The Royal College of General Practitioners' oral contraception study began in May 1968. Over a 14 month period 1400 general practitioners throughout the United Kingdom recruited about 23
000 women who were using oral contraceptives and 23
000 women who had never used them.11
The mean age at recruitment was 29 (standard deviation 6.6). All the women were married or living in a stable relationship and most were white. Baseline information collected included smoking habits, social class (based on husband's occupation), parity, and important medical history. After recruitment the general practitioners supplied information every six months about any hormonal preparations prescribed, any pregnancies and their outcome, all new episodes of illness (including cancer), and any surgery in women still under their observation. Women remained under follow-up by their general practitioner until they left the area of the recruiting doctor (about 56% of total cohort), their doctor left the study (13%), they obtained their contraceptives from a source other than the general practice (3%), they died (2%), or the study stopped follow-up by general practitioners (at the end of 1996, 26%).
In the mid-1970s three quarters of the original cohort was flagged at National Health Service central registries in Scotland and England so that subsequent cancers and deaths could be reported to the study, even if women were no longer under follow-up by their general practitioner. The remaining 24% of women could not be flagged because they or their doctor left the study before flagging started.
Two datasets were compiled. In both, women not flagged were included up until they were lost to follow-up (figure). In addition, the main dataset included information up to the date of the first relevant cancer or December 2004 (whichever came first) for flagged women still under observation by their doctors when such follow-up stopped in 1996, for flagged women lost to the study before 1996 who were aged 38 or more at the time of loss, and for flagged ever users lost to the study before 1996 who were younger than 38 at the time of loss. We excluded, from the time of loss, flagged never users younger than 38 and lost to general practitioner follow-up before 1996 because we did not know whether they subsequently started using oral contraceptives. We assumed that older never users were unlikely to have started oral contraceptives because 91% of women in the study who used oral contraceptives started to do so before age 38. This threshold was chosen as a balance between maximising the amount of data available for analysis and minimising the risk of misclassification of contraceptive status. Never users in the main dataset therefore were women who were known, or assumed, to have never used oral contraceptives.
Flow chart of Royal General Practitioners' oral contraception study. Values refer to numbers of women unless stated otherwise
The general practitioner observation dataset included cancers, periods of observation, and other relevant information obtained while women were under observation by their doctors up to the point of their being lost to follow-up, the first relevant cancer, or December 1996, when all observations by doctors stopped (whichever came first). This dataset had comprehensive information about type and duration of oral contraceptives used, information that could not be updated once women left observation. It also contained information about use of hormone replacement therapy while under general practitioner follow-up.
The main dataset had the largest amount of data and so provided the most precise risk estimates. In this paper we present cancer rates for ever and never users from both the main and general practitioner observation datasets; rates of any cancer in different age, parity, smoking, and social class subgroups of women in the main dataset; and cancer rates by duration and time since last use of oral contraceptives, using the general practitioner observation dataset (since complete information about this variable was only available in this dataset).
The cancers were coded using the international classification of diseases, eighth revision. They were grouped into three categories: individual cancer categories—large bowel or rectum (codes 153 and 154), gallbladder or liver (155 and 156), lung (162), melanoma (172), breast (174), invasive cervix (180), uterine body (182), ovary (183), central nervous system or pituitary (191 and 1943), site unknown (199), and other cancers (any event with a code between 140 and 209 not already mentioned); main gynaecological cancers combined (180, 182, and 183); and any cancer (140-209). Most cancers in the main dataset were notified by the central registries only (2342/3877 (60%) of any cancers). Of the 1651 any cancers in the general practitioner observation dataset, 840 (50.9%) were notified by the doctor, 116 (7.0%) by the central registries, and 695 (42.1%) by both. If a discrepancy occurred between sources we sought clarification from the doctor if possible. In 13 cases the date of cancer occurrence differed by more than three months and in 312 between one and three months. In each case we used the information notified by the doctor. In 30 cases the ICD-8 codes differed between the two sources. When the discrepancy could not be reconciled, the doctor notified information took precedence (24 cancers). On 19 occasions more than one cancer was reported for the same date and we were unable to check the original records. In these instances we recorded one event and coded it as cancer site unspecified.
We calculated unadjusted and directly standardised rates of first ever diagnosis of cancer among ever and never users of oral contraceptives using the dstdize program in Stata 9.2. Rates for the main dataset were standardised for age group (<30, 30-39, 40-49, 50-59, ≥60) and parity (0, 1, 2, ≥3) at the time of the event, and smoking (0, 1-14, ≥15 cigarettes daily) and social class (non-manual, manual) at recruitment. When analysing the general practitioner observation dataset we used the same variables (with collapsed age categories, <39, 40-49, ≥50, for duration and time since last use of oral contraception analyses), in addition to use of hormone replacement therapy (never, ever). We used the total population available in each dataset as the standard in each analysis. This, as well as allowing for different variables in each dataset, means that the results from the two datasets should not be compared directly.
We aggregated events (numerator) and periods of observation (denominator) according to each woman's status at each calendar month while under follow-up by her doctor, or that pertaining when she left such follow-up (except for age, which continued to change). Women recruited as never users who subsequently started oral contraception were included in the ever user group from the date of starting. We excluded events and periods of observation occurring in women with the same cancer before recruitment and events and periods of observation related to pregnancy, because pregnancy can affect the presentation and progress of some cancers. Only the first event in each cancer category was counted; we removed subsequent periods of observation for that woman from the denominator of analyses relating to the same cancer category but included them in analyses of other cancer groups (since the woman remained at risk of having another type of cancer). When analysing the risk of any cancer we counted only the first cancer (and censored subsequent periods of observation). The total number of any cancer in the tables therefore is less than the sum of each cancer category given separately, as women could have contributed data to more than one category. When calculating 95% confidence intervals we assumed approximate normality for the log of estimated relative risks.12
We tested trends for duration and time since last use of oral contraception using the log-linear trend test, by including them as metric explanatory variables with even spaced levels.12
For clarity of presentation we give only the standardised rates for analyses of the subgroup of duration and time since last use of oral contraception.