CONTRACEPTION
Oral contraceptives, venous thrombosis, and varicose veins ROYAL COLLEGE OF GENERAL PRACTITIONERS' ORAL CONTRACEPTION STUDY* SUMMARY. As part of a continuing major prospective survey of oral contraceptive users, analyses of the frequency of reporting of venous thrombosis have been reassessed and updated. The risk of idiopathic deep and superficial thrombosis in the leg is respectively four and two and a half times greater in oral contraceptive users than non-users. There is no evidence that the risk persists after oral contraceptives have been stopped. In the presence of varicose veins the reporting of superficial thrombosis is substantially increased in Pill users and non-users, and the risk is shown to be dependent upon the severity of the varicosities. Varicose veins have little influence on the development of deep vein thrombosis. No relationship has been found between the oestrogen dose or the progestogen content of the combined oral contraceptives and the occurrence of idiopathic deep vein throm¬ bosis in Pill users. In contrast, superficial venous thrombosis in oral contraceptive users is statisti¬ cally significantly related to both the oestrogen dose and the progestogen content of the Pill.
Introduction Oral Contraception Study is continuing THEprospective survey of total reported morbidity and The a
Study began mortality in a large group of women. in April 1968, and in the following 14 months 1,400 volunteer general practitioners in the UK recruited for observation 23,000 current oral contraceptive users and
a similar number of women matched for age and marital status who had never taken the Pill. In 1974 we published a lengthy interim report which reviewed all *Director: Dr Clifford R. Kay, cbe, md, ph.d, frcgp, RCGP
Manchester Research Unit, 8 Barlow Moor Road, Manchester M200TR.
©
Journal ofthe Royal College of General Practitioners,
393-399.
1978,28,
important findings (Royal College of General Practitioners, 1974). These included evidence of an increased risk experienced by oral contraceptive users of developing 'idiopathic' deep and superficial venous thrombosis of the leg. The respective relative risks were 5-66 and 1-48, and these values were similar to the estimates based on previous case-control studies (RCGP, 1967; Vessey and Doll, 1969; Sartwell et al., 1969; Boston Collaborative Drug Surveillance Program, 1973). At that time it was possible to carry out only a fairly simple computation for the exclusion of the most important pre-existing conditions which might influence the development of venous thrombosis. We later undertook a much more extensive and rigorous analysis, as explained further. The results briefly reported by Kay in 1975 did not materially alter our previous assessment. In this paper we present further analyses using the same method but including more recent data. We also investigate the extent to which the presence of varicose veins affects the risk of venous thrombosis of the leg in oral contraceptive users and non-users. Since our data are cumulative, the present results cannot provide independent confirmation of our previous assessments but must be regarded as supersedingthem. our
Method A detailed description of the design and organization of the Study, with an extensive discussion of the interpretation of the results, were included in our interim report (RCGP, 1974). Briefly, this is a survey which aims to record results of the normal clinical practices of the participating doctors. No special examinations are imposed on the patients in the Study. The diagnoses upon which the analyses are based are those made by the general practitioners using, where appropriate, the full resources of the NHS, including specialist advice and investigation. Women who were recruited as current oral contraceptive users and who have remained
Journal ofthe Royal College of General Practitioners, July 1978
393
Contraception Table 1. Methods used for the exclusion of conditions that might influence venous thrombosis. 1. Patients entirely excluded
a) Reported to have relevant medical disorders:
ICD codes (incl) 140- 209 239 Endocrine disorders 2400-2587* 2589-2799 Blood disorders 282284 286- 288 320- 344 Central neurological disorders 348- 349 disorders 429 390Circulatory 440- 448 573 Liver disorders 570Chronic renal disorders 580- 584 b) Patients admitted to hospital for medical treatment of any other diseases except cerebrovascular and venous thromboembolic
Malignantor unspecified 230neoplasms
disorders 2. Patients partially excluded
a) Surgical operations Calendar month of the
operation and the following calendar month,
and associated events. Calendar month after that b) Pregancy in which the last menstrual period before the pregnancy occurred to the calendar month following the end of the pregnancy inclusive, and associated events. c) Periods of observation and associated events following the first report of a cerebrovascular or venous thromboembolic disease.
