Oral Contraceptives and Nonfatal Stroke in Healthy Young Women HERSHEL JICK, M.D.; JANE PORTER, M.S.; and KENNETH J. ROTHMAN, Dr. P.H.; Boston, Massachusetts
The Boston Collaborative Drug Surveillance Program obtained medical histories on 2 9 premenopausal women with a discharge diagnosis of stroke. Of these women, 14 were otherwise healthy with no known predisposing illnesses. Eleven of the 14 patients were taking oral contraceptives just before admission compared with seven of 5 6 otherwise healthy control women ( 1 3 % ) . The relative risk estimate for stroke among oral contraceptive users compared with nonusers is 26 (lower 9 0 % one-sided confidence bound = 7.0). Cigarette smoking was only weakly associated with stroke in this group of women.
P R E V I O U S REPORTS suggest that women using oral contraceptives have a greater risk of stroke than nonusers (14). To evaluate this association further, we have examined data from the Boston Collaborative Drug Surveillance (BCDS) Program on oral contraceptive use and stroke. Our study was confined to potentially childbearing women who were otherwise healthy before their admitting illnesses and had no contraindication to oral contraceptive use. Subjects and Methods We obtained information for two groups of hospitalized patients enrolled in the BCDS Program. The first group consisted of patients admitted since 1969 to selected general medical wards of 21 hospitals in the United States, Great Britain, N e w Zealand, Canada, Germany, Italy, and Israel. The second consisted of patients admitted to general medical and surgical wards of 24 Boston-area hospitals in 1972. Each patient was interviewed by a specially trained nurse-monitor who obtained information on demographic characteristics, personal habits, medical history, and medications used before admission. The methods used to collect the information have been described in detail elsewhere (5, 6). For the case series we identified premenopausal women with a discharge diagnosis of one of the following: subarachnoid hemorrhage, cerebral hemorrhage, thrombosis of the carotid artery, cerebral thrombosis, occlusion of the basilar or carotid artery, cerebral infarction not otherwise specified, cerebral embolus, and cerebrovascular accident. Of the 32 women with one of these diagnoses, three were excluded because they were too ill to provide the relevant information. Fifteen were excluded because they had conditions that would predispose them to stroke: rheumatic heart disease (seven), previous stroke (two), • From the Boston Collaborative Drug Surveillance Program, Boston University Medical Center; and the Department of Epidemiology, Harvard University School of Public Health; Boston, Massachusetts. 58
recent childbirth (one), aplastic anemia (one), and chronic renal failure (one), or because of a history of an illness that may contraindicate oral contraceptive use: treated hypertension (two) and treated diabetes (one). We obtained the discharge summaries of all but two of the patients to check the evidence for the diagnoses. In most instances extensive diagnostic tests were carried out and there was little doubt about the accuracy of the diagnosis of stroke. For each case we selected four premenopausal control women matched for country, age within 4 years, and absence of the medical conditions used as exclusion criteria for the cases. Table 1 gives the primary discharge diagnoses for the control women. Results After exclusions, 14 patients remained, all apparently healthy premenopausal women (before admission) with no apparent contraindication to oral contraceptive use. The diagnoses for the 14 cases were cerebrovascular accident (five), cerebral thrombosis (four), occlusion of the carotid artery (two), subarachnoid hemorrhage (one), cerebral infarction (one), and cerebral embolus (one). Seven patients were from New Zealand, six from the United States, and one from Germany. All of the patients were white. Eleven of the 14 patients had a history of oral contraceptive use just before admission, compared with seven of the 56 (13%) control subjects. Despite the matching, the histories of oral contraceptive use for patients and their matched controls were not positively correlated. Under such circumstances, it is possible and desirable to analyze the data as if the two series were independent (7). From the crude data we estimated the relative risk to be 26 with an "exact" (8) one-sided 90% lower confidence bound of 7.0 (one-tail p = 2 X 10-6). Seven of the 14 patients were cigarette smokers at the time of admission, whereas among control subjects the Table 1. Primary Diagnoses of the Controls Diagnosis no. Gastrointestinal disorders Acute infections Neuropsychiatric disorders Asthma Musculoskeletal disorders Other Total
