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1.  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
2.  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
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.  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
5.  Injectable and Oral Contraceptive Use and Cancers of the Breast, Cervix, Ovary, and Endometrium in Black South African Women: Case–Control Study 
PLoS Medicine  2012;9(3):e1001182.
A case-control study conducted in South Africa provides new estimates of the risk of specific cancers of the female reproductive system associated with use of injectable and oral contraceptives.
Background
Oral contraceptives are known to influence the risk of cancers of the female reproductive system. Evidence regarding the relationship between injectable contraceptives and these cancers is limited, especially in black South Africans, among whom injectable contraceptives are used more commonly than oral contraceptives.
Methods and Findings
We analysed data from a South African hospital-based case–control study of black females aged 18–79 y, comparing self-reported contraceptive use in patients with breast (n = 1,664), cervical (n = 2,182), ovarian (n = 182), and endometrial (n = 182) cancer, with self-reported contraceptive use in 1,492 control patients diagnosed with cancers with no known relationship to hormonal contraceptive use. We adjusted for potential confounding factors, including age, calendar year of diagnosis, education, smoking, alcohol, parity/age at first birth, and number of sexual partners. Among controls, 26% had used injectable and 20% had used oral contraceptives. For current and more recent users versus never users of oral or injectable contraceptives, the odds ratios (ORs) for breast cancer were significantly increased in users of oral and/or injectable contraceptives (OR 1.66, 95% CI 1.28–2.16, p<0.001) and separately among those exclusively using oral (1.57, 1.03–2.40, p = 0.04) and exclusively using injectable (OR 1.83, 1.31–2.55, p<0.001) contraceptives; corresponding ORs for cervical cancer were 1.38 (1.08–1.77, p = 0.01), 1.01 (0.66–1.56, p = 0.96), and 1.58 (1.16–2.15, p = 0.004). There was no significant increase in breast or cervical cancer risk among women ceasing hormonal contraceptive use ≥10 y previously (p = 0.3 and p = 0.9, respectively). For durations of use ≥5 y versus never use, the ORs of ovarian cancer were 0.60 (0.36–0.99, p = 0.04) for oral and/or injectable contraceptive use and 0.07 (0.01–0.49, p = 0.008) for injectable use exclusively; corresponding ORs for endometrial cancer were 0.44 (0.22–0.86, p = 0.02) and 0.36 (0.11–1.26, p = 0.1).
Conclusions
In this study, use of oral and of injectable hormonal contraceptives was associated with a transiently increased risk of breast and cervical cancer and, for long durations of use, with a reduced risk of ovarian and endometrial cancer. The observed effects of injectable and of oral contraceptives on cancer risk in this study did not appear to differ substantially.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Hormonal contraceptives are among the most commonly used medications. Globally, more than 210 million women currently use either hormonal contraceptive pills or injectable contraceptives. Contraceptive pills usually contain manmade versions of the female sex hormones estrogen and progesterone (the combined oral contraceptive, or “pill”); most injectable hormonal contraceptives contain only manmade progesterone preparations. Hormonal contraceptives, which prevent pregnancy by disrupting the cyclical changes in estrogen and progesterone levels that prepare the body for pregnancy, have revolutionized birth control since they first became available in the early 1960s. However, it is now known that taking the pill also influences women's risk of developing cancers of the female reproductive system. Current and recent users have an increased risk of developing breast and cervical cancer (the cervix is the structure that connects the womb to the vagina) compared to never users, although this increased risk quickly disappears when women stop taking the pill. By contrast, women who have used the pill have a reduced risk of developing ovarian cancer and cancer of the womb (endometrial cancer) compared to never users that increases with the duration of pill use and persists for many years after use ceases. These effects on reproductive system cancers are thought to occur because these cancers depend on naturally occurring sex hormones for their development and growth.
Why Was This Study Done?
Although the evidence that the pill influences the risk of developing cancers of the female reproductive system is extensive, much less is known about how injectable hormonal contraceptives affect cancer risk. In this hospital-based case–control study (a study that compares the characteristics of people with and without a specific condition), the researchers investigate the relationship between the use of oral and injectable hormonal contraceptives and cancers of the breast, cervix, ovary, and endometrium among black South African women. Injectable contraceptives have been used for longer in South Africa than elsewhere and are used more commonly than oral contraceptives among black South African women.
What Did the Researchers Do and Find?
As part of the Johannesburg Cancer Case Control Study, which recruits black patients attending Johannesburg public referral hospitals for cancer treatment, the researchers compared hormonal contraceptive use in women with breast, cervical, ovarian, or endometrial cancer with contraceptive use in women diagnosed with other cancers such as lung, colon, and rectal cancers, which are not known to be influenced by hormonal contraceptives. Among the controls, a quarter had used injectable contraceptives and a fifth had used oral contraceptives. After adjusting for other factors that might influence cancer risk such as age, smoking, and number of sexual partners, the odds ratio (OR) of breast cancer among current and recent users of oral and/or injectable contraceptives compared to never users was 1.66. That is, the risk of developing breast cancer among current and recent users of hormonal contraceptives was 1.66 times that among never users. For women using oral contraceptives exclusively or injectable contraceptives exclusively, the ORs of breast cancer were 1.57 and 1.83, respectively. There were also increases in cervical cancer risk among current and recent users of hormonal contraceptives compared to never users, but no significant increase in breast or cervical cancer risk among women who had ceased hormonal contraceptive use more than ten years previously. Finally, the use of hormonal contraceptives for more than five years reduced the risk of both ovarian and endometrial cancer.
What Do These Findings Mean?
