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.     

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.     

Factor V leiden and venous thromboembolism in a woman taking second generation oral contraceptives: a case report]

The most common cause of thrombophilia is a point mutation in factor V gene (G1691A), leading to factor V Leiden synthesis, which is resistant to the inhibition by activated protein C. Administration of oral contraceptives is associated with an increased risk of venous thromboembolism in carriers of factor V Leiden mutation. We describe here a case of 44-year-old woman who developed right popliteal and superficial deep vein thrombosis after a 2-month use of a contraceptive which consists of 0.15 mg levonorgestrel and 0.03 mg ethynylestradiol. The mutation G1691A of factor V gene was detected with the polymerase chain reaction. No other inherited or acquired risk factors for thrombosis was found in this patient. Treatment with low molecular weight heparin and subsequently, oral anticoagulation was effective. Women with factor V Leiden should be discouraged from taking oral contraceptives. Screening for factor V Leiden in these women appears to be useful and contribute to the prevention of thrombosis in risk situations.     

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.)     

Thrombophilias and gynaecology

In gynaecology, women are exposed to sex steroids when using oral contraceptives, hormone replacement therapy or when undergoing in vitro fertilization treatment and ovulation induction. Oral contraceptives and the use of hormone replacement therapy increase the risk of venous thrombosis. The risk is highest in the first year of use and higher among women with clotting defects. Women taking third-generation oral contraceptives have an almost twofold increased risk of venous thrombosis compared with those taking second-generation oral contraceptives. Inherited clotting defects, which are themselves risk factors of venous thrombosis, (e.g. factor V Leiden mutation, deficiency of protein C, protein S or antithrombin, high plasma levels of factor VIII, and prothrombin mutation) appear synergistically increase the risk of venous thrombosis caused by oral contraceptives. Recent studies also point to an interaction between hormone replacement therapy and coagulation defects in causing venous thrombosis. Emerging studies show that in vitro fertilization treatment and ovulation induction are also risk factors for venous thrombosis; the role of coagulation defects in this association is not yet clear.     

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.     

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.     

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.     

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 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.     

Thromboembolism in pregnancy

Venous thromboembolism in pregnancy is a clinical emergency that has been associated with significant risk for maternal and fetal morbidity and mortality. The adaptation of the maternal hemostatic system to pregnancy predisposes women to an increased risk of thromboembolism. A timely diagnosis of deep venous thrombosis is crucial because up to 24% of patients with untreated deep venous thrombosis develop a pulmonary embolism. Recent clinical guidelines identify compression venous ultrasound as the best way to diagnose deep venous thrombosis in pregnancy and CT pulmonary angiography as the best way to diagnose pulmonary embolism in pregnancy. Therapy involves supportive care and anticoagulation with unfractionated or low molecular weight heparin, depending on the clinical scenario.     

Side and site of deep vein thrombosis in women using oral contraceptives

The anatomy of the thrombus in acute deep vein thrombosis (DVT) in women using oral contraceptives was studied in 277 reports on DVT received by the Swedish Adverse Drug Reaction Advisory Committee (SADRAC). The study revealed a similarity between the anatomy of DVT in women on oral contraceptives and that of DVT in pregnant women, suggesting a pharmacologic influence of the hormones in the pill on the pathogenesis of DVT in women on oral contraceptives. The anatomy of DVT in women on low-estrogen pills was identical with that of DVT in women on high-estrogen pills, suggesting an identical pharmacologic influence of the two types of pill on the pathogenesis of DVT in women on oral contraceptives.     

The natural history of postoperative venous thromboemboli in gynecologic oncology: a prospective study of 382 patients

Three hundred eighty-two patients who underwent major operations for gynecologic malignancy were studied prospectively to determine the natural history of postoperative venous thromboemboli. Iodine 125-labeled fibrinogen leg counting, to diagnose deep venous thrombosis, was performed daily. Sixty-three patients (17%) developed postoperative venous thromboembolic complications. Deep venous thrombosis initially arose in the calf veins in 52 patients. Twenty-seven percent of these thrombi lysed spontaneously. Four percent of thrombi in the calf veins progressed to deep venous thrombosis in the femoral vein, and 4% resulted in pulmonary emboli. Nine other patients developed proximal deep venous thrombosis without prior thrombosis in the calf veins. One patient with proximal deep venous thrombosis also had a pulmonary embolus. Two patients with no evidence of deep venous thrombosis on prospective 125I-labeled fibrinogen leg counting developed pulmonary emboli, including one fatal pulmonary embolus that was found at autopsy to have arisen from the internal iliac veins. Fifty percent of all venous thromboemboli were detected within 48 hours of operation, although two patients developed significant deep venous thrombosis and pulmonary emboli after discharge from the hospital. These results add important information to our understanding of this disease process, and raise issues related to appropriate treatment and prophylaxis of venous thromboembolism in patients after gynecologic operations.     

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.     

Venous thromboembolism in pregnancy

Venous thromboembolism remains a common cause of direct maternal deaths in high-income settings such as the United Kingdom. Pregnancy alone increases the risk of deep vein thrombosis and pulmonary embolus at least five-fold, and many women develop or have additional risk factors for venous thrombosis during pregnancy and the puerperium, the latter representing the period of highest risk. Early and repeated risk stratification and adequate thromboprophylaxis, usually with low molecular weight heparin, is the key to preventing venous thromboembolism (VTE). Women with a past history of VTE, and those affected by thrombophilia, require multidisciplinary care involving an obstetric haematologist. Women suspected of having acute thromboembolism should be commenced on empirical treatment promptly prior to diagnostic confirmation. Pulmonary embolism should be considered as a differential diagnosis in maternal collapse.     

Coagulation studies in women on combination type of oral contraceptives

In view of the controversy stemming from reports indicating young women who take combined types of oral contraceptives are at greater risk of venous thrombosis and cerebral or coronary thrombosis, a clinical investigation of blood coagulation changes among 41 oral contraceptive users and 25 controls was undertaken at the K.E.M. Hospital in Bombay, India. The 25 controls (Group A) were women who planned to begin using oral contraceptives but had not yet begun use. 16 of the 41 oral contraceptive users had been taking combined pills for 1 l/2 - 5 years (Group B) and the other 35 for more than 5 years (Group C). Coagulation parameters investigated were 1) prothrombin time; 2) partial thromboplastin time; 3) serum fibrinogen; 4) euglobulin clot lysis time; 5) platelet count; 6) platelet adhesiveness; and 7) platelet aggregation. Significant changes occurred in partial thromboplastin time, platelet count, platlet aggregation, and prothrombin time. Group B had a higher rise in prothrombin time than Group A and a rise in platelet aggregation and in partial thromboplastin time compared to Group A. Platelet counts were higher for both groups of oral contraceptive users than for the controls.     

Saga of the newer generation pills and the concept of risk

The World Health Organization is conducting a case-control study in centres in Africa, Asia, Europe and Latin America on the cardiovascular side effects of different types of oral contraceptives. Previous studies have mostly taken place in North America and Europe, and may not apply to women elsewhere. The first results, focusing only on possible vein problems, were published in December 1995.1 As with previous studies, it was found that oral contraceptives increase the risk of deep vein thrombosis and pulmonary embolism2 and that women using pills containing two newer progestogens - desogestrel and gestodene - seemed to have a higher risk of deep vein thrombosis than those containing older progestogens. This paper explains the significance of these results and describes how a number of European drug regulatory authorities and doctors reacted, what they advised women to do and what women actually did.