Cardiovascular issues with oral contraceptives: evidenced-based medicine

Recent studies of current oral contraceptives indicate that the risk of cardiovascular sequelae is low in young (age 20-24 years) reproductive-aged women. Venous thromboembolism remains the one event that occurs in users independent of the presence of risk factors. However, the attributable risk is small, in the range of 7 to 18 events per 100,000 women annually. This risk is proportional to estrogen dose until the level of 30-35 microg is reached; type of progestin may also influence risk, though recent studies are controversial. Modifiable risk factors for venous thromboembolism include the presence of hemostatic disorders, especially factor V Leiden, and perhaps obesity. Stroke is even more uncommon, with an attributable risk of about 1.5 events per 100,000 women annually. Cigarette smoking and hypertension are modifiable risk factors for both ischemic and hemorrhagic stroke; use of preparations with 50 microg of estrogen or higher and migraine headaches are risk factors for ischemic stroke. Eliminating risk factors among users substantially reduces the risk of ischemic stroke and virtually eliminates the risk of hemorrhagic stroke. Myocardial infarction is rare among young women, occurring at a rate of about 0.2 event per 100,000 women annually. Oral contraceptive users who are non-smoking and normotensive do not have an increased risk of myocardial infarction. However, the presence of these risk factors along with age acts synergistically to increase the risk among oral contraceptive users.     

Are factor V Leiden carriers who use oral contraceptives at extreme risk for venous thromboembolism?

BACKGROUND: Major concern was raised by an earlier study regarding oral contraceptive use in women with the factor V Leiden mutation. A more than 30-fold increase in relative risk for venous thromboembolism was reported; for homozygotes, the relative risk was as much as 100-fold or more. OBJECTIVE: To replicate the reported risk estimates with a new population-based case-control study. METHODS: Eighty women with a diagnosis of venous thromboembolism were consecutively identified and compared with population-based controls (n = 406). Factor V Leiden mutation was identified by genotype analysis. The evaluation was performed with conditional logistic regression (matched for 5-year age group). RESULTS: Matched, adjusted odds ratios (OR) for idiopathic venous thromboembolism in women without and with the factor V Leiden mutation who used oral contraceptives were 4.1 (95% confidence interval (CI) 2.1-7.8) and 10.2 (95% CI 1.2-88.4), respectively. The adjusted OR for factor V Leiden carriers was 2.0 (95% CI 1.0-4.4). The OR for women with the factor V Leiden mutation and oral contraceptive use versus no factor V Leiden mutation and no oral contraceptive use was 10.2 (95% CI 3.8-27.6). CONCLUSION: The results confirm the increased relative risk of idiopathic venous thromboembolism for users of oral contraceptives and factor V Leiden carriers. However, we suspect that the true risk for women who are factor V Leiden carriers may be increased two- to four-fold rather than seven-fold or more, and that the risk for the combination of factor V Leiden and oral contraceptive use may be increased in the order often- to 15-fold rather than over 30-fold.     

The effects of age, body mass index, smoking and general health on the risk of venous thromboembolism in users of combined oral contraceptives.

OBJECTIVES: To investigate the factors associated with idiopathic venous thromboembolism in combined oral contraceptive users and to estimate the crude and age-specific incidence rates ofidiopathic venous thromboembolism among this population. METHODS: The UK MediPlus Database and the General Practice Research Database were searched to identify women with evidence of venous thromboembolism while exposed to combined oral contraceptives. Cohort and nested case-control studies were carried out using the same methodology on both databases. We conducted a meta-analysis using the individual data for the cases and controls from the two case-control studies to identify factors associated with idiopathic venous thromboembolism in women using combined oral contraceptives. RESULTS: The incidence rate of idiopathic venous thromboembolism among oral contraceptive users was 39.4 per 100,000 exposed woman-years. The age-specific incidence rates were found to rise sharply after the age of 39 years. Factors identified as being significantly associated with idiopathic venous thromboembolism in women using combined oral contraceptives were: body mass index of 25 kg/m2 and over, the association rising dramatically in women with a body mass index of 35 kg/m2 or more; smoking; general ill health; and asthma. CONCLUSION: We believe that, before prescribing combined oral contraceptives, the venous as well as the arterial factors need to be considered and, in addition, age, obesity and smoking are all relevant when assessing an individual patient's risk.     