These findings indicate that, among black women in South Africa, the use of oral or injectable hormonal contraceptives is associated with a transiently increased risk of breast and cervical cancer, and that extended use of these contraceptives is associated with a reduced risk of ovarian and endometrial cancer. Moreover, they suggest that the effects of oral versus injectable contraceptives on cancer risk do not differ substantially, although for endometrial and ovarian cancer the small number of cases exposed to injectable contraceptives limits the accuracy of the risk estimates. Other limitations of this study include the possibility that the findings may be affected by uncontrolled confounding. That is, women who used hormonal contraceptives may have shared other unidentified characteristics that affected their cancer risk. Nevertheless, these findings provide new information about the effects of oral and injectable hormonal contraceptives on cancer risk that should help women make informed decisions about their choice of contraceptive method.
Additional Information
Please access these web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001182.
The US National Cancer Institute provides information on breast cancer (including personal stories from breast cancer survivors), cervical cancer, ovarian cancer, and endometrial cancer for patients and health professionals, and a fact sheet on oral contraceptives and cancer risk (in English and Spanish)
Cancer Research UK also provides information on breast cancer, cervical cancer, ovarian cancer, and endometrial cancer and information about the birth control pill and cancer risk
Eyes on the Prize, an online support group for women who have had cancers of the female reproductive system, has personal stories; further personal stories about breast, cervical, and ovarian cancer are provided by the charity Healthtalkonline
doi:10.1371/journal.pmed.1001182
PMCID: PMC3295825  PMID: 22412354
6.  Oral contraceptive use and mortality after 36 years of follow-up in the Nurses’ Health Study: prospective cohort study 
Objective To determine whether use of oral contraceptives is associated with all cause and cause specific mortality.
Design Prospective cohort study.
Setting Nurses’ Health Study, data collected between 1976 and 2012.
Population 121 701 participants were prospectively followed for 36 years; lifetime oral contraceptive use was recorded biennially from 1976 to 1982.
Main outcome measures Overall and cause specific mortality, assessed throughout follow-up until 2012. Cox proportional hazards models were used to calculate the relative risks of all cause and cause specific mortality associated with use of oral contraceptives.
Results In our population of 121 577 women with information on oral contraceptive use, 63 626 were never users (52%) and 57 951 were ever users (48%). After 3.6 million person years, we recorded 31 286 deaths. No association was observed between ever use of oral contraceptives and all cause mortality. However, violent or accidental deaths were more common among ever users (hazard ratio 1.20, 95% confidence interval 1.04 to 1.37). Longer duration of use was more strongly associated with certain causes of death, including premature mortality due to breast cancer (test for trend P<0.0001) and decreased mortality rates of ovarian cancer (P=0.002). Longer time since last use was also associated with certain outcomes, including a positive association with violent or accidental deaths (P=0.005).
Conclusions All cause mortality did not differ significantly between women who had ever used oral contraceptives and never users. Oral contraceptive use was associated with certain causes of death, including increased rates of violent or accidental death and deaths due to breast cancer, whereas deaths due to ovarian cancer were less common among women who used oral contraceptives. These results pertain to earlier oral contraceptive formulations with higher hormone doses rather than the now more commonly used third and fourth generation formulations with lower estrogen doses.
doi:10.1136/bmj.g6356
PMCID: PMC4216099  PMID: 25361731
7.  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
8.  Venous thrombosis in users of non-oral hormonal contraception: follow-up study, Denmark 2001-10 
Objective To assess the risk of venous thrombosis in current users of non-oral hormonal contraception.
Design Historical national registry based cohort study.
Setting Four national registries in Denmark.
Participants All Danish non-pregnant women aged 15-49 (n=1 626 158), free of previous thrombotic disease or cancer, were followed from 2001 to 2010.
Main outcome measures Incidence rate of venous thrombosis in users of transdermal, vaginal, intrauterine, or subcutaneous hormonal contraception, relative risk of venous thrombosis compared with non-users, and rate ratios of venous thrombosis in current users of non-oral products compared with the standard reference oral contraceptive with levonorgestrel and 30-40 µg oestrogen. Diagnoses were confirmed by at least four weeks of anticoagulation therapy after the diagnosis.
Results Within 9 429 128 woman years of observation, 5287 first ever venous thrombosis events were recorded, of which 3434 were confirmed. In non-users of hormonal contraception the incidence rate of confirmed events was 2.1 per 10 000 woman years. Compared with non-users of hormonal contraception, and after adjustment for age, calendar year, and education, the relative risk of confirmed venous thrombosis in users of transdermal combined contraceptive patches was 7.9 (95% confidence interval 3.5 to 17.7) and of the vaginal ring was 6.5 (4.7 to 8.9). The corresponding incidences per 10 000 exposure years were 9.7 and 7.8 events. The relative risk was increased in women who used subcutaneous implants (1.4, 0.6 to 3.4) but not in those who used the levonorgestrel intrauterine system (0.6, 0.4 to 0.8). Compared with users of combined oral contraceptives containing levonorgestrel, the adjusted relative risk of venous thrombosis in users of transdermal patches was 2.3 (1.0 to 5.2) and of the vaginal ring was 1.9 (1.3 to 2.7).
Conclusion Women who use transdermal patches or vaginal rings for contraception have a 7.9 and 6.5 times increased risk of confirmed venous thrombosis compared with non-users of hormonal contraception of the same age, corresponding to 9.7 and 7.8 events per 10 000 exposure years. The risk was slightly increased in women using subcutaneous implants but not in those using the levonorgestrel intrauterine system.
doi:10.1136/bmj.e2990
PMCID: PMC3349780  PMID: 22577198
9.  Risk Prediction for Breast, Endometrial, and Ovarian Cancer in White Women Aged 50 y or Older: Derivation and Validation from Population-Based Cohort Studies 
PLoS Medicine  2013;10(7):e1001492.
