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1.  Mortality associated with oral contraceptive use: 25 year follow up of cohort of 46 000 women from Royal College of General Practitioners’ oral contraception study 
BMJ : British Medical Journal  1999;318(7176):96-100.
Objective
To describe the long term effects of the use of oral contraceptives on mortality.
Design
Cohort study with 25 year follow up. Details of oral contraceptive use and of morbidity and mortality were reported six monthly by general practitioners. 75% of the original cohort was “flagged” on the NHS central registers.
Setting
1400 general practices throughout Britain.
Subjects
46 000 women, half of whom were using oral contraceptives at recruitment in 1968-9. Median age at end of follow up was 49 years.
Main outcome measures
Relative risks of death adjusted for age, parity, social class, and smoking.
Results
Over the 25 year follow up 1599 deaths were reported. Over the entire period of follow up the risk of death from all causes was similar in ever users and never users of oral contraceptives (relative risk=1.0, 95% confidence interval 0.9 to 1.1; P=0.7) and the risk of death for most specific causes did not differ significantly in the two groups. However, among current and recent (within 10 years) users the relative risk of death from ovarian cancer was 0.2 (0.1 to 0.8; P=0.01), from cervical cancer 2.5 (1.1 to 6.1; P=0.04), and from cerebrovascular disease 1.9 (1.2 to 3.1, P=0.009). By contrast, for women who had stopped use ⩾10 years previously there were no significant excesses or deficits either overall or for any specific cause of death.
Conclusion
Oral contraceptives seem to have their main effect on mortality while they are being used and in the 10 years after use ceases. Ten or more years after use ceases mortality in past users is similar to that in never users.
Key messagesThis 25 year follow up of 46 000 UK women found a decrease in mortality from ovarian cancer and an increase in mortality from circulatory diseases and cervical cancer among women were using oral contraceptives or had used them in the past 10 years10 or more years after stopping use mortality was similar in past users and never usersOral contraceptives seem to have their main effect on mortality mainly while they are being used and in the 10 years after stopping useThere is little evidence to suggest any persistent adverse effect 10 or more years after use of oral contraceptives ceases
PMCID: PMC27684  PMID: 9880284
2.  Cancer risk among users of oral contraceptives: cohort data from the Royal College of General Practitioner's oral contraception study 
BMJ : British Medical Journal  2007;335(7621):651.
Objective To examine the absolute risks or benefits on cancer associated with oral contraception, using incident data.
Design Inception cohort study.
Setting Royal College of General Practitioners' oral contraception study.
Participants Directly standardised data from the Royal College of General Practitioners' oral contraception study.
Main outcome measures Adjusted relative risks between never and ever users of oral contraceptives for different types of cancer, main gynaecological cancers combined, and any cancer. Standardisation variables were age, smoking, parity, social class, and (for the general practitioner observation dataset) hormone replacement therapy. Subgroup analyses examined whether the relative risks changed with user characteristics, duration of oral contraception usage, and time since last use of oral contraception.
Results The main dataset contained about 339 000 woman years of observation for never users and 744 000 woman years for ever users. Compared with never users ever users had statistically significant lower rates of cancers of the large bowel or rectum, uterine body, and ovaries, tumours of unknown site, and other malignancies; main gynaecological cancers combined; and any cancer. The relative risk for any cancer in the smaller general practitioner observation dataset was not significantly reduced. Statistically significant trends of increasing risk of cervical and central nervous system or pituitary cancer, and decreasing risk of uterine body and ovarian malignancies, were seen with increasing duration of oral contraceptive use. Reduced relative risk estimates were observed for ovarian and uterine body cancer many years after stopping oral contraception, although some were not statistically significant. The estimated absolute rate reduction of any cancer among ever users was 45 or 10 per 100 000 woman years, depending on whether the main or general practitioner observation dataset was used.
Conclusion In this UK cohort, oral contraception was not associated with an overall increased risk of cancer; indeed it may even produce a net public health gain. The balance of cancer risks and benefits, however, may vary internationally, depending on patterns of oral contraception usage and the incidence of different cancers.
doi:10.1136/bmj.39289.649410.55
PMCID: PMC1995533  PMID: 17855280
3.  The risk of serious illness among oral contraceptive users: evidence from the RCGP's oral contraceptive study. 
The British Journal of General Practice  1998;48(435):1657-1662.
