lnt
J Gynaccol Obstet
16: 529- 534, 1979
Smoking, Age and the Pill John McEwan King 's College Hospital, London, England
ABSTRACT McEwan J (King's College Hospital, London, England). Smoking, age and the pill. lntj Gynaecol Obstet 16: 529- 534, 1979 A brief outline is given of alterations in the normal physiology caused by cigarette smoking, aging and taking combined oral contraceptive pills. There are similarities in some of these effects. Evidence is considered regarding the health risks of using the pill and the relationship of these risks to the age of the woman and her smoking habit. This evidence is derived from recent epidemiologic studies carried out in Britain on some aspects of morbidity and the death rates ascribable to the pill. The implications for prescribing clinicians are discussed and indications are given for reducing the overall risks to life and health for pill users.
Cigarette smoking exposes the body system to the toxic effects of tar, nicotine and carbon monoxide. The first acts on tissues in the respiratory system; nicotine and carbon monoxide are absorbed into the bloodstream and possibly cause the effect of smoking on the heart. The heart is then subject to an increased risk of arrhythmias and the transient constriction of peripheral blood vessels, a condition easi ly observed in the fingernails of a young person. Chronic heavy smoking a lso increases atherosclerotic deposits in the arterial walls. Age causes a risk of increase in blood pressure, increased deposits of lipids and loss of elasticity in the arterial walls. The constituents of the pill also affect the cardiovascular system . Estrogen increases the cardiac output, probably by inducing skin vasodilatation (7), and increases certain clotting factors in the blood and platelet aggregation while decreasing fibrinolytic activity (10). Estrogen a lso raises certain blood lipid levels and causes a significant increase in blood pressure in a small proportion of women on the pill,
about six per 1000. Progestogens probably contribute to the last effect if present in high dosage. It is perhaps no surprise to find an interactive determination of adverse effects from these three factors and this has been revealed from epidemiologic studies. Many years ago, t he Royal College of General Practitioners (RCGP) ( 11) , Vessey and Doll (15, 16) and Sartwell et al (14) drew attention to the relationship between venous thrombosis, pulmonary embolism and the pill. Table I provides a summary adapted from Doll (1). These studies showed that the risk was increased three times in the group of women who were 35 years and older, over that in younger women. Inman and Vessey (3) showed that mortality from these conditions and from cerebral thrombosis was similarly affected by age (Tab le II) . Originally it was thought that cigarette smoking might influence this effect of the pill, but the suggestion cou ld not be substantiated and the lack of an effect was recently confirmed by data from the Boston Collaborative Drug Survei llance Program (6). It became clear in the late 1960s that the pill possibly produced very serious adverse effects on the cardiovascu lar system, but the risks cou ld not then be precisely quantified from case-control studies (2). Soon after, two large prospective surveys were set up in Britain . It was reported very early from both these that pill users were more likely to smoke than nonusers and the pill group included a higher proportion of very heavy smokers (Tables Ill and IV) (4, 18) . Subsequently, all of the findings in these two surveys were subject to standardization procedures for smoking and for age. In the RCGP study, six subgroups were used for smoking and seven for age which, together with similar groupings for social class and parity, led to 1764 cells in each of the groups under study: pill takers, former takers and controls (12). Vessey used four subgroups for age (the age range at entry was 25- 39 years) and three groups for smoking which, wit h parity and social
lntj Gynaecol Obstt l 16
530 McEwan
Table 1. Observed and expected incidence of deep vein thrombosis or pulmonary embolism in women by users and nonusers of oral contraceptives (0Cs) 8 • No. of OC No. of Non-OC Users Affected Users Affected Relative Expected Risks Expected from from for Non-OC Control Control Source of Data Observed Groups Groups Users Observed General practice consultations British hospitals Deaths in Britain American hospitals 8
5 42 16 53
Source: R. Doll (1 ).
Table Ill. Incidence of smoking in women in the Royal College of General Practitioners Study8 . No. of Pill Cigarettes Takers Controls Smoked (N = 14 940) per Day (N = 17 077) % % at Entry 0
1-4 5-9 10-14 15-19 2::20 8
15 42 10 76
18.0 72.5 21 .8 110.0
3 .0:1 6.3:1 8.3:1 4.0:1
Source: R. Doll (1 ).