Ruth Pfeiffer and colleagues describe models to calculate absolute risks for breast, endometrial, and ovarian cancers for white, non-Hispanic women over 50 years old using easily obtainable risk factors.
Please see later in the article for the Editors' Summary
Background
Breast, endometrial, and ovarian cancers share some hormonal and epidemiologic risk factors. While several models predict absolute risk of breast cancer, there are few models for ovarian cancer in the general population, and none for endometrial cancer.
Methods and Findings
Using data on white, non-Hispanic women aged 50+ y from two large population-based cohorts (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [PLCO] and the National Institutes of Health–AARP Diet and Health Study [NIH-AARP]), we estimated relative and attributable risks and combined them with age-specific US-population incidence and competing mortality rates. All models included parity. The breast cancer model additionally included estrogen and progestin menopausal hormone therapy (MHT) use, other MHT use, age at first live birth, menopausal status, age at menopause, family history of breast or ovarian cancer, benign breast disease/biopsies, alcohol consumption, and body mass index (BMI); the endometrial model included menopausal status, age at menopause, BMI, smoking, oral contraceptive use, MHT use, and an interaction term between BMI and MHT use; the ovarian model included oral contraceptive use, MHT use, and family history or breast or ovarian cancer. In independent validation data (Nurses' Health Study cohort) the breast and ovarian cancer models were well calibrated; expected to observed cancer ratios were 1.00 (95% confidence interval [CI]: 0.96–1.04) for breast cancer and 1.08 (95% CI: 0.97–1.19) for ovarian cancer. The number of endometrial cancers was significantly overestimated, expected/observed = 1.20 (95% CI: 1.11–1.29). The areas under the receiver operating characteristic curves (AUCs; discriminatory power) were 0.58 (95% CI: 0.57–0.59), 0.59 (95% CI: 0.56–0.63), and 0.68 (95% CI: 0.66–0.70) for the breast, ovarian, and endometrial models, respectively.
Conclusions
These models predict absolute risks for breast, endometrial, and ovarian cancers from easily obtainable risk factors and may assist in clinical decision-making. Limitations are the modest discriminatory ability of the breast and ovarian models and that these models may not generalize to women of other races.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 2008, just three types of cancer accounted for 10% of global cancer-related deaths. That year, about 460,000 women died from breast cancer (the most frequently diagnosed cancer among women and the fifth most common cause of cancer-related death). Another 140,000 women died from ovarian cancer, and 74,000 died from endometrial (womb) cancer (the 14th and 20th most common causes of cancer-related death, respectively). Although these three cancers originate in different tissues, they nevertheless share many risk factors. For example, current age, age at menarche (first period), and parity (the number of children a woman has had) are all strongly associated with breast, ovarian, and endometrial cancer risk. Because these cancers share many hormonal and epidemiological risk factors, a woman with a high breast cancer risk is also likely to have an above-average risk of developing ovarian or endometrial cancer.
Why Was This Study Done?
Several statistical models (for example, the Breast Cancer Risk Assessment Tool) have been developed that estimate a woman's absolute risk (probability) of developing breast cancer over the next few years or over her lifetime. Absolute risk prediction models are useful in the design of cancer prevention trials and can also help women make informed decisions about cancer prevention and treatment options. For example, a woman at high risk of breast cancer might decide to take tamoxifen for breast cancer prevention, but ideally she needs to know her absolute endometrial cancer risk before doing so because tamoxifen increases the risk of this cancer. Similarly, knowledge of her ovarian cancer risk might influence a woman's decision regarding prophylactic removal of her ovaries to reduce her breast cancer risk. There are few absolute risk prediction models for ovarian cancer, and none for endometrial cancer, so here the researchers develop models to predict the risk of these cancers and of breast cancer.
What Did the Researchers Do and Find?
Absolute risk prediction models are constructed by combining estimates for risk factors from cohorts with population-based incidence rates from cancer registries. Models are validated in an independent cohort by testing their ability to identify people with the disease in an independent cohort and their ability to predict the observed numbers of incident cases. The researchers used data on white, non-Hispanic women aged 50 years or older that were collected during two large prospective US cohort studies of cancer screening and of diet and health, and US cancer incidence and mortality rates provided by the Surveillance, Epidemiology, and End Results Program to build their models. The models all included parity as a risk factor, as well as other factors. The model for endometrial cancer, for example, also included menopausal status, age at menopause, body mass index (an indicator of the amount of body fat), oral contraceptive use, menopausal hormone therapy use, and an interaction term between menopausal hormone therapy use and body mass index. Individual women's risk for endometrial cancer calculated using this model ranged from 1.22% to 17.8% over the next 20 years depending on their exposure to various risk factors. Validation of the models using data from the US Nurses' Health Study indicated that the endometrial cancer model overestimated the risk of endometrial cancer but that the breast and ovarian cancer models were well calibrated—the predicted and observed risks for these cancers in the validation cohort agreed closely. Finally, the discriminatory power of the models (a measure of how well a model separates people who have a disease from people who do not have the disease) was modest for the breast and ovarian cancer models but somewhat better for the endometrial cancer model.
What Do These Findings Mean?