Periods of observation
(women years) Total Excluded Residual
Takers 60,632 26,150 34,482
Ex-takers Controls
35,992 110,065 21,223 62,981 14,769 47,084
*Premenstrual disorders are coded to category 2588.
continuously on the Pill are categorized as 'takers'. The group also includes, from the time of change, those women originally recruited as 'controls' who later became oral contraceptive users. Thus, the control results represent the experience of a group of women
who have never used the Pill. From the time a taker stops the Pill, she is regarded as an 'ex-taker'. Subsequent experience of the Pill by an ex-taker has
394
been excluded from the present analyses. In summary, the experience of the taker group represents first segment Pill usage during the course of the Study, while the subsequent first segment of non-use forms the extaker category. The contribution of each Study patient to her appropriate contraceptive category is measured in calendar months, and the computer calculations are based on women-months of observation. The tabulations, however, show event rates per thousand women years. The diseases are categorized according to the contraceptive status of the woman at the time the diagnoses were made. The development of venous thrombosis is commonly influenced by pre-existing conditions. As a result of medical and self-selection the occurrence of these is known to differ between the contraceptive categories. Thus, comparisons can be properly made only if we consider those reported thrombotic events occurring in women without known relevant pre-existing conditions .the so-called 'idiopathic' venous thromboembolic diseases. The complex computation required for the calculation of idiopathic events is detailed in Table 1. The rates in each of the three contraceptive categories have been standardized by the indirect method for age, parity, cigarette consumption, and social class. The experience of the total residual population has been used as the standard. Cerebrovascular diseases have also been investigated, but the results will be reported separately. We have generally used the International Classifi¬ cation of Diseases (WHO, 1965) for coding morbidity and mortality. The classification unfortunately fails to distinguish between deep and superficial venous throm¬ bosis in the leg. As before, we have used our own classification for these diseases and this is shown in the tables.
Results Table 2 shows our main findings. There is a highly significant increased risk of deep and superficial thrombosis of the leg in takers compared with controls. The risk of deep vein thrombosis in current oral contraceptive users is 4-17 times greater than in the nonusers, and this estimate is in close conformity with those of other studies. The corresponding relative risk of 2 41 for superficial lesions is similar to the finding in the RCGP case-control study in 1967. Although the trends are similar, in the two other disease categories (Table 2) the numbers are small and the differences do not reach statistical significance. The number of cases in both these categories is too small to warrant further consideration in this paper. It is important to note that the rates in ex-takers do not differ materially from those in the controls. This implies that there is no residual effect on venous thrombosis after the Pill has been stopped. .
Journal ofthe Royal College of General Practitioners, July 1978
Contraception
TWY thousand women years. =
*p
Oral contraceptives, venous thrombosis, and varicose veins ROYAL COLLEGE OF GENERAL PRACTITIONERS' ORAL CONTRACEPTION STUDY* SUMMARY. As part of a continuing major prospective survey of oral contraceptive users, analyses of the frequency of reporting of venous thrombosis have been reassessed and updated. The risk of idiopathic deep and superficial thrombosis in the leg is respectively four and two and a half times greater in oral contraceptive users than non-users. There is no evidence that the risk persists after oral contraceptives have been stopped. In the presence of varicose veins the reporting of superficial thrombosis is substantially increased in Pill users and non-users, and the risk is shown to be dependent upon the severity of the varicosities. Varicose veins have little influence on the development of deep vein thrombosis. No relationship has been found between the oestrogen dose or the progestogen content of the combined oral contraceptives and the occurrence of idiopathic deep vein throm¬ bosis in Pill users. In contrast, superficial venous thrombosis in oral contraceptive users is statisti¬ cally significantly related to both the oestrogen dose and the progestogen content of the Pill.
Introduction Oral Contraception Study is continuing THEprospective survey of total reported morbidity and The a
Study began mortality in a large group of women. in April 1968, and in the following 14 months 1,400 volunteer general practitioners in the UK recruited for observation 23,000 current oral contraceptive users and
a similar number of women matched for age and marital status who had never taken the Pill. In 1974 we published a lengthy interim report which reviewed all *Director: Dr Clifford R. Kay, cbe, md, ph.d, frcgp, RCGP
Manchester Research Unit, 8 Barlow Moor Road, Manchester M200TR.
©
Journal ofthe Royal College of General Practitioners,
393-399.
