Oral contraceptives use and liver tumours: a review

Of the nine epidemiologic controlled studies reporting on the relationship between oral contraceptives use and hepatic tumours, three have findings specifically on the association of oral contraceptives use and hepatocellular adenomas. The strength of this association is reported to be dependent more on long-term oral contraceptive use. Three other studies have reported similar relationships of oral contraceptives use with hepatocellular carcinoma, whereas the remaining three other studies have reported no association between oral contraceptives use and hepatocellular carcinoma. There is however, an increased risk of hepatocellular carcinoma as the duration of oral contraceptives use increases. The risk of developing hepatocellular adenomas is higher in oral contraceptives users over 30 years of age than in the younger age groups. These tumours occur more often in oral contraceptive users taking pills with high doses of estrogens and progestogens; while they are not only associated with oral contraceptives containing mestranol, but also those containing ethinylestradiol.     

Association between oral contraceptives and myocardial infarction. A review

Analysis of the association between oral contraceptive use and the development of myocardial infarction in women less than 50 years of age shows that cigarette smoking is the most important factor in increasing the likelihood of myocardial infarction. This effect is independent of oral contraceptive use but oral contraceptive use also appears to be a risk factor; however, their use in the absence of other predisposing factors appears to have only a small effect on increasing the risk of dying from myocardial infarction. This small increase is of the same order of magnitude as the increased risk of death from thromboembolic disease. Oral contraceptive users more than 30 years of age who have other factors that increase the likelihood of myocardial infarction appear to have a substantially higher death rate.     

Risk of vascular disease in women. Smoking, oral contraceptives, noncontraceptive estrogens, and other factors.

We investigated the relation in women of various factors to risk of myocardial infarction, subarachnoid hemorrhage, other strokes, and venous thromboembolism. Smoking significantly increased risk of all four diseases, whereas oral contraceptive use was associated with an increase only in risk of subarachnoid hemorrhage and venous thromboembolism. Use of noncontraceptive estrogens was not associated with increased risk of any of these diseases. Hypertension, hypercholesterolemia, obesity, gallbladder disease, and nondrinking of alcohol were all associated with increased risk of myocardial infarction, whereas only hypertension and hypercholesterolemia were associated with increased risk of other strokes. Cigarette smoking was overwhelmingly the most important risk factor for vascular disease in women. Smoking should be considered a contraindication to oral contraceptive use, or at the very least, women wishing to use oral contraceptives should be strongly urged not to smoke.     

Barrier contraceptive methods and preeclampsia

Recent investigations have suggested that women who use barrier methods of contraception may be at increased risk for preeclampsia. We used data from two prospective pregnancy studies to examine the relationship between contraceptive use before conception and preeclampsia. The preeclampsia rates among women using barrier contraceptives were not significantly higher than the rates in women using nonbarrier contraceptives or the rates in women using no contraceptives in either study. The odds ratios for preeclampsia in barrier contraceptive users in the two studies were 0.89 (95% confidence interval [Cl], 0.71 to 1.12) and 0.85 (95% Cl, 0.49 to 1.45) compared with nonbarrier contraceptive users and 0.91 (95% Cl, 0.71 to 1.16) and 0.81 (95% Cl, 0.48 to 1.35) compared with women using no contraceptives. After adjusting for other risk factors, we found no association between preeclampsia and barrier contraceptive use. Additional studies are needed to resolve this issue; however, we would recommend that women not be advised to avoid barrier contraceptives unless more data linking their use to preeclampsia appear.     

The relationship of tubal infertility to barrier method and oral contraceptive use

We studied past contraceptive use in 283 nulliparous infertile women who had a diagnosis of tubal adhesions or occlusion and in 3833 women admitted for delivery at seven collaborating hospitals from 1981 to 1983. The relative risk of tubal infertility associated with barrier contraceptive use or oral contraceptive use was calculated using multivariate logistic regression to control for confounding by region, age, religion, education, smoking, number of sexual partners, time since menarche, and use of other contraceptive methods. Women who had ever used barrier methods of contraception were at a significantly decreased risk of tubal infertility (relative risk = 0.6; 95% confidence limits, 0.5 and 0.8). When type of barrier method used for the longest time was evaluated, those who used the diaphragm or condoms plus spermicides were at lower risk than those who used condoms or spermicides alone. Overall, past use of oral contraceptives neither increased nor decreased a woman's risk of tubal infertility, but there was evidence that the association between oral contraceptives and tubal infertility may vary by the amount of estrogen and type of progestogen in the oral contraceptive used. We conclude that contraceptive users who use barrier methods that combine both a mechanical and chemical barrier, such as diaphragms, cervical caps, and condoms plus spermicides, have the clearest protection against tubal damage.     