These findings show that breast, ovarian, and endometrial cancer can all be predicted using information on known risk factors for these cancers that is easily obtainable. Because these models were constructed and validated using data from white, non-Hispanic women aged 50 years or older, they may not accurately predict absolute risk for these cancers for women of other races or ethnicities. Moreover, the modest discriminatory power of the breast and ovarian cancer models means they cannot be used to decide which women should be routinely screened for these cancers. Importantly, however, these well-calibrated models should provide realistic information about an individual's risk of developing breast, ovarian, or endometrial cancer that can be used in clinical decision-making and that may assist in the identification of potential participants for research studies.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001492.
This study is further discussed in a PLOS Medicine Perspective by Lars Holmberg and Andrew Vickers
The US National Cancer Institute provides comprehensive information about cancer (in English and Spanish), including detailed information about breast cancer, ovarian cancer, and endometrial cancer;
Information on the Breast Cancer Risk Assessment Tool, the Surveillance, Epidemiology, and End Results Program, and on the prospective cohort study of screening and the diet and health study that provided the data used to build the models is also available on the NCI site
Cancer Research UK, a not-for-profit organization, provides information about cancer, including detailed information on breast cancer, ovarian cancer, and endometrial cancer
The UK National Health Service Choices website has information and personal stories about breast cancer, ovarian cancer, and endometrial cancer; the not-for-profit organization Healthtalkonline also provides personal stories about dealing with breast cancer and ovarian cancer
doi:10.1371/journal.pmed.1001492
PMCID: PMC3728034  PMID: 23935463
10.  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
11.  Ovarian Cancer and Body Size: Individual Participant Meta-Analysis Including 25,157 Women with Ovarian Cancer from 47 Epidemiological Studies 
PLoS Medicine  2012;9(4):e1001200.
A reanalysis of published and unpublished data from epidemiological studies examines the association between height, body mass index, and the risk of developing ovarian cancer.
Background
Only about half the studies that have collected information on the relevance of women's height and body mass index to their risk of developing ovarian cancer have published their results, and findings are inconsistent. Here, we bring together the worldwide evidence, published and unpublished, and describe these relationships.
Methods and Findings
Individual data on 25,157 women with ovarian cancer and 81,311 women without ovarian cancer from 47 epidemiological studies were collected, checked, and analysed centrally. Adjusted relative risks of ovarian cancer were calculated, by height and by body mass index.
Ovarian cancer risk increased significantly with height and with body mass index, except in studies using hospital controls. For other study designs, the relative risk of ovarian cancer per 5 cm increase in height was 1.07 (95% confidence interval [CI], 1.05–1.09; p<0.001); this relationship did not vary significantly by women's age, year of birth, education, age at menarche, parity, menopausal status, smoking, alcohol consumption, having had a hysterectomy, having first degree relatives with ovarian or breast cancer, use of oral contraceptives, or use of menopausal hormone therapy. For body mass index, there was significant heterogeneity (p<0.001) in the findings between ever-users and never-users of menopausal hormone therapy, but not by the 11 other factors listed above. The relative risk for ovarian cancer per 5 kg/m2 increase in body mass index was 1.10 (95% CI, 1.07–1.13; p<0.001) in never-users and 0.95 (95% CI, 0.92–0.99; p = 0.02) in ever-users of hormone therapy.
Conclusions
Ovarian cancer is associated with height and, among never-users of hormone therapy, with body mass index. In high-income countries, both height and body mass index have been increasing in birth cohorts now developing the disease. If all other relevant factors had remained constant, then these increases in height and weight would be associated with a 3% increase in ovarian cancer incidence per decade.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Cancer of the ovaries, usually referred to as ovarian cancer, is the fifth leading cause of cancer death in women, and, unfortunately, symptoms (such as abdominal pain and swelling) usually occur late in the disease process; fewer than one-third of ovarian cancers are detected before they have spread outside of the ovaries. There is no definitive evidence that screening reduces mortality from ovarian cancer, and given the poor prognosis of advanced ovarian cancer, there has been much research over recent years to increase understanding of this serious condition. There are recognized risk factors that increase the chance of developing ovarian cancer, such as increasing age, having fewer children, not having used oral contraceptives, and use of menopausal hormone therapy. Age and oral contraceptive use have by far the biggest impact on ovarian cancer risk.
Why Was This Study Done?
To date, there is no definitive information about the relevance of women's height, weight, and body mass index to their subsequent risk of developing ovarian cancer. There have been roughly 50 epidemiological studies of ovarian cancer, but only about half of these studies have published results on the association between body size and ovarian cancer risk, and so far, these findings have been inconsistent. Therefore, the researchers—an international collaboration of researchers studying ovarian cancer—re-analyzed the available epidemiological evidence to investigate the relationship between ovarian cancer risk and adult height, weight, and body mass index, and to examine the consistency of the findings across study designs.
What Did the Researchers Do and Find?
After an extensive literature search, the researchers identified 47 eligible studies that collected individual data on women's reproductive history, use of hormonal therapies, height, weight, and/or body mass index, and in which the principal investigators of each study accepted the invitation from the researchers to be involved in the re-analysis. The researchers combined data from the different studies. To ensure that women in one study were only directly compared with controls (similar women without ovarian cancer) in the same study, all analyses were routinely stratified by study, center within study, age, parity, use of oral contraceptives, use of hormonal therapy for menopause, and menopausal status or hysterectomy.
