Saturday 8 October
MORTALITY AMONG
ORAL-CONTRACEPTIVE USERS Royal College of General Practitioners’ Oral Contraception Study* In a large prospective study carried out in the United Kingdom, the death-rate from diseases of the circulatory system in women who had used oral contraceptives was five times that of controls who had never used them; and the death-rate in those who had taken the pill continuously for 5 years or more was ten times that of the controls. The excess deaths in
Summary
oral-contraceptive users were due to a wide range of vascular conditions. The total mortality-rate in women who had ever used the pill was increased by 40%, and this was due to an increase in deaths from circulatory diseases of 1 per 5000 ever-users per year. The excess was substantially greater than the death-rate from complications of pregnancy in the controls, and was double the death-rate from accidents. The excess mortality-rate increased with age, cigarette smoking, and duration of oral contraceptive use. Introduction THE Oral Contraception Study of the Royal College of General Practitioners is a continuing long-term prospective study of approximately 46 000 women of childbearing age in the United Kingdom. It began in 1968 and is designed to evaluate the effects of oral contraceptives on health. Women were recruited by 1400 general practitioners who have recorded all new episodes of illness
reported by
the
study population.
A
comprehensive
of the illnesses in those using oral contraceptives continuously ("takers"), those who stopped using them during the course of the study ("ex-takers"), and those who had never used them ("controls") was published in May, 1974.’ This paper discusses the deaths recorded during the follow-up period until June, 1976, which covers some 200 000 women-years of observation. account
Methods The study design, methods of data collection, analytical techniques, and the potential sources of bias have already been
discussed in detail.’ In summary, 23 000 current takers and 23 000 controls who were matched by age and marital status to the takers, were recruited over a 14-month period. Controls who later became oral-contraceptive users were included in the *
author: Dr VALERIE BERAL, department of medical statisand epidemiology, London School of Hygiene and Tropical Medicine, B’’;-Cl. Director Dr CLIFFORD R. KAY, R.C.G.P. Research Unit,
Pnnopa)
ucs
Manchester.
1977
"taker" category from the time of change. Ex-takers who resumed oral-contraceptive use were thereafter excluded from the present analyses. At 6-monthly intervals the general practitioners report on the occurrence of illness, pregnancy, or death and on the details of oral-contraceptive use in the study population. For all deaths the general practitioners report the cause of death in the same format as is required for the death certificate. The underlying cause of death was coded by C.R.K. using the 8th revision of the International Classification of Diseases (I.C.D.) and checked by V.B. The deaths in the takers, ex-takers, and controls are related to the respective cumulative calendar-months of observation in each group and expressed as rates per 100 000 women-years. In certain analyses the takers and ex-takers are grouped together as "ever-users". Mortality-rates are standardised by the indirect method,’ using the total population rates as standard. 17 women who died from conditions which had been diagnosed before their recruitment have been excluded from these analyses.
Results Table i compares the mortality-rates from various in ever-users of oral contraceptives with those in controls. The number of deaths, mortality-rates, and women-years of observation are shown in table ta when all periods of pregnancy and related deaths are excluded, and in table ib when they are included. When pregnancy is excluded, the total women-years of observation is similar in the ever-users and the controls. The controls have double the pregnancy-rate of the ex-takers, thus, when pregnancy is included the periods of observation are greater in the controls than the ever-users. Irrespective of the inclusion or exclusion of pregnancy, however, there is a 40% increase in total mortality-rate among the ever-users. This is because the increase in the womenyears of observation in the controls was accompanied by only 2 additional deaths from complications of pregnancy. (There is no program to standardise the rates for age, parity, smoking, and social class; but standardisation for these factors when pregnancy was excluded had no appreciable effect on the comparisons between the two groups.) Since the inclusion-of pregnancy does not alter the comparisons of death-rates in ever-users and controls, and for consistency with earlier reports,’ all periods of pregnancy and associated deaths are excluded from the subsequent analyses. Table ia shows that the standardised mortality-rate from the circulatory diseases in ever-users is 4-7 times that of controls, from nonrheumatic heart disease and hypertension it is 4-0 times that of controls, and from cerebrovascular disease it is 4.7 times the control rate. The excess total mortality in ever-users can be accounted for by the excess deaths from circulatory diseases. causes
8041
728 Table n details the causes of death by oral-contraceptive use. The diversity of circulatory diseases among the
oral-contraceptive
ever-users
is
notable, although the
number of deaths from any single disease is small. Table in shows the standardised mortality-rates from certain diseases of the circulatory system by contraceptive use at the time of death. The mortality-rate from all circulatory diseases in the takers is 4-9 times that of the controls and in the ex-takers is 4.3times that of the controls. A review of the records of the 8 ex-takers who died from circulatory diseases revealed that 2 had discontinued oral-contraceptive use when they were found to be hypertensive, and later died of malignant hypertension. The other 6 ex-takers stopped using oral contraceptives for non-medical reasons. None of the 4 who died of subarachnoid haemorrhage had been reported to be
hypertensive.
