiovascular risk and androgen excess. Am J Med 1995; 98 Suppl: 27S-32S. Dahlgren E, Jansen PO, Johansson S, et al. Polycystic ovary syndrome and risk for myocardial infaction. Evaluated from a risk factor model based on a prospective population study. Acta Obstet Gynaecol Scand 1992; 71: 599-604. Birdsall MA, Farquhar CM, White HD. Association between polycystic ovaries and extent of coronary artery disease in women having cardiac catherization. Ann Int Med 1997; 126: 32-35. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocrine Rev 1997; 18: 774-800. Cohen J. Laparoscopic procedures for treatment of infertility related to polycystic ovary syndrome. Hum Reprod Update 1996; 2: 337-344. Pelosi MA, Pelosi III MA. Laparoscopic electrosurgical furrowing technique for the treatment of polycystic ovaries. J Am Assoc Gynecol Laparoscopists 1996; 4: 57-62. Pauthier S, Fernandez H, Lelaidier C, et al. Endoscopic laser co2 treatment of infertility due to polycystic ovary syndrome. Contraception Fertile Sexaulite 1997; 25: 147-151. Burghen GA, Givens JR, Kitabchi AE. Correlation of hyperandrogenism with hyperinsulinism in polycystic ovary disease. J Clin Endocrinol Metab 1980; 50: 113-116. DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 1988; 37: 667-687. Barbieri RL, Hornstein MD. Hyperinsulinemia and ovarian hyperandrogenism: cause and effect. Endocrinol Metab Clin North Am 1988; 17: 685-703. Moghetti P, Tose F, Castello R, et al. The insulin resistance in women with hyperandrogenism is partially reversed by antiandrogen treatment: evidence that androgens impair insulin action in women. J Clin Endocrinol Metab 1996; 81: 952-960. Legro R, Finegood D, Dunaif A. A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metabol 1998; 83: 2694-2698. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17a activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 1996; 335: 617-623. Kiddy DS, Hamilton-Fairley D, Seppala M, et al. Diet-induced changes in sex hormone binding globulin and free testosterone in women with normal or polycystic ovaries: correlation with serum insulin and insulin-like growth factor-I. Clin Endocrinol 1989; 31: 757-763. Kiddy DS, Hamilton-Fairley D, Bush A, et al. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin Endocrinol 1992; 36: 105-111. Jakubowicz DJ, Nestler JE. 17 α-Hydroxyprogesterone responses to leuprolide and serum androgens in obese women with and without polycystic syndrome after dietary weight loss. J Clin Endocrinol Metab 1997; 82: 556-560. Derman RJ. Effects of sex steroids on womens' health: implications for practitioners. Am J Med 1995; 98 Suppl: 137S-143S. Velaquez EM, Mendoza S, Hamer T, et al. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinaemia, insulin resistance, hyperandrogenaemia and systolic blood pressure whilst facilitating normal menses and pregnancy. Metab Clin Exper 1994; 43: 647-654. Velaquez EM, Mendoza S, Wang P, et al. Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein(a) and immunoreactive insulin levels in patients with the polycystic ovary syndrome. Metab Clin Exper 1997; 46: 454-457. Nestler JE, Jakubowicz DJ. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c170 α activity and serum androgens. J Clin Endocrinol Metab 1997; 82: 4075-4079. Acbay O, Gundogdu S. Can metformin reduce insulin resistance in polycystic ovary syndrome? Fertil Steril 1996; 65: 946-949. Ehrmann DA, Cavaghan MK, Imperial J, et al. Effects of metformin on insulin secretion, insulin action and ovarian steroidogenesis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997; 82: 524-530. Nestler J, Jakubowicz D, Evans W, et al. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med 1998; 338: 1876-1880. Dunaif A, Scott D, Finegood D, et at. The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab 1996; 81: 3299-3306. Ehrmann DA, Schneider DJ, Sobel BE, et al. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997; 82: 2108-2116. Sattar N, Hopkinson Z, Greer I. Insulin-sensitising agents in polycystic-ovary syndrome. Lancet 1998; 351: 305-307. Clark AM, Ledger W, Galletly C, et al. Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women. Hum Reprod 1995; 10: 2705-2712. Targher G, Alberto M, Zenere M, et al. Cigarette smoking and insulin resistance in patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 1997; 82: 3619-3624. Dahlgren E, Friberg L, Johansson S, et al. Endometrial carcinoma; ovarian dysfunction -- a risk factor in young women. Eur J Obstet Gynaecol Reprod Biol 1991; 41: 143-150. Ho S, Tan K, Pang M, Ho T. Endometrial hyperplasia and the risk of endometrial carcinoma. Singapore Med J 1997; 38: 11-15. Nader S, Riad-Gabriel M, Saad M. The effect of a desogestrel-containing oral contraceptive on glucose tolerance and leptin concentrations in hyperandrogenic women. J Clin Endocrinol Metab 1997; 82: 3074-3077. Fauser BCJM, Van Heusden AM. Manipulation of human ovarian function: physiological concepts and clinical consequences. Endocrine Rev 1997; 18: 71-106. Belisle S, Love E. Clinical efficacy and safety of cyproterone acetate in severe hirsutism: results of a multicentered Canadian study. Fertil Steril 1986; 46: 1015-1020. Nestler JE. Role of hyperinsulinaemia in the pathogenesis of the polycystic ovary syndrome, and its clinical implications. Semin Reprod Endocrinol 1997; 15: 111-122. Utiger RD. Insulin and the polycystic ovary syndrome. N Engl J Med 1996; 335: 657-658. Paradisi G, Fulghesu A, Ferrazzani S, et al. Endocrino-metabolic features in women with polycystic ovary syndrome during pregnancy. Human Reprod 1998; 13: 542-546. Anttila L, Karjala K, Penttila R, et al. Polycystic ovaries in women with gestational diabetes. Obstet Gynecol 1998; 92: 13-16. (Received 27 Jan, accepted 21 Jul, 1998) Author's details Sydney, NSW. Warren Kidson, MB BS, FRACP, Visiting Endocrinologist, Prince of Wales Hospital Randwick and Visiting Physician, Royal Hospital for Women, Paddington, NSW. Reprints: Dr Warren Kidson, 24 Blenheim Street, Randwick, NSW 2031. E-mail: wkidsonATmedeserv.com.au Make a comment Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

Warren Kidson

Clinical trials in developing countries: scientific and ethical issues David M Studdert and Troyen A Brennan Since the 1994 finding that intensive zidovudine treatment of mothers and infants can dramatically reduce perinatal transmission of human immunodeficiency virus, this treatment has been widely adopted in developed countries. In developing countries, trials of less-intensive (and cheaper) regimens have gone ahead, many funded by foreign governments and the United Nations. Controversy has erupted over these trials, particularly over their use of placebo controls. Do differences in healthcare needs and budgets justify different ethical standards in the developed and the developing world? MJA 1998; 169: 545-548 For editorial comment, see McNeill Introduction - The arguments - Ethical principles in international human research - Efficacy and use of placebo - Standard of care: is it relative? - References - Authors' details - - More articles on Ethics - ©MJA1998 Introduction Controversy over AIDS clinical trials in developing countries has galvanised public attention and divided the medical research community.1-4 The trials in question, in sub-Saharan Africa and Thailand, use randomised, placebo-controlled methods to test the effectiveness of interventions in preventing perinatal transmission of human immunodeficiency virus (HIV).5,6 At least nine of these trials have received US government funding through the Centers for Disease Control (CDC) or National Institutes of Health (NIH), while five are funded by other foreign governments, and one by the United Nations Program on AIDS (UNAIDS). Background to the controversy is shown in the Box. Debate was sparked in September 1997 by an article5 and an editorial13 in the New England Journal of Medicine. The editorial likened the trials to the notorious Tuskegee study of untreated syphilis (1938-1972),14 a US government study that continued to follow the natural progression of syphilis in a cohort of poor African American males long after penicillin became widely available. This comparison prompted two prominent members of the journal's editorial board to resign,15 and drew a rebuttal from the CDC and NIH.8 In October 1997, investigators discontinued use of placebos in an NIH-funded study of two short-course zidovudine regimens in Ethiopia.16 Then, in February 1998, the CDC and the Thai government announced that their placebo-controlled study of a short-course zidovudine regimen in Thailand had shown a 51% reduction in perinatal HIV transmission rates.17 At the same time, they announced that further use of placebos would cease