BACKGROUND: So far, no-one has attempted to evaluate the overall balance of serious, but not necessarily fatal, disease among a cohort of oral contraceptive users. AIM: To emprirically assess the balance of risk of serious illness among a cohort of oral contraceptive users followed up for up to 28 years. METHODS: Oral contraceptive-associated serious disease was defined as that which is often life-threatening and/or associated with long-term disability, and which has been found, or postulated, to be associated with use of combined oral contraceptives. Data from the Royal College of General Practitioners' (RCGP) Oral Contraception Study were examined to determine the rate of such conditions during 335,181 woman-years of observation in 'ever users' and 228,727 woman-years in 'never users'. The rates were standardized for age, parity, social class, and smoking. RESULTS: Compared with never users, ever users had a small increased risk of any serious disease (relative risk = 1.17; 95% confidence interval = 1.09-1.25). Ever users had an excess risk of cerebrovascular disease, pulmonary embolism, and venous thromboembolism, and reduced risk of ovarian and endometrial cancer. The increased risk was seen only in younger women; by the age of 50, ever users had the same risk as never users. The risk appeared to be confined to women using older oral contraceptives containing 50 micrograms or more of oestrogen. CONCLUSIONS: Past users of older, higher dose oral contraceptives can be reassured that the small increased risk of serious disease seen during current use does not persist after stopping, and that latent effects do not appear later in life. Currently available oral contraceptives, containing less than 50 micrograms of oestrogen accompanied by the progestogen, levonorgestrel, or norethisterone acetate, do not appear to be associated with an increased net risk of serious disease.
PMCID: PMC1313240  PMID: 10071398
4.  Oral contraceptives and malignant melanoma. 
British Journal of Cancer  1991;63(3):430-433.
Several studies have suggested that prolonged use of oral contraceptives may increase a woman's risk of developing malignant melanoma. In the Royal College of General Practitioners' Oral Contraception Study, 31 cases of malignant melanoma (code 172--International Classification of Diseases, 8th Revision) have been reported among ever-users and 27 cases among never-users. The risk ratio (RR) (indirectly standardised for age, parity, social class and smoking) was 0.92 (95% confidence interval (CI) 0.55-1.54). There was no significant trend with duration of oral contraceptive use, although those women who had used the pill for at least 10 years had an elevated RR of 1.77 (95% CI 0.80-3.90). The Oxford/Family Planning Association Study has recorded 15 cases among ever-users and 17 cases among never-users; the standardised risk ratio was 0.85 (95% CI 0.42-1.70). None of the rates observed in any duration of use category was materially different from those observed in never-users. The results available so far from the two studies suggest that oral contraceptive use is probably not associated with an increased risk of malignant melanoma.
PMCID: PMC1971847  PMID: 2003986
5.  Comparison of cause of death coding on death certificates with coding in the Royal College of General Practitioners Oral Contraception Study. 
A comparison has been made between the coding of the cause of death by (a) the Royal College of General Practitioners (RCGP) during the Oral Contraception Study and (b) the Office of Population Censuses and Surveys (OPCS) or the General Register Office for Scotland (GRO) on death certificates for the same subjects. Broad grouping of the International Classification of Diseases (ICD) showed close agreement between RCGP and OPCS or GRO coding for all deaths which occurred from the start of the Oral Contraception Study in 1968 up to December 1978. Moreover, where discrepancies occurred there were no systematic differences between ever-users of oral contraceptive and non-users. Detailed examinations of discrepancies in the coding of the causes of those deaths included in the RCGP publication of October 1977 shows that our previous estimate of mortality risk associated with oral contraceptives would not be materially altered by the use of death certificate information.
PMCID: PMC1052120  PMID: 7264534
6.  Oral contraceptives and rheumatoid arthritis: new data from the Royal College of General Practitioners' oral contraception study. 
Annals of the Rheumatic Diseases  1990;49(10):744-746.
From data available at April 1987 it was found that the standardised risk ratio for rheumatoid arthritis between current users of oral contraceptives and never users was 0.82 (95% confidence interval 0.59 to 1.15); the ratio between former users and never users was 0.94 (95% confidence interval 0.72 to 1.22). Important secular trends have occurred within our study population. The incidence of rheumatoid arthritis among former and never users has declined over the past two decades. Current users have not experienced this temporal trend, and the ratio between current and never users has, therefore, approached unity. These secular changes may explain why some studies have found that oral contraceptives have a protective effect, while others have been unable to show such an effect.
PMCID: PMC1004223  PMID: 2241261
7.  Mortality among oral contraceptive users: 20 year follow up of women in a cohort study. 
BMJ : British Medical Journal  1989;299(6714):1487-1491.