Risk of cardiovascular diseases with oral contraceptives

Oral contraceptive pills (OCs) are widely used method of contraception for its effectiveness and easier compliance. However, adverse effects associated with OCs use notably the increased risk of cardiovascular diseases (CVD), manifesting as ischaemic and haemorrhagic stroke, myocardial infarction (MI) and venous thromboembolic diseases were reported soon after their introduction to the market in the early 1960s. Various modifications were made in an attempt to lower these risks including a reduction in the estrogen dose and changes in the progestogen compound. Currently used OCs containing the new progestin (Levonorgestrel, Desogestrel, gestodene or norgestimate) classified as low dose because all contain less than 35 microg of ethinyl estradiol. Despite their low steroid content, all have proved to be highly effective. The rationale of this reviewed study based upon cardiovascular risks in relation to these monophasic low-dose oral contraceptives. To review all relevant articles it is concluded that the risk for cardiovascular disease is lower with current preparations of oral contraceptives. Cardiovascular diseases occur mainly among oral contraceptive users who smoke or have predisposing factors--such as age more than 35 years, overweight, diabetes & hypertension.     

Oral contraceptives and risk of breast cancer

Use of oral contraceptives (OCs) by women before age 25 or first full-term pregnancy has been theorized to increase the risk of breast cancer. While multiple studies have reported a positive relationship between early use and subsequent breast cancer development, numerous researchers have concluded there is no effect. One reason for the varied results may be the case control methodology utilized by the majority of studies and its associated biases including selection, information, and recall bias. Other theories include an undetected latent effect, changing dosages and formulations, earlier breast cancer diagnosis and follow-up among OC users, and chance. While more research is needed, the weight of evidence supports no increased risk of breast cancer among OC users, including women less than 25 years of age and before first full-term pregnancy. Hence, it seems unnecessary to change the current approach toward OC use.     

Oral contraceptive agents and breast cancer: a population-based case-control study

In this population-based case-control study that was conducted in Adelaide, South Australia, and which involved 395 case subjects and 386 control subjects who were aged 20 years to 69 years, the adjusted relative risk of breast cancer for women who had ever used oral contraceptive agents was 1.06 (95% confidence interval [CI], 0.70-1.60). Relative risks that were associated with use of oral contraceptive agents for one month to 18 months and for 19 months or more before a first pregnancy were 1.09 (95% CI, 0.45-2.62) and 1.67 (95% CI, 0.63-4.42), respectively, but the trend was not statistically significant. Relatively-little variation in risk was found in association with the total duration of the use of oral contraceptive agents and with years since the first and the last use of oral contraceptive agents. When the risk of breast cancer in association with the use of oral contraceptive agents was examined across levels of risk factors of breast cancer (history of benign breast disease, family history of breast cancer and parity), the only relative risk which deviated markedly from unity was that which was associated with use of oral contraceptive agents in women with a history of benign breast disease; however, the relative risk of 1.77 (95% CI, 0.35-8.97) was not statistically significant. In conclusion, the results of this study support those of the majority of previous studies in showing no overall relationship between the use of oral contraceptive agents and the risk of breast cancer.     

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. Women who conceive soon after discontinuing oral contraceptive therapy may be especially at risk to this hazard. An increase in vitamin A levels in women taking oral contraceptives has been confirmed. 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. The authors were not able to demonstrate 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 conceiving soon after discontinuing oral contraceptive, has any detrimental effect on the outcome of pregnancy. It seems unlikely that women conceiving soon after discontinuing oral contraceptive therapy run any teratogenic risk from increased vitamin A levels.     

Do oral contraceptives prevent rheumatoid arthritis?