in both this study and another in Cote d'Ivoire.11 The CDC, NIH, UNAIDS, and France's National Agency for AIDS Research (ANRS) have called for international dialogue on the "far-reaching scientific and policy implications of these findings".12 Nonetheless, a range of other foreign-sponsored clinical trials continue in developing countries, as does the debate about their ethics. To date, this debate appears to have generated more heat than light: the lines of arguments are often unclear, and it is difficult to isolate the central points of disagreement. For example, both critics and defenders of the trials claimed that the Thai findings vindicated their respective positions.18 In this article, we outline the main arguments and propose a framework for analysing some of the scientific and ethical issues. The arguments The critics' main objection to the trials is that investigators withhold an effective therapy from women and children who are randomised into control arms. Deprivation of a therapy known to be effective, albeit in an intensive and expensive form, has been construed as "ethical relativism".13,19 It is argued that this violates the principle that protections given to human subjects abroad should be "no less exacting" than those given in sponsoring countries.20 Two similar studies under way in the US gave all participants access to zidovudine and other antiretroviral drugs.5Arguments from defenders of the trials are interrelated, but may be divided roughly into three categories: First, it is argued that significant differences in resources and health conditions between countries can alter the balance that must be struck between risks (to study participants) and benefits (to study participants and others).8,21,22 In other words, a study may be acceptable in one country but not another because of differences in wealth or burdens of disease between the two. Second, the technical superiority of placebo-controlled methods is argued to have ethical implications.8,23 Faster answers are said to be possible with enrolment of fewer subjects. Defenders also attach moral weight to the fact that absolute, rather than marginal, benefits may be measured. At stake in this distinction, it is argued, is the difference between results that lead to life-saving policies, and results that simply raise new questions. Finally, defenders attach importance to satisfaction of process requirements.8,24,25 For example, they highlight the support and participation of host country governments and the approval of ethics review committees in the host and sponsoring countries. Study subjects' consent to participate is also highlighted, although critics have questioned whether this consent is truly "informed".26 More ardent defenders combine strands of difference and process arguments and caution against an "imperialism"27 that would second-guess the willing participation of individuals in the developing world. Ethical principles in international human research A decade ago, Marcia Angell (now Executive Editor of the New England Journal of Medicine) asked whether ethical standards should be "substantially the same everywhere, or is it inevitable that they differ from region to region, reflecting local beliefs and custom?"28 Today it is widely accepted that all research subjects are entitled to minimum guarantees that are transnational and non-negotiable.29 Realisation of these entitlements is, of course, a separate matter. However, institutional mechanisms for promulgating and applying human subject protections have advanced considerably, hurried on by several scandals and major public inquiries.30,31 Many countries, including Australia, New Zealand, and the United States, use formal ethics review committees and similar criteria to evaluate any government-funded study involving human subjects, wherever and however it is conducted. Among the minimum guarantees, formalised in the World Health Organization's Declaration of Helsinki32 and reiterated in guidelines promulgated by governments and institutions, are: The study must have a valid scientific design and be performed by qualified persons. It must strike a reasonable balance between the predictable risks and foreseeable benefits to the subjects or others, with the proviso that the subjects' interests should never be subordinate to those of science and society. All