The RCGP Oral Contraception Study started in May 1968 when 1400 general practitioners throughout the United Kingdom recruited approximately 23
000 women who were using oral contraceptives and a similar number of women who had never used this method of birth control.1
All the women were married or living as married, most were white, and their mean age at recruitment was 29 (SD 6.6) years. Information collected at baseline included parity, smoking habits, social class (based on husband’s occupation), and relevant medical history. The general practitioners subsequently supplied, at six monthly intervals, information about any hormonal preparations prescribed, any pregnancies and their outcome, all new episodes of illness, any surgery, and any deaths occurring in women still under their observation. Women remained under general practice follow-up until they left the area of the recruiting doctor (approximately 56% of total cohort), the doctor left the study (13%), they obtained their contraceptives from a source other than the general practitioner (3%), they died (2%), or the study stopped general practice follow-up at the end of 1996 (26%).
In the mid 1970s, approximately three quarters of the original cohort (n=35
104) were “flagged” at National Health Service central registries in Scotland and England, so that subsequent cancers and deaths would be reported to the study, even if the woman was no longer under general practice follow-up. The remaining 24% of women could not be flagged because they, or their general practitioner, left the study before flagging took place.
We assembled two datasets, both of which included data until the end of general practice follow-up on women who had not been flagged (figure). The full dataset also included periods of observation up to the date of death or June 2007 (whichever came first) for all flagged women still in the study when general practice follow-up ended in 1996, flagged never and ever oral contraceptive users lost to the study before 1996 who were aged 38 years or older at time of loss, and flagged ever users lost to the study before 1996 who were younger than 38 years at the time of loss. Flagged never users younger than 38 years and lost to general practice follow-up before 1996 were censored from the time of loss because we did not know whether the women subsequently started using oral contraceptives. We assumed that older never users were unlikely to have done so, as 91% of women in the study who used oral contraceptives started before the age of 38. Never users in the full dataset, therefore, were women known, or assumed, to have never used oral contraceptives.
Flow chart of RCGP Oral Contraception Study
The general practice observation subset included periods of observation, deaths, and other relevant information obtained while women were under observation by general practitioners, up to their point of being lost to general practice follow-up, death, or December 1996 when general practice follow-up ended (whichever came first). This subset contained information about use of hormone replacement therapy while under general practice follow-up, as well as comprehensive data about the type and duration of oral contraceptives used.
The deaths were coded using ICD-8 (international classification of diseases, 8th revision). We grouped them into individual cancer categories: large bowel and rectum (ICD-8 code 153-154), gallbladder and liver (155-156), lung (162), melanoma (172), breast (174), invasive cervix (180), uterine body (182), ovary (183), central nervous system and pituitary (191 and 1943), site unknown (199), and other cancers (any death coded between 140 and 209 not already mentioned); main gynaecological cancers combined (180, 182, and 183); any cancer (140-209); ischaemic heart disease (410-414), other heart (420-429), cerebrovascular disease (430-438), other circulatory (any death coded 390-458 not already mentioned); all circulatory disease combined (390-458); all digestive disease (520-577); liver disease (570-573); violent deaths (800-999, E800-999); suicide (E950-959); all other causes (any death with a code not already mentioned); and any death (000-999, all E codes). These groupings were broadly similar to those used in our most recent mortality report,4
and we used them for ease of comparison.
Most deaths in the full dataset were notified by the central registries only (75% (3437/4611) of all deaths). Of the 1184 deaths in the general practice observation subset, 160 (14%) were notified by the general practitioner only, 25 (2%) by the central registries only, and 999 (84%) by both sources. If a discrepancy between sources occurred, we sought clarification from the general practitioner whenever possible. Three deaths occurred for which the event date differed by more than three months and 52 for which the discrepancy in dates was between one and three months. In each case, we used the information notified by the general practitioner. For 28 deaths, differences in the ICD-8 codes could not be reconciled, so we used the information notified by the general practitioner. On 12 occasions, date of death preceded other general practice observation data, and in these circumstances we assumed that the woman was still alive and removed the inconsistent date of death.
We used relative risk to measure associations between use of oral contraceptives and mortality. We aggregated deaths (numerator) and periods of observation (denominator) according to each woman’s status at each calendar month while under general practice follow-up or that pertaining when she left such follow-up (except for age, which continued to change). We included women recruited as never users who subsequently started oral contraception in the pill user group from the date of starting.
We used the dstdize program in Stata 10.1 to calculate unadjusted and directly standardised death rates among ever users and never users of oral contraceptives. We standardised rates for the full dataset for smoking (0, 1-14, ≥15 cigarettes daily) and social class (non-manual, manual) at recruitment, parity (0, 1, 2, ≥3) at 1996 or time of death, and age group (<30, 30-39, 40-49, 50-59, 60-69, ≥70 years) at 2007 or time of death. When analysing the general practice observation subset, we used the same variables (with collapsed age categories (<39, 40-49, ≥50) for analyses of the duration of oral contraceptive use), in addition to use of hormone replacement therapy during general practice follow-up (never, ever). As higher mortality in older women may mask the effects of stopping oral contraception in younger women in the general practice observation subset, we examined risk of death by time since stopping oral contraception among women aged under 45 years, adjusting for age group (<30, 30-34, 35-39, 40-44), parity, social class, and smoking. We used this cut-off age because few women in the cohort used hormone replacement therapy before the age of 45. We used the total population (ever users and never users) available for each analysis as the standard. As the standard populations and adjusting variables were different in each analysis, the results should not be compared directly.
We assumed approximate normality for the log of estimated relative risks when calculating 95% confidence intervals.6
We calculated the log-linear test for trend for duration of oral contraception use by including each category as a metric explanatory variable with evenly spaced levels and using the Stata command stmh. We did not calculate trends for time since last use, as the data were too sparse for many categories of death. For clarity of presentation, we have shown only standardised rates for the analyses of duration of use and time since last use of oral contraception.