1276 CAUSE OF DEATH BY ORAL-CONTRACEPTIVE

USE, FOR WOMEN

WITH PRE-EXISTENT DISEASE AT ENTRY

Letters to the Editor MORTALITY IN WOMEN ON ORAL CONTRACEPTIVES

*** Readers of the report from the Royal College of General Practitioners (Oct. 8, p. 729) must have been puzzled by the layout of the latter part of this article as it appeared in th published version (but not in the preprints). Not only were th Conclusions and Discussion sections transposed but also th< last two paragraphs of the Discussion appeared at the end oj the Results; and these two paragraphs cover some of the point! raised in correspondence. Correct reprints of this article, page size and with the original pagination, will be available from The Lancet, free of charge. We apologise to Dr Beral and Di Kay for marring their paper.-ED.L. their smoking during the study period. National statistics for 1968 to 1976 indicate that women have generally attained their peak cigarette consumption by the age 25-29 and that few are likely to take up smoking after the age of 25. Thus it seems unlikely that cigarette consumption increased appreciably during the follow-up period. Prospective studies have demonstrated, for men at least, that "smoking at entry" is a valid indicator of subsequent smoking habits, and that it is a good predictor of smoking-associated mortality.’ The magnitude of the excess mortality among ever-users is too great to be explained by even substantial changes in smoking habit. Dr Heiby (Dec. 3, p. 1172) is concerned about certain aspects of the data analysis. We agree with him that an agestandardisation procedure which allows for the aging of women during the study period is more desirable than one based on their age at entry (which was used in tables I, III, and IV of the R.C.G.P. report). The data presented in tables v and vi of the report do take the aging of the population into account, however. From the data in table v, subdivided into 5-year age-groups, we estimate the ratio of the age-standardised mortality-rates from circulatory diseases in ever-users to controls to be 5-4 to 1. When the ratios are similarly calculated for the takers and ex-takers separately, we estimate them to be 6.0 0 to 1 and 4-5 5 to 1, respectively. These ratios are not standardised for other factors. A computer program is being developed which will simultaneously standardise for age, smoking, parity, and social class, as well as allowing for the aging of the study population. Such a refinement of the analysis would be expected to have a small effect on the standardised rates presented in tables i, III, and iv of the report. Heiby also criticises other techniques which he, wrongly, claims were used in the analysis. Smoking was standardised on the basis of six subcategories (see appendix 2 of Oral Contraceptives and Health’). The denominators used in table vi were not calculated in the way Heiby suggested. They are correct. His recalculation is, therefore, inappropriate. Dr Haack and Dr McKean (Nov. 12, p. 1024) propose that the excess mortality among pill-users may reflect their "flamboyant life style". To explain the increase in risk with duration of use, they would also need to postulate that women who take the pill continuously for 5 years or longer are more flamboyant still than short-term users. We do not have information on alcohol, marihuana, or other drug use about which they inquire; but if alcohol use is more common among pillusers, as they suggest, this might protect them from coronary heart-disease.s Dr Detering and Dr Hartmann (Nov. 12, p. 1024) are also concerned with the self-selection of oral-contraceptive users. They argue that the high mortality-rate among the ex-takers indicates that they were at an increased

creasing

SIR,-We would like to respond to various questions and comments on the R.C.G.P. report on the mortality of oral-con-

traceptive users. Dr Fowler (Oct. 22, p. 379) and Dr Ravenholt (Nov. 12, p. 1023) have inquired about the 17 women who died from chronic conditions diagnosed before the women were recruited into the study. The accompanying table lists their oral-contraceptive use at entry and their subsequent causes of death. There were only 3 deaths from circulatory disease (I.C.D. 390-458). Had these 3 women been included in our analyses they would have made no appreciable difference to the comparisons between ever-users and controls. In general the takers were a healthier group of women than the controls when they entered the study.l.2 This is illustrated by the 7 excess deaths from pre-existing breast cancer in the controls. In fact, only 1 taker but 17 controls were reported to have a history of breast cancer when they were recruited (rates of 0.04 per 1000 and 0.72 per 1000, respectively). This was to be expected since breast cancer is usually regarded as a contraindication to pill use. Thus it is rare to find current pillusers with a past history of breast cancer. Since only current pill-users or never users were recruited into the study, the pilltaking group was essentially free from recognised breast cancer at the onset of the study. Similar selection processes occurred with other chronic diseases; the proportion of women with a history of various circulatory diseases, including diabetes and toxaemia of pregnancy, was also initially lower in takers than controls.’ It

