Oral contraceptive pills and the risk of venous thromboembolism

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

Use of oral contraceptives in women of older reproductive age

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

Oral contraceptives: a reassessment

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

Oral contraception

An orally administered formulation intended to prevent pregnancy. Oral contraception in women is available in two formulations: products containing both oestrogen and progestogen – combined oral contraceptives (COCs, The Pill) and those containing progestogen alone – progestogen-only pills (POPs, The Mini-Pill).COCs first became available in the UK in 1961 and have become an extremely safe, effective and popular method of reversible contraception. They also benefit from having non-contraceptive health benefits.This article aims to outline the advantages and disadvantages of taking oral contraception and important aspects of safe prescribing.Initially the article will focus on the COC pill, with the differences arising with the progestogen-only pill outlined later.     

Oral contraception

Oral contraception for women is available in two formulations; products containing both oestrogen and progestogen – combined oral contraceptives (COCs, the pill); and those containing progestogen alone – progestogen-only pills (POPs, the mini-pill). COCs first became available in the UK in 1961 and have become an extremely safe, effective and popular method of reversible contraception. They also have non-contraceptive health benefits. This article aims to outline the advantages and disadvantages of taking oral contraception and the important aspects of safe prescribing, focusing first on COCs and then outlining how POPs differ.     

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.     

Erroneous clinical diagnosis of leg vein thrombosis in women on oral contraceptives

Most studies demonstrating an increased risk of venous thromboembolism in women on oral contraceptives are based on clinical manifestations of the disease. Because of the fallibility of the clinical diagnosis of suspected leg vein thrombosis, Doppler ultrasonic evaluation (with a 93% accuracy compared to venography) was performed for clinical manifestations in deep vein thrombosis in 54 women taking birth control pills and 75 women of similar age who were not on contraceptives. The clinical diagnosis was confirmed by Doppler in only 16.7% of the women taking contraceptives and 30.7% of women not taking contraceptives (P = 0.052). This study suggests that the clinical diagnosis of leg vein thrombosis is frequently erroneous, particularly in women taking oral contraceptives. Future investigations reporting venous thromboembolism associated with oral contraceptives should be based on diagnoses validated by accurate objective techniques.     

Contraceptive choices in women with coagulation disorders

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

Oral contraceptives increase deep venous thrombosis in smoking women

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

Update on oral contraceptive pills and postcoital contraception.

Modern oral contraceptive pills are safe for the majority of American women. The most important contraindications to oral contraceptive pill use are a history of thrombophlebitis or thromboembolism while on the pill or during pregnancy, smoking over 15 cigarettes daily if over 35 years of age, active liver disease, hypertension, diabetes, a lipid disorder, or breast cancer. A history of gestational diabetes is not an absolute contraindication to oral contraceptive pill use, but women with such a history must be encouraged to exercise and eat properly to reduce the high risk of developing overt diabetes. Couples should be encouraged to use condoms to reduce the risk of sexually transmitted diseases. Most antibiotics do not decrease the effectiveness of the pill. Nonuse of contraception among adolescents and older couples is the most common reason for failure. Postcoital contraceptive pills are available but are not completely effective. The use of modern contraceptives is almost always safer than nonuse.     

The health effects of oral contraceptives: misperceptions, controversies, and continuing good news

This review on the risks and benefits of oral contraceptives clarifies the risks and misperceptions, and discusses 10 potential health benefits. In the U.S. where maternal mortality is about 20.6/100,000, the risk of death from pills ranges from 1.8 for nonsmokers to 6.5 for smokers. It is likely that most of the small existing mortality risk of pill use is due to thromboembolism. Atherosclerosis, the major cause of death for U.S. women, may be reduced by the pill. It is still controversial whether pills increase risk of hepatocellular carcinoma and malignant melanoma; they protect against endometrial cancer (the 3rd greatest cancer killer) and ovarian (the 4th) cancer; they may increase risk slightly in some subgroups for breast and cervical cancer, although data are conflicting. Pills also protect against ectopic pregnancy, benign breast disease, pelvic inflammatory disease, ovarian cysts, iron deficiency anemia and possibly uterine fibroids and osteoporosis. It is no longer held that orals protect against toxic shock syndrome or rheumatoid arthritis. It is estimated that oral contraceptives avert 50,000 hospital admissions per year in the U.S.     

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.     

Screening for factor V Leiden mutation before prescribing combination oral contraceptives.

OBJECTIVE: To evaluate the cost-effectiveness of screening for factor V Leiden mutation in women in the United States who use combination oral contraceptives. DESIGN: Cost-effectiveness analysis. SETTING: A national research reference laboratory, a university medical center, and an academic health center managed care organization. PATIENT(S): Women of reproductive age in the United States. INTERVENTION(S): Baseline risk estimates of venous thromboembolic disease in the general population and in carriers of factor V Leiden mutation were calculated using available data. MAIN OUTCOME MEASURE(S): The number of women who would require factor V Leiden testing and the cost of identifying this cohort to prevent one death caused by venous thromboembolic disease before prescribing combination oral contraceptives. RESULT(S): To prevent one venous thromboembolic death attributable to the use of oral contraceptives in women with factor V Leiden mutation, >92,000 carriers would need to be identified and stopped from using these pills. The estimated charge to prevent this one death would exceed $300 million. If the price of testing were discounted to 34.5% of current charges, the cost still would be between $105 million and $130 million. CONCLUSION(S): Screening for factor V Leiden mutation before prescribing combination oral contraceptives is not a cost-effective use of U.S. health care dollars. The best and most cost-effective screening tool we have is taking a thorough personal and family history related to venous thromboembolic events.     