Table II. Annual risks per 1 00 000 women of deep vein thrombosis, pulmonary embolism or cerebral thrombosis in healthy women in Britain 8 • Hospital Deaths Admission Oral Aged Aged Aged Contra16-40 20-34 35-44 ceptive Years Use Years Years 1.5 3.9 Used 50 0 .2 0.5 6 Not Used 8
2.0 11 .5 4.2 19.0
x2 =
189; p
52 6 8 14 9 12
58 6 7 13 7 8
class standardizat ion, led to 72 cells in each group using a different contraceptive method (17). Since the British Committee on Safety of Medicines at the end of 1969 recommended that the daily dose of es trogen should not exceed 50 JLg, the incidence of venous thromboembolism has greatly declined. A great deal of anx iety has arisen more recently over the question of excess death rates in pill users and the risk of acute myocardial infarction an d of other cardiovascular conditions, particularly cerebrovascular lesions. Mann et al (9) studied the proportion of pill users in a case-control survey of 63 relatively young married women (under 45 years) adm itted to the hospital with acute myocardial infarction during 19681972, compared with 189 hospital controls matched fo r marital status, age group and year of admission to the hospita l (Table V) . Twenty-nine percent (29%) had used the pill during the month before adm ission compared with 8% of the controls, that is, a risk of 4.5: 1.0 (p < 0.001) . Further analysis showed that a number of a lternative risk factors contributed to the likelihood of acute myocardial infarction, such as diabetes, hypertension , obesity, famili a l hyperlipoproteinemia and particularly cig-
< 0 .001. Source: C. R. Kay eta/ (4).
Table IV. Incidence of smoking in women in the Oxford study8 • No. of Cigarettes Pill Smoked Other per Day Takers % % at Entry 72.8 62.3 0 5 .1 5.0 1-4 13. 0 15.1 5-14 9 .1 17.6 2::15 8 No change in findings after data was controlled for age, parity and social class. Source: M. P. Vessey eta/ (18).
lnt J Gynaecol Obstet 16
Table V. Oral contraceptive (OC) use by myocardial infarction (MI) and control patients in hospital patients from 1968-1972 8 • Ml Patients Controls (N =58) (N = 166) % % OC Use Never used Used during month before admission Used only >1 month before admission 8
x2 =
60
80
29
8
10
12
13.58; df = 1; p < 0.001 . Source: J . I. Mann eta/ (9).
Smoking, age and tlu pill
arette smoking. In fact, only one patient who had an infarct while on the pill had none of these additional risk factors. The estimated relative risk in pill users after standardization for these factors is shown in Table VI. Cigarette smoking is clearly an important factor, but the predominance of pill users in the infarction group is shown for different degrees of cigarette consumption in Table VII. The numbers are small and statistically significant (p < 0.01) only when smokers are considered together. Mann and Inman (8) reported simultaneously a study of 153 deaths from myocardial infarction in women under 50 years during 1973. General practice controls were used for a retrospective comparison wh ich selected women matched for age and marital status. There was a significant ly higher proportion of oral contraceptive users in those dying from myocardial infarction (p < 0.001) , and the risk was greater in those aged 40- 44 years (4. 7: 1.0) than in those under 40 (2.8: 1.0) . Un fortun ately, it was not possible to acq uire adequate informat ion about cigarette smoking; but hypertension and diabetes, indicated by evidence of treatments given, were significantly more common in the infarction patients. There was nevertheless an associat ion with pill use when women with these conditions were excluded . It was also found that duration of pill use was longer in infarction patients than in the controls, 70 % having used the pill for more than two years in the infarction group compared with 42 % in the controls (Tab le VIII). Toward the end of 1977, reports were puolished on deaths of pill users in the RCGP Oral Contraception Study (13) and those in the Oxford/Family Planning Assoc iat ion Study (19). An excess mortality risk was found in current pill takers and former pill takers ascribab le to a ll circu latory conditions
Table VI. Estimated relative risk of myocardial infarction in current pill users after standardization for possible confounding variables 8 . Relative Significance Variable Risk Level x2 Standardized Estimate Cigarette smoking Hypertension · Preeclamptic toxemia Obesity All the above simultaneously Overall risk o
3.2 4 .1
6.83 10.75
p < 0 .01 p = 0 .001
3.9 4.4
10.16 12.72
p p
< 0 .01 < 0 .001
3.1
5.93
p
< 0 .01
4.5
Source: J. I. Mann et a/ (9).