Oral contraceptives and epithelial ovarian cancer. Does dose matter?

OBJECTIVE: To determine the risk of ovarian cancer among women who use low-estrogen-dose oral contraceptives. STUDY DESIGN: The study used data on white women under 70 years of age who had been enrolled in a population-based case-control study conducted between 1986 and 1988 in three western Washington counties. Women with ovarian cancer (n = 276) were ascertained through a population-based cancer registry, and controls (n = 391) were selected by random digit dialing. Unconditional logistic regression was used to estimate the risk of ovarian cancer associated with oral contraceptive use. RESULTS: After adjustment for age and parity, women who took oral contraceptives for at least three months were at decreased risk of ovarian cancer (odds ratio [OR] 0.8, 95% confidence interval [CI] 0.5-1.1) relative to women who never used this form of contraception. The reduced risk of ovarian cancer was present among women whose only preparation contained a low (< 50 micrograms ethinyl estradiol or < 80 micrograms mestranol) (OR 0.6, 95% CI 0.3-1.1) and high (OR 0.8, 95% CI 0.5-1.2) estrogen dose. CONCLUSION: While our results are limited in their statistical precision and by the inability of many subjects to recall the brands of oral contraceptives that they took, they suggest that the newer, low-estrogen-dose oral contraceptives confer a benefit regarding ovarian cancer risk similar to that conferred by earlier, high-estrogen-dose formulations.     

Correcting misconceptions about oral contraceptives

Although the majority of American women believe that oral contraceptives can cause serious health problems such as cancer or heart disease, the scientific literature does not support these beliefs. Oral contraceptives actually protect against endometrial and ovarian cancer. The increased incidence of cardiovascular disease in oral contraceptive users, including myocardial infarction, appears to be caused by thrombosis and not atherosclerosis. The studies suggesting an increased risk of cardiovascular disease in oral contraceptive users were published in the late 1970s and therefore used a data base of women ingesting formulations containing 50 micrograms of estrogen or more. More recently published data involving healthy women taking mainly lower estrogen dose preparations suggest that there is no increased incidence of myocardial infarction or stroke. Nearly all published studies indicate that there is no increased risk of myocardial infarction in former users of oral contraceptives. Animal data actually suggest that oral contraceptives may have a protective effect against atherosclerosis, even in the presence of lowered high-density lipoprotein levels. The low-dose triphasic and monophasic formulations are effective, safe methods of contraception that can be used by most healthy women of reproductive age.     

Is oral contraceptive use still associated with an increased risk of fatal myocardial infarction? Report of a case-control study.

OBJECTIVE--To investigate the association between fatal myocardial infarction and use of modern low-dose oral contraceptives. DESIGN--A case-control study. SETTING--General practices throughout England and Wales. SUBJECTS--161 women aged under 40 dying from myocardial infarction during 1986-1988. Living controls (2 per case), matched for age and marital status, were chosen from general practice lists. Information was collected during structured interviews with general practitioners, and from postal questionnaires sent to surviving partners of the cases and to control women. MAIN OUTCOME MEASURES--Mortality from myocardial infarction in relation to many risk factors, notably oral contraception, as measured by relative risk. RESULTS--After allowing for the confounding effects of medical risk factors and for surgical sterilization, the overall relative risk associated with both current and past use of oral contraceptives was estimated to be 1.9 (95% CI 0.7 to 4.9, and 1.0 to 3.5 respectively). The relative risk associated with current use of preparations containing 50 micrograms of oestrogen, however, was estimated to be 4.2 (0.5 to 39.2). At least some of the relative risk associated with oral contraceptive use is likely to be attributable to the confounding effect of cigarette smoking, but it is impossible to estimate how much from the available data. CONCLUSIONS--If there was an increased risk of fatal myocardial infarction associated with oral contraceptive use in 1986-1988 it is likely to have been less than two-fold; in this study risks were slightly, but not significantly, elevated with both current and previous use. It may be that any increase in risk is associated solely with the older combined preparations containing 50 micrograms of oestrogen.     