OBJECTIVE--To see whether the use of oral contraceptives influences mortality. DESIGN--Non-randomised cohort study of 17,032 women followed up on an annual basis for an average of nearly 16 years. SETTING--17 Family planning clinics in England and Scotland. SUBJECTS--Women recruited during 1968-74. At the time of recruitment each woman was aged 25-39, married, a white British subject, willing to participate, and either a current user of oral contraceptives or a current user of a diaphragm or intrauterine device (without previous exposure to the pill). MAIN OUTCOME MEASURES--Overall mortality and cause specific mortality. RESULTS--238 Deaths occurred during the follow up period. The main analyses concerned women entering the study while using either oral contraceptives or a diaphragm or intrauterine device. The overall relative risk of death in the oral contraceptive users was 0.9 (95% confidence interval 0.7 to 1.2). Though the numbers of deaths were small in most individual disease categories, the trends observed were generally consistent with findings in other reports. Thus the relative risk of death in the oral contraceptive users was 4.9 (95% confidence interval 0.7 to 230) for cancer of the cervix, 3.3 (95% confidence interval 0.9 to 17.9) for ischaemic heart disease, and 0.4 (95% confidence interval 0.1 to 1.2) for ovarian cancer. There was a linear trend in the death rates from cervical cancer and ovarian cancer (in opposite directions) with total duration of oral contraceptive use. Death rates from breast cancer (relative risk 0.9; 95% confidence interval 0.5 to 1.4) and suicide and probable suicide (relative risk 1.1; 95% confidence interval 0.3 to 3.6) were much the same in the two contraceptive groups. In 1981 the relative risk of death in oral contraceptive users from circulatory diseases as a group was reported to be 4.2 (95% confidence interval 2.3 to 7.7) in the Royal College of General Practitioners oral contraception study. The corresponding relative risk in this study was only 1.5 (95% confidence interval 0.7 to 3.0). CONCLUSIONS--These findings contain no significant evidence of any overall effect of oral contraceptive use on mortality. None the less, only small numbers of deaths occurred during the study period and a significant adverse (or beneficial) overall effect might emerge in the future. Interestingly, the mortality from circulatory disease associated with oral contraceptive use was substantially less than that found in the Royal College of General Practitioners study.
PMCID: PMC1838344  PMID: 2514858
8.  Oral contraception and eye disease: findings in two large cohort studies 
AIM—To investigate the relation between oral contraceptive use and certain eye diseases.
METHODS—Abstraction of the relevant data from the two large British cohort studies of the effects of oral contraception, the Royal College of General Practitioners' (RCGP) Oral Contraception Study and the Oxford-Family Planning Association (Oxford-FPA) Contraceptive Study. Both cohort studies commenced in 1968 and were organised on a national basis. Between them they have accumulated over 850 000 person years of observation involving 63 000 women.
RESULTS—The conditions considered in the analysis were conjunctivitis, keratitis, iritis, lacrimal disease, strabismus, cataract, glaucoma, retinal detachment, and retinal vascular lesions. With the exception of retinal vascular lesions, there was no consistent evidence of important increases in risk of eye diseases in users of oral contraception. There was about a twofold increase in the risk of retinal vascular lesions in recent pill users in both studies (statistically significant only in the RCGP study). The increase was not limited to any specific type of lesion and may well reflect diagnostic bias.
CONCLUSION—Oral contraceptive use does not appear to increase the risk of eye disease, with the possible exception of retinal vascular lesions.

 Keywords: oral contraception; eye disease; cohort studies
PMCID: PMC1722595  PMID: 9722322
9.  Impact of lifestyle in middle-aged women on mortality: evidence from the Royal College of General Practitioners' Oral Contraception Study 
Background
Although many individuals have multiple lifestyle risk factors, few studies have investigated the impact of lifestyle risk factor combinations among women.
Aim
To investigate the relationship between individual and combinations of lifestyle risk factors in middle-aged women with subsequent mortality, and to estimate the associated population attributable risks.
Design of study
Prospective cohort study.
Setting
Royal College of General Practitioners' (RCGP) Oral Contraception Study, UK.
Method
In 1994–1995, women remaining under follow-up in the RCGP Oral Contraception Study were sent a lifestyle survey, from which modifiable risk factors were identified: pack-years smoked, physical inactivity, never drinking versus consuming at least 7 units of alcohol weekly, and being underweight, overweight, or obese. The cohort was followed to December 2006 or death. Population attributable risks were calculated.
Results
Of 10 059 women studied, 896 died. Pack-years smoked (11–20 years: adjusted hazard ratio [HR] = 1.82, 95% confidence interval [CI] = 1.46 to 2.27; >20 years: adjusted HR = 2.34, 95% CI = 2.00 to 2.74); never drinking alcohol (adjusted HR = 1.66, 95% CI = 1.34 to 2.05); being underweight (adjusted = HR 1.66, 95% CI = 1.03 to 2.68); and physical inactivity (<15 hours/week: adjusted HR = 1.73, 95% CI = 1.46 to 2.04) were significantly associated with mortality compared with their respective reference group. Women with multiple lifestyle risk factors had higher mortality risks than those reporting one factor. The population attributable risk of the combination of smoking, physical inactivity, body mass index outside normal range, and alcohol (never drinking or excess intake) was 59% (95% CI = 31% to 78%).