study subjects must consent to participate, a decision that must be made without duress or coercion and only after details of the study are provided. When investigators from one country conduct research in another country, it is appropriate to add to this list of minimum guarantees the requirement that: The research must hold the promise of direct, tangible, and significant benefit to the host country population, if not to the study subjects themselves.8 However, determining whether such benefits are likely to accrue can be problematic, because researchers and government officials in the host country will often have a vested interest in ensuring that the research proceeds. Efficacy and use of placebo Satisfaction of the above process requirements is a necessary, but not sufficient, basis for ethical research. A second inquiry is needed before accepting placebo-controlled studies: does the drug or intervention proposed for randomisation have proven therapeutic efficacy? If so, then a placebo-controlled study design is ethically suspect.33 Investigators will not be in the state of "equipoise", or indeterminacy, necessary to avoid conscious provision of inferior treatment to study subjects.34The zidovudine trials might be said to present the "easy case" for such analysis. Findings from the ACTG 076 protocol in 1994 were compelling, and the recent Thai results must now deepen concern about continued use of placebos in any zidovudine study, whether in Thailand or elsewhere. However, there are important subtleties. Firstly, efficacy may or may not be generalisable across countries with wide disparities in baseline levels of health status, healthcare services, and burdens of disease.8,25,35 Whether this problem raises serious doubts about the efficacy of the ACTG 076 regimen in sub-Saharan Africa is debatable, especially after the Thai results. However, it does illustrate a more general point -- failure to separate the question of efficacy, at least initially, from considerations about whether a universal standard of care is applicable may obscure important scientific questions. Another complication is that judgements about efficacy can be problematic when the scientific evidence is equivocal. For example, several years ago our own human subjects committee at the Harvard School of Public Health considered a protocol for a placebo-controlled study of the effect of vitamin A and multivitamins on perinatal HIV transmission in Tanzania. The decision to approve the study was difficult because data on the prophylactic benefits of micronutrient supplementation for HIV-infected women were inconclusive, and remain so today. (However, recently published findings show other pregnancy-outcome benefits36 which would enter the ethical calculation were a similar protocol reviewed today.) How is equivocal evidence on efficacy to be weighed? Although the efficacy question has ethical implications, we believe it is a technical or scientific question at the outset. Hence, it may be useful for the ethics review committee to require investigators to summarise the evidence for efficacy of an intervention. If efficacy is established anywhere, the investigators should satisfy a threshold level of doubt about its applicability to their study site. However, this task subjects the investigators to competing pressures, requiring them to demonstrate to ethics committees and sponsors that their hypothesis is valid and that the intervention has some reasonable expectation of an effect, while simultaneously marshalling evidence for doubt. To guard against this conflict, ethics review committees may wish to convene independent scientific panels to evaluate evidence on efficacy. When efficacy is established or is in the "grey area", committees might also require investigators to report on potential alternative approaches -- such as "equivalence"37 or "observational"38 study designs. In summary, given that fundamental requirements of human subjects research are met, poor evidence about efficacy should allay many ethical concerns. On the other hand, when the proposed intervention has known efficacy -- or there is a sound basis for inferring efficacy -- and no alternative study approach is feasible, a further question arises: is it ethically acceptable to confine subjects in the control arm to treatments which are considered substandard in