1978,28,
important findings (Royal College of General Practitioners, 1974). These included evidence of an increased risk experienced by oral contraceptive users of developing 'idiopathic' deep and superficial venous thrombosis of the leg. The respective relative risks were 5-66 and 1-48, and these values were similar to the estimates based on previous case-control studies (RCGP, 1967; Vessey and Doll, 1969; Sartwell et al., 1969; Boston Collaborative Drug Surveillance Program, 1973). At that time it was possible to carry out only a fairly simple computation for the exclusion of the most important pre-existing conditions which might influence the development of venous thrombosis. We later undertook a much more extensive and rigorous analysis, as explained further. The results briefly reported by Kay in 1975 did not materially alter our previous assessment. In this paper we present further analyses using the same method but including more recent data. We also investigate the extent to which the presence of varicose veins affects the risk of venous thrombosis of the leg in oral contraceptive users and non-users. Since our data are cumulative, the present results cannot provide independent confirmation of our previous assessments but must be regarded as supersedingthem. our
Method A detailed description of the design and organization of the Study, with an extensive discussion of the interpretation of the results, were included in our interim report (RCGP, 1974). Briefly, this is a survey which aims to record results of the normal clinical practices of the participating doctors. No special examinations are imposed on the patients in the Study. The diagnoses upon which the analyses are based are those made by the general practitioners using, where appropriate, the full resources of the NHS, including specialist advice and investigation. Women who were recruited as current oral contraceptive users and who have remained
Journal ofthe Royal College of General Practitioners, July 1978
393
Contraception Table 1. Methods used for the exclusion of conditions that might influence venous thrombosis. 1. Patients entirely excluded
a) Reported to have relevant medical disorders:
ICD codes (incl) 140- 209 239 Endocrine disorders 2400-2587* 2589-2799 Blood disorders 282284 286- 288 320- 344 Central neurological disorders 348- 349 disorders 429 390Circulatory 440- 448 573 Liver disorders 570Chronic renal disorders 580- 584 b) Patients admitted to hospital for medical treatment of any other diseases except cerebrovascular and venous thromboembolic
Malignantor unspecified 230neoplasms
disorders 2. Patients partially excluded
a) Surgical operations Calendar month of the
operation and the following calendar month,
and associated events. Calendar month after that b) Pregancy in which the last menstrual period before the pregnancy occurred to the calendar month following the end of the pregnancy inclusive, and associated events. c) Periods of observation and associated events following the first report of a cerebrovascular or venous thromboembolic disease.
Periods of observation
(women years) Total Excluded Residual
Takers 60,632 26,150 34,482
Ex-takers Controls
35,992 110,065 21,223 62,981 14,769 47,084
*Premenstrual disorders are coded to category 2588.
continuously on the Pill are categorized as 'takers'. The group also includes, from the time of change, those women originally recruited as 'controls' who later became oral contraceptive users. Thus, the control results represent the experience of a group of women
who have never used the Pill. From the time a taker stops the Pill, she is regarded as an 'ex-taker'. Subsequent experience of the Pill by an ex-taker has
394
been excluded from the present analyses. In summary, the experience of the taker group represents first segment Pill usage during the course of the Study, while the subsequent first segment of non-use forms the extaker category. The contribution of each Study patient to her appropriate contraceptive category is measured in calendar months, and the computer calculations are based on women-months of observation. The tabulations, however, show event rates per thousand women years. The diseases are categorized according to the contraceptive status of the woman at the time the diagnoses were made. The development of venous thrombosis is commonly influenced by pre-existing conditions. As a result of medical and self-selection the occurrence of these is known to differ between the contraceptive categories. Thus, comparisons can be properly made only if we consider those reported thrombotic events occurring in women without known relevant pre-existing conditions .the so-called 'idiopathic' venous thromboembolic diseases. The complex computation required for the calculation of idiopathic events is detailed in Table 1. The rates in each of the three contraceptive categories have been standardized by the indirect method for age, parity, cigarette consumption, and social class. The experience of the total residual population has been used as the standard. Cerebrovascular diseases have also been investigated, but the results will be reported separately. We have generally used the International Classifi¬ cation of Diseases (WHO, 1965) for coding morbidity and mortality. The classification unfortunately fails to distinguish between deep and superficial venous throm¬ bosis in the leg. As before, we have used our own classification for these diseases and this is shown in the tables.
Results Table 2 shows our main findings. There is a highly significant increased risk of deep and superficial thrombosis of the leg in takers compared with controls. The risk of deep vein thrombosis in current oral contraceptive users is 4-17 times greater than in the nonusers, and this estimate is in close conformity with those of other studies. The corresponding relative risk of 2 41 for superficial lesions is similar to the finding in the RCGP case-control study in 1967. Although the trends are similar, in the two other disease categories (Table 2) the numbers are small and the differences do not reach statistical significance. The number of cases in both these categories is too small to warrant further consideration in this paper. It is important to note that the rates in ex-takers do not differ materially from those in the controls. This implies that there is no residual effect on venous thrombosis after the Pill has been stopped. .
Journal ofthe Royal College of General Practitioners, July 1978
Contraception
TWY thousand women years. =
*p