was in order to reduce this selection bias that we excluded from the analyses those women whose death resulted from chronic disease diagnosed before recruitment. Dr Lloyd (Oct. 29, p. 922) has suggested that "it is the controls rather than the pill takers who deviate most from England and Wales as a whole", because the controls’ death-rate from circulatory diseases is particularly low. As has already been discussed in the R.C.G.P. report and by Professor Vessey and his colleagues (Oct. 8, p. 731) the overall death-rates in both study populations are lower than those in the general population. The age-standardised rates for England and Wales presented by Lloyd do not apply to the R.C.G.P. study population, as they were calculated for the older Oxford/Family Planning Association study population. Nevertheless, the female population of reproductive age in England and Wales contains women who have taken the pill as well as women who have not. If the ever-users have a higher mortality-rate from circulatory diseases than women of comparable age in England and Wales, then the controls would be expected to have a lower mortality-rate. Lloyd has also suggested that the excess mortality among ever-users could be accounted for by pill takers in-

1. 2.

of General Practitioners. Oral London: Pitman. 1974.

Royal College

Contraceptives

and Health.

Vessey, M., Doll, R., Peto, R., Johnson, B., Wiggins, P. J. biosoc. Sci. 1976, 8, 373.

3. Lee, P. N., Statistics of Smoking in the United

Kingdom. Tobacco Research

Council, 1976. 4. Doll, R., Hill, A. B. Br. med. J. 1964, i, 1399. 5. Yano, K., Rhoads, G. C., Kagan, A. New Engl. J. Med. 1977, 297, 405.

1277 risk from circulatory disease before they began taking the pill. Alternative hypotheses are also plausible; for example, that the excess mortality among the ex-takers reflects a residual effect of the pill. That blood-pressure declines within 3 months of stopping the pill does not necessarily imply, as they suggest, that other pill-associated effects would be similarly reversible. Before we can understand the implications of the raised mortality-rate in ex-takers we need to know if it is related to the length of time since the pill was discontinued. At present the numbers are too small to permit such an analysis. Your editorial (Oct. 8, p. 747) and Dr May (Oct. 20, p. 922) have drawn attention to the need to define confidence limits for our risk estimates. Using a method suggested by R. Peto (personal communication) we estimate the 95% confidence limits for the ratios of the death-rates in ever-users to controls to range from 1-7 to 14.0 for all circulatory diseases (I.C.D. 390-458), from 1.3 to 26-0 for all non-rheumatic heart-disease (I.C.D. 400-429), and from 1.2 to 21-4 for all cerebrovascular disease (I.C.D. 430-438). Finally from our personal correspondence we have learned that there is some misunderstanding about the type of pill used by the study population. 79% of the women-years of observations in the takers relate to pills containing 50 jig oestrogen or less, and a large majority of these relate to the 50 fLg dosage. London School of

Hygiene &

Tropical Medicine, London WC1E 7HT

VALERIE BERAL

R.C.G.P. Oral Contraception Study, 8 Barlow Moor Road, Manchester M20 0TR

CLIFFORD KAY

SIR,-The reports on mortality and oral-contraceptive use in your issue of Oct. 8 will be of interest to both medical and lay communities. While the role of cigarette smoking in oralcontraceptive users has again been stressed, the pathogenesis of the increased mortality remains unclear. There is a strong body of evidence showing increased serum lipids (particularly triglycerides) in women taking oral contraceptives,1.2 while there is suggestive evidence that cigarette smoking by itself may be associated with increased serum-lipids.3·4 PLASMA TRIGLYCERIDE AND CHOLESTEROL VALUES

(mg/dl)

*p

Mortality in women on oral contraceptives.

1276 CAUSE OF DEATH BY ORAL-CONTRACEPTIVE USE, FOR WOMEN WITH PRE-EXISTENT DISEASE AT ENTRY Letters to the Editor MORTALITY IN WOMEN ON ORAL CONTRA...
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