Effects of third-generation oral contraceptives on high-sensitivity C-reactive protein and homocysteine in young women

OBJECTIVE: To evaluate the effect of third-generation oral contraceptives on high-sensitivity C-reactive protein (CRP), homocysteine, and lipids levels in a population of young, fertile, nonobese women. METHODS: Blood markers were evaluated in 277 healthy white women (mean age 23 years and mean body-mass index 21 kg/m(2)). Seventy-seven oral contraceptive users were compared with 200 non-oral contraceptive users. Progressive cutoffs of high-sensitivity CRP and homocysteine levels were examined. RESULTS: Levels of high-sensitivity CRP posing a high risk of cardiovascular disease (3.0 to less than 10.0 mg/L) were found in 27.3% of oral contraceptive users and in 8.5% of non-oral contraceptive users (odds ratio 4.04; 95% confidence interval [CI] 1.99-8.18). Levels of high-sensitivity CRP at intermediate risk (1.0 to less than 3.0 mg/L) were found in 32.5% of oral contraceptive users and in 11.0% of non-oral contraceptive users (odds ratio 3.89; 95% CI 2.03-7.46). Notably, non-oral contraceptive users were 8.65 (95% CI 4.39-17.1) times as likely to demonstrate a protective level of high-sensitivity CRP (less than 0.5 mg/L) compared with oral contraceptive users. Oral contraceptive use increased serum triglycerides (P<.001) and total cholesterol P=.001); however, high-density lipoprotein, not low-density lipoprotein, contributed to this increase. A decreased ratio of low-density lipoprotein to high-density lipoprotein cholesterol was observed in oral contraceptive users compared with nonusers (P=.016). Oral contraceptive use did not affect homocysteine levels. CONCLUSION: Third-generation oral contraceptive use increases low-grade inflammatory status measured by high-sensitivity CRP concentrations. Alteration of inflammatory status in oral contraceptive users could affect the risk of venous thromboembolism, cardiovascular disease, and other oral contraceptive-associated adverse conditions in young women.     

The effects of oral estrogen-progestin compounds on blood coagulation factors

Oral contraceptives increase the levels of coagulation Factors II (prothrombin), VII (proconvertin), IX (plasma thromboplastin component), and X (Stewart factor) which form the prothrombin complex or vitamin-K-dependent factors. These factors occur in the progressive clotting process initiated by ruptured endothelium (intrinsic mechanism) or by tissue thromboplastin (extrinsic). Although Factors I (fibrinogen), VII, VIII (antihemophilic), IX, X, and platelets are increased in pregnancy, thromboembolism is more likely to occur in the postpartum period. During 1966-1967, 51 deaths and 183 nonfatal cases of thromboembolism among pill users were reported to the U.S. Food and Drug Administration. Several women known to have experienced a thromboembolism while using oral contraception had a second thromboembolic episode when the pill was resumed. In one of these women, coagulation factors were observed to rise during the second course of steroids when the second thromboembolism occurred. Further evidence associating thromboembolism and oral contraceptives comes from British case-controlled retrospective data and from studies with oral estrogens and progestins for menstrual indications. Research on animal models and screening tests is underway.     

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.     

Relationship of migraine headache and stroke to oral contraceptive use

Are oral contraceptive users who also suffer from migraine headaches at higher risk of having a cerebrovascular accident? The data are inconclusive in establishing that women who used the relatively higher-dose pills prescribed in the 1960s have a higher risk of either thrombotic or hemorrhagic stroke. Furthermore, a review of the literature does not support the belief that those women who use oral contraceptives have a higher incidence of migraine headache. The available data do not indicate that migraine headache is necessarily a contraindication to prescribing oral contraceptives.     

Thromboembolic risk in pregnant women with SARS-CoV-2 infection – A systematic review

The infection by SARS-CoV-2 is associated with a thromboembolic complications risk theoretically increased. Pregnancy, isolated, is considered a pro-thrombotic state.This systematic review has the main goal to evaluate the thromboembolic risk in pregnant women with COVID-19 disease, namely for pulmonary embolism (PE) and deep vein thrombosis (DVT). The secondary goal is the evaluation of the need for thromboprophylaxis in these cases.Three databases - PubMed, Scopus and Web of Science – were searched on October 2021, using the following Mesh terms and keywords: “(covid-19 OR SARS-CoV-2 OR Covid) AND (pregnancy) AND (coagulopathy OR blood coagulation disorders OR thrombotic complications OR thromboembolic risk OR venous thromboembolism OR venous thrombosis)”. Information about thrombotic complications in pregnancy and thromboprophylaxis was collected, by two independent reviewers.In total, 12 articles were analyzed, corresponding to 18205 pregnant women with SARS- CoV-2 infection. A total of 85 cases of thromboembolic events were diagnosed (0.46%, 95% CI 0.37–0.58%), of which only 17 reported the use of thromboprophylaxis (20.00%, 95% CI 12.10–30.08%). There were 3 deaths due to thromboembolic complications (3.53%, 95% CI 0.73–9.97%).In conclusion, in pregnant women, the SARS-CoV-2 infection increases the risk of thromboembolic complications. However, the risk is not greater than in the general population. It is recommended thromboprophylaxis with low molecular weight heparin for hospitalized pregnant women, and in groups with moderate to high thromboembolic risk at home self-isolation.