The 47 studies were conducted in 14 countries and comprised a total of 25,157 women with ovarian cancer (mostly from Europe and North America) and 81,311 women without ovarian cancer. The researchers found a significant increase in relative risk (1.07) of ovarian cancer per 5 cm increase in height. Furthermore, this risk did not vary depending on other studied factors—age, year of birth, education, age at menarche, parity, menopausal status, smoking, alcohol consumption, having had a hysterectomy, having first degree relatives with ovarian or breast cancer, use of oral contraceptives, or use of menopausal hormone therapy. However, the researchers found that for body mass index, the risks depended on whether women had ever taken menopausal hormone therapy: the relative risk for ovarian cancer per 5 kg/m2 increase in body mass index was 1.10 in women who had never taken menopausal hormone therapy but was only 0.95 in women who had previously taken menopausal hormone therapy.
What Do These Findings Mean?
These findings suggest that increasing height can be considered as a risk factor for ovarian cancer and that in women who have never taken menopausal hormone therapy, increased body mass index can be considered an additional risk factor. These findings have public health implications, especially in high-income countries, because the average height of women has increased by about 1 cm per decade and average body mass index has increased by about 1 kg/m2 per decade. The findings suggest an associated increase in ovarian cancer incidence of 3% per decade if all other factors relevant for ovarian cancer remain constant.
Additional Information
Please access these web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001200.
The following organizations give more information on ovarian cancer which may be of use to patients: MedicineNet, the US National Cancer Institute, Ovarian Cancer National Alliance, Macmillan Cancer Support
doi:10.1371/journal.pmed.1001200
PMCID: PMC3317899  PMID: 22606070
12.  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
13.  Hormonal contraception and risk of venous thromboembolism: national follow-up study 
Objective To assess the risk of venous thrombosis in current users of different types of hormonal contraception, focusing on regimen, oestrogen dose, type of progestogen, and route of administration.
Design National cohort study.
Setting Denmark, 1995-2005.
Participants Danish women aged 15-49 with no history of cardiovascular or malignant disease.
Main outcome measures Adjusted rate ratios for all first time deep venous thrombosis, portal thrombosis, thrombosis of caval vein, thrombosis of renal vein, unspecified deep vein thrombosis, and pulmonary embolism during the study period.
Results 10.4 million woman years were recorded, 3.3 million woman years in receipt of oral contraceptives. In total, 4213 venous thrombotic events were observed, 2045 in current users of oral contraceptives. The overall absolute risk of venous thrombosis per 10 000 woman years in non-users of oral contraceptives was 3.01 and in current users was 6.29. Compared with non-users of combined oral contraceptives the rate ratio of venous thrombembolism in current users decreased with duration of use (<1 year 4.17, 95% confidence interval 3.73 to 4.66, 1-4 years 2.98, 2.73 to 3.26, and >4 years 2.76, 2.53 to 3.02; P<0.001) and with decreasing dose of oestrogen. Compared with oral contraceptives containing levonorgestrel and with the same dose of oestrogen and length of use, the rate ratio for oral contraceptives with norethisterone was 0.98 (0.71 to 1.37), with norgestimate 1.19 (0.96 to 1.47), with desogestrel 1.82 (1.49 to 2.22), with gestodene 1.86 (1.59 to 2.18), with drospirenone 1.64 (1.27 to 2.10), and with cyproterone 1.88 (1.47 to 2.42). Compared with non-users of oral contraceptives, the rate ratio for venous thromboembolism in users of progestogen only oral contraceptives with levonorgestrel or norethisterone was 0.59 (0.33 to 1.03) or with 75 μg desogestrel was 1.12 (0.36 to 3.49), and for hormone releasing intrauterine devices was 0.90 (0.64 to 1.26).
Conclusion The risk of venous thrombosis in current users of combined oral contraceptives decreases with duration of use and decreasing oestrogen dose. For the same dose of oestrogen and the same length of use, oral contraceptives with desogestrel, gestodene, or drospirenone were associated with a significantly higher risk of venous thrombosis than oral contraceptives with levonorgestrel. Progestogen only pills and hormone releasing intrauterine devices were not associated with any increased risk of venous thrombosis.
doi:10.1136/bmj.b2890
PMCID: PMC2726928  PMID: 19679613
14.  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
15.  Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data Meta-analysis 
PLoS Medicine  2015;12(1):e1001778.
In a meta-analysis of individual participant data, Charles Morrison and colleagues explore the association between hormonal contraception use and risk of HIV infection in sub-Saharan Africa.
Background
Observational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC.
Methods and Findings
Eligible studies measured HC exposure and incident HIV infection prospectively using standardized measures, enrolled women aged 15–49 y, recorded ≥15 incident HIV infections, and measured prespecified covariates. Our primary analysis estimated the adjusted hazard ratio (aHR) using two-stage random effects meta-analysis, controlling for region, marital status, age, number of sex partners, and condom use. We included 18 studies, including 37,124 women (43,613 woman-years) and 1,830 incident HIV infections. Relative to no HC use, the aHR for HIV acquisition was 1.50 (95% CI 1.24–1.83) for DMPA use, 1.24 (95% CI 0.84–1.82) for NET-EN use, and 1.03 (95% CI 0.88–1.20) for COC use. Between-study heterogeneity was mild (I2 < 50%). DMPA use was associated with increased HIV acquisition compared with COC use (aHR 1.43, 95% CI 1.23–1.67) and NET-EN use (aHR 1.32, 95% CI 1.08–1.61). Effect estimates were attenuated for studies at lower risk of methodological bias (compared with no HC use, aHR for DMPA use 1.22, 95% CI 0.99–1.50; for NET-EN use 0.67, 95% CI 0.47–0.96; and for COC use 0.91, 95% CI 0.73–1.41) compared to those at higher risk of bias (pinteraction = 0.003). Neither age nor herpes simplex virus type 2 infection status modified the HC–HIV relationship.