the sponsoring country? Standard of care: is it relative? The current debate is devoting much energy to the question of whether different conditions abroad can justify lower standards of care, especially when the differences arise from resource inequities. This question is certainly raised by some of the AIDS trials under scrutiny, as the ACTG 076 regimen has become a standard treatment for seropositive pregnant women in the United States and many other developed countries.39 However, the larger question is whether non-conformity with sponsoring-country standards is a sufficient basis for stopping any placebo-controlled study abroad, or whether clear-cut answers to the efficacy question in this particular case merely help to explain why the trials are objectionable. Lurie and Wolfe note, "as a model of an ethically conducted study",5 a comparison in Thailand of three short zidovudine regimens with a regimen similar to the ACTG 076 regimen. A placebo-controlled design was considered and rejected by our human subjects committee at the Harvard School of Public Health.5 Although the recent Thai findings17 were not at hand, the committee and investigators agreed that an equivalence design could achieve the study's main goals. In addition, the committee was mindful of anecdotal evidence that a regimen similar to ACTG 076 was soon to be widely available in Thailand. One interpretation of the committee's decision is that it underscores a commitment to an inviolable standard of care. However, a better account of deliberations is that the standard-of-care question was not directly considered, because an alternative study approach was feasible, and there was genuine doubt about whether the placebo treatment even met the host country's standard of care. Had neither of these factors been present, then the standard-of-care question would have been under consideration as the primary basis for approving or rejecting the study protocol. We hesitate to predict the outcome. A careful, global dialogue is needed on how international medical research involving human subjects should deal with inevitable differences in standards of care. Rigid adherence to a universal standard of care will narrow, perhaps even eliminate, the opportunities for placebo-controlled studies in the developing world. It is not clear that the research community, or the majority of citizens in any country, are ready to embrace this consequence, particularly as the gap in resources and disease burden between developed nations and sub-Saharan Africa continues to widen.40 References Annas GJ, Grodin MA. An apology is not enough. Boston Sunday Globe 1997 May 18; Sect C: 1. Stolberg SG. U. S. AIDS research abroad sets off outcry over ethics. New York Times 1997 Sep 18; Sect A: 1. AIDS in Africa. The Economist 1997; Sep 27: 19. Stolberg SG. Job itself in doubt as new feud looms on surgeon general. New York Times 1998 February 5; Sect A: 1. Lurie P, Wolfe SM. Unethical trials of interventions to reduce perinatal transmission of the human immunodeficiency virus in developing countries. N Engl J Med 1997; 337: 853-855. Phanuphak P. Ethical issues in studies in Thailand of vertical transmission of HIV. N Engl J Med 1998; 338: 834-835. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. N Engl J Med 1994; 331: 1173-1180. Varmus H, Satcher D. Ethical complexities of conducting research in developing countries. N Engl J Med 1997; 337: 1003-1005. Waldholz M. AZT price cut for third world mothers-to-be. Wall Street Journal 1998 Mar 5: Sect B: 1. Frenkel LM, Cowles MK, Shapiro DE, et al. Analysis of the maternal components of the AIDS clinical trial group 076 zidovudine regimen in the prevention of mother-to-infant transmission of human immunodeficiency virus type 1. J Infect Dis 1997; 175: 971-974. Centers for Disease Control. Update on CDC Collaborative research studies on perinatal HIV prevention in the developing world: preliminary results find short-course AZT effective. 1998 Feb:<http://www.cdc.gov/nchstp/od/Perinatal> Centers for Disease Control and Prevention (CDC), The Joint United Nations Programme on HIV/AIDS (UNAIDS), The National Institutes of Health (NIH), and The Agence Nationale de Recherche sur le SIDA (ANRS). Joint statement. 