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1.  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
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.  Mortality among contraceptive pill users: cohort evidence from Royal College of General Practitioners’ Oral Contraception Study 
Objective To see if the mortality risk among women who have used oral contraceptives differs from that of never users.
Design Prospective cohort study started in 1968 with mortality data supplied by participating general practitioners, National Health Service central registries, or both.
Setting 1400 general practices throughout the United Kingdom.
Participants 46 112 women observed for up to 39 years, resulting in 378 006 woman years of observation among never users of oral contraception and 819 175 among ever users.
Main outcome measures Directly standardised adjusted relative risks between never and ever users for all cause and cause specific mortality.
Results 1747 deaths occurred in never users of oral contraception and 2864 in ever users. Compared with never users, ever users of oral contraception had a significantly lower rate of death from any cause (adjusted relative risk 0.88, 95% confidence interval 0.82 to 0.93). They also had significantly lower rates of death from all cancers; large bowel/rectum, uterine body, and ovarian cancer; main gynaecological cancers combined; all circulatory disease; ischaemic heart disease; and all other diseases. They had higher rates of violent deaths. No association between overall mortality and duration of oral contraceptive use was observed, although some disease specific relations were apparent. An increased relative risk of death from any cause between ever users and never users was observed in women aged under 45 years who had stopped using oral contraceptives 5-9 years previously but not in those with more distant use. The estimated absolute reduction in all cause mortality among ever users of oral contraception was 52 per 100 000 woman years.
Conclusion Oral contraception was not associated with an increased long term risk of death in this large UK cohort; indeed, a net benefit was apparent. The balance of risks and benefits, however, may vary globally, depending on patterns of oral contraception usage and background risk of disease.
doi:10.1136/bmj.c927
PMCID: PMC2837145  PMID: 20223876
4.  Effects of changes in smoking status on risk estimates for myocardial infarction among women recruited for the Royal College of General Practitioners' Oral Contraception Study in the UK 
STUDY OBJECTIVE: To determine whether changes in smoking status among women recruited for the Royal College of General Practitioners' Oral Contraception Study affected previous risk estimates for myocardial infarction. DESIGN: (1) Postal survey between November 1994 and July 1995 of women still under general practitioner observation. Validation of the smoking information supplied by the women on the questionnaire by comparison with that reported by the general practitioner at recruitment to the main study. (2) Nested case-control study of 103 cases of myocardial infarction, matched with 309 controls, to see if different risk estimates were obtained when smoking status at recruitment or smoking status at time of event were used in the analysis. SETTING: 650 general practices throughout the United Kingdom. PARTICIPANTS: 10,073 women who responded to the questionnaire (85.4% of 11,797 sent out). MAIN RESULTS: There was good agreement between smoking information recorded by the general practitioner at recruitment and that supplied retrospectively by respondents to the questionnaire. The risk estimates for myocardial infarction associated with use of combined oral contraceptives (COCs) were almost identical irrespective of whether smoking status at recruitment or at time of event was used for the statistical adjustment. This was because few women stopped smoking while also using COCs. In fact, fewer regular smokers who have ever used COCs reported stopping smoking than never users. The risk estimates for myocardial infarction associated with smoking were smaller when smoking habits at recruitment was used than when smoking habits at time of event was used. CONCLUSIONS: Previous results from the Oral Contraception Study regarding the effects of COCs are unlikely to have been biased by changes in the smoking habits of the cohort, but the effects of smoking have probably been underestimated. There is still a need for effective health education regarding the risks associated with smoking, particularly among users of COCs.
 
PMCID: PMC1756732  PMID: 9799875
5.  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
6.  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
7.  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
8.  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
9.  Cigarette smoking and parity as risk factors for the development of symptomatic gall bladder disease in women: results of the Royal College of General Practitioners' oral contraception study. 
Gut  1994;35(1):107-111.
The effects of cigarette smoking and parity on the development of symptomatic gall bladder disease remain controversial. These relations have been examined in a cohort of 46,000 women followed for up to 19 years during the Royal College of General Practitioners' (RCGP) oral contraception study. During follow up, 1087 women were recorded as experiencing their first ever episode of symptomatic cholelithiasis (International Classification of Diseases, 8th revision (ICD-8) 574) or cholecystitis (ICD-8 575). Smokers were more likely to develop symptomatic gall bladder disease than non-smokers (relative risk 1.19; 95% confidence intervals (95% CI) 1.06 to 1.34) and there was a significant trend with the number of cigarettes smoked daily (test for trend chi 2 = 7.58, p < 0.01). This relation was most apparent among never users of oral contraceptives, although similar trends were found among current and former users. A significant direct relation between symptomatic gall bladder disease and parity was also found (test for trend chi 2 = 21.89, p < 0.001). When all were examined together a trend of increasing risk with lower social class was also found (test for trend chi 2 = 5.72, p = 0.02). Current users of oral contraceptives had a moderately increased risk of symptomatic gall bladder disease (relative risk 1.15; 95% CI 0.99 to 1.34), unlike former users (relative risk 1.03; 95% CI 0.90 to 1.18). These results suggest that smoking and parity are important risk factors for the development of symptomatic gall bladder disease in women.