53 1
Table VII. Oral contraceptive users among myocardial infarction (MI) and control patients by smoking habit from 1968-1972. No. of Patients Using Pill Cigarettes at Time Smoked of Episode per Day at Time of Ml Episode Patients Controls 0 3/16 8/78 1-14 2/8 2/44 ~ 15 11/33 4/32 Total 16/57 =28. 1% 14/154 = 9 .1% All smokersb 13/41 =3 1.7% 6/76 = 7.9% o
Source: J . /. Mann et a/ (9).
b
p
60
Age (at death) in Years
15-34
35-49c
Age Standardizedc
Ratio of Age-Standardized Rate to That of Controls
3. 7 (2) 8.5 (3)
7.9 (3) 33 .0 (4) 113.8 (9)
5.2 (5) 17.5 (7) 50 .5 (9)
1.0 3.4 9 .7
a·
• Source: Royal College of General Practitioners (13). b Number of deaths in parentheses. c Linear trends, p < 0. 01 .
seen even more clearly than before that prescribers should advise all patients on the pill not to smoke, to keep th eir weight down to average levels and to have their blood pressure checked regularly. It seems probable that any woman aged 30 to 34 years, who has ta ken the pill continuously. for five years, should be advised to change to an alternative method of fertility control. We have no evidence at present to suggest that deaths from circulatory conditions are aggravated by longer duration of pill use in younger women , or that intermittent episodes of medication rather than continuous use have any beneficial effect. Clearly, these are important issues that need further study.
REFERENCES I. Doll R : The long-term effects of steroid contraceptives. J Biosoc Sci 2:367, 1970.
2. Doll R, Vessey MP : Eva lua ti on of ra re a dverse effects on systemic contraceptives. Br Med Bull 26:33, 19 70. 3. Inma n WHW , Vessey MP : Investigation of deaths from pulmona ry coronary a nd cerebra l thrombosis a nd embolism in women of childbearin g age. Br Med J 2:1 93, 1968. 4. K ay CR, Smith A, Richards B: Smoking habits of ora l contraceptive users. La ncet 2: 1228, 1969. 5. Ku enssberg EV , Dewhurst J : Mort a lit y in women on ora l contracepti ves. La ncet 2:757, 19 77. 6. Lawson DH , Da vidson JF, Jick H : Ora l contrace ptive use a nd venous thromboembolism: a bsence of an efTect of smoking. Br Med J 2:729, 19 77 . 7. Lehtovirt a P : J Obstet Gynaecol Br Commonw 8 1:526, 1974. 8. Ma nn Jl , Inma n WHW: Ora l contracepti ves a nd dea th from myocardial infa rction. Br Med J 2:245, 19 75. 9. Ma nn JI, Vessey MP, Thorogood M , Doll R : M yocardia l infa rcti on in youn g women with specia l reference 10 ora l contracepti ve prac tice. Br Med J 2:24 1, 1975 . 10. Poller L, Thomson JM , Thomas W : Br M ed J 4:648, 197 1. II. Royal College of Genera l Practitioners: O ra l contraception a nd thrombo-embolic disease. J Coli Gen Pract 13:267, 1967.
lnt j Gynaecol Obstet 16
534
McEwan
12. Royal College of General Practitioners: Oral Con traceptives and Health. Pitman, London, 1974. 13. Royal College of General Practitioners Oral Contraception Study: Mortality among oral contracepti ve users. Lancet 2: 727, 1977. 14. Sartwell PE, Masi AT, Arthes FG, Greene GR, Smi th HE: Thromboembolism and oral contraceptives: an epidem iological case-con trol study. Am J Epidem iol 90:365, 1969. 15. Vessey MP, Doll R : Invest igation of relation between use of oral con tracept ives a nd thromboembolic disease. Br Med J 2: 199, 1968. 16. Vessey MP, Doll R: In vestigation of relation between use of oral con traceptives and thromboembolic disease: a further report. Br M ed J 2:65 1, 1969. 17. Vessey M , Doll R , Peto R , J ohnson B, Wiggins P: A longterm follow-up stud y of women using different methods of contraception, an interim report. J Biosoc Sci 8:373, 1976. 18. Vessey MP, Doll R, Peto R, Redman CWG: C haracteristics
Jntj Gynaecol Obstet 16
of women using different methods of contracep tion . Some preliminary findin gs from a prospective study. Int J Epidemiol 1:1 19, 1972. 19. Vessey MP, McPherson K, Johnson B: Mortality among wom en participating in the Oxford/Family Planning Associat ion contraceptive stud y. Lancet 2:73 1, 1977.