Conclusions
This IPD meta-analysis found no evidence that COC or NET-EN use increases women’s risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.
Editors’ Summary
Background
AIDS has killed about 36 million people since the first recorded case of the disease in 1981. About 35 million people (including 25 million living in sub-Saharan Africa) are currently infected with HIV, the virus that causes AIDS, and every year, another 2.3 million people become newly infected with HIV. At the beginning of the epidemic, more men than women were infected with HIV. Now, about half of all adults infected with HIV are women. In 2013, almost 60% of all new HIV infections among young people aged 15–24 years occurred among women, and it is estimated that, worldwide, 50 young women are newly infected with HIV every hour. Most women become infected with HIV through unprotected intercourse with an infected male partner—biologically, women are twice as likely to become infected through unprotected intercourse as men. A woman’s risk of becoming infected with HIV can be reduced by abstaining from sex, by having one or a few partners, and by always using condoms.
Why Was This Study Done?
Women and societies both benefit from effective contraception. When contraception is available, women can avoid unintended pregnancies, fewer women and babies die during pregnancy and childbirth, and maternal and infant health improves. However, some (but not all) observational studies (investigations that measure associations between the characteristics of participants and their subsequent development of specific diseases) have reported an association between hormonal contraceptive use and an increased risk of HIV acquisition by women. So, does hormonal contraception increase the risk of HIV acquisition among women or not? Here, to investigate this question, the researchers undertake an individual participant data meta-analysis of studies conducted in sub-Saharan Africa (a region where both HIV infection and unintended pregnancies are common) to compare the incidence of HIV infection (the number of new cases in a population during a given time period) among women using and not using hormonal contraception. Meta-analysis is a statistical method that combines the results of several studies; an individual participant data meta-analysis combines the data recorded for each individual involved in the studies rather than the aggregated results from each study.
What Did the Researchers Do and Find?
The researchers included 18 studies that measured hormonal contraceptive use and incident HIV infection among women aged 15–49 years living in sub-Saharan Africa in their meta-analysis. More than 37,000 women took part in these studies, and 1,830 became newly infected with HIV. Half of the women were not using hormonal contraception, a quarter were using depot-medroxyprogesterone acetate (DMPA; an injectable hormonal contraceptive), and the remainder were using combined oral contraceptives (COCs) or norethisterone enanthate (NET-EN, another injectable contraceptive). After adjustment for other factors likely to influence HIV acquisition (for example, condom use), women using DMPA had a 1.5-fold increased risk of HIV acquisition compared to women not using hormonal contraception. There was a slightly increased risk of HIV acquisition among women using NET-EN compared to women not using hormonal contraception, but this increase was not statistically significant (it may have happened by chance alone). There was no increased risk of HIV acquisition associated with COC use. DMPA use was associated with a 1.43-fold and 1.32-fold increased risk of HIV acquisition compared with COC and NET-EN use, respectively. Finally, neither age nor herpes simplex virus 2 infection status modified the effect of hormonal contraceptive use on HIV acquisition.
What Do These Findings Mean?
The findings of this individual patient data meta-analysis provide no evidence that COC or NET-EN use increases a woman’s risk of acquiring HIV, but add to the evidence suggesting that DMPA use increases the risk of HIV acquisition. These findings are likely to be more accurate than those of previous meta-analyses that used aggregated data but are likely to be limited by the quality, design, and representativeness of the studies included in the analysis. These findings nevertheless highlight the need to develop additional safe and effective contraceptive options for women at risk of HIV, particularly those living in sub-Saharan Africa, where although contraceptive use is generally low, DMPA is the most widely used hormonal contraceptive. In addition, these findings highlight the need to initiate randomized controlled trials to provide more definitive evidence of the effects of hormonal contraception, particularly DMPA, on HIV risk.
Additional Information.
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001778.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment, including personal stories about living with HIV/AIDS and a news report on this meta-analysis
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including detailed information on women, HIV, and AIDS, and on HIV and AIDS in South Africa (in English and Spanish); personal stories of women living with HIV are available
The World Health Organization provides information on all aspects of HIV/AIDS (in several languages); information about a 2012 WHO technical consultation about hormonal contraception and HIV
The 2013 UNAIDS World AIDS Day report provides up-to-date information about the AIDS epidemic and efforts to halt it; UNAIDS also provides information about HIV and hormonal contraception
doi:10.1371/journal.pmed.1001778
PMCID: PMC4303292  PMID: 25612136
16.  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
17.  Benefits and risks of hormonal contraception for women 
Scientific background
A large proportion of women of reproductive age in Germany use various methods of pregnancy prevention (contraception), among them various hormone-based methods. Hormonal contraceptives may be divided into combined estrogen-progestogen contraceptives (pills, skin patches, vaginal rings), progestogen-only contraceptives (pills, injections, implants, hormone spirals) and emergency contraceptives.
Research questions
The evaluation addressed the question of benefits and risks of hormonal contraceptives, their economic effects as well as their ethical-social and legal implications.
Methods
A systematic literature search was conducted in April 2006 starting from 2000. The evaluation is primarily based on systematic reviews.
Results
In perfect use, all hormonal contraceptives excluding emergency contraceptives proved to be the most effective reversible contraceptive methods (rate of unintended pregnancies 0.05% to 0.3%). However, the typical use of oral contraceptives, injections, skin patches, and vaginal rings, which also considers possible application errors, showed a lower contraceptive efficacy (rate of unintended pregnancies 3% to 8%). It was lower than that of copper spirals.
