Oral contraceptives and cardiovascular mortality

Several epidemiological studies have demonstrated at the individual level an elevated risk of cardiovascular death for women who have been using oral contraceptives. Nevertheless, there has been no detectable increase in the number of cardiovascular deaths during the last fifteen years in countries where the use of oral contraceptives has become widespread. In this paper, we have tried to analyse this apparent contradiction and to discuss the causal nature of the relationship linking oral-contraceptives and cardiovascular death. For this purpose, we present a bibliographical summary of the relevant studies as well as an analysis of the trend in cardiovascular deaths among women in France from 1968 to 1975.     

Oral contraceptives, lipids and cardiovascular disease

Evidence for the involvement of changes in lipid metabolism and oral contraceptive use in the development of cardiovascular disease is briefly reviewed with particular reference to the main object of the article, to assess the effect of different oral contraceptive formulations on serum lipid levels. The preferred formulations should contain a low dose of ethynyloestradiol and should not increase serum levels of cholesterol and LDL-C or reduce those of HDL-C. Such formulations appear to be the triphasic one containing ethynyloestradiol and levonorgestrel and the ethynyloestradiol-desogestrel combination, which appears to be unique in that it may actually increase HDL-C. However other determinants in addition to effects on lipid metabolism will be important in deciding the choice of an oral contraceptive. Any changes which do occur in serum lipid concentrations with OC use appear within the first three months and do not appear to be progressive with continued use after this time.     

Side effects and compliance with low- and conventional-dose oral contraceptives among adolescents

Oral contraceptives are the most popular birth control method for teenagers, yet many teens discontinue use of these contraceptives prematurely. The need to minimize any potential long-term medical complications from the use of contraceptive hormones must be balanced with the desirability of increasing acceptance of contraceptives by adolescents. There has been concern that the use of socalled “low-dose” estrogen preparations, although decreasing the likelihood of complications, may lead to side effects that make compliance less certain. The present study comparing two commonly used oral contraceptive preparations, one low dose, one conventional dose, tests the hypothesis that among adolescents an association exists between oral contraceptive side effects and compliance. Using a double-blind crossover method, 55 sexually active adolescent females received two months each of a preparation containing 35 μg ethinyl estradiol and 0.5 mg norethindrone and another containing 50 μg mestranol and 1.0 mg norethindrone. The 50-μg preparation was associated with fewer side effects when administered during the first two months. No differences in side effects were noted in the latter two months, but there was a slight increase in weight gain when compared with the 35-μg preparation. The most common side effect was intermenstrual bleeding with the 35-μg pill. There was no documented relationship between the occurrence of side effects and compliance.     

Oral contraceptives and thromboembolism

Recent independent studies undertaken in Britain have demonstrated s tatistically for the first time the increased risk of thromboembolic dis ease among women taking oral contraceptives. The Royal College of General Practitioners study suggests that the risk is increased about 6-fold by pregnancy and about 3-fold by oral contraceptives. The Statistical Research Unit of the M.R.C. listed 29 women with deep-vein thrombosis or pulmonary embolism of whom 14 had been taking oral contraceptives. Of 36 controls with other conditions only 3 were using the pill. The Committee on Safety of Drugs study reports 378 deaths in married women aged 15-44 during 1966; in 261 thromboembolic disease was mentioned on the death certificate. Coronary thrombosis was not associated but cerebral thrombosis and pulmonary embolism were possibly related to use of oral contraceptives. Deaths attributable to oral contraceptive use were approximately 3 per 100,000 users per year. In England and Wales the annual death rate for full-term pregnancies is 12 per 100,000 population. Death rate following abortions for unwanted pregnancies is higher. Advantages of oral contraceptives are, for many women, greater than the risks of iatrogenic morbidity or mortality. However, safer contraceptives must be sought as well as means of discovering which women may be at greatest risk from thromboembolism.     

Oral contraceptives and neoplasia: An introduction

A reassessment of the risks of using oral contraceptives regarding cancer of the cervix, endometrium, ovary, breast and biliary system was commissioned in the form of a series of reviews, published in the journal Contraception, June 1991: this is the introduction to the reports. Since 1977, the risks of developing epithelial ovarian cancer and endometrial cancer have been clearly shown to be reduced and that protection persists for years even in ex-pill users. The chance of getting hepatocellular carcinoma is slightly higher in developed countries, still extremely rare; while not noticeably increased in those developing countries that have high liver cancer rates. The likelihood of getting cervical cancer is increased in some studies but not in others, reflecting the difficult problem of controlling of patterns of sexual behavior in this area. Even though broad analyses of breast cancer risks are reassuring, some detailed studies that focus on certain age groups of women do find increased breast cancer. A special multi-center, hospital-based, case-control study in developing countries, sponsored by WHO, concluded that the results of studies on cancer from developing countries are applicable to developing countries as well. So the overall benefits of using oral contraceptives outweigh the risks, both for women in areas where maternal morbidity and mortality are high, because of the effectiveness of the pill in preventing pregnancy; and in industrialized areas, where the benefits of preventing ovarian cancer alone is enough to make pill use safer than other methods, such as the condom. There appears to be no way to predict cancer risks for any subgroup of women who should avoid taking the pill.     

