Mortality among oral contraceptive users: 20 year follow up of women in a cohort study.

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.     

Breast cancer and oral contraceptives: findings in Oxford-Family Planning Association contraceptive study.

Among the 17 032 women taking part in the Oxford-Family Planning Association contraceptive study, 72 were first diagnosed as having breast cancer between the date they were admitted to the study and 1 September 1980. The relative risk of developing the disease in women who had used oral contraceptives in comparison with those who had never used them was estimated to be 0.96 (95% confidence limits 0.59 to 1.63). Among women aged under 35 years, the corresponding relative risk (based on only 14 women with breast cancer) was estimated to be 0.61. No relation was apparent between the risk of developing breast cancer and duration of oral-contraceptive use or interval since first oral-contraceptive use in any age group. The data in this study are thus reassuring; but observations based on women with long-term use of oral contraceptives, especially those starting to use the preparations at an early age, are few.     

Vitamin A,Pregnancy, and Oral Contraceptives

It has been shown that women receiving oral contraceptives have increased levels of serum vitamin A. High vitamin A levels may constitute a teratogenic hazard and it has been suggested that women who conceive soon after discontinuing oral contraceptive therapy may be especially at risk to this hazard.We have confirmed a significant increase in vitamin A levels in women taking oral contraceptives. During early pregnancy there is no significant difference in vitamin A levels between women who have recently been taking oral contraceptives and those who have not. We have been unable to show that either taking oral contraceptives shortly before pregnancy or a high vitamin A level during the first trimester of pregnancy, comparable to that of a woman taking oral contraceptives, has any detrimental effect on the outcome of pregnancy. It seems unlikely that women who conceive soon after discontinuing oral contraception run any teratogenic risk from increased vitamin A levels.     

Oral contraceptive use in older women and fatal myocardial infarction.

A previous study of women who had died from myocardial infarction and of a control group of women matched with them for age suggested a fivefold increase in the risk of death from myocardial infarction among users of oral contraceptive aged 40-44 years compared with women not using such preparations. Only a small proportion of women in the infarction and control groups had used oral contraceptives, however, so the margin of error was wide. We therefore investigated a further 54 women in this age group who died from myocardial infarction and compared their oral contraceptive histories with those of age-matched, living controls. Combination of the findings from the present investigation with the previous results have enabled a revised estimate of a threefold increase in risk to be made. Although this risk estimate is similar to that previously shown for a younger age group, the total mortality attributable to complications associated with the use of oral contraceptives remained considerably greater among women over the age of 40.     

Ovarian neoplasms,functional ovarian cysts,and oral contraceptives.

The incidence of ovarian neoplasms and functional ovarian cysts diagnosed at laparotomy or laparoscopy among the 17,000 women taking part in the Oxford Family Planning Association contraceptive study was investigated. Epithelial cancer of the ovary was only 25% as common among those who had ever taken oral contraceptives as those who had never done so (95% confidence interval 8% to 67%). There was little evidence of any important association between use of oral contraceptives and benign teratoma or cystadenoma. Functional cysts of the ovary occurred much less commonly in women who had recently (in the six months preceding diagnosis) taken combined oral contraceptives (but not in those who had taken progestogen only oral contraceptives) than in those who had never taken oral contraceptives or had taken them in the past. This protective effect was more pronounced for corpus luteum cysts (78% reduction; 95% confidence interval 47% to 93%) than for follicular cysts (49% reduction; 95% confidence interval 20% to 70%). It is estimated that about 28 (95% confidence interval 16 to 35) operations for functional ovarian cysts are avoided among every 100,000 women who take oral contraceptives each year.     

Return of fertility after use of the injectable contraceptive Depo Provera: up-dated data analysis

796 Thai women who stopped using the long-acting injectable contraceptive depot medroxyprogesterone acetate (DMPA, Depo Povera), 437 women who stopped using oral contraceptives and 125 women who had an IUD removed to have a planned pregnancy, were followed up to ascertain the delay to conception after the end of contraception and to determine the proportion of women who did not conceive in the 4 years after discontinuation. The median delay to conception was 5.5 months plus the estimated duration of the effect of the last injection of DMPA, 3 months for oral contraceptives and 4.5 months after discontinuing the IUD. The proportion of women who did not conceive within 9 months after discontinuation of DMPA is similar to that of ex-IUD users, and by 3 years to that of the ex-pill sample. There is no evidence to suggest that prolonged use of DMPA increases the delay to conception. The return of fertility among never pregnant ex-users resembled that of ever pregnant ex-users. There were comparable proportons of live births among ex-DMPA users and ex-pill users and both of these showed higher proportions of live-births than ex-IUD users. There was no evidence to suggest that previous use of DMPA had any significant adverse effect on the outcome of pregnancy of the subsequent births. This study did not show any association between infertility and the previous use of DMPA or other contraceptives.     

