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 Combined Contraceptive Vaginal Ring: an Update

The combined contraceptive vaginal ring releases 120 μg of etonogestrel and 15 μg of ethinylestradiol per day for at least a 3-week period. It is as effective as combined oral contraceptive pills with similar side effects but better cycle control. The ring is not associated with weight gain and may have many non-contraceptive benefits including a positive effect on sexual function, dysmenorrhea, premenstrual syndrome, and heavy menstrual bleeding. Contraindications are the same as for combined oral contraceptives, and serious complications are rare. The risk of venous thromboembolism with the ring is comparable with that of combined oral contraceptives. The rate of acceptability of the ring is high, and most women, including adolescents, can use the ring.     

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.     

Health benefits of oral contraceptives

A sizeable literature corroborates the multiple health benefits of oral contraceptive use. The first estrogen/progestin combination pills were marketed to treat a variety of menstrual disorders. Although currently used oral contraceptives no longer carry FDA-approved labeling for these indications, they remain important therapeutic options for a variety of gynecologic conditions. Well-established gynecologic benefits include a reduction in dysmenorrhea and menorrhagia, iron-deficiency anemia, ectopic pregnancy, and PID. Although older, higher-dose pills reduced the incidence of ovarian cysts, low-dose pills suppress follicular activity less consistently. Nevertheless, cycle-related symptoms, including functional cysts, dysmenorrhea, chronic pelvic pain, and ovulation pain (mittelschmerz), generally improve. Women with polycystic ovary syndrome note improvement in bleeding patterns and a reduction in acne and hirsutism. Symptoms from endometriosis also improve with oral contraceptive therapy. Current data suggest that oral contraceptive therapy increases bone density and that past use decreases fracture risk. Oral contraceptives also improve acne, a major health concern of young women. Oral contraceptives provide lasting reduction in the risk of two serious gynecologic malignancies--ovarian and endometrial cancer. The data with respect to ovarian cancer are compelling enough to recommend the use of oral contraceptives to women at high risk by virtue of family history, positive carrier status of the BRCA mutations, or nulliparity, even if contraception is not required. Health care providers must counsel women regarding these benefits to counteract deeply held public attitudes and misconceptions regarding oral contraceptive use. Messages should focus on topics of interest to particular groups of women. The fact that oral contraceptives increase bone mineral density and reduce ovarian cancer is of great interest to women in their forties and helps influence use and compliance in this group. In contrast, the beneficial effects of oral contraceptives on acne resonates with younger women. Getting the good news out about the benefits of oral contraceptives will enable more women to take advantage of their positive health effects.     

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.     

Kontrazeption

During treatment with ovulation inhibitors, severe adverse effects are very rare, e.g. venous thromboembolism, myocardial infarction, and stroke. The risk increases in women with a predisposition or risk factors. Healthy, nonsmoking females of normal weight and with nonremarkable family history can be treated with low-dose combined hormonal contraceptives, whereas for patients at risk or contraindications for ovulation inhibitors, other safe and reliable contraceptive methods are available.     

Oral contraceptives, thrombosis and haemostasis

The use of oral contraceptives is a well-established acquired risk factor for venous thrombosis. In 1995, a number of epidemiological studies were published which suggested that women who use third generation oral contraceptives that contain desogestrel or gestodene as progestagen are exposed to a two- to threefold higher risk for venous thrombosis than women using second generation oral contraceptives which contain levonorgestrel. In this paper, the effects of oral contraceptives on the haemostatic system are discussed. It appears that plasma from oral contraceptive users is resistant to the anticoagulant action of activated protein C (APC). This phenomenon, called acquired APC resistance, is more pronounced in users of desogestrel or gestodene-containing oral contraceptives than in women who use oral contraceptive pills with levonorgestrel. On the basis of these observations, it was proposed that acquired APC resistance may be the mechanistic basis of the increased risk for venous thrombosis during oral contraceptive use and for the further increased thrombotic risk of third generation oral contraceptive users. Furthermore, the results of a recent cross-over study are discussed. This study indicated that a large number of other haemostatic parameters were changed during oral contraceptive use. Some of these changes were more pronounced on desogestrel-containing oral contraceptives. The cross-over study also showed that the increased fibrinolytic activity during OC use is counterbalanced by an enhanced activity of thrombin-activatable fibrinolysis inhibitor (TAFI), a protein that participates in the inhibition of fibrinolysis.     

