Smoking and use of oral contraceptives: impact on thrombotic diseases.

OBJECTIVES: The study was intended to evaluate the effects of oral contraceptives and smoking on the risks of arterial and venous thromboembolic diseases among young women. STUDY DESIGN: The study included a survey of data from published epidemiologic studies and evaluation of registry records of all Danish women discharged from the hospital from 1980 through 1993 after a first thromboembolic event. Questionnaires returned by survivors of such events and by control women during the period from 1994 through 1995 were analyzed. RESULTS: In the 1980-1993 data the absolute risk of thrombotic diseases was seen to increase rapidly with age-exponentially for acute myocardial infarction or cerebral thromboembolic attack, linearly for venous thromboembolism-with risks of arterial diseases exceeding those of venous diseases. In the 1994-1995 data the relative risk of thrombotic diseases was seen to increase among users of oral contraceptives irrespective of age. Risk of venous thromboembolism (but not of acute myocardial infarction or cerebral thromboembolic attack) declined as duration of current oral contraceptive use lengthened, risk of acute myocardial infarction or cerebral thromboembolic attack was significantly decreased as ethinyl estradiol doses were reduced, and the relative risk (compared with nonusers of oral contraceptives) for arterial thromboembolic disease among users of desogestrel or gestodene (in conjunction with midrange or low doses of ethinyl estradiol) was lower than the relative risk among users of second-generation progestogens (in conjunction with midrange doses of ethinyl estradiol). The combination of smoking with oral contraceptive use may have a synergistic effect on risks of acute myocardial infarction and cerebral thromboembolic attack (but not of venous thromboembolism), particularly among users of high-dose (50 micrograms) ethinyl estradiol preparations. CONCLUSION: Among the formulations currently marketed in Denmark, where only the progestins desogestrel and gestodene are available with low-dose (20 micrograms) ethinyl estradiol (and only desogestrel was available in that form at the time of our studies), we prefer these third-generation oral contraceptives for smokers. We might also consider such oral contraceptives for women >35 years old as long as they had no other risk factors for thrombotic arterial diseases.

PIP: This study assesses the effects of cigarette smoking and oral contraceptive (OC) use on the risks of arterial and venous thromboembolic diseases among women in their reproductive years. A survey of published epidemiologic studies is included together with an evaluation of registry records of Danish women discharged from hospitals from 1980 through 1993 after a first thromboembolic event. Analysis was made of questionnaires sent to survivors of such an event and to control women during the period from 1994 through 1995. The study also includes an evaluation of thrombotic disease prevalence, determination of OC influence on the risk of the disease, and comparison of disease prevalence among smoking and nonsmoking users of OC. Results showed that the risk of acute myocardial infarction among OC users was significantly higher than among non-OC users. OC use had less of an effect on acute myocardial infarction risk than on the risk of cerebral thromboembolic attack. The risk of venous thromboembolism among users of OC was influenced by the duration of OC use; the shorter the use, the higher the risk, while smoking had little effect. Epidemiologic studies suggest that arterial disease risk in young (men/women) decreases within 5-10 years of smoking cessation. Smoking, with a low dose of OC, acted as an independent risk factor for myocardial infarction and cerebral attack. The absolute risk for older nonusers and nonsmokers was higher by 10-fold than the risk for younger counterparts. Thus, among the formulations available in Denmark, preference is given to third-generation OCs for young female smokers and for smoking women over age 35, provided they have no other risk factor for thrombotic arterial disease.

Estimates of the risk of cardiovascular death attributable to low-dose oral contraceptives in the United States.

OBJECTIVE: Our purpose was to estimate the annual risk of death in the United States from cardiovascular disease attributable to low-dose combination oral contraceptives. STUDY DESIGN: Estimates of the risk of death from cardiovascular disease attributable to low-dose oral contraceptives were modeled on data from studies published through 1997 and from age-specific mortality rates in the United States for 1993 and 1994. RESULTS: Attributable risk of death from cardiovascular disease resulting from oral contraceptive use is 0.06 and 3.0 per 100,000 nonsmokers 15 to 34 years of age and 35 to 44 years of age, respectively. In smokers this risk increases, respectively, to 1.73 and 19.4 per 100,000 users in these 2 age groups; however, 97% and 85% of this risk is due to the combined effects of smoking and using oral contraceptives. The attributable risk of death from cardiovascular disease in nonsmoking oral contraceptive users is lower than the risk of death from pregnancy in nonusers of oral contraceptives at all ages; however, among smoking oral contraceptive users more than 35 years of age, the excess risk of death from oral contraceptives is higher than the risk of death from pregnancy. CONCLUSION: There is virtually no excess attributable risk of death from cardiovascular disease related to oral contraceptive use in young women. However, smokers more than 35 years of age should use a nonestrogen contraceptive.