there is
no
standardise the data in table v but it is unlikely that the procedure alter the comparisons between ever-
program
for these factors, would materially users and controls.
to
TABLE II--CAUSE OF DEATH BY ORAL-CONTRACEPTIVE USE
’
Table iv compares the standardised mortality-rates from circulatory and total diseases in ever-users of oral contraceptives and controls according to the women’s cigarette consumption at recruitment into the study. The ratio of the mortality-rate in ever-users to controls is 4.7 to 1 for non-smokers, and 4.4 to 1 for smokers. Because of the small number of deaths in the nonsmokers, only the excess deaths in smokers is statistically
significant. Table v compares the mortality-rates from circulatory and total diseases in ever-users of oral contraceptives and controls by the women’s age at the time of death. The rates increase with age, but at all ages they are higher in ever-users than in controls. When these data were re-analysed, classifying women by their age at entry into the study, a similar increase in each age-specific mortality-rate was noted among the ever-users; standardisation for smoking, parity, and social class made no important difference to the rates. At present TABLE 1-7MORTALITY-RATE PER
100 000
*Cancer deaths in ever users: 1 large intestine; 1 rectum; 1 pancreas; 2 lung; 1 connective tissue; 1 melanoma; 3 breast; 1 cervix;1 kidney; 1 brain; 1 leukaemia. Cancer deaths in controls: 1 oesophagus; 1 stomach ; 1 large intestine; 1 rectum; 1 peritoneum; 2 lung; 6 breast; 3 ovary;1 vulva;1 Hodgkin’s disease; 2 leukaemia.
WOMEN-YEARS FROM VARIOUS CAUSES BY ORAL-CONTRACEPTIVE USE
(a) excluding pregnancy (standardised for age at entry, parity, (b) including pregnancy (unstandardised rates).
Because the
rates
for each
cause are
rates. -
standardised
separately there
are
small
soeial class, and
discrepancies between
the
smoking).
sum
of the individual
rates
and the "total"
729 TABLE III-MORTALITY-RATE PER
100 000
USE AT TIME OF DEATH
WOMEN-YEARS FROM VARIOUS DISEASES OF THE CIRCULATORY SYSTEM BY CONTRACEPTIVE FOR AGE AT ENTRY, PARITY, SOCIAL CLASS, AND
shows the mortality-rate from circulatory by duration of oral-contraceptive use. The is analysis confined to women who had been using oral contraceptives continuously up to the time of death (takers). With increasing duration of use there is a striking increase in the ratio of the age-standardised mortalityrate of ever-users to that of controls. Those who had taken the pill for 5 years or more experienced a rate which was 9.7times that of controls. All the deaths in women with a duration of use of 5 years or longer occurred at age 35 or older. As yet there are only small
Table diseases
SMOKING)
(STANDARDISED
vi
TABLE VI-MORTALITY-RATE PER
100 000
DISEASES OF CIRCULATORY SYSTEM
WOMEN-YEARS FROM
(I.C.D. 390-458) BY
DURATION OF CONTINUOUS ORAL-CONTRACEPTIVE USE
*Tests for linear treands, P
MORTALITY AMONG
ORAL-CONTRACEPTIVE USERS Royal College of General Practitioners’ Oral Contraception Study* In a large prospective study carried out in the United Kingdom, the death-rate from diseases of the circulatory system in women who had used oral contraceptives was five times that of controls who had never used them; and the death-rate in those who had taken the pill continuously for 5 years or more was ten times that of the controls. The excess deaths in
Summary
oral-contraceptive users were due to a wide range of vascular conditions. The total mortality-rate in women who had ever used the pill was increased by 40%, and this was due to an increase in deaths from circulatory diseases of 1 per 5000 ever-users per year. The excess was substantially greater than the death-rate from complications of pregnancy in the controls, and was double the death-rate from accidents. The excess mortality-rate increased with age, cigarette smoking, and duration of oral contraceptive use. Introduction THE Oral Contraception Study of the Royal College of General Practitioners is a continuing long-term prospective study of approximately 46 000 women of childbearing age in the United Kingdom. It began in 1968 and is designed to evaluate the effects of oral contraceptives on health. Women were recruited by 1400 general practitioners who have recorded all new episodes of illness
reported by
the
study population.