Oral contraceptives: a risk factor for uncontrolled blood pressure among hypertensive women

The objective of the study was to assess the association between systolic and diastolic blood pressure (SBP and DBP) and the use of oral contraceptives (OC) in hypertensive women. In a prospective cross-sectional study, we evaluated 171 women who were referred to the Hypertension Outpatient Clinic of Hospital de Clínicas de Porto Alegre; 66 current users of OC, 26 users of other contraceptive methods and 79 women who were not using contraception. The average of six blood pressure readings was used to establish the usual blood pressure of the participants. Current OC users were compared with users of other methods and with patients not using contraception. Main outcome measures were SBP and DBP among the different groups, and prevalence of uncontrolled hypertension (SBP >or= 140 mmHg and DBP >or= 90 mmHg). DBP was higher in OC users (100.2 +/- 15.9 mmHg) than in patients using other contraceptive methods (93.4 +/- 14.7 mmHg) and not using contraceptives (93.3 +/- 14.4 mmHg, p = 0.016). Women using OC for more than 8 years presented higher age-adjusted blood pressure levels than women using OC for shorter periods. Patients using OC had poor blood pressure control (p for trend = 0.046) and a higher proportion of them presented moderate-severe hypertension. These results were independent of antihypertensive drug use. In a logistic regression model, we found that current OC use was independently and significantly associated with prevalence of uncontrolled hypertension. It is concluded that hypertensive women using OC present a significant increase in DBP and poor blood pressure control, independent of age, weight and antihypertensive drug treatment.     

Oral contraceptives and the liver

A brief review of the literature concerning the effects of oral contraceptives on liver function is presented. Evidence generally suggests that although oral contraceptives do effect the excretory function of liver cells, it is of little clinical importance. It is believed that estrogens and progesterones in a much greater dosage than is currently (1966) present in oral contraceptives would have to be given to do any damage. Treatment with oral contraceptives is nonetheless inadvisable if previous cholestasis of pregnancy, primary biliary cirrhosis, or a hereditary disorder of hepatic excretory function is present. If bilirubinuria or jaundice occur during treatment, the pill should be withdrawn.     

Oral contraceptives and breast cancer

The question of a possible association between prolonged early use of combined oral contraceptives (COCs) and an increased risk of breast cancer remains unresolved, despite the existence of at least 10 large-scale case-control studies and 5 large cohort studies. The marked differences in the findings of different studies, especially with regard to COC use before the first full-term pregnancy, may reflect differences in COC formulations, precise patterns of use, or risk factors for breast cancer. The variation in study results may also be explained by a latency effect, in which a period of perhaps 15 years or more has to elapse before adverse effects of COCs on the breast become apparent. Even the large-scale epidemiologic investigations currently in progress (e.g., a nationwide study of breast cancer in British women up to 35 years of age, a study in the Netherlands, and a multicenter study coordinated by the World Health Organization) may not provide conclusive answers, since widespread prolonged early use of COCs is a relatively recent phenomenon and breast cancer is not common in young women. Moreover, COC formulations have changed over time, meaning that any risk found to be associated with preparations used in the 1960s and 1970s may not apply to present-day COCs. Finally, there is a need for more basic research on both the normal human breast and on breast cancer, especially in relation to the effects of endogenous and exogenous hormones.     

Oral contraceptives and breast cancer

An attempt is made to summarize the results of recently conducted epidemiological studies relating to the possible adverse effects of oral contraceptives (OCs) on breast cancer. Evaluation of the safety of OCs is difficult. An important reason is that since preparations were introduced to the American market in 1959 the formulation of pills and the dosage of constituents have both changed markedly. A number of other considerations to be born in mind when evaluating the relevant literature were identified by a recent World Health Organization (WHO) Scientific Group. These include the following: there is usually a considerable latent period between 1st exposure to a carcinogen and the development of overt malignancy; and it is possible that exposure to contraceptive steroids may be particularly important at certain critical periods during reproductive life. After age, the most important risk factors during early life are a young age at menarche and a late age at 1st full term birth. There factors appear to operate independently and so the longer the period between menarche and 1st full term birth, the higher is the risk of breast cancer. A girl whose menarche occurs before age 12 is approximately twice as likely to develop breast cancer later in life as a girl whose menarche occurs after age 14. Similarly, a woman whose first full term birth occurs after age 35 is about 3 times more likely to develop breast cancer than a woman who gives birth before age 20. Nulliparous women have an intermediate risk. Other known risk factors include a family history of breast cancer, a past history of benign breast disease, and increased body weight. Possibly the most serious problem from an epidemiological perspective is the interrelationship between calendar time, age, and OC exposure. OC seems to be clearly associated with a decreased risk of benign breast disease of sufficient severity to require biopsy and the evidence is that the reduction in risk increases with duration of use. The epidemiological evidence available regarding OCs and breast cancer is reassuring. Data have been obtained from case control studies and cohort studies. A table summarizes the main features of 12 case control studies. Results of both groups of studies are reassuring in relation to breast cancer, yet there is usually a long period between exposure to a carcinogen and the development of overt malignancy and OCs have been in widespread use for only a relatively short time. Women who have never used OCs seem to present with more clinically advanced tumors than women who have used them. The differences in staging are reflected in patterns of survival. The difference may be due to a greater awareness of breast disease in OC users, but it could represent a beneficial biological effect of OCs.     

Oral contraceptives and skin neoplasia

A possible association between oral contraception and the development of cutaneous melanoma has been raised largely because of the hyperpigmentation of pregnancy and the effect pregnancy may have on the outcome of established disease. Present evidence suggests there is no causal link between oral contraceptive (OC) use and melanoma (or with benign melanocytic nevi), nor has a specific subgroup of women or subtype of melanoma been consistently implicated as being at increased risk of this disease due to use of OCs.     

Oral contraceptives and life expectancy

Life expectancy for women in the United States is 77.34 years; women who take oral contraceptives (OCs) for five years before the age of 30 can expect to live about four days longer. This is due primarily to protection against ovarian and endometrial cancers. For women taking pills for five years in their thirties there is a maximum loss of 18 days on the average that is attributable to OC use, and for women over 45 this rises to 80 days. The decreased life expectancy is due mainly to the increased mortality from myocardial infarction and stroke. This is substantially less than life lost due to use of a variety of other substances, most notably tobacco.