PIP: The annual risk of death in the US from cardiovascular disease attributable to low-dose combination oral contraceptives (OCs) was estimated through use of data from studies published in 1980-1997 and from age-specific mortality rates for 1993 and 1994. Four cardiovascular disease categories were included: myocardial infarction, venous thromboembolism and pulmonary embolism, ischemic stroke, and hemorrhagic stroke. The overall risk of death from cardiovascular disease among nonsmoking users of low-dose OCs is 0.06/100,000 women in the 15-34 year age group and 3.03/100,000 women in the 35-44 year age group. For young nonsmokers, the excess mortality risk associated with OC use is smaller than the risk of death from pregnancy, whether terminated by abortion or carried to term. Among OC users who smoke, the risk of cardiovascular mortality is 1.73/100,000 in 15-34 year olds and 19.4/100,000 in women 35-44 years old; however, 97% and 85% of this risk, respectively, is composed of the combined OC-smoking risk. Among smoking OC users over 35 years of age, the excess risk of death from OCs exceeds the risk of death from pregnancy. Young nonsmokers raise their risk of death from cardiovascular disease by less than 10% (0.60-0.65/100,000) by using OCs, while young women who do not use OCs increase their risk of death by 260% (0.60-1.57/100,000) by smoking cigarettes. For older women, the corresponding increases are 95% among nonsmoking OC users and 315% among smoking nonusers. These estimates indicate that women over 35 years of age who smoke should not be permitted to use either low- or high-dose OCs because of the excess attributable risk of death from cardiovascular disease.

Cerebral infarction in young women: analysis of 130 cases.

UNLABELLED: The aim of this study was to determine the risk factors and mechanism of cerebral infarction in young women. METHODS: We evaluated 130 consecutive women younger than 41 years of age with cerebral infarction and compared the risk factors with a control group of 122 healthy, age-matched women. RESULTS: The leading risk factors in patients with cerebral infarction were migraine (15%), tobacco use (15%), and oral contraceptive (OC) use (12%). Cerebral arteriograms were abnormal in 59% of patients (57 of 96). The causes of cerebral infarction were cardiac embolism in 36%, nonatherosclerotic vasculopathy in 25%, hematologic disorders in 8%, and migraine in 8%. The etiology could not be determined in 23% of patients. CONCLUSION: Migraine and OCs are independent risk factors for cerebral infarction in young women. The leading etiologies were rheumatic valve disease and nonatherosclerotic vasculopathy, hematologic disturbances, and migraine were responsible for a few cases.

PIP: This study examines the risk factors and mechanism of cerebral infarction in 130 women younger than 41 years of age with cerebral infarction. A control group of 122 healthy, age-matched women were used for comparison. Each patient underwent the following: complete blood count, biochemical profile, lipid profile, venereal disease laboratory test, erythrocyte sedimentation rate, and rheumatologic profile (rheumatoid factor, antinuclear antibodies, anti-DNA, C-reactive protein). All patients underwent computed tomography or magnetic resonance imaging, transthoracic or transesophageal echocardiography; while transcranial Doppler or sonography of vessels of the neck and cerebral angiography were performed electively. The results of evaluation revealed that the leading factors among patients with cerebral infarction were migraine (15%), tobacco use (15%), and oral contraceptive (OC) use (12%). Cerebral arteriograms were abnormal in 59% of patients. The causes of cerebral infarction were cardiac embolism (36%), nonatherosclerotic vasculopathy (25%), hematologic disorders (8%), and migraine (8%). The etiology could not be determined in 23% of patients. Migraine and OCs were considered as independent risk factors for cerebral infarction in young women.

Oral contraceptives and the risk of subarachnoid hemorrhage: a meta-analysis.

OBJECTIVE: The objective of this study is to estimate the risk of subarachnoid hemorrhage produced by oral contraceptive use. METHODS: Studies published since 1960 were identified using MEDLINE, Cumulated Index Medicus, Dissertation Abstracts On-line, and bibliographies of pertinent articles. Two independent reviewers screened published cohort and case-control studies that evaluated the risk of subarachnoid hemorrhage associated with oral contraceptives. Eleven of 21 pertinent studies met predefined quality criteria for inclusion in the meta-analysis. Relative risk (RR) estimations evaluating subarachnoid hemorrhage risk in oral contraceptive users compared with nonusers were extracted from each study by two independent reviewers. Study heterogeneity was assessed by design type, outcome measure (mortality versus incidence), exposure measure (current versus ever use), prevailing estrogen dose used, and control for smoking and hypertension. RESULTS: The overall summary RR of subarachnoid hemorrhage due to oral contraceptive use was 1.42 (95% CI, 1.12 to 1.80; p = 0.004). When the two study results failing to control for smoking were excluded from the analysis, a slightly greater effect was seen, with an RR of 1.55 (95% CI, 1.26 to 1.91; p < 0.0001). In the six studies controlling for smoking and hypertension the RR was 1.49 (95% CI, 1.20 to 1.85; p = 0.0003). High-estrogen oral contraceptives appeared to impart a greater risk than low-dose preparations in studies controlling for smoking, but the difference was not significant (high-dose RR, 1.94; 95% CI, 1.06 to 3.56; low-dose RR, 1.51; 95% CI, 1.18 to 1.92). CONCLUSIONS: This meta-analysis of observational studies suggests that oral contraceptive use produces a small increase in the risk of subarachnoid hemorrhage.