Conclusion
Assuming a causal relationship between lifestyle and mortality, avoidance of four lifestyle risk factors would have prevented 60% of the deaths. The importance of avoiding smoking and undertaking physical inactivity during midlife should continue to be emphasised.
doi:10.3399/bjgp10X515052
PMCID: PMC2913736  PMID: 20822689
epidemiology; follow-up studies; lifestyle; mortality; women
10.  New oral contraception study: pilot trial report 
As a preliminary to a new large cohort study of steroidal contraception, two pilot studies have been carried out. The first estimated that the prevalence of never-use of oral contraceptives among sexually active women aged 16 to 29 years was only 5.1% which means it will be impractical to recruit never-user controls for the main study. The prevalence of cigarette smoking in ever-users of oral contraceptives was 37% in contrast to never-users of whom only 20% smoked.
The second pilot study tested the acceptability of a new recruitment procedure. Two hundred and seventy doctors recruited 1574 women — 98% of these women understood and accepted the need to record their National Health Service number. The mean age of this patient cohort was 22.5 years, 65% were single and 37% were cigarette smokers. One-tenth of women had had coitus before the age of 16 years, but only 4% had started using oral contraceptives before that age.
PMCID: PMC1960675  PMID: 3499506
11.  Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9 
Objective To assess the risk of venous thromboembolism from use of combined oral contraceptives according to progestogen type and oestrogen dose.
Design National historical registry based cohort study.
Setting Four registries in Denmark.
Participants Non-pregnant Danish women aged 15-49 with no history of thrombotic disease and followed from January 2001 to December 2009.
Main outcome measures Relative and absolute risks of first time venous thromboembolism.
Results Within 8 010 290 women years of observation, 4307 first ever venous thromboembolic events were recorded and 4246 included, among which 2847 (67%) events were confirmed as certain. Compared with non-users of hormonal contraception, the relative risk of confirmed venous thromboembolism in users of oral contraceptives containing 30-40 µg ethinylestradiol with levonorgestrel was 2.9 (95% confidence interval 2.2 to 3.8), with desogestrel was 6.6 (5.6 to 7.8), with gestodene was 6.2 (5.6 to 7.0), and with drospirenone was 6.4 (5.4 to 7.5). With users of oral contraceptives with levonorgestrel as reference and after adjusting for length of use, the rate ratio of confirmed venous thromboembolism for users of oral contraceptives with desogestrel was 2.2 (1.7 to 3.0), with gestodene was 2.1 (1.6 to 2.8), and with drospirenone was 2.1 (1.6 to 2.8). The risk of confirmed venous thromboembolism was not increased with use of progestogen only pills or hormone releasing intrauterine devices. If oral contraceptives with desogestrel, gestodene, or drospirenone are anticipated to increase the risk of venous thromboembolism sixfold and those with levonorgestrel threefold, and the absolute risk of venous thromboembolism in current users of the former group is on average 10 per 10 000 women years, then 2000 women would need to shift from using oral contraceptives with desogestrel, gestodene, or drospirenone to those with levonorgestrel to prevent one event of venous thromboembolism in one year.
Conclusion After adjustment for length of use, users of oral contraceptives with desogestrel, gestodene, or drospirenone were at least at twice the risk of venous thromboembolism compared with users of oral contraceptives with levonorgestrel.
doi:10.1136/bmj.d6423
PMCID: PMC3202015  PMID: 22027398
12.  Endometrial and ovarian cancer and oral contraceptives--findings in a large cohort study. 
British Journal of Cancer  1995;71(6):1340-1342.
Many case-control studies have shown that oral contraceptives protect against endometrial cancer and epithelial ovarian cancer, but little information is available from cohort studies. The findings from the Oxford Family Planning Association contraceptive study are reported here; the relative risks for ever users of oral contraceptives in comparison with never users were 0.1 (95% confidence interval 0.0-0.7) for endometrial cancer and 0.4 (95% confidence interval 0.2-0.8) for ovarian cancer. There was a strong negative relationship between duration of oral contraceptive use and ovarian cancer risk. Thus, in comparison with never users of oral contraceptives, the relative risk for users of up to 48 months' duration was 1.0 (95% confidence interval 0.4-2.5), while the relative risk for users of 97 months' duration or more was only 0.3 (95% confidence interval 0.1-0.7).
PMCID: PMC2033840  PMID: 7779735
13.  A case-control study of the possible association between oral contraceptives and malignant melanoma. 
British Journal of Cancer  1981;44(1):45-50.