Valued Outcomes in the Selection of a Contraceptive Method

The perceptions and values of a sample of 106 women towards four contraceptive methods (oral contraceptives, intrauterine device, diaphragm and foam-and-condoms) were evaluated in the light of 24 identified issues of concern. The choice of a contraceptive method appears to represent a trade-off among negatively valued outcomes—the “best” method being least likely to incur undesirable consequences.     

Oral Contraceptives and Breast Neoplasia: A Retrospective Study

Between 1 December 1968 and 31 December 1971 345 women aged 16-39 years with a lump in the breast (90 malignant and 255 benign) were interviewed at five London teaching hospitals together with 347 matched controls suffering from acute medical or surgical conditions or admitted to hospital for routine elective surgery. Questions were asked about each patient''s medical, obstetric, menstrual, contraceptive, and social histories.The data do not suggest that the use of oral contraceptives is related in any way to the risk of breast cancer but provide some evidence that the preparations may actually protect against benign breast disease. This protective effect is largely confined to women who continue to use oral contraceptives and have used them altogether for more than two years. Such women appear to have only about 25% as great a risk of being admitted to hospital for a breast biopsy as women who have never used oral contraceptives at all.     

Blood pressure and contraceptive use

In a survey of 461 women routinely attending family planning clinics those taking oral contraceptives had significantly higher mean systolic and diastolic blood pressures than those using non-hormonal contraception. There appeared to be a dose-response relation of blood pressure to the progestogen component of two oral contraceptives with an identical 30 μg ethinyloestradiol component. This supports the idea that the progestogen as well as the oestrogen component has an aetiological role in the rise in blood pressure. There was a significant correlation of blood pressure with duration of current use of oral contraceptive but not with total duration of use. There was also a significant negative correlation of blood pressure with time since oral contraceptives were last taken, and women who had stopped using oral contraceptives over a month previously had similar blood pressures to those who had never taken them. In women taking oral contraceptives those who had either a history of hypertension in pregnancy or a family history of hypertension had significantly higher mean blood pressures than those who did not. Both systolic and diastolic blood pressures correlated independently with weight and body mass index, but controlling for the effect of this and age did not affect the above relations. No significant differences in mean blood pressures were found between different ethnic groups, and there was no relation of blood pressure to reported marital state, social class, parity, smoking, or alcohol use.Any oral contraceptive that has a less adverse effect on blood pressure has implications for general prescribing policy; thus even small differences in the progestogen contents of low-dose oestrogen pills may be important.     

Risk of venous thromboembolism in women with polycystic ovary syndrome: a population-based matched cohort analysis

Background:

There is an increased risk of venous thromboembolism among women taking oral contraceptives. However, whether there is an additional risk among women with polycystic ovary syndrome (PCOS) is unknown.

Methods:

We developed a population-based cohort from the IMS LifeLink Health Plan Claims Database, which includes managed care organizations in the United States. Women aged 18–46 years taking combined oral contraceptives and who had a claim for PCOS (n = 43 506) were matched, based on a propensity score, to control women (n = 43 506) taking oral contraceptives. Venous thromboembolism was defined using administrative coding and use of anticoagulation. We used Cox proportional hazards models to assess the relative risk (RR) of venous thromboembolism among users of combined oral contraceptives with and without PCOS.

Results:

The incidence of venous thromboembolism among women with PCOS was 23.7/10 000 person-years, while that for matched controls was 10.9/10 000 person-years. Women with PCOS taking combined oral contraceptives had an RR for venous thromboembolism of 2.14 (95% confidence interval [CI] 1.41–3.24) compared with other contraceptive users. The incidence of venous thromboembolism was 6.3/10 000 person-years among women with PCOS not taking oral contraceptives; the incidence was 4.1/10 000 person-years among matched controls. The RR of venous thromboembolism among women with PCOS not taking oral contraceptives was 1.55 (95% CI 1.10–2.19).