PIP: Both case-control and cohort studies have evaluated the risk of subarachnoid hemorrhage (SAH) among oral contraceptive (OC) users and identified relative risks as low as 0.5 and as high as 6.5. To determine whether OC use is indeed a risk factor for SAH after accounting for the variability in study designs and results, a meta-analysis was conducted of the 11 salient independent studies included in the research literature. The summary estimate of effect for all studies was a relative risk (RR) of 1.42 (95% confidence interval (CI), 1.12-1.80). There was a trend toward smaller RRs in the most recent studies, presumably as a result of decreases in the estrogen dose of modern OCs. In the 6 studies that controlled for both smoking and hypertension, the summary RR was 1.49 (95% CI, 1.20-1.85). Only 2 of the 11 studies found a protective effect of current OC use on SAH risk, and it was nonsignificant. Taken together, these studies support a weak positive association between OC use and SAH risk. In the US, an additional 430 patients each year with OC-related SAH would be expected. For most women, the SAH risk is inconsequential in evaluating the decision about OC use. However, for women at high risk of SAH due to unruptured aneurysms, a strong positive family history, smoking, or hypertension, it may be advisable to consider alternative contraceptive methods until more data are available.

Fatal stroke and use of oral contraceptives: findings from a case-control study.

A case-control study of women less than 40 years of age in England and Wales was performed to evaluate the risk of fatal stroke associated with the use of the newer, low-dose oral contraceptives. Included were 296 cases with subarachnoid hemorrhage, 105 cases with other hemorrhagic stroke, and 21 cases with occlusive stroke, all of which occurred during 1986-1988. Two living controls per case, matched for age and marital status, were chosen from the general practice lists. The power of the study was such that the minimum significant increased relative risk of subarachnoid hemorrhage associated with ever having used oral contraceptives that could have been detected with 90% certainty was 1.6; the equivalent value for occlusive stroke was 28.4. Relative risk was estimated by conditional logistic regression allowing for matching. The adjusted relative risk of subarachnoid hemorrhage associated with oral contraceptives was estimated to be 1.1 (95% confidence interval (CI) 0.6-1.9) for current use and 1.3 (95% CI 0.9-1.8) for ever use, while the equivalent relative risk of an occlusive stroke associated with ever use was 4.4 (95% CI 0.8-24.4). Oral contraceptive use may be associated with a small increase in the risk of subarachnoid hemorrhage. These data are consistent with a substantial increase in the risk of occlusive stroke associated with oral contraceptive use.

PIP: Epidemiologists compared data on 434 cases of fatal stroke which occurred between 1986-88 in England and Wales with data on 1268 living matched controls to determine the association between use of the newer, low dose oral contraceptives (OCs) and the risk of stroke. History of hypertension was significantly associated with a 9-fold rise in the risk of subarachnoid hemorrhage (p.001) and an 8-fold rise in the risk of any hemorrhagic stroke. History of preeclampsia was also significantly associated with subarachnoid hemorrhage (p.01) and any hemorrhagic stroke. Cigarette smoking had a 2.6-fold increased risk of subarachnoid hemorrhage (p.001). The epidemiologists found an estimated relative risk of subarachnoid hemorrhage related to current OC use to be only 1.1 and when they controlled for confounding factors it was still small and insignificant (1.3). The power of the study showed the lowest significant increased relative risk of subarachnoid hemorrhage related to OC use that epidemiologists could have detected with 90% certainty to be 1.6. When the epidemiologists controlled for confounding factors, the insignificant relative risk of occlusive stroke associated with OC use was 4.4 while the power of the study indicated it to be 28.4. This was consistent with other studies, but other studies found the association to be significant. These findings revealed a possible small increase in the risk of subarachnoid hemorrhage associated with OC use.

Cause-specific mortality among Koreans, Chinese and Americans in Japan, 1973-1982.