1998 Feb 18:<http://www.unaids.org/highband/press/cdcjs8> Angell M. The ethics of clinical research in the third world. N Engl J Med 1997; 337: 847-849. Jones JH. Bad blood: the Tuskegee syphilis experiment. New York: Free Press, 1993. Altman LK. AIDS experts leave journal after studies are criticized. New York Times 1997 October 15; Sect A: 1. Another HIV-1 trial loses placebo control. Lancet 1997; 350: 831. Centers for Disease Control. Short-course regimen of AZT proven effective in reducing perinatal HIV transmission: offers hope for reducing mother-to-child HIV transmission in developing world. 1998 Feb 24. <http://www.cdc.gov/od/oc/media/ pressrel/r980224.html> US ends placebo use in foreign AIDS study. Chicago Tribune 1998 Feb 19: Sect N: 14. Angell M. Tuskegee revisited. Wall Street Journal 1997 Oct 28; Sect A: 22. World Health Organization. International ethical guidelines for biomedical research involving human subjects. Geneva: Council for International Organizations of Medical Sciences, 1993. Bagenda D, Muske-Mudido P. A look at ... ethics and AIDS. Washington Post 1997 Sep 28; Sect C: 3. Saba J, Ammann A. A cultural divide on AIDS research. New York Times 1997 Sep 20; Sect A: 15. Simonds RJ, Rogers MF, Dondero TJ. Ethics of placebo-controlled trials of zidovudine to prevent the perinatal transmission of HIV in the third world [letter]. N Engl J Med 1998; 338: 836-837. Study volunteers support placebo-controlled AIDS trials; AZT to prevent vertical transmission of HIV in South Africa. AIDS Weekly Plus 1997 Oct 27: 24. Mbidde EK. Ethics of placebo-controlled trials of zidovudine to prevent the perinatal transmission of HIV in the third world [letter]. N Engl J Med 1998; 338: 837. French HW. AIDS research in Africa: juggling risks and hopes. New York Times 1997 Oct 9: Sect A: 1. Cohen J. Ethics of AZT studies in poorer countries attacked. Science 1997; 276: 1022. Angell M. Ethical imperialism? Ethics in international collaborative clinical research. N Engl J Med 1988; 319: 1081-1083. Penslar RL. Research ethics: cases and materials. Bloomington: Indiana University Press, 1995. Report of the Committee of Inquiry into Allegations Concerning the Treatment of Cervical Cancer at the National Women's Hospital and into Other Related Matters. Report. Auckland: Government Printing Office, 1988. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Belmont report: ethical principles for the protection of human subjects research. Washington, DC: Government Printing Office, 1988. World Medical Association, Declaration of Helsinki IV. Adopted by the 18th World Medical Assembly, Helsinki 1964, as amended by the 41st World Medical Assembly, Hong Kong, 1989. <http://www.nih.gov/grants/oprr/irb_appendices.html#j6> Chalmers TC. The clinical trial. Milbank Mem Fund Q 1981; 59: 324-339. Freedman B. Equipoise and the ethics of clinical research. N Engl J Med 1987; 317: 141-145. Merson MH. Ethics of placebo-controlled trials of zidovudine to prevent the perinatal transmission of HIV in the third world [letter]. N Engl J Med 1998; 338: 836. Fawzi WW, Msamanga GI, Spiegelman D, et al. Randomized trial of effects of vitamin supplements on pregnancy outcomes and T cell counts in HIV-infected women in Tanzania. Lancet 1998; 351: 1477-1482. Ware JH, Antman EM. Equivalence trials. N Engl J Med 1997; 337: 1159-1161. Blanche S. Ethics of placebo-controlled trials of zidovudine to prevent the perinatal transmission of HIV in the third world [letter]. N Engl J Med 1998; 338: 837-838. Recommendations of the US Public Health Service Task Force on the use of zidovudine to reduce perinatal transmission of human immunodeficiency virus. MMWR Morb Mortal Wkly Rep 1994; 43 (RR-11): 1-20. United Nations Development Program. Human Development Report. New York: Oxford University Press, 1997. Authors' details Department of Health Policy and Management, Harvard School of Public Health, Boston, MA, USA. David M Studdert, LLB, ScD, MPH, Instructor; and Fellow in Medical Ethics, Harvard Medical School, Boston, MA; currently, Social Scientist, RAND Corporation, Santa Monica, CA, USA. Troyen A Brennan, MD, JD, MPH, Professor of Law and Public Health; and Professor of Medicine, Harvard Medical School, Boston, MA. Reprints: Dr D M Studdert, RAND Corporation, 1700 Main Street, Santa Monica, CA 90407-2138 USA. E-mail: studdertATrand.org - Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>". <URL: http://www.mja.com.au/>

David M Studdert · Troyen A Brennan