Interpretation:

We found a 2-fold increased risk of venous thromboembolism among women with PCOS who were taking combined oral contraceptives and a 1.5-fold increased risk among women with PCOS not taking oral contraceptives. Physicians should consider the increased risk of venous thromboembolism when prescribing contraceptive therapy to women with PCOS.Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age. The National Institutes of Health criteria estimates its prevalence in the United States to be between 6% and 10%, while the Rotterdam criteria estimates the prevalence to be as high as 15%.¹ Although its cause is not entirely known, the diagnostic criteria include oligo- or anovulation, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovaries.² Women often present with clinical manifestations of high androgen levels, including facial hair growth (hirsutism), acne vulgaris and hair loss on the scalp. Previous studies reported the prevalence of impaired glucose tolerance to be 31.1%–35.2% and the prevalence of type 2 diabetes to be 7.5%–9.8% among women with PCOS.^3,4 A recent consensus workshop reported that the prevalence of several known risk factors for cardiovascular disease (hypertension, diabetes, abdominal obesity, psychological factors, smoking, altered apoA1/ApoB ratios) are doubled among women with PCOS compared with matched controls.^1,5Combined oral contraceptives are the mainstay treatment for PCOS. However, they are also known to elevate the risk of venous thromboembolism and cardiovascular disease.⁶ To date, contraceptive studies involving women with PCOS have focused mainly on efficacy, evaluating the effect of combined oral contraceptives on the reduction of hirsutism and hyperandrogenism.^7,8 Two studies assessed the metabolic effects of combined oral contraceptives in PCOS, but these studies had small sample sizes and could not evaluate for cardiovascular events.^9,10Although women with PCOS have an increase in both cardiovascular risk factors and subclinical cardiovascular disease,¹¹ recent guidelines have concluded there are no data in the literature assessing the association between the use of oral contraceptives and cardiovascular disease among women with PCOS.² Because combined oral contraceptives are the mainstay treatment, our objective was to determine whether women with PCOS taking combined oral contraceptives have a greater risk of venous thromboembolism compared with other contraceptive users. We also examined whether women with PCOS not taking oral contraceptives had an increased risk of venous thromboembolism compared with the general population.     

Oral Contraceptives,Depression, and Libido

Depression, headaches, and libido were rated in 272 women before starting a contraceptive method and at intervals during the first year of use—54 were fitted with an intrauterine device (I.U.D.) and 218 used one of three oral contraceptives. Side effects caused 25% of the oral contraceptive group and 13% of the I.U.D. group to stop the method. Depression, headaches, and loss of libido were the most common reasons for stopping oral contraceptives and breakthrough bleeding was the most common reason for stopping the I.U.D.The group of women who stopped or changed their oral contraceptives during the survey were compared with the group who remained on the same oral contraceptive throughout. The former had higher mean depression and neuroticism scores at the first clinic visit and contained more women with a history of premenstrual weepiness, depression during pregnancy, outpatient psychiatric treatment, and treatment with antidepressants. Changes in the depression, headache, and libido ratings throughout the survey are presented.     

The return of the pharmaceutical industry to the market of contraception

In the 1980s and 1990s, the litigious climate in the US had a catastrophic effect on sales of many major contraceptives. Although oral contraceptives escaped controversy, the intrauterine device (IUD) and Norplant(R) were two targets of damaging litigation. The IUD was withdrawn from the market in 1985. Since 1994 when the attacks began against Norplant, its US sales have dramatically declined, even though no fault has been found in the method or its development. In general, pharmaceutical companies were extremely hesitant to develop new contraceptives during this period. The bleak outlook, however, began to shift in the late 1990s, as fertility rates began to decrease worldwide and contraceptive users increased. By 2025, 2500 million women will comprise the customer base for contraception. Global pharmaceutical companies are now participating in expanding markets overseas and have launched and continue to develop a range of new long-term reversible, and highly effective, contraceptive products outside the traditional oral contraceptive field. Two new contraceptives on the way to the US market are: Mirena, a levonorgestrel-releasing intrauterine system manufactured by Schering-Leiras; and Implanon, a single implant system manufactured by Organon of the Netherlands. Other birth control methods soon to be launched include: emergency contraceptives, the contraceptive patch, monthly contraceptive injections, mifepristone for medical abortion, and modified oral contraceptives.     