A
comprehensive
of the illnesses in those using oral contraceptives continuously ("takers"), those who stopped using them during the course of the study ("ex-takers"), and those who had never used them ("controls") was published in May, 1974.’ This paper discusses the deaths recorded during the follow-up period until June, 1976, which covers some 200 000 women-years of observation. account
Methods The study design, methods of data collection, analytical techniques, and the potential sources of bias have already been
discussed in detail.’ In summary, 23 000 current takers and 23 000 controls who were matched by age and marital status to the takers, were recruited over a 14-month period. Controls who later became oral-contraceptive users were included in the *
author: Dr VALERIE BERAL, department of medical statisand epidemiology, London School of Hygiene and Tropical Medicine, B’’;-Cl. Director Dr CLIFFORD R. KAY, R.C.G.P. Research Unit,
Pnnopa)
ucs
Manchester.
1977
"taker" category from the time of change. Ex-takers who resumed oral-contraceptive use were thereafter excluded from the present analyses. At 6-monthly intervals the general practitioners report on the occurrence of illness, pregnancy, or death and on the details of oral-contraceptive use in the study population. For all deaths the general practitioners report the cause of death in the same format as is required for the death certificate. The underlying cause of death was coded by C.R.K. using the 8th revision of the International Classification of Diseases (I.C.D.) and checked by V.B. The deaths in the takers, ex-takers, and controls are related to the respective cumulative calendar-months of observation in each group and expressed as rates per 100 000 women-years. In certain analyses the takers and ex-takers are grouped together as "ever-users". Mortality-rates are standardised by the indirect method,’ using the total population rates as standard. 17 women who died from conditions which had been diagnosed before their recruitment have been excluded from these analyses.
Results Table i compares the mortality-rates from various in ever-users of oral contraceptives with those in controls. The number of deaths, mortality-rates, and women-years of observation are shown in table ta when all periods of pregnancy and related deaths are excluded, and in table ib when they are included. When pregnancy is excluded, the total women-years of observation is similar in the ever-users and the controls. The controls have double the pregnancy-rate of the ex-takers, thus, when pregnancy is included the periods of observation are greater in the controls than the ever-users. Irrespective of the inclusion or exclusion of pregnancy, however, there is a 40% increase in total mortality-rate among the ever-users. This is because the increase in the womenyears of observation in the controls was accompanied by only 2 additional deaths from complications of pregnancy. (There is no program to standardise the rates for age, parity, smoking, and social class; but standardisation for these factors when pregnancy was excluded had no appreciable effect on the comparisons between the two groups.) Since the inclusion-of pregnancy does not alter the comparisons of death-rates in ever-users and controls, and for consistency with earlier reports,’ all periods of pregnancy and associated deaths are excluded from the subsequent analyses. Table ia shows that the standardised mortality-rate from the circulatory diseases in ever-users is 4-7 times that of controls, from nonrheumatic heart disease and hypertension it is 4-0 times that of controls, and from cerebrovascular disease it is 4.7 times the control rate. The excess total mortality in ever-users can be accounted for by the excess deaths from circulatory diseases. causes
8041
728 Table n details the causes of death by oral-contraceptive use. The diversity of circulatory diseases among the
oral-contraceptive
ever-users
is
notable, although the
number of deaths from any single disease is small. Table in shows the standardised mortality-rates from certain diseases of the circulatory system by contraceptive use at the time of death. The mortality-rate from all circulatory diseases in the takers is 4-9 times that of the controls and in the ex-takers is 4.3times that of the controls. A review of the records of the 8 ex-takers who died from circulatory diseases revealed that 2 had discontinued oral-contraceptive use when they were found to be hypertensive, and later died of malignant hypertension. The other 6 ex-takers stopped using oral contraceptives for non-medical reasons. None of the 4 who died of subarachnoid haemorrhage had been reported to be
hypertensive.