Address for reprints: John McEwan 5th Floor, New Ward Block King's College Hospital Den mark Hill London SE 5 England
J Gynaccol Obstet
16: 529- 534, 1979
Smoking, Age and the Pill John McEwan King 's College Hospital, London, England
ABSTRACT McEwan J (King's College Hospital, London, England). Smoking, age and the pill. lntj Gynaecol Obstet 16: 529- 534, 1979 A brief outline is given of alterations in the normal physiology caused by cigarette smoking, aging and taking combined oral contraceptive pills. There are similarities in some of these effects. Evidence is considered regarding the health risks of using the pill and the relationship of these risks to the age of the woman and her smoking habit. This evidence is derived from recent epidemiologic studies carried out in Britain on some aspects of morbidity and the death rates ascribable to the pill. The implications for prescribing clinicians are discussed and indications are given for reducing the overall risks to life and health for pill users.
Cigarette smoking exposes the body system to the toxic effects of tar, nicotine and carbon monoxide. The first acts on tissues in the respiratory system; nicotine and carbon monoxide are absorbed into the bloodstream and possibly cause the effect of smoking on the heart. The heart is then subject to an increased risk of arrhythmias and the transient constriction of peripheral blood vessels, a condition easi ly observed in the fingernails of a young person. Chronic heavy smoking a lso increases atherosclerotic deposits in the arterial walls. Age causes a risk of increase in blood pressure, increased deposits of lipids and loss of elasticity in the arterial walls. The constituents of the pill also affect the cardiovascular system . Estrogen increases the cardiac output, probably by inducing skin vasodilatation (7), and increases certain clotting factors in the blood and platelet aggregation while decreasing fibrinolytic activity (10). Estrogen a lso raises certain blood lipid levels and causes a significant increase in blood pressure in a small proportion of women on the pill,
about six per 1000. Progestogens probably contribute to the last effect if present in high dosage. It is perhaps no surprise to find an interactive determination of adverse effects from these three factors and this has been revealed from epidemiologic studies. Many years ago, t he Royal College of General Practitioners (RCGP) ( 11) , Vessey and Doll (15, 16) and Sartwell et al (14) drew attention to the relationship between venous thrombosis, pulmonary embolism and the pill. Table I provides a summary adapted from Doll (1). These studies showed that the risk was increased three times in the group of women who were 35 years and older, over that in younger women. Inman and Vessey (3) showed that mortality from these conditions and from cerebral thrombosis was similarly affected by age (Tab le II) . Originally it was thought that cigarette smoking might influence this effect of the pill, but the suggestion cou ld not be substantiated and the lack of an effect was recently confirmed by data from the Boston Collaborative Drug Survei llance Program (6). It became clear in the late 1960s that the pill possibly produced very serious adverse effects on the cardiovascu lar system, but the risks cou ld not then be precisely quantified from case-control studies (2). Soon after, two large prospective surveys were set up in Britain . It was reported very early from both these that pill users were more likely to smoke than nonusers and the pill group included a higher proportion of very heavy smokers (Tables Ill and IV) (4, 18) . Subsequently, all of the findings in these two surveys were subject to standardization procedures for smoking and for age. In the RCGP study, six subgroups were used for smoking and seven for age which, together with similar groupings for social class and parity, led to 1764 cells in each of the groups under study: pill takers, former takers and controls (12). Vessey used four subgroups for age (the age range at entry was 25- 39 years) and three groups for smoking which, wit h parity and social
lntj Gynaecol Obstt l 16
530 McEwan
Table 1. Observed and expected incidence of deep vein thrombosis or pulmonary embolism in women by users and nonusers of oral contraceptives (0Cs) 8 • No. of OC No. of Non-OC Users Affected Users Affected Relative Expected Risks Expected from from for Non-OC Control Control Source of Data Observed Groups Groups Users Observed General practice consultations British hospitals Deaths in Britain American hospitals 8
5 42 16 53
Source: R. Doll (1 ).
Table Ill. Incidence of smoking in women in the Royal College of General Practitioners Study8 . No. of Pill Cigarettes Takers Controls Smoked (N = 14 940) per Day (N = 17 077) % % at Entry 0
1-4 5-9 10-14 15-19 2::20 8
15 42 10 76
18.0 72.5 21 .8 110.0
3 .0:1 6.3:1 8.3:1 4.0:1
Source: R. Doll (1 ).