The effects of age,body mass index,smoking and general health on the risk of venous thromboembolism in users of combined oral contraceptives

Objectives To investigate the factors associated with idiopathic venous thromboembolism in combined oral contraceptive users and to estimate the crude and age-specific incidence rates of idiopathic venous thromboembolism among this population.

Methods The UK MediPlus Database and the General Practice Research Database were searched to identify women with evidence of venous thromboembolism while exposed to combined oral contraceptives. Cohort and nested case-control studies were carried out using the same methodology on both databases. We conducted a meta-analysis using the individual data for the cases and controls from the two case-control studies to identify factors associated with idiopathic venous thromboembolism in women using combined oral contraceptives.

Results The incidence rate of idiopathic venous thromboembolism among oral contraceptive users was 39.4 per 100 000 exposed woman-years. The age-specific incidence rates were found to rise sharply after the age of 39 years. Factors identified as being significantly associated with idiopathic venous thromboembolism in women using combined oral contraceptives were: body mass index of 25 kg/m² and over, the association rising dramatically in women with a body mass index of 35 kg/m² or more; smoking; general ill health; and asthma.

Conclusion We believe that, before prescribing combined oral contraceptives, the venous as well as the arterial factors need to be considered and, in addition, age, obesity and smoking are all relevant when assessing an individual patient's risk.     

Oral contraceptives and thromboembolism: A reassessment

The relationship between oral contraceptive usage and thromboembolism is controversial. Since thromboembolism is often undiagnosed, both clinically and at routine autopsy, most epidemiologic analyses rest on a very uncertain factual base. There are increases in blood coagulation factors in oral contraceptive users similar to, but less than, those seen in pregnancy, which isnot associated with increased thromboembolism. Hematologists emphasize that these changes do not define a “hypercoagulable” state, and they do not define or predict the occurrence of thrombosis. Intrinsic vascular wall changes, unrelated to drug use, may play a role in sporadic cases of thromboembolism. When the incidence of thromboembolism in very large Phase III trials of conventional oral contraceptives is compared to that in other populations (patients admitted to the hospital, women who visit a physician, pregnant women, or users of nonestrogenic oral contraceptives), no difference is seen. Epidemiologic studies by the “case-control” (“trohoc”) method consistently show an increased “relative risk” associated with oral contraceptive use in subjects with “idiopathic” thromboembolism but no increased risk in thromboembolism patients as a whole or in those with predisposing factors. This retrospective epidemiologic technique, its particular applications, and the inferences drawn are open to serious criticism, as are studies claiming a relationship between estrogen dose and thromboembolism incidence. An Australian prospective survey found no increased risk among users, and a large British study which initially reported an increased risk is currently undergoing recalculation. The only controlled clinical experiment (with random assignment of subjects to vaginal versus high-estrogen contraceptives) showed no increased incidence in the drug-treated group. Statistical associations derived from “trohoc” studies do not establish causal relationships; moreover, their risk estimates are in conflict with the findings of large Phase III clinical surveys including subjects using estrogen-free contraceptives, with at least one prospective clinical survey, and with a randomized, controlled clinical trial. The data relating estrogen dosage to thromboembolism incidence are ambiguous, at best. Thus, the claim of a causal relationship between oral contraceptive steroids and thromboembolism does not appear to be firmly founded, and the belief that predisposing factors increase the risk to contraceptive users is equally insubstantial.     

Oral contraception: safety issues re-examined.

Oral contraceptives are highly effective contraceptive agents that are used throughout the world. However, misperceptions about the safety of oral contraceptives as well as a relative lack of information concerning their numerous and important noncontraceptive benefits may limit their use and place women at increased risk for unintended pregnancy. Safety issues concerning the use of oral contraceptives have largely been laid to rest; indeed, except for a slight increased risk of venous thromboembolism in combination oral contraceptive users, conventional oral contraceptive use is not associated with an increased risk for cardiovascular events. In addition, fears regarding breast cancer development in OC users have been unsubstantiated by the plethora of available data. Clinicians must provide accurate and empathetic counseling concerning the safety and applicability of oral contraceptives and other pregnancy prevention methods.     