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proportion was 23 of 56 (41%). Among smokers, there was no substantial difference in the amount smoked comparing patients and control subjects. All of the seven patients who never smoked were oral contraceptive users. The average duration of oral contraceptive use among users, adjusted for age, was 4.4 years for patients and 3.7 years for control subjects. None of the patients had used oral contraceptives for less than 3 months and four had been users for more than 6 years. In Table 2 the age distribution of subjects by oral contraceptive use shows that the estimated effect is large in each of the age strata, and no trend of effect with age is apparent. The age range was 19 to 49 years for the patients and 15 to 49 years for the control subjects. The ages of the three patients in the youngest age stratum were 19, 20, and 22 years. Discussion
The present study provides additional evidence that oral contraceptives increase the risk of nonfatal stroke in otherwise healthy women with no known predisposing illnesses. Our results for nonfatal stroke are similar to those recently reported for fatal stroke by the Royal College of General Practitioners (3) and Vessey, McPherson, and Johnson (4), despite the fact that a majority of cases in the current study had a thrombotic origin, whereas a majority of cases in the British studies resulted from hemorrhage. The preponderance of hemorrhagic stroke in the British studies probably reflects the fact that hemorrhagic stroke is often fatal, whereas thrombotic stroke is not (1). The estimate of relative risk for oral contraceptive users derived from the current data is substantially higher than that originally reported by the Collaborative Group for the Study of Stroke in Young Women (CGSS) (1). There are several possible explanations. First, the number of cases in the present study is small, and, therefore, the confidence interval around the estimate is wide. Second, all but one patient in our series had thrombotic stroke and the relative risk estimate (among whites) in the CGSS study was highest for thrombotic patients. Third, we included only those women who were apparently in excellent health before their illness. We excluded patients with treated hypertension or diabetes or with a history of rheumatic heart disease, whereas such women were included in the CGSS study. If, as is likely, these conditions predispose to stroke even in the absence of oral contraceptive use, the inclusion of such women would tend to lead to a lower estimate of relative risk. In our study, as in the report by the CGSS, cigarette smoking was only weakly associated with stroke in healthy young women. Likewise, smoking is not a strong risk factor for venous thromboembolic disease in healthy young women (9). In contrast, smoking is strongly related to the risk of myocardial infarction in such women (10). Although the current results indicate that oral contraceptives markedly increase the risk of stroke in healthy young women, it is worth emphasizing that the illness is rare in this population.
Table 2 . Oral Contraceptive Use among Patients with Stroke and Controls according to Age
Age of Patient
Oral Contraceptive Users
yrs.
The Boston Collaborative Drug Surveillance Program obtained medical histories on 2 9 premenopausal women with a discharge diagnosis of stroke. Of these women, 14 were otherwise healthy with no known predisposing illnesses. Eleven of the 14 patients were taking oral contraceptives just before admission compared with seven of 5 6 otherwise healthy control women ( 1 3 % ) . The relative risk estimate for stroke among oral contraceptive users compared with nonusers is 26 (lower 9 0 % one-sided confidence bound = 7.0). Cigarette smoking was only weakly associated with stroke in this group of women.