Mortalities from selected causes from 1973 to 1982 among Koreans, Chinese, and Americans residing in Japan were compared with those of Japanese. In the Korean population, besides the well-documented excess in mortalities from liver cancer, lung cancer, liver cirrhosis and male tuberculosis, a rather prominent elevation was observed for mortalities from female tuberculosis and diabetes mellitus in both sexes. Distinctive features in the Chinese population were increased mortalities from liver cancer and female lung cancer and lowered mortality from stomach cancer, and these findings are consistent with the observations among Chinese in other areas. Mortalities from diabetes mellitus and liver cirrhosis was moderately increased in this population as well. Americans in Japan by and large showed a mortality pattern similar to that in the US although mortality from stroke among female Americans was rather elevated during the period 1973-1977. Epidemiological studies on Koreans and Chinese in Japan with reference to their lifestyle are strongly required.

Cerebrovascular deaths before and after the appearance of oral contraceptives.

The mortality of cerebrovascular diseases in Denmark was analysed for men and women 15-44 years of age, in a 14-year period before and after the appearance of oral contraceptives (OC) in 1966. 1,670 deaths were registered over 28 years, during which the female incidence of cerebrovascular deaths increased by 19% (P less than 0.025), while the male mortality was unchanged. Women showed a percentage increase in deaths from cerebral thromboembolic attacks (CTA) of 33%, men a fall of 14%. The increase of female CTA deaths was most pronounced in the young fertile group, the age group with a high OC use. A relative risk of CTA of 3.3-4.5 for OC users compared with non-users could explain the CTA trend difference between women and men. No other single risk factor responsible for the observed trends could be identified. Both women and men had a significant increase in the mortality of subarachnoidal hemorrhages, and a significant fall in the mortality of intracerebral hemorrhages.

PIP: The aim of this study was to investigate cerebrovascular deaths in Denmark in 15-44 year old men and women for the 14-year period prior to the introduction of oral contraceptives (OCs) in late 1966 compared with the subsequent 14 years. Study data were derived from annual vital statistics from 1953-80. A total of 1670 cerebrovascular deaths were recorded over the 28 years reviewed. During this period, the female incidence of cerebrovascular deaths increased by 19% while male mortality was constant. However, there were differences within the 3 subgroups of cerebrovascular deaths. In terms of cerebral thromboembolism, there was a 33% increase among women in the death rate between the 2 periods studied contrasted with a 14% decline in deaths among men. The female rate increase was most marked in the 15-34-year age group. Deaths from subarachnoid hemorrhage increased significantly for both sexes between the 2 periods--38% for men and 67% for women. Here, the increases in mortality were greatest for men and women 35-44 years of age. Finally, deaths from intracerebral hemorrhages fell by 37% for men and 22% for women during the study periods. The etiology of cerebral thromboembolism is multifactorial, involving factors such as diet, hypertensive control, cigarette smoking, and occupational thrombogenic factors. However, the dramatic increase of 33% recorded among women in deaths from cerebral thromboembolism after 1966 seems to suggest that OCs have played a significant role in the changes in female deaths from this cause. Further epidemiological studies are necessary to support or reject the hypothesis that OCs have had a major impact on the mortality profile of young women in recent years.

Women and coronary artery disease: a review of the literature.

PIP: This article reviews the literature on women and coronary artery disease (CAD) and seeks to answer 4 questions: Are there differences in risk factors between men and women? Do the clinical manifestations of CAD differ between the sexes? What is the course of the disease for women? What, if any, are the rehabilitation factors specific to women? Most of the research was conducted prior to 1979, and its focus is on the male response to CAD. Nonetheless, available research suggests that women have basically the same risk factors as men--smoking, hypertension, diabetes mellitus, hypercholesteremia, sedentary life style, obesity, Type A personality, and family history. A female specific risk factor is pre- and postmenopausal exogenous estrogen therapy. Smoking is a major contributing risk factor in women, especially when associated with estrogen therapy. In healthy premenopausal women who take oral contraceptives (OCs) and smoke, the risk of nonfatal myocardial infarction ranges from 1/8400/year in women 27-37 years to 1/250 for women 44-45 years. Women under the age of 45 years who take OCs and have 3 other risk factors increase their risk of CAD 128-fold. In terms of clinical manifestations, women tend to present with symptoms of angina while men usually present with a myocardial infarction or sudden death. Women with angina have a better prognosis and lower mortality rate than men with angina. There are no apparent differences in the medical management of men and women with CAD. There is virtually no information on how women adapt to CAD after the initial cardiac ischemic event, so it its difficult to say whether women have different needs or concerns in the recovery process. It is important for health professionals to research the natural history of CAD in women and to describe women's susceptibility, preclinical risk factors, clinical manifestations, and outcome.^ieng