Table II. Annual risks per 1 00 000 women of deep vein thrombosis, pulmonary embolism or cerebral thrombosis in healthy women in Britain 8 • Hospital Deaths Admission Oral Aged Aged Aged Contra16-40 20-34 35-44 ceptive Years Use Years Years 1.5 3.9 Used 50 0 .2 0.5 6 Not Used 8
2.0 11 .5 4.2 19.0
x2 =
189; p
52 6 8 14 9 12
58 6 7 13 7 8
class standardizat ion, led to 72 cells in each group using a different contraceptive method (17). Since the British Committee on Safety of Medicines at the end of 1969 recommended that the daily dose of es trogen should not exceed 50 JLg, the incidence of venous thromboembolism has greatly declined. A great deal of anx iety has arisen more recently over the question of excess death rates in pill users and the risk of acute myocardial infarction an d of other cardiovascular conditions, particularly cerebrovascular lesions. Mann et al (9) studied the proportion of pill users in a case-control survey of 63 relatively young married women (under 45 years) adm itted to the hospital with acute myocardial infarction during 19681972, compared with 189 hospital controls matched fo r marital status, age group and year of admission to the hospita l (Table V) . Twenty-nine percent (29%) had used the pill during the month before adm ission compared with 8% of the controls, that is, a risk of 4.5: 1.0 (p < 0.001) . Further analysis showed that a number of a lternative risk factors contributed to the likelihood of acute myocardial infarction, such as diabetes, hypertension , obesity, famili a l hyperlipoproteinemia and particularly cig-
< 0 .001. Source: C. R. Kay eta/ (4).
Table IV. Incidence of smoking in women in the Oxford study8 • No. of Cigarettes Pill Smoked Other per Day Takers % % at Entry 72.8 62.3 0 5 .1 5.0 1-4 13. 0 15.1 5-14 9 .1 17.6 2::15 8 No change in findings after data was controlled for age, parity and social class. Source: M. P. Vessey eta/ (18).
lnt J Gynaecol Obstet 16
Table V. Oral contraceptive (OC) use by myocardial infarction (MI) and control patients in hospital patients from 1968-1972 8 • Ml Patients Controls (N =58) (N = 166) % % OC Use Never used Used during month before admission Used only >1 month before admission 8
x2 =
60
80
29
8
10
12
13.58; df = 1; p < 0.001 . Source: J . I. Mann eta/ (9).
Smoking, age and tlu pill
arette smoking. In fact, only one patient who had an infarct while on the pill had none of these additional risk factors. The estimated relative risk in pill users after standardization for these factors is shown in Table VI. Cigarette smoking is clearly an important factor, but the predominance of pill users in the infarction group is shown for different degrees of cigarette consumption in Table VII. The numbers are small and statistically significant (p < 0.01) only when smokers are considered together. Mann and Inman (8) reported simultaneously a study of 153 deaths from myocardial infarction in women under 50 years during 1973. General practice controls were used for a retrospective comparison wh ich selected women matched for age and marital status. There was a significant ly higher proportion of oral contraceptive users in those dying from myocardial infarction (p < 0.001) , and the risk was greater in those aged 40- 44 years (4. 7: 1.0) than in those under 40 (2.8: 1.0) . Un fortun ately, it was not possible to acq uire adequate informat ion about cigarette smoking; but hypertension and diabetes, indicated by evidence of treatments given, were significantly more common in the infarction patients. There was nevertheless an associat ion with pill use when women with these conditions were excluded . It was also found that duration of pill use was longer in infarction patients than in the controls, 70 % having used the pill for more than two years in the infarction group compared with 42 % in the controls (Tab le VIII). Toward the end of 1977, reports were puolished on deaths of pill users in the RCGP Oral Contraception Study (13) and those in the Oxford/Family Planning Assoc iat ion Study (19). An excess mortality risk was found in current pill takers and former pill takers ascribab le to a ll circu latory conditions
Table VI. Estimated relative risk of myocardial infarction in current pill users after standardization for possible confounding variables 8 . Relative Significance Variable Risk Level x2 Standardized Estimate Cigarette smoking Hypertension · Preeclamptic toxemia Obesity All the above simultaneously Overall risk o
3.2 4 .1
6.83 10.75
p < 0 .01 p = 0 .001
3.9 4.4
10.16 12.72
p p
< 0 .01 < 0 .001
3.1
5.93
p
< 0 .01
4.5
Source: J. I. Mann et a/ (9).