Long-term oral contraceptive use does not affect trabecular bone density

To determine whether long-term exposure to exogenous estrogen in oral contraceptives influences trabecular bone mass in premenopausal women, we studied 25 closely matched, healthy, premenopausal women, who were recruited from an active obstetrics and gynecology practice. Eleven women had never used oral contraceptives, and 14 women had used oral contraceptives for a minimum of 67 months. All oral contraceptive users had used preparations that provided a minimum of 50 micrograms mestranol per day. Trabecular bone density was determined by quantitative single-energy computerized tomography of the L1-3 lumbar vertebral bodies. Trabecular bone density was similar for both the control group and the oral contraceptive users, 160.6 +/- 6.9 versus 161.2 +/- 7.4 mg/ml, respectively. The power to detect a 15% difference in bone density between these two samples was 0.87. We concluded that long-term, premenopausal oral contraceptive use has no effect on vertebral bone density.     

Contraceptive choices in women with coagulation disorders

When compared with older reports on the thromboembolic effects of high-dose oral contraceptives, new studies with low-dose oral contraceptives have a significantly reduced risk of thromboembolism. In the absence of risk factors such as smoking or inherited disorders predisposing to thrombosis, the modern low-dose oral contraceptive (< 50 μg of estrogen) is a safe and effective choice for contraception in women without symptoms who have family histories of sporadic thromboembolism. An intrauterine device or some form of barrier method is recommended for women who have a personal history of venous thrombus disease. The low-dose oral contraceptive may be a good choice in women taking oral anticoagulants because of the risk of teratogenic effects of anticoagulants and the risks of intraperitoneal bleeding associated with ovulation. In addition, oral contraceptives help diminish the excessive menstrual bleeding often seen in these women. (Am J Obstet Gynecol 1993;168:1990-3.)     

Oral contraceptives increase deep venous thrombosis in smoking women

There is consistent evidence that the use of oral contraceptives and is associated with increased risk of deep vein thrombosis. The study objective was to assess age specific incidence of deep venous thrombosis and pulmonary embolism in women 20 to 50 years of age associated with the use of oral contraceptives, and smoking habit. A case-control study of vein thrombosis was conducted in National Heart Hospital in Sofia. The study consists of studies for vascular events (peripheral vascular disease) during hormonal therapy. We found that cigarette smoking aggravates venous thromboembolism and pulmonary embolism the in women using oral contraceptives, v. The effect of smoking alone on venous tromboembolism was not found significant. Most probably different factors that increase the incidence of vascular narrowing or occlusion might explain the association between deep venous thrombosis, complicated pulmonary thromboembolism oral contraceptives use and smoking in women in pre-menopausal age.     

Oral progestogen-only contraceptives and cardiovascular risk: results from the Transnational Study on Oral Contraceptives and the Health of Young Women.

BACKGROUND: The risk of cardiovascular disease associated with progestogen-only pills has rarely been studied so far. METHODS: In the Transnational case-control study we were looking for a potential cardiovascular disease risk with oral progestogen-only pills in women aged 16-44 years. A total of 1058 cases of myocardial infarction, thromboembolic cerebrovascular accident or venous thromboembolism, and 3808 controls unaffected by these diseases, were enrolled. The group of women who had either used oral progestogen-only pills or no oral contraceptives included 394 cardiovascular disease cases (123 cases of myocardial infarction, 90 cases of thromboembolic cerebrovascular accident and 181 cases of venous thromboembolism) and 2366 controls. RESULTS: The adjusted (matched) odds ratio (OR) for all cardiovascular diseases combined for women using progestogen-only pills compared with non-users of oral contraceptives was 0.84 (95% confidence interval (CI), 0.45-1.58). The adjusted ORs for myocardial infarction, thromboembolic cerebrovascular accidents and venous thromboembolism for users of progestogen-only pills were 0.94 (95% CI, 0.31-2.91), 1.60 (95% CI, 0.24-0.72) and 0.68 (95% CI, 0.28-1.66), respectively. Hence, there was no significant increase in cardiovascular disease risk associated with progestogen-only pill use. The association between cardiovascular disease and established risk factors (smoking and hypertension) was confirmed. CONCLUSION: Although limited by the small number of exposed cases, our data suggest that there is no convincing evidence for an increased risk of cardiovascular disease associated with progestogen-only pill use.     