PMCID: PMC1374643  PMID: 8307429
10.  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
11.  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
12.  Oral contraceptives, reproductive factors and risk of inflammatory bowel disease 
Gut  2012;62(8):1153-1159.
Background
Oral contraceptive use has been associated with risk of Crohn’s disease (CD) and ulcerative colitis (UC).
Objective
To determine whether this association is confounded or modified by other important lifestyle and reproductive factors.
Design
A prospective cohort study was carried out of 117 375 US women enrolled since 1976 in the Nurses Health Study I (NHS I) and 115 077 women enrolled since 1989 in the Nurses’ Health Study II (NHS II) with no prior history of UC or CD. These women had provided information every 2 years, on age at menarche, oral contraceptive use, parity, menopause status and other risk factors. Diagnoses of CD and UC were confirmed by review of medical records. Cox proportional hazards models were used to calculate HRs and 95% CIs.
Results
Among 232 452 women with over 5 030 196 person-years of follow-up, 315 cases of CD and 392 cases of UC were recorded through 2007 in NHS II and 2008 in NHS I. Compared with never users of oral contraceptives, the multivariate-adjusted HRs for CD were 2.82 (95% CI 1.65 to 4.82) among current users and 1.39 (95% CI 1.05 to 1.85) among past users. The association between oral contraceptives and UC differed according to smoking history (pheterogeneity = 0.04). Age at menarche, age at first birth and parity were not associated with risk of UC or CD.
Conclusion
In two large prospective cohorts of US women, oral contraceptive use was associated with risk of CD. The association between oral contraceptive use and UC was limited to women with a history of smoking.
doi:10.1136/gutjnl-2012-302362
PMCID: PMC3465475  PMID: 22619368
13.  Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case-control study using United States claims data 
Objective To compare the risk of non-fatal venous thromboembolism in women receiving oral contraceptives containing drospirenone with that in women receiving oral contraceptives containing levonorgestrel.
Design Nested case-control and cohort study.
Setting The study was based on information from PharMetrics, a United States based company that collects information on claims paid by managed care plans.
Participants The study encompassed all women aged 15 to 44 years who received an oral contraceptive containing either drospirenone or levonorgestrel after 1 January 2002. Cases were women with current use of a study oral contraceptive and a diagnosis of venous thromboembolism in the absence of identifiable clinical risk factors (idiopathic venous thromboembolism). Up to four controls were matched to each case by age and calendar time.
Main outcome measures Odds ratios comparing the risk of non-fatal venous thromboembolism in users of the two contraceptives; incidence rates and rate ratios of non-fatal venous thromboembolism for users of each of the study contraceptives.
Results 186 newly diagnosed, idiopathic cases of venous thromboembolism were identified in the study population and matched with 681 controls. In the case-control analysis, the conditional odds ratio for venous thromboembolism comparing use of oral contraceptives containing drospirenone with use of those containing levonorgestrel was 2.3 (95% confidence interval 1.6 to 3.2). The incidence rates for venous thromboembolism in the study population were 30.8 (95% confidence interval 25.6 to 36.8) per 100 000 woman years among users of oral contraceptives containing drospirenone and 12.5 (9.61 to 15.9) per 100 000 woman years among users of oral contraceptives containing levonorgestrel. The age adjusted incidence rate ratio for venous thromboembolism for current use of oral contraceptives containing drospirenone compared with those containing levonorgestrel was 2.8 (2.1 to 3.8).
Conclusions The risk of non-fatal venous thromboembolism among users of oral contraceptives containing drospirenone seems to be around twice that of users of oral contraceptives containing levonorgestrel, after the effects of potential confounders and prescribing biases have been taken into account.
doi:10.1136/bmj.d2151
PMCID: PMC3081040  PMID: 21511805
14.  Oral contraceptive use and risk of melanoma in premenopausal women 
British Journal of Cancer  1999;81(5):918-923.