Two studies have suggested that the risk of rheumatoid arthritis in women using oral contraceptives is less than half that of nonusers. When a third study from the Mayo Clinic failed to confirm these findings, it was criticized for inclusion of ineligible subjects, misclassification of oral contraceptive use, and inadequate statistical power. Recent expansion of the Mayo Clinic's data resources provided a unique opportunity to resolve the controversy, and a new population-based case-control study was undertaken. In comparison with the previous study, the new investigation had 2.2 times as many eligible cases and more complete ascertainment of oral contraceptive use via access to the records of Planned Parenthood of Minnesota. Comparing any prior use of oral contraceptives with never having used them, the relative risk of rheumatoid arthritis estimated from 182 cases and their 182 matched controls was 1.1 (95% confidence interval 0.7 to 1.7). The relative risk for current use was 1.3 (95% confidence interval, 0.7 to 2.4). The lack of a protective effect was independent of age, disease severity, and disease end point (date of confirmed diagnosis or symptom onset).     

Chronic inflammatory bowel disease, cigarette smoking, and use of oral contraceptives: findings in a large cohort study of women of childbearing age

Since the start in 1968 of the Oxford Family Planning Association contraceptive study 31 women have developed ulcerative colitis and 18 have developed Crohn's disease, giving incidences of 0.15 and 0.09/1000 woman years respectively. The incidence of ulcerative colitis in women who were non-smokers on entry to the study was 0.17/1000 woman years and the incidence in smokers was 0.11/1000 woman years. The findings for Crohn's disease were entirely different, the corresponding incidences being 0.05 and 0.17/1000 woman years respectively. Both ulcerative colitis and Crohn's disease were more common among women currently using oral contraceptives than among those not doing so. Incidences per 1000 woman years for ulcerative colitis were 0.26 in users and 0.11 in non-users; for Crohn's disease the incidences were 0.13 and 0.07 respectively. Though the association between the use of oral contraceptives and chronic inflammatory bowel disease cannot be regarded as established, the effects of smoking have been shown consistently in many studies. This observation provides an important clue to the aetiology of chronic inflammatory bowel disease.     

Oral contraceptives and blood pressure

Both cross-sectional and longitudinal analysis of data from 13,358 women showed that oral contraceptive use is associated with a slight but statistically significant (P lesser than .05) rise in mean blood pressure, which is reversible. The age-adjusted proportion of oral contraceptive users with a blood pressure over 140/90 mm Hg was about three times that on nonusers. These findings are caused by a uniform upward shift in the blood pressure distribution of oral contraceptive users compared to nonusers. Women continuing oral contraceptive use had no appreciably greater change in blood pressure between two visits than persistent nonusers. The clinical implications of a mild contraceptive-induced blood pressure elevation (systolic, 5 to 6 mm Hg; diastolic, 1 to 2 mm Hg) remain unsettled but disturbing.     

Oral contraceptives and cervical cancer risk in Costa Rica. Detection bias or causal association?

To examine the relationship between cervical cancer and oral contraceptive (OC) use, we analyzed data from a population-based, case-control study in Costa Rica. Women aged 25 to 58 years in whom cervical cancer was diagnosed and reported to the National Tumor Registry were examined as two separate case groups: invasive cervical cancer and carcinoma in situ (CIS). Controls were women aged 25 to 58 years identified through a national survey. Women who had used OCs had no increased risk of invasive cervical cancer compared with women who had never used OCs (relative risk, 0.8; 95% confidence interval, 0.5 to 1.3). Women who had used OCs had an increased risk of CIS compared with those who had never used OCs (relative risk, 1.6; 95% confidence interval, 1.2 to 2.2). However, further analyses indicated that this increased risk was confined to those who had recently used OCs. Also, the risk of CIS was not elevated in subgroups in which a history of cervical smears was not strongly linked to OC use. The elevated risk of CIS among OC users may therefore reflect a bias caused by enhanced detection of disease rather than a causal association.     