In a case-control study, we investigated 169 women aged 15-49 years with malignant melanoma notified to the Oxford and South Western cancer registries during the years 1971-1976, together with 507 matched controls. Data about medical, reproductive, drug and smoking histories were obtained both by reviewing general practitioner (GP) records and from the women themselves by postal questionnaires. There was no significant evidence of any overall increase in the risk of melanoma in oral contraceptive (OC) users (data from GP records-ever use vs never use, relative risk (RR) 1.34, 95% confidence limits 0.92-1.96; corresponding data from postal questionnaires-RR 1.13, limits 0.73-1.75). However, although not significant, the risk estimated from data in the postal questionnaires was higher in women who had used OCs for 5 years or more (use greater than or equal to 5 years vs never use, RR 1.57, limits 0.83-3.03). Previously demonstrated risk factors for melanoma, such as fair skin, blond or red hair and Celtic origin were found to be commoner in the cases than in the controls. Data from the Oxford/Family Planning Association contraceptive study were also examined. Unexpectedly there was a strong suggestion of a negative association between OC use and melanoma risk, but the analysis was based on only 12 women with the disease.
PMCID: PMC2010646  PMID: 7259960
14.  Cardiovascular sequelae of toxaemia of pregnancy. 
Heart  1997;77(2):154-158.
OBJECTIVE: To determine whether the rate of cardiovascular disease is different among parous women with a general practitioner reported history of toxaemia of pregnancy than among those not reported to have experienced toxaemia, or among nulliparous women. DESIGN: Prospective cohort study. SETTING: 1400 general practitioners throughout the United Kingdom. SUBJECTS: Women who had never used oral contraceptives who were recruited to the Royal College of General Practitioners' oral contraception study (original cohort about 23000). MAIN OUTCOME MEASURES: Age, social class, and smoking standardised incidence rates for hypertensive disease, acute myocardial infarction, other acute ischaemic heart disease, other chronic ischaemic heart disease, angina pectoris, total ischaemic heart disease, total cerebrovascular disease, and total venous thromboembolic disease in the three groups. RESULTS: Compared with parous women with no history of toxaemia, those who had experienced toxaemia had a significantly increased risk of hypertensive disease (relative risk (RR) 2.35), acute myocardial infarction (RR 2.24), chronic ischaemic heart disease (RR 1.74), angina pectoris (RR 1.53), all ischaemic heart disease (RR 1.65), and venous thromboembolism (RR 1.62). The rates for all cerebrovascular disease and peripheral vascular disease were also increased but not significantly. Nulliparous women were more likely to develop hypertension or all cerebrovascular disease later in life than parous women without a history of toxaemia. CONCLUSIONS: A history of toxaemia of pregnancy increases the risk of several distinct cardiovascular conditions later in life. Although causality cannot be inferred (other characteristics of the women may account for both an increased risk of toxaemia and a risk of subsequent vascular disease), the findings merit further research because of their potential importance.
PMCID: PMC484665  PMID: 9068399
15.  Hormonal contraceptive use and risk of HIV-1 transmission: a prospective cohort analysis 
The Lancet Infectious Diseases  2011;12(1):19-26.
Summary
Background
Hormonal contraceptives are used widely but their effects on HIV-1 risk are unclear.
Methods
We followed 3790 heterosexual HIV-1 serodiscordant couples from seven African countries participating in two longitudinal HIV-1 incidence studies. Among hormonal contraceptive users (including injectable and oral contraceptive users) and nonusers, we compared rates of HIV-1 acquisition in women and HIV-1 transmission from women to men.
Findings
Among 1314 couples in which the HIV-1 seronegative partner was female, HIV-1 acquisition rates were 6.61 and 3.78 per 100 person-years among hormonal contraceptive users and nonusers (adjusted hazard ratio [AHR]=1.98, 95% confidence interval [CI] 1.06–3.68, p=0.03). Among 2476 couples in which the HIV-1 seronegative partner was male, HIV-1 transmission rates from women to men were 2.61 and 1.51 per 100 person-years in those whose partners currently used versus did not use hormonal contraception (AHR=1.97, 95% CI 1.12–3.45, p=0.02). In subgroup analysis, injectable contraceptive users had increased risk for acquiring and transmitting HIV-1 to their partner and HIV-1 seropositive women using injectable contraception had higher genital HIV-1 RNA concentrations, suggesting a mechanism for increased transmission risk. Oral contraceptives were used too infrequently to draw definitive conclusions about HIV-1 risk.