Melanoma has been increasing in white populations. Incidence rates rise steeply in women until about age 50, suggesting oestrogen as a possible risk factor. Oestrogens can increase melanocyte count and melanin content and cause hyperpigmentation of the skin. We examined prospectively the association between oral contraceptive (OC) use and diagnoses of superficial spreading and nodular melanoma among 183 693 premenopausal white women in the Nurses’ Health Study (NHS) and the Nurses’ Health Study II (NHS II) cohorts. One hundred and forty six cases were confirmed in NHS during follow-up from 1976 to 1994, and 106 cases were confirmed in NHS II from 1989 to 1995. Skin reaction to sun exposure, sunburn history, mole counts, hair colour, family history of melanoma, parity, height and body mass index were also assessed and included in logistic regression models. A significant twofold increase in risk of melanoma (relative risk (RR) = 2.0, 95% confidence interval (CI) 1.2–3.4) was observed among current OC users compared to never users. Risk was further increased among current users with 10 or more years of use (RR = 3.4, 95% CI 1.7–7.0). Risk did not appear elevated among past OC users, even among those with longer durations of use, and risk did not decline linearly with time since last use. In conclusion, risk of premenopausal melanoma may be increased among women who are current OC users, particularly among those with longer durations of use. Further research is needed to determine whether low-dose oestrogen pills in particular are associated with an increase in risk and to describe possible interactions between OC use and sun exposure or other risk factors for melanoma. © 1999 Cancer Research Campaign
doi:10.1038/sj.bjc.6690787
PMCID: PMC2374297  PMID: 10555769
melanoma; oral contraceptives; oestrogen; premenopausal
15.  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
16.  Combined impact of lifestyle factors on mortality: prospective cohort study in US women 
Objective To evaluate the impact of combinations of lifestyle factors on mortality in middle aged women.
Design Prospective cohort study.
Setting Nurses’ health study, United States.
Participants 77 782 women aged 34 to 59 years and free from cardiovascular disease and cancer in 1980.
Main outcome measure Relative risk of mortality during 24 years of follow-up in relation to five lifestyle factors (cigarette smoking, being overweight, taking little moderate to vigorous physical activity, no light to moderate alcohol intake, and low diet quality score).
Results 8882 deaths were documented, including 1790 from cardiovascular disease and 4527 from cancer. Each lifestyle factor independently and significantly predicted mortality. Relative risks for five compared with zero lifestyle risk factors were 3.26 (95% confidence interval 2.45 to 4.34) for cancer mortality, 8.17 (4.96 to 13.47) for cardiovascular mortality, and 4.31 (3.51 to 5.31) for all cause mortality. A total of 28% (25% to 31%) of deaths during follow-up could be attributed to smoking and 55% (47% to 62%) to the combination of smoking, being overweight, lack of physical activity, and a low diet quality. Additionally considering alcohol intake did not substantially change this estimate.
Conclusions These results indicate that adherence to lifestyle guidelines is associated with markedly lower mortality in middle aged women. Both efforts to eradicate cigarette smoking and those to stimulate regular physical activity and a healthy diet should be intensified.
doi:10.1136/bmj.a1440
PMCID: PMC2658866  PMID: 18796495
18.  Recurrent pregnancies during oral contraception 
The records of the Royal College of General Practitioners' Oral Contraception Study were examined for those women who had become pregnant while using combined oral contraceptive pills. Analysis reveals that these women are much more likely than average to have further failures if they resume taking the Pill (seven failures in 35 women-years, compared with one in 500 women-years for the whole study). This finding could occur through some factor in the patient's personality (patient failure) or through some factor in the patient's metabolism.
PMCID: PMC2157991  PMID: 859153
19.  Effects of a combined lifestyle score on 10-year mortality in Korean men and women: a prospective cohort study 
BMC Public Health  2012;12:673.
Background
Most studies that have evaluated the association between combined lifestyle factors and mortality outcomes have been conducted in populations of Caucasian origin. The objective of this study was to examine the association between combined lifestyle scores and the risk of mortality in Korean men and women.
Methods
The study population included 59,941 Koreans, 30–84 years of age, who had visited the Severance Health Promotion Center between 1994 and 2003. Cox regression models were fitted to establish the association between combined lifestyle factors (current smoker, heavy daily alcohol use, overweight or obese weight, physical inactivity, and unhealthy diet) and mortality outcomes.
Results
During 10.3 years of follow-up, there were 2,398 cases of death from any cause. Individual and combined lifestyle factors were found to be associated with the risk of mortality. Compared to those having none or only one risk factor, in men with a combination of four lifestyle factors, the relative risk for cancer mortality was 2.04-fold, for non-cancer mortality 1.92-fold, and for all-cause mortality 2.00-fold. In women, the relative risk was 2.00-fold for cancer mortality, 2.17-fold for non-cancer mortality, and 2.09-fold for all-cause mortality. The population attributable risks for all-cause mortality for the four risk factors combined was 44.5% for men and 26.5% for women.