Depressive Symptoms and Oral Contraceptives

Of 261 women who completed a self-rating scale for measuring depression, 168 were taking oral contraceptives and 93 were using physical methods of contraception. Of the group of women taking oral contraceptives 6·6% were more severely depressed than any of the control group. There was a significant variation in the depth of depression related to the day of the menstrual cycle in the control group. This association was not found in the oral contraceptive group, where premenstrual depression was limited to the one or two days preceding menstruation.Women taking a contraceptive containing lynoestrenol 2·5 mg. and mestranol 0·075 mg. showed a significantly increased incidence of pessimism, feelings of dissatisfaction, crying, and tension, compared with women taking other oral contraceptives and the control group.     

Actinomyces-like organisms in cervical smears from women using intrauterine contraceptive devices.

Cervical smears from 293 users of intrauterine contraceptive devices attending family planning clinics in East Fife, Dundee, and Angus were stained by Papanicolaou and Gram''s methods and examined for actinomyces-like organisms. Of the 128 women using plastic devices, 40 gave smears positive for these organisms. In contrast only two positive smears were obtained from the 165 women using devices containing copper and none from a control group of 300 women taking oral contraceptives. Colonisation was more common in women whose plastic devices had been in situ for over two years. Correlations between the presence of these organisms and recorded incidences of pain and both clinical and cytological evidence of inflammation of the lower genital tract were highly significant (p = 0.00001, p < 0.00001, and p < 0.00001 respectively). The results suggest that plastic intrauterine contraceptive devices predispose to colonisation by actinomyces-like organisms, particularly after long-term use. Hence if the apparently bacteriostatic action of copper devices is confirmed these should probably be more widely used.     

Oral contraceptives and myocardial infarction: results of the MICA case-control study

ObjectivesTo determine the association between myocardial infarction and use of different types of oral contraception in young women.DesignCommunity based case-control study. Data from interviews and general practice records.SettingEngland, Scotland, and Wales.ParticipantsCases (n=448) were recruited from women aged between 16 and 44 who had suffered an incident myocardial infarction between 1 October 1993 and 16 October 1995. Controls (n=1728) were women without a diagnosis of myocardial infarction matched for age and general practice.ResultsThe adjusted odds ratio for myocardial infarction was 1.40 (95% confidence interval 0.78 to 2.52) for all combined oral contraceptive users, 1.10 (0.52 to 2.30) for second generation users, and 1.96 (0.87 to 4.39) for third generation users. Subgroup analysis by progestagen content did not show any significant difference from 1, and there was no effect of duration of use. The adjusted odds ratio for third generation users versus second generation users was 1.78 (0.66 to 4.83). 87% of cases were not exposed to an oral contraceptive, and 88% had clinical cardiovascular risk factors or were smokers, or both. Smoking was strongly associated with myocardial infarction: adjusted odds ratio 12.5 (7.29 to 21.5) for smoking 20 or more cigarettes a day.ConclusionsThere was no significant association between the use of oral contraceptives and myocardial infarction. The modest and non-significant point estimates for this association have wide confidence intervals. There was no significant difference between second and third generation products.

Key message

• There is no evidence of a difference between second and third generation oral contraceptives on risk of myocardial infarction
• There is no significantly increased risk of myocardial infarction in users of oral contraceptives
• Of women aged under 45 years who suffered a myocardial infarction, 87% were not taking any oral contraceptive
• Of women who suffered myocardial infarction, 88% had one or more known cardiovascular risk factors
• Young women who wish to preserve cardiovascular health should be advised to stop smoking, above all else

     

Oral contraception and risk of a cerebral thromboembolic attack: results of a case-control study.