Case of ischemic colitis in a young adolescent associated with triphasic hormonal contraceptive therapy: a case report and review of the literature

There has been speculation that third generation hormonal contraceptives may be less prone to inducing clotting than the earlier generation products. We present a case of colonic ischemia in a young adolescent receiving pharmacotherapy with a third-generation hormonal contraceptive. Ischemic colitis is an uncommon adverse effect in young adolescents associated with hormonal contraception, especially the third generation agents. We believe this case to be the second-youngest patient reported with ischemic colitis due to this therapy. Clinical vigilance is recommended for women presenting with abdominal pain, with or without hematochezia, who are receiving hormonal contraceptive therapy. Since their introduction in the early 1960's, the combination hormonal contraceptives have been utilized by millions of women for both contraceptive and non-contraceptive purposes. Although a variety of adverse effects can be experienced by individuals taking these agents, it has been demonstrated that these agents are associated with an increased risk of venous and arterial thromboses. Publications more consistently report on the cardiovascular-, pulmonary-, peripheral vascular-, or cerebrovascular-based thrombotic events associated with these agents. During the past several decades changes have been incorporated in the dose and types of compounds included in the combination hormonal contraceptive products in an attempt to reduce the risk of coagulation and other adverse effects. Less common and less frequently publicized are the gastrointestinal-based thrombotic events that result in ischemia and presents as severe abdominal pain, with or without hematochezia. We report an uncommon case of reversible colonic ischemia in who we believe to be the second-youngest adolescent female reported in the literature (youngest aged 16 years) to have this diagnosis associated with the use of a newer, third-generation oral combination hormonal contraceptive (Naranjo scale of 7; Probable).     

Oral contraceptive steroid plasma concentrations in smokers and non-smokers

A study was performed to find out whether the overall rate of metabolism of oral contraceptives is affected by smoking and whether this explains the increased incidence of cardiovascular disease in users of oral contraceptives who smoke. Plasma ethinyloestradiol and norgestrel concentrations in 311 women using oral contraceptives were similar in smokers and non-smokers. The overall rate of metabolism of contraceptive steroids does not therefore seem to be affected by cigarette smoking.     

Toxic shock syndrome and the vaginal contraceptive sponge

Thirteen confirmed cases of toxic shock syndrome temporally related to use of the vaginal contraceptive sponge have been reported. The observed risk of toxic shock syndrome in sponge users may be elevated above estimated background rates, but this risk remains very low. Traumatic manipulation of the sponge, use during menstruation or the puerperium, and prolonged retention of the sponge may additionally increase toxic shock syndrome risk. As with all contraceptives, risks must be balanced against benefits.     

Sex steroid hormones and breast cancer: is there a link with oral contraceptives and hormone replacement therapy?

OBJECTIVE: To determine whether use of sex steroid hormones for contraception and hormone replacement therapy alters the risk of breast cancer, and whether the risk varies with their composition, duration of use, the period of a woman's life when the hormones are used, and after successful treatment for breast cancer. DATA SOURCES: The results of important epidemiological reports, readily available from the English literature and published since 1981, were evaluated, using reports of basic scientific work as a background to the problem. STUDY SELECTION: An attempt was made to obtain most of the relevant reports. Twenty case-control and seven cohort studies were available on the oral contraceptive pill (OCP) and eleven case-control and five cohort studies on hormone replacement therapy (HRT). DATA EXTRACTION: The relative risk estimates for breast cancer (and their 95% confidence intervals) determined by each report were tabulated according to the specific conditions of analysis, for example users under age 25, duration of use. Results by meta-analysis from previous studies were also used to determine risk. A significant positive association was present when the risk estimate exceeded 1.0 and the 95% confidence interval did not cross 1.0. DATA SYNTHESIS: Among OCP users, the vast majority of reports showed no significant risk of breast cancer--overall, longest duration of use, and use before first full-term pregnancy. However, a positive association between breast cancer and users under age 25 was found in three of eight reports. Similarly, the majority of reports showed no significant risk of breast cancer among HRT users, overall as well as in relation to duration of use and interval since first use. There was no increased risk with additional progestogen; it may be protective. An improved prognosis was found in users who developed breast cancer. On the limited data, use of hormones for postmenopausal symptoms did not appear to be harmful to women who had been successfully treated for breast cancer. CONCLUSIONS: The review revealed good evidence that use of sex steroid hormones had no significant effect on the risk of breast cancer, whether given for contraception or hormone replacement. There was some concern about increased risk with prolonged use of the OCP, especially in younger women. At present, use of these hormones is a matter of informed choice, with individual considerations of the risk-benefit ratio.     