Conclusion
This study suggests that having a high (unhealthy) lifestyle score, in contrast to a low (healthy) score, can substantially increase the risk of death by any cause, cancer, and non-cancer in Korean men and women.
doi:10.1186/1471-2458-12-673
PMCID: PMC3490935  PMID: 22900981
Lifestyle factor; Mortality; Cohort study; Population attributable risk
20.  Oral contraceptive use and estrogen/progesterone receptor negative breast cancer among African-American women 
Background
Oral contraceptive formulations have changed over time, making it relevant to assess the effect of more recent formulations on breast cancer risk. In addition, some studies have found stronger positive associations of oral contraceptive use with estrogen receptor negative (ER−) than with ER positive (ER+) breast cancer. We carried out the first assessment of the effect of oral contraceptive use on the incidence of breast cancer classified by receptor status among African-American women, a group disproportionately affected by ER− cancer.
Methods
We followed 53,848 Black Women's Health Study participants from 1995–2007 through biennial health questionnaires, on which participants reported information about incident breast cancer, oral contraceptive use, and breast cancer risk factors. Pathology information was obtained on receptor status for 789 incident cases. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were derived from Cox regression models with control for confounding factors.
Results
Ever use of oral contraceptives was more strongly associated with ER−PR− breast cancer (279 cases, IRR=1.65, 95% CI 1.19–2.30) than with ER+PR+ cancer (386 cases, IRR=1.11, 95% CI 0.86–1.42). The risk of ER−PR− breast cancer increased with increasing duration of use among recent users.
Conclusions
These results indicate that oral contraceptive formulations used in recent decades increase breast cancer risk in African-American women, with a greater effect for ER− than ER+ cancer.
Impact
Mechanisms to explain an adverse influence of oral contraceptive use on ER− breast cancer need to be elucidated.
doi:10.1158/1055-9965.EPI-10-0428
PMCID: PMC2919607  PMID: 20647407
21.  Third generation oral contraceptives and risk of venous thrombosis: meta-analysis 
BMJ : British Medical Journal  2001;323(7305):131.
Objective
To evaluate quantitatively articles that compared effects of second and third generation oral contraceptives on risk of venous thrombosis.
Design
Meta-analysis.
Studies
Cohort and case-control studies assessing risk of venous thromboembolism among women using oral contraceptives before October 1995.
Main outcome measures
Pooled adjusted odds ratios calculated by a general variance based random effects method. When possible, two by two tables were extracted and combined by the Mantel-Haenszel method.
Results
The overall adjusted odds ratio for third versus second generation oral contraceptives was 1.7 (95% confidence interval 1.4 to 2.0; seven studies). Similar risks were found when oral contraceptives containing desogestrel or gestodene were compared with those containing levonorgestrel. Among first time users, the odds ratio for third versus second generation preparations was 3.1 (2.0 to 4.6; four studies). The odds ratio was 2.5 (1.6 to 4.1; five studies) for short term users compared with 2.0 (1.4 to 2.7; five studies) for longer term users. The odds ratio was 1.3 (1.0 to 1.7) in studies funded by the pharmaceutical industry and 2.3 (1.7 to 3.2) in other studies. Differences in age and certainty of diagnosis of venous thrombosis did not affect the results.
Conclusions
This meta-analysis supports the view that third generation oral contraceptives are associated with an increased risk of venous thrombosis compared with second generation oral contraceptives. The increase cannot be explained by several potential biases.
What is already known on this topicThird generation oral contraceptives have been reported to increase the risk of venous thrombosis compared with second generation oral contraceptivesThe findings have been vigorously debated, with suggestions that the results can be explained by confounding or bias, or both.What this study addsWomen taking third generation oral contraceptives have a 1.7-fold increased risk of venous thrombosis compared with those taking second generation oral contraceptivesRisk is highest in first time usersThe biases were not large enough to account for the observed results
PMCID: PMC34722  PMID: 11463678
22.  A pooled analysis of 10 case–control studies of melanoma and oral contraceptive use 
British Journal of Cancer  2002;86(7):1085-1092.