Interleukin-6 and antiphospholipid antibodies in women with contraceptive-related thromboembolic disease

OBJECTIVE: The aim of this study was to explore the possible (joint) contributing role of interleukin-6 (IL-6) and antiphospholipid antibodies to the occurrence of the venous thromboembolism in women using oral contraceptives. METHODS: Interleukin-6 and antiphospholipid antibodies (anti-beta2-glycoprotein I antibody-immunoglobulin M [IgM], G [IgG], and A [IgA]; anticardiolipin-IgM and IgG; antiphosphatidylserine-IgM and IgG) were measured in 30 women (median age 41, range 28-49 years) in the stable period (on average 3.5 years) after first venous thromboembolism. Sixteen patients used oral contraceptives during the episode of venous thromboembolism (oral contraceptives group), whereas 14 patients did not (non-oral contraceptives group). Thirty-seven age-matched, healthy women served as controls RESULTS: Compared with controls, the oral contraceptives group had elevated IL-6 (median interquartile range 2.3 [1.1-4.3] versus 1.4 [0-2.0] pg/mL, P <.05). The oral contraceptives group had elevated anti-beta2-glycoprotein I antibody-IgM in comparison with both the non-oral contraceptives group (median interquartile range 47.5 [2.0-77.0] versus 29.50 [11.00-45.50] OD(450), P <.06) and controls (47.5 [2.0-77.0] versus 17.5 [3.5-30.0] OD(450), P <.001). Interleukin-6 level in the non-oral contraceptives group was related to obesity, whereas such a relation was not found in the oral contraceptives group, suggesting the presence of another factor (oral contraceptive use), which stimulates IL-6 production. Of particular interest is our finding that elevated IL-6 levels correlated significantly positively with elevated anti-beta2-glycoprotein I antibody-IgG in patients who were users of oral contraceptives (but not overweight, n = 10) (r = 0.56, P <.05) CONCLUSION: The results suggest a new hypothesis that, in susceptible women, use of oral contraceptives induces production of IL-6, which stimulates production of anti-beta2-glycoprotein I. Thus, the prothrombotic profile is aggravated and could facilitate occurrence of venous thromboembolism. This remains to be elucidated in further studies.     

Oestrogen containing oral contraceptives decrease prostacyclin production (author's transl)

To study the production of antiaggregatory PGI2 (prostacyclin) the authors, observed 3 groups of women: 1) 34 women on combined OCs (oral contraceptives) for a period of 4 months--7 years; 2) 11 women starting contraception with progestogen only pills, or with low-dose estrogen pills; they were followed for a period of 3 months; and, 3) 24 women who had never been on OC. Blood samples were taken every month and examined. Results showed that: 1) the prolonged use of combined OCs was associated with decreased production of PG12, especially in relation to the length of OC treatment; 2) PG12 production was not affected by contraception with progestogens only; and, 3) no modifications were found in users of low-dose estrogen pills. The principal biological funcion of PG12 is to inhibit platelet aggregation, and to keep a proper dilatation of the blood vessels. Thus, suppression of PGI2 can be associated with an increased risk of venous and arterial thromboembolism in OC users. While the risk of thromboembolism may be decreased with low-dose estrogen treatment, risk of arterial thromoboembolism is not decreased, since OCs exercise a lesser influence on areterial thrombosis.     