there is
no
standardise the data in table v but it is unlikely that the procedure alter the comparisons between ever-
program
for these factors, would materially users and controls.
to
TABLE II--CAUSE OF DEATH BY ORAL-CONTRACEPTIVE USE
’
Table iv compares the standardised mortality-rates from circulatory and total diseases in ever-users of oral contraceptives and controls according to the women’s cigarette consumption at recruitment into the study. The ratio of the mortality-rate in ever-users to controls is 4.7 to 1 for non-smokers, and 4.4 to 1 for smokers. Because of the small number of deaths in the nonsmokers, only the excess deaths in smokers is statistically
significant. Table v compares the mortality-rates from circulatory and total diseases in ever-users of oral contraceptives and controls by the women’s age at the time of death. The rates increase with age, but at all ages they are higher in ever-users than in controls. When these data were re-analysed, classifying women by their age at entry into the study, a similar increase in each age-specific mortality-rate was noted among the ever-users; standardisation for smoking, parity, and social class made no important difference to the rates. At present TABLE 1-7MORTALITY-RATE PER
100 000
*Cancer deaths in ever users: 1 large intestine; 1 rectum; 1 pancreas; 2 lung; 1 connective tissue; 1 melanoma; 3 breast; 1 cervix;1 kidney; 1 brain; 1 leukaemia. Cancer deaths in controls: 1 oesophagus; 1 stomach ; 1 large intestine; 1 rectum; 1 peritoneum; 2 lung; 6 breast; 3 ovary;1 vulva;1 Hodgkin’s disease; 2 leukaemia.
WOMEN-YEARS FROM VARIOUS CAUSES BY ORAL-CONTRACEPTIVE USE
(a) excluding pregnancy (standardised for age at entry, parity, (b) including pregnancy (unstandardised rates).
Because the
rates
for each
cause are
rates. -
standardised
separately there
are
small
soeial class, and
discrepancies between
the
smoking).
sum
of the individual
rates
and the "total"
729 TABLE III-MORTALITY-RATE PER
100 000
USE AT TIME OF DEATH
WOMEN-YEARS FROM VARIOUS DISEASES OF THE CIRCULATORY SYSTEM BY CONTRACEPTIVE FOR AGE AT ENTRY, PARITY, SOCIAL CLASS, AND
shows the mortality-rate from circulatory by duration of oral-contraceptive use. The is analysis confined to women who had been using oral contraceptives continuously up to the time of death (takers). With increasing duration of use there is a striking increase in the ratio of the age-standardised mortalityrate of ever-users to that of controls. Those who had taken the pill for 5 years or more experienced a rate which was 9.7times that of controls. All the deaths in women with a duration of use of 5 years or longer occurred at age 35 or older. As yet there are only small
Table diseases
SMOKING)
(STANDARDISED
vi
TABLE VI-MORTALITY-RATE PER
100 000
DISEASES OF CIRCULATORY SYSTEM
WOMEN-YEARS FROM
(I.C.D. 390-458) BY
DURATION OF CONTINUOUS ORAL-CONTRACEPTIVE USE
*Tests for linear treands, P