Data regarding the effects of oral contraceptive use on women's risk of melanoma have been difficult to resolve. We undertook a pooled analysis of all case–control studies of melanoma in women completed as of July 1994 for which electronic data were available on oral contraceptive use along with other melanoma risk factors such as hair colour, sun sensitivity, family history of melanoma and sun exposure. Using the original data from each investigation (a total of 2391 cases and 3199 controls), we combined the study-specific odds ratios and standard errors to obtain a pooled estimate that incorporates inter-study heterogeneity. Overall, we observed no excess risk associated with oral contraceptive use for 1 year or longer compared to never use or use for less than 1 year (pooled odds ratio (pOR)=0.86; 95% CI=0.74–1.01), and there was no evidence of heterogeneity between studies. We found no relation between melanoma incidence and duration of oral contraceptive use, age began, year of use, years since first use or last use, or specifically current oral contraceptive use. In aggregate, our findings do not suggest a major role of oral contraceptive use on women's risk of melanoma.
British Journal of Cancer (2002) 86, 1085–1092. DOI: 10.1038/sj/bjc/6600196 www.bjcancer.com
© 2002 Cancer Research UK
doi:10.1038/sj.bjc.6600196
PMCID: PMC2364185  PMID: 11953854
melanoma; oral contraceptives; pooled analysis; case–control studies
23.  Risk factors for uterine fibroids: reduced risk associated with oral contraceptives. 
Risk factors for pathologically confirmed uterine leiomyomas (fibroids) were investigated using data from the Oxford Family Planning Association study, a long term follow up study of women using various methods of contraception. For each of 535 women who had had a fibroid an individual control was selected who matched the patient on age, date of entry into the cohort, and family planning clinic at recruitment and who was alive (and still being followed up) at the date the patient underwent surgery for fibroids. Case-control analysis showed that reproductive experiences were closely linked to development of fibroids. Risk of fibroids decreased consistently with increasing number of term pregnancies; women with five term pregnancies had only a quarter of the risk of women who had had none. Risk also decreased consistently with increasing duration of oral contraceptive use; the risk of fibroids was reduced by some 31% in women who had used oral contraceptives for 10 years. Risk was strongly related to weight: women who weighed under 55 kg had a particularly low risk, and overall the risk rose roughly 21% for each 10 kg increase. Cigarette smoking was associated with a decreased risk of fibroids; smokers of 20 cigarettes a day had a risk roughly two thirds that of non-smokers. These risk factors have all previously been identified as risk factors for endometrial cancer; this strongly suggests that the underlying risk factor is "unopposed" oestrogen.
PMCID: PMC1341047  PMID: 3730804
24.  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
25.  Pregnancy and oral contraceptive use do not significantly influence outcome in long term rheumatoid arthritis 
Annals of the Rheumatic Diseases  2002;61(5):405-408.
Background: Oral contraceptives (OC) and pregnancy are known to have an influence on the risk of onset of rheumatoid arthritis (RA). Pregnancy itself has beneficial effects on the activity of the disease, with relapses post partum. It is not known, however, whether OC and pregnancies influence the ultimate outcome of RA.
Objectives: To explore whether OC use and pregnancies influence the 12 year outcome in RA as measured by radiological damage and disability.
Methods: In a prospective inception cohort of 132 female patients with recent RA according to the 1987 American College of Rheumatology criteria—a cohort initially gathered to study the association between hormonal factors and the onset of RA—outcome was assessed in a follow up after 12 years. The outcome was evaluated in 112 (85%) women by the radiological damage of hands and feet as measured with the Sharp score modification van der Heijde (SHS), the damage of the large joints measured with the Larsen score (LS) of large joints (0–60), and the disability measured with the Health Assessment Questionnaire (HAQ). The median values of each outcome variable were calculated for several subgroups of patients stratified for OC use and pregnancies before and after onset of the disease and the tertiles of the total number of months of OC use and of pregnancies. The association of OC use and pregnancies before and after onset of the disease with the outcome variables was calculated using Spearman's rank correlation (rs). The combined influence of OC use and pregnancies on the SHS, LS, and HAQ at 12 years was estimated using ordinal polytomous logistic regression.
Results: The median values of the SHS, LS, and HAQ showed a trend towards less radiological joint damage and less disability in women with long term OC use and multiple pregnancies. This difference, however, was not significant, except for the HAQ score in women with three or more pregnancies in life. There was no association between pregnancies, however defined, and any parameter of RA outcome after 12 years (maximum rs=-0.10). The only significant correlation was found between OC use before symptom onset and the LS (rs=-0.22, p<0.05). The combination of hormonal variables explained no more than a maximum of 3% of the variance of the 12 year outcome as measured by the SHS.
Conclusion: OC use and pregnancy do not significantly influence outcome in long term RA. There is, however, a trend for patients with multiple pregnancies and long term OC use to have less radiographic joint damage and a better functional level.
doi:10.1136/ard.61.5.405
PMCID: PMC1754092  PMID: 11959763

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