Interpretation
Women should be counseled about potentially increased risk of HIV-1 acquisition and transmission with hormonal contraception, particularly injectable methods, and about the importance of dual protection with condoms to decrease HIV-1 risk. Non-hormonal or lower-dose hormonal contraceptive methods should be considered for women with or at-risk for HIV-1.
Funding
National Institutes of Health (R03 HD068143, R01 AI083034, P30 AI027757, and T32 AI007140) and the Bill and Melinda Gates Foundation (26469 and 41185).
doi:10.1016/S1473-3099(11)70247-X
PMCID: PMC3266951  PMID: 21975269
HIV-1; serodiscordant couples; Africa; hormonal contraception
16.  Breast cancer and the pill--a further report from the Royal College of General Practitioners' oral contraception study. 
British Journal of Cancer  1988;58(5):675-680.
An analysis of the occurrence of breast cancer in this long-term prospective cohort study shows a significant relative risk (RR) in women who have ever used oral contraceptives (OC) of 3.33 in women age 30 to 34 years at diagnosis and an RR of 5.88 (P = 0.0011) in women who were parity 1 at the time of diagnosis. In women below the age of 35 years the RR of 2.38 was not significant. There was no increased risk in women over the age of 35 years. A significant trend relating to duration of use was demonstrable in women who were parity 1 in the analysis of both current and ever-users. An analysis by time since stopping OC use revealed a significant trend in all ever-users, but the trends were much steeper in women of parity 1 or aged 30 to 34 years at diagnosis. There was no evidence that the increased rates in OC users were related to the oestrogen or progestogen dose. The 5 year survival rate in users diagnosed under the age of 35 years was significantly poorer than in comparable non-users. It is possible that the increased rates in younger OC users might be due to an accelerated presentation of breast cancer in those women who would otherwise have been diagnosed at a later time. The non-significant excess risk in users under 35 years of age was approximately 1 in 7,000 users per year. The unresolved discrepancies between the results of the published studies make it impossible at the present time to decide whether or not OC use is associated with an increased risk of breast cancer.
PMCID: PMC2246833  PMID: 3219280
17.  Breast cancer and oral contraceptives: findings in Royal College of General Practitioners' study. 
The incidence of breast cancer was studied among women taking part in the continuing cohort study organised by the Royal College of General Practitioners. An overall relative risk of 1.19 (not significant) was found in those who had used oral contraceptives. The risk ratio in women under 35 years old was 2.81, but this too was not significant. There was evidence that the estimated increased risk for younger women could be a chance occurrence. No convincing evidence of any adverse effects of oral contraceptives on breast cancer has been shown, but because of the long latent period of this tumour there is a need for longer observation.
PMCID: PMC1506508  PMID: 6788214
18.  Risk of venous thromboembolism among users of third generation oral contraceptives compared with users of oral contraceptives with levonorgestrel before and after 1995: cohort and case-control analysis 
BMJ : British Medical Journal  2000;321(7270):1190-1195.
Objective
To compare the risk of idiopathic venous thromboembolism among women taking third generation oral contraceptives (with gestodene or desogestrel) with that among women taking oral contraceptives with levonorgestrel.
Design
Cohort and case-control analyses derived from the General Practice Research Database.
Setting
UK general practices, January 1993 to December 1999.
Participants
Women aged 15-39 taking third generation oral contraceptives or oral contraceptives with levonorgestrel.
Main outcome measures
Relative incidence (cohort study) and odds ratios (case-control study) as measures of the relative risk of venous thromboembolism.
Results
The adjusted estimates of relative risk for venous thromboembolism associated with third generation oral contraceptives compared with oral contraceptives with levonorgestrel was 1.9 (95% confidence interval 1.3 to 2.8) in the cohort analysis and 2.3 (1.3 to 3.9) in the case-control study. The estimates for the two types of oral contraceptives were similar before and after the warning issued by the Committee on Safety of Medicines in October 1995. A shift away from the use of third generation oral contraceptives after the scare was more pronounced among younger women (who have a lower risk of venous thromboembolism) than among older women. Fewer cases of venous thromboembolism occurred in 1996 and later than would have been expected if the use of oral contraceptives had remained unchanged.
Conclusions
These findings are consistent with previously reported studies, which found that compared with oral contraceptives with levonorgestrel, third generation oral contraceptives are associated with around twice the risk of venous thromboembolism.
PMCID: PMC27524  PMID: 11073511
19.  Association Between Tampon Use and Choosing the Contraceptive Vaginal Ring 
Obstetrics and gynecology  2010;115(4):735-739.
Objective
To estimate whether tampon users are more likely to select the contraceptive vaginal ring than combined oral contraceptive pills (OCPs).