53 1
Table VII. Oral contraceptive users among myocardial infarction (MI) and control patients by smoking habit from 1968-1972. No. of Patients Using Pill Cigarettes at Time Smoked of Episode per Day at Time of Ml Episode Patients Controls 0 3/16 8/78 1-14 2/8 2/44 ~ 15 11/33 4/32 Total 16/57 =28. 1% 14/154 = 9 .1% All smokersb 13/41 =3 1.7% 6/76 = 7.9% o
Source: J . /. Mann et a/ (9).
b
p
60
Age (at death) in Years
15-34
35-49c
Age Standardizedc
Ratio of Age-Standardized Rate to That of Controls
3. 7 (2) 8.5 (3)
7.9 (3) 33 .0 (4) 113.8 (9)
5.2 (5) 17.5 (7) 50 .5 (9)
1.0 3.4 9 .7
a·
• Source: Royal College of General Practitioners (13). b Number of deaths in parentheses. c Linear trends, p < 0. 01 .
seen even more clearly than before that prescribers should advise all patients on the pill not to smoke, to keep th eir weight down to average levels and to have their blood pressure checked regularly. It seems probable that any woman aged 30 to 34 years, who has ta ken the pill continuously. for five years, should be advised to change to an alternative method of fertility control. We have no evidence at present to suggest that deaths from circulatory conditions are aggravated by longer duration of pill use in younger women , or that intermittent episodes of medication rather than continuous use have any beneficial effect. Clearly, these are important issues that need further study.
REFERENCES I. Doll R : The long-term effects of steroid contraceptives. J Biosoc Sci 2:367, 1970.
2. Doll R, Vessey MP : Eva lua ti on of ra re a dverse effects on systemic contraceptives. Br Med Bull 26:33, 19 70. 3. Inma n WHW , Vessey MP : Investigation of deaths from pulmona ry coronary a nd cerebra l thrombosis a nd embolism in women of childbearin g age. Br Med J 2:1 93, 1968. 4. K ay CR, Smith A, Richards B: Smoking habits of ora l contraceptive users. La ncet 2: 1228, 1969. 5. Ku enssberg EV , Dewhurst J : Mort a lit y in women on ora l contracepti ves. La ncet 2:757, 19 77. 6. Lawson DH , Da vidson JF, Jick H : Ora l contrace ptive use a nd venous thromboembolism: a bsence of an efTect of smoking. Br Med J 2:729, 19 77 . 7. Lehtovirt a P : J Obstet Gynaecol Br Commonw 8 1:526, 1974. 8. Ma nn Jl , Inma n WHW: Ora l contracepti ves a nd dea th from myocardial infa rction. Br Med J 2:245, 19 75. 9. Ma nn JI, Vessey MP, Thorogood M , Doll R : M yocardia l infa rcti on in youn g women with specia l reference 10 ora l contracepti ve prac tice. Br Med J 2:24 1, 1975 . 10. Poller L, Thomson JM , Thomas W : Br M ed J 4:648, 197 1. II. Royal College of Genera l Practitioners: O ra l contraception a nd thrombo-embolic disease. J Coli Gen Pract 13:267, 1967.
lnt j Gynaecol Obstet 16
534
McEwan
12. Royal College of General Practitioners: Oral Con traceptives and Health. Pitman, London, 1974. 13. Royal College of General Practitioners Oral Contraception Study: Mortality among oral contracepti ve users. Lancet 2: 727, 1977. 14. Sartwell PE, Masi AT, Arthes FG, Greene GR, Smi th HE: Thromboembolism and oral contraceptives: an epidem iological case-con trol study. Am J Epidem iol 90:365, 1969. 15. Vessey MP, Doll R : Invest igation of relation between use of oral con tracept ives a nd thromboembolic disease. Br Med J 2: 199, 1968. 16. Vessey MP, Doll R: In vestigation of relation between use of oral con traceptives and thromboembolic disease: a further report. Br M ed J 2:65 1, 1969. 17. Vessey M , Doll R , Peto R , J ohnson B, Wiggins P: A longterm follow-up stud y of women using different methods of contraception, an interim report. J Biosoc Sci 8:373, 1976. 18. Vessey MP, Doll R, Peto R, Redman CWG: C haracteristics
Jntj Gynaecol Obstet 16
of women using different methods of contracep tion . Some preliminary findin gs from a prospective study. Int J Epidemiol 1:1 19, 1972. 19. Vessey MP, McPherson K, Johnson B: Mortality among wom en participating in the Oxford/Family Planning Associat ion contraceptive stud y. Lancet 2:73 1, 1977.
Address for reprints: John McEwan 5th Floor, New Ward Block King's College Hospital Den mark Hill London SE 5 England