Contraceptive efficacy of the pill

Some women who use the pill are at a high risk of unplanned pregnancy. Health practitioners must evaluate drug medication data, gastrointestinal disturbances, and determine a patient's ability to use the pill effectively to identify those at high risk. Of the many types of contraceptives, the pill still comes the closest to being the most effective contraceptive. Nevertheless, the expected failure rate is lower than actual user rate due to a variety of reasons, such as forgetfulness in taking the tablets and temporary malabsorption problems. Since combined preparations of the pill such as the triphasic pill effect the hypothalamic-pituitary region, the endometrium, and the cervical mucosa, one would expect a high level of protection. Evidence indicates, however, that the triphasic pill is comparatively less effective than the fixed dose oral contraceptives. Additionally, studies reveal that certain women should not use oral contraceptives (e.g. women who smoke) because of increased risk to their health. Several benefits have been identified, however, in those women who are not considered high risk, such as a reduction in dysmenorrhea and irregular menstrual bleeding. Unfortunately, little is known on how to detect noncompliant users or how to motivate them to use the pill effectively. Yet research into alternative delivery routes, such as dermal patches and implants, has not reached the commercial level. In Australia, 25% of women of reproductive age choose oral contraceptives.     

Use of oral contraceptives by women with epilepsy

Oral contraceptives have not been associated with exacerbation of epilepsy despite warnings in package inserts. No clinical study has provided scientific evidence of worsening of seizures in epileptic women who use oral contraceptives, and improvement in seizure control has occurred in some cases. The main concern about use of oral contraceptives in this population is their effectiveness in preventing conception. Failure rates are higher in groups of women taking enzyme-inducing antiepileptic drugs. The degree of increased metabolism of estrogen and progestin components is highly variable and unpredictable among individuals. Use of higher doses increases protection against conception but also increases the risk of side effects, particularly in patients in whom no enzyme induction occurs. The strength of hormones in the pill should be selected individually when initiating use. Some women may require higher doses for full contraceptive effect.     

Cancer risks and the contraceptive pill. What is the evidence after nearly 25 years of use?

The question of whether the steroidal components in oral contraceptives (OCs) may have an initiating or promotional influence on the development of cancer continues to be raised as a public health issue. It is estimated that since the introduction of OCs nearly 25 years ago, more than 150 million women have used 1 or more types of the formulation and nearly 1 billion woman-years of exposure to the steroids have accumulated. Contraceptive practice in Australia would indicate that about 25% of women of reproductive age are using OCs. The debate about the OC's carcinogenic potential has recently been reopened with 2 reports in "The Lancet" of an association between the incidence of breast and cervical cancer and OC usage. Biologically the relationship between the contraceptive steroids and cancer must continue to be regarded as the most important concern with the longterm use of OCs. The demonstration of receptors to these steriods in these organs, in both normal and malignant tissues, further increases the speculation that the steroid hormones have a biological role in carcinogenesis in these target organs. Theoretical reasons exist for the concern about carcinogenesis and contraceptive steroids. This paper reviews the available evicence. Data can be derived only from large-scale epidemiological research, by means of case-control or cohort studies. No clear evidence exists that OCs cause or increase the chance of developing any cancer in the female genital tract and the breast. In fact, OC offers a significant protection against the development of endometrial and ovarian cancer, especially to those women who have taken OCs for a long time. The association between the risk of breast cancer and OC use is less certain, but factors such as the history of benign breast disease, a close relationship with breast cancer, or nulliparity -- previously considered to be important -- do not appear to contribute significantly to the risk. The weight of evidence indicates that no increased risk of breast cancer exists, even in those younger women aged less than 25 years who decide to use OCs before their 1st full-term pregnancy. There is some evidence that suggests that the risk of cervical neoplasia -- dysplasia, carcinoma-in-situ and invasive carcinoma -- may increase slightly in OC users but the actual part played by the patient's sexual history under these circumstances remains to be defined. There is now strong evidence to implicate multiplicity of sexual partners and wart virus infection in carcinogenesis of the uterine cervix. There does not appear to be an overall relationship between OCs and malignant melanoma. Overall, the evidence is reassuring. The low-dose combined OC can be considered safe, not only in terms of cardiovascular and thromboembolic risks, but also in relation to carcinogenesis.