The risk of venous thromboembolism increased three to six times in users of hormonal contraceptives, the risks of stroke and myocardial infarction two to three times. The risk declined after discontinuation of use. The effects were estrogen-dose and progestogen-type dependent.
The use of hormonal contraceptives showed a relative risk of ovarian and endometrial carcinomas of approximately 0.5 or 0.7, of breast and cervical cancer of approximately 1.2 or 1.6. The effect remained several years after discontinuation of use. The results concerning hepatocellular carcinoma suggested a carcinogenic effect.
In women with acne, an improvement due to use of hormonal contraceptives was proven. Cervical chlamydial infections were more frequent in users of hormonal contraception. Headache appeared mostly only at the beginning of the use of combined oral contraceptives. Progestogen-only contraceptives worsened the results of the glucose tolerance test. A review of low evidence reported further risks of hormonal contraceptives (concerning menstrual problems, ovarian cysts, bone density, thyroid diseases and rheumatoid arthritis) as well as further benefits (concerning blood pressure and Crohn’s disease).
Hormonal spirals were shown to be more effective than spirals which do not release hormones. In emergency contraception, Levonorgestrel was more effective than the Yuzpe method. Most other proven differences between hormonal contraceptives were related to menstrual problems.
After spirals with or without hormone release, the other hormonal contraceptives were shown in typical use to be the second most cost-effective reversible methods of contraception.
Discussion
The addressed questions could be answered only on relatively low evidence level, partly only for applications with estrogen doses which are not used in Germany any more. The transferability of the results of the analysed primary health-economics studies on the current situation in Germany is limited (clinical assumptions from out-dated information sources of low evidence levels, cost assumptions from the American health system).
Conclusions
In perfect use, hormonal contraceptives have to be classified as the most effective reversible contraceptive methods. For the individual decision concerning the use of hormonal contraception, benefits should be related to the additional risks. Alternative methods such as spirals should be prioritised if perfect use seems to be impossible. In this case, spirals are also preferable from health-economics perspective. No ethical-social or legal conclusions can be derived from the available data.
PMCID: PMC3011324  PMID: 21289940
18.  Oral contraceptives and cancers of the breast and of the female genital tract. Interim results from a case-control study. 
British Journal of Cancer  1986;54(2):311-317.
We analysed data from a case-control investigation conducted in Milan, Northern Italy, to evaluate the relation between the use of combination oral contraceptives and the risk of cancers of the breast, ovary, endometrium and cervix uteri. For the present analysis, 776 cases of histologically confirmed breast cancer, 406 of epithelial ovarian cancer and 170 of endometrial cancer aged under 60 were compared with a group of 1,282 subjects below age 60 admitted for a spectrum of acute conditions apparently unrelated to oral contraceptive use or to any of the known or potential risk factors for the diseases under study. Likewise, 225 cases of invasive cervical cancer were compared with 225 age-matched inpatient controls, and 202 cases of cervical intra-epithelial neoplasia with 202 outpatient controls identified in the same screening clinics. The age-adjusted relative risk estimates for ever vs. never use of combination oral contraceptives were 1.04 (95% confidence interval (CI) 0.73-1.37) for breast cancer, 0.68 (95% CI = 0.48-0.97) for epithelial ovarian cancer, 0.50 (95% CI = 0.23-1.12) for endometrial cancer, 1.49 (95% CI = 0.88-2.55) for cervical cancer and 0.77 (95% CI = 0.50-1.18) for cervical intra-epithelial neoplasia. The risk of ovarian cancer decreased and that of invasive cervical cancer increased with longer duration of use. Neither duration of oral contraceptive use nor time since first or last use significantly altered a user's risk of other neoplasms considered. Likewise, analysis of sub-groups of age, parity or other potentially important covariates did not show any important interaction, and allowance for them by means of logistic regression did not materially modify any of the results. These data confirm that combination oral contraceptives confer some protection against ovarian and endometrial cancers but may increase the risk of invasive cervical cancer if used for several years, and indicate that the past or current pattern of oral contraceptive use in Italy is unlikely materially to affect the risk of breast cancer.
PMCID: PMC2001528  PMID: 3741766
19.  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
20.  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
21.  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
22.  Oral contraceptives and breast cancer: final report of an epidemiological study. 
British Journal of Cancer  1983;47(4):455-462.
During 1968-1980, 1176 women aged 16-50 years with newly diagnosed breast cancer and a like number of matched controls were interviewed at 9 teaching hospitals in London and Oxford and asked about their use of oral contraceptives. The results were reassuring. A few statistically significant differences in oral contraceptive use were found between the breast cancer and control groups, but the data were subdivided in many ways so that some "significant" differences would have been expected through the play of chance alone. Certainly no patterns of risk emerged which would suggest that any of the associations were causal. It must be stressed, however, that the data are still sparse in some important subcategories--for example, only small numbers of both cases and controls had prolonged oral contraceptive use before their first term pregnancy. For this reason, it is important that information on the possible relationship between pill use and breast cancer should continue to be collected. Women who had never used oral contraceptives presented with appreciably more advanced tumours than those who had been using oral contraceptives during the year before detection of cancer, while past users were in an intermediate position. These differences in staging were reflected in the pattern of survival. Possible explanations for these observations include "surveillance bias" among oral contraceptive users leading to earlier diagnosis and a beneficial biological effect of oral contraceptives on tumour growth and spread. Women with breast cancer reported never having used any method of contraception and heavy cigarette smoking (greater than or equal to 15 per day) significantly less often than controls. We could find no obvious explanation for the former observation, but suspect that the latter reflects the unrepresentative smoking habits of our hospital controls rather than a protective effect of smoking against breast cancer.