Contraception in women with renal failure (author's transl)

Contraception in women affected by renal insufficiency aims at preserving their fertility potential while waiting for a kidney transplant which may make childbearing possible. In older women contraception aims at avoiding a pregnancy which may worsen their condition. Women with renal insufficiency and aged 40-50 must avoid combined oral contraceptives. An IUD would be the best choice as well as progestational agents in regular doses 21 days a month, from the 5th to the 25th day of the cycle. Given the different metabolic impact of each progestational agent the choice remains with the gynecologist after a careful consideration of the patient's condition. Contraception by low-dose progestational agents may be advisable in some patients. Women undergoing periodic hemodialysis usually have normally ovulating cycles. An IUD would not be advisable since it may cause anemia, the same for low-dose progestational agents. The continued administration of high-dose progestational agents would be better suited for this group of patients, alternated with combined sequential pills in women with normal lipid and cholesterol levels. Women who have had a kidney transplant must wait at least 2 years before becoming pregnant. During this period mechanical contraception and the IUD are not indicated, and neither are combined contraceptives because of the risk of vascular side effects; continued or discontinued administration of low-dose progestin would be the method of choice. Alternating the different contraceptive methods is a possibility at every stage of the disease. Patients must be carefully checked at regular intervals.     

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.     

Venous thromboembolism in relation to oral contraceptive use

The relation of the risk of venous thromboembolism to the use of oral contraceptives was assessed in a hospital-based study of 61 women suffering from a first episode of idiopathic deep vein thrombosis or pulmonary embolism (cases) and 1278 women admitted for trauma or respiratory infections (controls). Twenty (33%) of the cases and 121 (9%) of the controls had used oral contraceptives within the previous month, yielding an age-adjusted relative risk estimate of 8.1 (95% confidence interval 3.7 to 18) for recent users relative to never-users. For women using oral contraceptives containing less than 50 micrograms estrogen, the relative risk estimate was 11 (3.7 to 22); for preparations with 50 micrograms estrogen, it was 5.5 (2.1 to 15); and for preparations with more than 50 micrograms estrogen, it was 11 (3.9 to 30). Past use of oral contraceptives was not associated with an increased risk. The data suggest that the risk of venous thromboembolism is increased for recent oral contraceptive users relative to nonusers, even if women use oral contraceptives containing low doses of estrogen. Confidence intervals were wide, however, so that a reduction in the risk for users of lower dose formulations relative to users of higher dose formulations cannot be ruled out. Selection bias, if present, would have resulted in overestimation of the relative risk, but should not have distorted the comparisons according to dosage.     

Contraceptive choice and prevalence of cervical dysplasia and carcinoma in situ.

Whether use of oral contraceptives is associated with subsequent development of cervical neoplasia is an important public health question. Before evaluating this issue, we must determine if choosing oral contraceptives identifies a woman who is intrinsically at high risk of developing cervical neoplasia. We have examined the demographic and reproductive characteristics as well as cervical premalignant changes manifest by 15- to 44-year-old black women who enrolled in a public family-planning clinic. When compared to IUD acceptors, oral contraceptive acceptors did not have a disproportionately large number of women with traits which predicted for high risk of developing cervical neoplasia. Oral contraceptive acceptors, compared to IUD acceptors, did not have a higher prevalence rate of carcinoma in situ. Oral contraceptive acceptors with no Pap smears prior to initial choice of contraceptive method did have a 1.4-fold higher prevalence rate of cervical dysplasia than IUD acceptors. These results suggest that the deicision to use oral contraceptives, per se, does not identify a group of women at higher risk to develop cervical carcinoma in situ. Such a decision may, however, identify a group with a small increased propensity for developing cervical dysplasia.     

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.     

Reversible contraception for the woman over 35 years of age.

Methods of reversible contraception, oral contraceptives, intrauterine devices, and Norplant (systemic progestin-only contraceptive; Wyeth-Ayerst, Radnor, PA), can be used for women over 35 years of age. Oral contraceptive formulations are safe and effective for healthy women up to the age of menopause. Oral contraceptives in women who do not smoke cigarettes do not result in a significant increased risk for cardiovascular disease. The incidence of breast cancer is not increased in women who have used oral contraceptives. A slight increase was found in younger women who had been on oral contraceptives based on a reanalysis of the contraceptive and steroid hormone study of the Centers for Disease Control. A reduction in the incidence of ovarian epithelial neoplasia by 40% was found in three European case-control studies. Two intrauterine devices are currently available on the US market: Paragard (GynoPharma, Somerville, NJ) and Progestasert (Alza Corp., Palo Alto, CA). Both of these provide highly effective contraception. A World Health Organization prospective randomized study found that there was an increase in pelvic inflammatory disease rates in the first 20 days after intrauterine device insertion. The intrauterine device itself did not increase the pelvic inflammatory disease incidence rates. The Norplant system exerts its contraceptive action through ovulation inhibition and alteration of cervical mucus. The major consumer complaint is irregular or prolonged uterine bleeding, which can be controlled by oral estrogen.     

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.     