OBJECTIVE--To assess the risk of cerebral thromboembolism in women using low dose oral contraceptives. DESIGN--A retrospective case-control study. SETTING--All Danish medical, neurological, neurosurgical, and gynaecological departments. SUBJECTS--All 794 women in Denmark aged 15-44 who had suffered a cerebral thromboembolic attack during 1985-9 and 1588 age matched randomly selected controls. RESULTS--Of 692/1584 case/control questionnaires sent out, 590/1396 (85.3%/88.1%) were returned. Among the cases, 15 refused to participate, 69 had a revised or unreliable diagnosis, 40 had had thromboembolic disease previously, 13 were pregnant, and 152 had a disease predisposing to a cerebral thromboembolic attack. Of the 323 cases without a known predisposition, 320 reported use or non-use of oral contraception. Among the 1396 controls, eight refused to participate, were mentally retarded, or lived abroad; 18 returned an uncompleted questionnaire; 17 had had thromboembolic disease previously; 31 were pregnant; and 130 had a disease predisposing to a cerebral thromboembolic attack. Thus 1198 non-predisposed controls were available, among whom 1197 reported use or non-use of oral contraception. Among the 320 cases, 116 (36.3%) were oral contraceptive users at the time of the cerebral thromboembolic attack. By comparison there were 191 users (16.0%) among the 1197 controls, giving a crude odds ratio of 3.0. After multivariate analysis, including confounder control for age, smoking, years of schooling, and trend in use of different types of oral contraceptives during 1985-90, pills containing 50 micrograms oestrogen were associated with an odds ratio for cerebral thromboembolic attack of 2.9 (95% confidence interval 1.6 to 5.4), those containing 30-40 micrograms oestrogen an odds ratio of 1.8 (1.1 to 2.9), those containing progestogen only an odds ratio of 0.9 (0.4 to 2.4). The odds ratio did not change with increasing age or with duration of oral contraceptive use. A 50% increased risk of a cerebral thromboembolic attacks among cigarette smokers (after confounder control) was independent of oral contraception status and age. CONCLUSION--Low dose oral contraceptives are associated with an increased risk of cerebral thromboembolic attack. Combined or sequential pills containing 30-40 micrograms oestrogen are associated with a one third reduced risk compared with preparations containing 50 micrograms oestrogen. Progestogen only pills did not increase the risk of a cerebral thromboembolic attack.     

Incidence,trends, and risks of ectopic pregnancy in a population of women.

In a 20-year longitudinal study on ectopic pregnancy in a defined population of women aged 15-39 years the rate of ectopic pregnancy per 1000 diagnosed conceptions increased from 5.8 during 1960-4 to 11.1 during 1975-9. The mean annual incidence of ectopic pregnancy per 1000 women increased from 0.6 to 1.2 during the same period. The numbers of ectopic pregnancies per 1000 diagnosed conceptions increased with increasing age of the women and were 4.1, in the teenage group 6.9, in women aged 20-29 years, and 12.9 in women aged 30-39. Among 20- to 29-year-old sexually active women at risk of pregnancy who had never had acute salpingitis the rates of ectopic pregnancy per 100 woman-years were the same in those who did not use contraceptives as in those using non-medicated or copper-medicated intrauterine contraceptive devices (IUCDs; 0.3/100 woman years). The risk of an ectopic pregnancy increased sevenfold after acute salpingitis. These findings confirm the increased risk of ectopic pregnancy after salpingitis and suggest that the increase in the incidence of ectopic pregnancy in Lund from 1960 to 1979 was partly accounted for by the use of IUCDs.     

Oral contraceptive use and venous thromboembolism: absence of an effect of smoking.

We conducted a case-control study to test the hypothesis that women smokers who use oral contraceptives have an increased risk of developing venous thrombosis. Patients and controls were drawn from two sets of hospital patients already included in the Boston Collaborative Drug Surveillance Programme. Sixty patients with uncomplicated thromboembolism were matched with 180 controls with other diagnoses; all were premenopausal women taking oral contraceptives. Patients with conditions that might predispose to thromboembolism or be related to smoking were excluded. We found no association between smoking habits and thromboembolism. Similarly, we found no association between thromboembolism, smoking, and duration of oral contraceptive use. Thus we conclude that differences in fibrinolytic activity between smokers and non-smokers are not major factors in the aetiology of uncomplicated thromboembolism in women using oral contraceptives.     

Effect of oral contraceptives and pregnancy on erythrocyte deformability and surface charge.

Erythrocyte deformability and surface charge were studied in normal premenopausal women, oral contraceptive users, and pregnant women. The increased incidence of thrombosis in women taking oral contraceptives could not be explained by decreased erythrocyte deformability or surface charge. However, the decreased erythrocyte deformability of late pregnancy may relate to thrombosis during this period and to increased hemolysis in patients with certain hemoglobinopathies.     

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.