Methods
The Contraceptive Choice Project is a longitudinal study of 10,000 St. Louis-area women promoting the use of long-acting, reversible methods of contraception and evaluating user continuation and satisfaction for all reversible methods. We performed univariable and multivariable analyses of the 311 women who were asked about tampon use at the time of enrollment and who chose the contraceptive vaginal ring or OCPs to assess the association of tampon use and choice of combined hormonal method.
Results
Among contraceptive vaginal ring and OCP users, 247 (79%) reported using tampons. Contraceptive vaginal ring users were not significantly different than OCP users in terms of age, race or ethnicity, marital status, insurance, BMI, and parity. Adjusted analysis indicates tampon users were more likely to choose the contraceptive vaginal ring instead of OCPs (adjusted RR=1.34; 95%CI: 1.01–1.78). Women with previous contraceptive vaginal ring experience were also more likely to choose the contraceptive vaginal ring (adjusted RR=1.96; 95%CI: 1.6–2.4). Recent OCP use did not influence method choice.
Conclusion
In our baseline analysis of the Contraceptive Choice Project, tampon users were more likely to choose the contraceptive vaginal ring than OCPs. Use of tampons could be considered an indicator for the initial acceptability of the contraceptive vaginal ring, but all women should be offered the contraceptive vaginal ring regardless of experience with tampon use.
doi:10.1097/AOG.0b013e3181d41c4a
PMCID: PMC3119479  PMID: 20308832
20.  Oral bisphosphonates may not decrease hip fracture risk in elderly Spanish women: a nested case–control study 
BMJ Open  2013;3(2):e002084.
Objectives
To evaluate the association between the long-term use of bisphosphonates and the risk of hip fracture compared to never use among women aged 65 years or older.
Design
Case–control study nested in a cohort.
Setting
General practice research database operated by the Spanish Medicines Agency.
Participants
Cases of hip fracture were defined as women aged 65 years or older with a validated first diagnosis of hip fracture between 2005 and 2008. Five controls free of hip fracture were matched on age and calendar-year with each case.
Interventions
Information on bisphosphonate use, hip fractures, comedication and comorbidities was collected.
Primary outcomes
Hip fracture risk comparing bisphosphonate users versus never users.
Secondary outcomes
Hip fracture risk comparing bisphosphonate users versus never users by individual drugs.
Results
The study included 2009 incident hip fractures and 10 045 matched controls. Hip-fracture risk did not differ between bisphosphonate users and never users, adjusted OR=1.09 (95% CI 0.94 to 1.27). No association was observed between hip fracture risk and cumulative duration of bisphosphonate treatment. However, when treatment duration is analysed as time since first prescription, hip fracture risks of the different subgroups compared to never users obtained were as follows: <1 year, OR 0.85 (95% CI 0.60 to 1.21); 1 to <3 years, OR 1.02 (95% CI 0.82 to 1.26); ≥3 years, OR 1.32 (95% CI 1.05 to 1.65) (p for trend=0.03).
Conclusions
Ever use of oral bisphosphonates was not associated with a decreased risk of hip fracture in women aged 65 or older as compared to never use. No association was observed between hip fracture risk and cumulative duration of bisphosphonate treatment. However, when treatment duration is analysed as time since first prescription, a statistically significant increased risk for hip fracture was observed in patients exposed to bisphosphonates over 3 years.
Trial Registration
Spanish Ministry of Health. TRA-071
doi:10.1136/bmjopen-2012-002084
PMCID: PMC3586051  PMID: 23430594
CLINICAL PHARMACOLOGY; EPIDEMIOLOGY; PRIMARY CARE
21.  Pain and subsequent mortality and cancer among women in the Royal College of General Practitioners Oral Contraception Study. 
Recent research suggested associations between pain and subsequent all-cause and cancer-specific mortality. This study examined death and cancer development within six years of reporting pain, among women in the Royal College of General Practitioners Oral Contraception Study. We found no associations between 'any' or 'chronic' pain and subsequent all-cause mortality or cancer. We found a higher risk of death from respiratory disease among women reporting pain (adjusted odds ratio [AOR] = 2.5), a higher mortality among women reporting chronic chest pain (AOR = 1.75), and a higher risk of subsequent cancer among women reporting head or abdomen pain. Given the high prevalence of pain symptoms, these findings may be important, and warrant further research.
PMCID: PMC1314492  PMID: 12564277
22.  Inverse association of NSAID use and ovarian cancer in relation to oral contraceptive use and parity 
British journal of cancer  2008;98(11):1781-1783.