Combined hormonal contraceptives and venous thromboembolism: putting the risks into perspective

To date, 13 studies have provided data on the risk of venous thromboembolism associated with combined oral contraceptives containing drospirenone or the norelgestromin-containing contraceptive patch. The studies varied in their conclusions about whether these methods are associated with higher risks than combined oral contraceptives containing other progestins: the primary reported measures of association (adjusted odds ratios, incidence rate ratios, or hazard ratios) ranged from 0.9 to 3.3. All of the studies had weaknesses in population selection, data validity or completeness, or analysis that may have led to biased or spurious findings. Venous thromboembolism is rare; if the contraceptive methods of interest do confer a higher risk of thromboembolism, only an additional 5-10 per 10,000 users per year would be affected. The important message for patients, clinicians, and policy makers is that the benefits of all contraceptive methods markedly outweigh their risks, primarily because they prevent pregnancy, an inherently hazardous condition. Product labels for hormonal contraceptives should emphasize their substantial health benefits and established safety.     

Hepatic adenoma and focal nodular hyperplasia.

Hepatic adenoma and focal nodular hyperplasia are benign lesions of the liver. The incidence of these conditions has been increasing since 1970. Hepatic adenoma primarily affects young women of childbearing age who have a long history of using oral contraceptives, while focal nodular hyperplasia has a wider age distribution and is not associated with the use of oral contraceptives. The most extensive complication of hepatic adenoma is intratumoral or intraperitoneal hemorrhage, which occurs in 50 to 60 per cent of patients. Patients with focal nodular hyperplasia are usually asymptomatic and rarely experience complications. Hepatic adenoma is distinct from focal nodular hyperplasia both in its clinical behavior and its pathologic features; the two can usually be differentiated radiographically using a combination of radionuclide scanning and angiography. There is a proved association between the use of oral contraceptives and the development of hepatic adenoma; the longer the duration of oral contraceptive use, the more the risk of having hepatic adenoma develop. In addition, users of oral contraceptives who have hepatic adenoma develop are likely to have larger tumors and higher rates of bleeding and rupture than nonusers who have hepatic adenoma develop. Although hepatic adenomas may regress after discontinuation of oral contraceptive use, this is not a consistent finding. In addition, it has now been demonstrated that hepatic adenomas do undergo malignant transformation and that this can be detected by measuring the alpha-fetoprotein level. Focal nodular hyperplasia may be a precursor for fibrolamellar hepatocellular carcinoma. Elective resection of hepatic adenoma has a mortality rate of less than 1 per cent, while the mortality rate with free rupture is 5 to 10 per cent. Because of the relative safety of elective versus emergency resection and the potential for malignant change, the treatment of choice for hepatic adenoma is surgical resection.     

Comparison of cycle control with a combined contraceptive vaginal ring and oral levonorgestrel/ethinyl estradiol

OBJECTIVE: The purpose of this study was to compare cycle control and tolerability of the NuvaRing (NV Organon, Oss, The Netherlands), a novel combined contraceptive vaginal ring, with a standard combined oral contraceptive pill. STUDY DESIGN: Healthy women aged 18 to 40 years who requested contraception received either NuvaRing or a combined oral contraceptive containing 30 microg ethinyl estradiol and 150 microg levonorgestrel for 6 cycles in 3 similarly designed studies. Each cycle comprised 3 weeks of ring or pill use, followed by 1 ring- or pill-free week. RESULTS: Two hundred forty-seven women began the studies, 121 women with NuvaRing and 126 women with the combined oral contraceptive. Withdrawal bleeding occurred in virtually all cycles in both groups. In the NuvaRing groups, the incidence of irregular bleeding was < or =5% in all cycles; this was lower than the combined oral contraceptive groups (5.4%-38.8%). Furthermore, the incidence of a normal intended bleeding pattern was significantly higher in the NuvaRing groups than in the combined oral contraceptive groups (P <.01). Both contraceptives were well tolerated. CONCLUSION: NuvaRing has excellent cycle control and is well tolerated.     

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.     

Risks and mechanisms of cardiovascular events in users of oral contraceptives

Three large British studies on the vascular effects of oral contraceptives have established that the risk of thrornboembolic episodes, both venous and arterial, rises with increasing estrogen dose. Two of these studies have also demonstrated a dose-dependent relationship between the progestogenic component of oral contraceptives and the risk of arterial disease, though not of venous events. In men, high levels of factor VII coagulant activity, VII_c, and plasma fibrinogen are associated with an increased risk for ischemic heart disease. In view of the dose-dependent relationship between estrogen and these two clotting factors, especially VII_c, it is likely that the effects of oral contraceptive usage on the risk for thromboembolism are mediated substantially through the level of coagulability. The relationship between the progestogenic component of oral contraceptives and the risk for arterial disease is probably related, at least in part, to the effects of progestogens on blood pressure.