PMCID: PMC2011321  PMID: 6849791
23.  Use of Oral Contraceptives, Intrauterine Devices and Tubal Sterilization and Cancer Risk in a Large Prospective Study, from 1996 to 2006 
The association of contraceptive methods, including oral contraceptives (OC), intrauterine devices (IUD) and tubal sterilization (TS), with overall and site-specific cancer were prospectively investigated in a cohort of 66,661 Chinese women in Shanghai; 76.7% of whom used contraception. During a median follow up time of 7.5 years, 2,250 women were diagnosed with cancer. Ever-use of any contraceptive method was not associated with overall cancer risk [adjusted hazard ratio (HRadj)=1.02, 95% CI 0.92–1.12]. Use of any contraceptive method was associated with increased risk of rectal cancer (HRadj=1.68, 95% CI 1.08–2.62) and reduced risk of thyroid cancer (HRadj=0.63, 95% CI 0.38–1.04). Risk of gallbladder cancer increased with ever use of OC (HRadj=2.38, 95% CI 1.26–4.49). IUD use was associated with a possible reduced risk of thyroid cancer (HRadj=0.64, 95% CI 0.38–1.07). Longer duration of IUD use decreased risk for breast, thyroid, and lung cancers. Ever having a TS was associated with increased uterine body cancer (HRadj=2.50, 95% CI 1.47–4.25) and decreased risk of stomach cancer (HRadj =0.59, 95% CI 0.39–0.91). We did not find any contraceptive method to be related to the risk of ovarian cancer but the analyses were based on few events. Although chance findings are a likely explanation for some of the associations found in our study, these findings may suggest that various contraceptive methods or reproductive patterns may play a role in the etiology of cancer.
doi:10.1002/ijc.24232
PMCID: PMC2666967  PMID: 19170208
intrauterine device; neoplasms; oral contraceptives; tubal sterilization; China
24.  Different combined oral contraceptives and the risk of venous thrombosis: systematic review and network meta-analysis 
Objective To provide a comprehensive overview of the risk of venous thrombosis in women using different combined oral contraceptives.
Design Systematic review and network meta-analysis.
Data sources PubMed, Embase, Web of Science, Cochrane, Cumulative Index to Nursing and Allied Health Literature, Academic Search Premier, and ScienceDirect up to 22 April 2013.
Review methods Observational studies that assessed the effect of combined oral contraceptives on venous thrombosis in healthy women. The primary outcome of interest was a fatal or non-fatal first event of venous thrombosis with the main focus on deep venous thrombosis or pulmonary embolism. Publications with at least 10 events in total were eligible. The network meta-analysis was performed using an extension of frequentist random effects models for mixed multiple treatment comparisons. Unadjusted relative risks with 95% confidence intervals were reported. The requirement for crude numbers did not allow adjustment for potential confounding variables.
Results 3110 publications were retrieved through a search strategy; 25 publications reporting on 26 studies were included. Incidence of venous thrombosis in non-users from two included cohorts was 1.9 and 3.7 per 10 000 woman years, in line with previously reported incidences of 1-6 per 10 000 woman years. Use of combined oral contraceptives increased the risk of venous thrombosis compared with non-use (relative risk 3.5, 95% confidence interval 2.9 to 4.3). The relative risk of venous thrombosis for combined oral contraceptives with 30-35 µg ethinylestradiol and gestodene, desogestrel, cyproterone acetate, or drospirenone were similar and about 50-80% higher than for combined oral contraceptives with levonorgestrel. A dose related effect of ethinylestradiol was observed for gestodene, desogestrel, and levonorgestrel, with higher doses being associated with higher thrombosis risk.
Conclusion All combined oral contraceptives investigated in this analysis were associated with an increased risk of venous thrombosis. The effect size depended both on the progestogen used and the dose of ethinylestradiol.
doi:10.1136/bmj.f5298
PMCID: PMC3771677  PMID: 24030561
25.  General practitioner notes as a source of information for case-control studies in young women. UK National Case-Control Study Group. 
STUDY OBJECTIVE--The UK National Case-Control Study was carried out to investigate the relationship between oral contraceptive use and breast cancer risk. This study investigates whether general practitioner notes could be used as the sole data source for epidemiological studies of young women and what the effect would be on non-response and recall bias. DESIGN--Case-control study with data on gynaecological, obstetric, and contraceptive history collected at interview and from general practitioners' notes. Information from these two sources was compared. SETTING--This was a population-based study. PARTICIPANTS--Altogether 755 women with breast cancer aged under 36 years at diagnosis, each with an age-matched control, participated in the study. Response rates at interview were 72% and 89% for cases and controls but GP data were available for 90% of the 1049 case and first-selected control pairs. MAIN RESULTS--There was generally good agreement between the two data sources with respect to obstetric history and gynaecological procedures (hysterectomy, oophorectomy, and tubal ligation). The use of intra-uterine devices, or diaphragm, and partner's vasectomy were not reliably recorded in the GP's notes. The overall results of the UK study would have been qualitatively the same with respect to the relationship between oral contraceptive use and breast cancer risk if GP notes only had been used, in spite of the fact that only about half of all oral contraceptive usage was recorded in the notes. Response rates would have been higher, recall bias eliminated, and the cost of the study halved. CONCLUSIONS--When planning case-control studies in young women, the possibility of using GP notes as the primary data source should be considered. Lack of data on potential confounding factors is a possible drawback to such use. The practice of destroying GP's notes shortly after the death of patients seriously restricts the possibility of using these notes when studying rapidly fatal conditions.
PMCID: PMC1059901  PMID: 8138777

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