We examined the association between NSAID use and ovarian cancer by potential effect modifiers, parity and oral contraceptive use, in a population-based case-control study conducted in Wisconsin and Massachusetts. Women reported prior use of NSAIDs and information on risk factors in a telephone interview. A total of 487 invasive ovarian cancer cases and 2653 control women aged 20–74 years were included in the analysis. After adjustment for age, state of residence and other covariates, ever use of NSAIDs was inversely associated with ovarian cancer in never users of oral contraceptives (odd ratio [OR]=0.58, 95% confidence interval [CI] 0.42–0.80) but not for ever users (OR=0.98, 95% CI 0.71–1.35) (p-interaction=0.03). A reduced risk with NSAID use was also noted in nulliparous women (OR=0.47, 95% CI 0.27–0.82) but not among parous women (OR=0.81, 95% CI 0.64–1.04) (p-interaction=0.05). These results suggest that use of NSAIDs were beneficial to women at greatest risk for ovarian cancer.
doi:10.1038/sj.bjc.6604392
PMCID: PMC2410126  PMID: 18506182
ovarian cancer; non-steroidal anti-inflammatory drugs; parity; oral contraceptives
23.  Inverse association of NSAID use and ovarian cancer in relation to oral contraceptive use and parity 
British Journal of Cancer  2008;98(11):1781-1783.
We examined the association between non-steroidal anti-inflammatory drug (NSAID) use and ovarian cancer by potential effect modifiers, parity and oral contraceptive use, in a population-based case–control study conducted in Wisconsin and Massachusetts. Women reported prior use of NSAIDs and information on risk factors in a telephone interview. A total of 487 invasive ovarian cancer cases and 2653 control women aged 20–74 years were included in the analysis. After adjustment for age, state of residence and other covariates, ever use of NSAIDs was inversely associated with ovarian cancer in never users of oral contraceptives (odds ratio (OR)=0.58, 95% confidence interval (CI) 0.42–0.80) but not for ever users (OR=0.98, 95% CI 0.71–1.35) (P-interaction=0.03). A reduced risk with NSAID use was also noted in nulliparous women (OR=0.47, 95% CI 0.27–0.82) but not among parous women (OR=0.81, 95% CI 0.64–1.04) (P-interaction=0.05). These results suggest that use of NSAIDs were beneficial to women at greatest risk for ovarian cancer.
doi:10.1038/sj.bjc.6604392
PMCID: PMC2410126  PMID: 18506182
ovarian cancer; non-steroidal anti-inflammatory drugs; parity; oral contraceptives
24.  Risk factors for acute myocardial infarction in women: evidence from the Royal College of General Practitioners' oral contraception study. 
BMJ : British Medical Journal  1989;298(6667):165-168.
To determine the pattern of risk factors for acute myocardial infarction associated solely with women a nested case-control study was carried out on cohort data collected during the Royal College of General Practitioners' oral contraception study. Smoking (adjusted relative risk 1.7 for light smokers and 4.3 for heavy smokers), hypertension (2.4), toxaemia of pregnancy (2.8), and diabetes mellitus (6.9) were associated with a significantly increased risk of myocardial infarction. There was no significant trend of risk with social class. Current use of the pill increased the risk only among women who also smoked (relative risk 20.8 for heavy smokers). Previous use of the pill did not influence the risk of myocardial infarction. If heavy smokers also had a history of toxaemia of pregnancy their risk of myocardial infarction was further increased (relative risk 41.0). Other variables associated solely with women, such as parity, hysterectomy, and hormone replacement therapy, had little effect on the risk of having a myocardial infarction. Overall, smoking was the most important independent risk factor and had a strong influence on risks associated with other factors.
PMCID: PMC1835478  PMID: 2493841
25.  Oral contraceptives and breast cancer: results from an expanded case-control study. 
British Journal of Cancer  1989;60(3):375-381.
The relationship between oral contraceptives and breast cancer was evaluated among 2,022 cases and 2,183 controls participating in a multicentre breast cancer screening programme. Ever use of oral contraceptives was not related to breast cancer risk (RR = 1.0, 95% CI 0.9-1.2), and no overall patterns of increasing or decreasing risks were observed according to the duration of use, or time since first or most recent use. Although we had no women with extended periods of oral contraceptive use early in life, no evidence of adverse effects attributable to short-term use before age 25, before first live birth or during the perimenopausal period were observed. Further, oral contraceptives did not interact with other breast cancer risk factors, except among those with a history of two or more breast biopsies (RR = 2.0). Analyses by stage of disease revealed that risk was related to the duration of oral contraceptive use: greater than or equal to 5 years use was associated with reduced risk for in situ cancer (RR = 0.59) and increased risks for invasive cancers (RR = 1.5 and 1.4 respectively for small and large lesions). These data suggest that oral contraceptive effects may vary by stage of disease, but provide no overall evidence of an association between oral contraceptives and breast cancer.
PMCID: PMC2247191  PMID: 2789945

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