Oral contraceptives: a reassessment

Cardiovascular risks attributable to oral contraceptive use may now be subdivided into those that appear to be secondary to the estrogen component, i.e., venous thrombosis, pulmonary embolism, and those linked to the progestin component, i.e., small vessel disease including myocardial infarction and cerebrovascular accident. It appears that venous risk is attributable to subtle changes in clotting factors, while arterial risk may be secondary to changes in glucose and lipid metabolism. In order to determine which women are at greatest risk from oral contraceptive use, Spellacy et al. has developed a risk scoring form that aids in the screening process. After excluding women with an absolute contraindication to pill use, women at greatest risk for cardiovascular disease related to oral contraceptive use are those with a family history of hyperlipidemia, gestational or overt diabetics, hypertensives, and smokers over the age of 35. The gradual reduction by manufacturers of the steroid content of oral contraceptives appears to have lessened the incidence of adverse effects. Our current knowledge of risk factors permits the clinician to reduce exposure to oral contraceptive-related mortality by as much as 86 per cent. As we continue to search for ways to reduce risk among oral contraceptive users, it is important to note that more than 25 per cent of women are still taking formulations containing 50 micrograms of estrogen. It becomes the responsibility of the practicing physician to "step-down" these patients to lower-dose preparations such as the multiphasics. Such preparations also represent optimal therapy for first-time pill users.     

Use of oral contraceptives in women of older reproductive age

Evidence of increased risk for cardiovascular disease in oral contraceptive users of older reproductive age is based on early data involving formulations containing higher doses of estrogen and progestin than those in use today. In addition, early studies included patients who would not receive oral contraceptives with today's more stringent prescribing criteria. When these data were carefully analyzed, a significant increase in myocardial infarction was noted only in oral contraceptive users with concemitant risk factors for cardiovascular disease. Analysis of other studies also showed a significant increase in the incidence of cardiovascular disease and mortality only in oral contraceptive users older than age 35 years who smoked. A recent long-term cohort study of women without risk factors for cardiovascular disease who mainly used oral contraceptives containing ≤50 μg estrogen showed no increased risk of myocardial infarction or cerebrovascular accident with oral contraceptive use. Use of oral contraceptives containing <50 μg estrogen has not been shown to be associated with an increased risk of cardiovascular disease in healthy, nonsmoking women 35 to 45 years of age.     

Oral contraceptives and benign breast disease: a case-control study

The relationship between benign breast disease and use of oral contraceptives was analyzed in a case-control study conducted in Milan with 288 cases of clinically relevant and histologically confirmed benign breast disease and 285 age-matched controls with a spectrum of acute conditions apparently unrelated to use of oral contraceptives. Compared to the risk for women who had never used oral contraceptives, the relative risk for users was 1.0 (95% confidence interval: 0.6 to 1.5). There was no significant association with duration of use; however, a significantly lower relative risk was found in women using oral contraceptives during the year before breast biopsy (relative risk: 0.4; 95% confidence interval: 0.2 to 0.8). The protection in current users increased with increasing duration of use. In spite of this finding, the overall results of the present study do not support the hypothesis that oral contraceptive use protects against development of histologically confirmed and clinically relevant benign breast disease.     

Oral contraceptive pills and the risk of venous thromboembolism

Information on the association between combined oral contraceptives (OCs) and cardiovascular disease risks has been derived almost exclusively from studies in developed countries. To assess this relationship in developing countries, where the risk factors for cardiovascular disease may be different, a case-control study of venous thromboembolism, stroke, and myocardial infarction was carried out in 21 centers in 17 countries in Africa, Asia, Europe, and Latin America. The World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception enrolled 3800 cases of stroke, venous thromboembolism, and myocardial infarction and 11,200 matched controls. Studies in the UK had suggested that OCs containing desogestrel and gestodene doubled the risk of venous thromboembolism compared with levonorgestrel and norethindrone-containing OCs. The multi-center study identified an overall risk of venous thromboembolism in the lower range of that reported in developed countries, an increased risk soon after starting OC use but elimination of such risk within a few months after pill discontinuation, and slightly increased risk among obese women and those with a history of high blood pressure during pregnancy. Unexpected was the finding that women who use OCs containing desogestrel or gestodene may be at double the risk of blood clotting in the veins compared with users of OCs containing levonorgestrel or norethindrone. Although these findings remain controversial, several countries have modified OC prescribing practices to eliminate women at high risk of cardiovascular disease.