P R E V I O U S REPORTS suggest that women using oral contraceptives have a greater risk of stroke than nonusers (14). To evaluate this association further, we have examined data from the Boston Collaborative Drug Surveillance (BCDS) Program on oral contraceptive use and stroke. Our study was confined to potentially childbearing women who were otherwise healthy before their admitting illnesses and had no contraindication to oral contraceptive use. Subjects and Methods We obtained information for two groups of hospitalized patients enrolled in the BCDS Program. The first group consisted of patients admitted since 1969 to selected general medical wards of 21 hospitals in the United States, Great Britain, N e w Zealand, Canada, Germany, Italy, and Israel. The second consisted of patients admitted to general medical and surgical wards of 24 Boston-area hospitals in 1972. Each patient was interviewed by a specially trained nurse-monitor who obtained information on demographic characteristics, personal habits, medical history, and medications used before admission. The methods used to collect the information have been described in detail elsewhere (5, 6). For the case series we identified premenopausal women with a discharge diagnosis of one of the following: subarachnoid hemorrhage, cerebral hemorrhage, thrombosis of the carotid artery, cerebral thrombosis, occlusion of the basilar or carotid artery, cerebral infarction not otherwise specified, cerebral embolus, and cerebrovascular accident. Of the 32 women with one of these diagnoses, three were excluded because they were too ill to provide the relevant information. Fifteen were excluded because they had conditions that would predispose them to stroke: rheumatic heart disease (seven), previous stroke (two), • From the Boston Collaborative Drug Surveillance Program, Boston University Medical Center; and the Department of Epidemiology, Harvard University School of Public Health; Boston, Massachusetts. 58
recent childbirth (one), aplastic anemia (one), and chronic renal failure (one), or because of a history of an illness that may contraindicate oral contraceptive use: treated hypertension (two) and treated diabetes (one). We obtained the discharge summaries of all but two of the patients to check the evidence for the diagnoses. In most instances extensive diagnostic tests were carried out and there was little doubt about the accuracy of the diagnosis of stroke. For each case we selected four premenopausal control women matched for country, age within 4 years, and absence of the medical conditions used as exclusion criteria for the cases. Table 1 gives the primary discharge diagnoses for the control women. Results After exclusions, 14 patients remained, all apparently healthy premenopausal women (before admission) with no apparent contraindication to oral contraceptive use. The diagnoses for the 14 cases were cerebrovascular accident (five), cerebral thrombosis (four), occlusion of the carotid artery (two), subarachnoid hemorrhage (one), cerebral infarction (one), and cerebral embolus (one). Seven patients were from New Zealand, six from the United States, and one from Germany. All of the patients were white. Eleven of the 14 patients had a history of oral contraceptive use just before admission, compared with seven of the 56 (13%) control subjects. Despite the matching, the histories of oral contraceptive use for patients and their matched controls were not positively correlated. Under such circumstances, it is possible and desirable to analyze the data as if the two series were independent (7). From the crude data we estimated the relative risk to be 26 with an "exact" (8) one-sided 90% lower confidence bound of 7.0 (one-tail p = 2 X 10-6). Seven of the 14 patients were cigarette smokers at the time of admission, whereas among control subjects the Table 1. Primary Diagnoses of the Controls Diagnosis no. Gastrointestinal disorders Acute infections Neuropsychiatric disorders Asthma Musculoskeletal disorders Other Total
Annals of Internal Medicine 8 9 : 5 8 - 6 0 1 9 7 8
Downloaded From: http://annals.org/ by a University of California San Diego User on 01/03/2017
12 9 9 6 4 16 56 © 1 9 7 8 American College of Physicians
proportion was 23 of 56 (41%). Among smokers, there was no substantial difference in the amount smoked comparing patients and control subjects. All of the seven patients who never smoked were oral contraceptive users. The average duration of oral contraceptive use among users, adjusted for age, was 4.4 years for patients and 3.7 years for control subjects. None of the patients had used oral contraceptives for less than 3 months and four had been users for more than 6 years. In Table 2 the age distribution of subjects by oral contraceptive use shows that the estimated effect is large in each of the age strata, and no trend of effect with age is apparent. The age range was 19 to 49 years for the patients and 15 to 49 years for the control subjects. The ages of the three patients in the youngest age stratum were 19, 20, and 22 years. Discussion
The present study provides additional evidence that oral contraceptives increase the risk of nonfatal stroke in otherwise healthy women with no known predisposing illnesses. Our results for nonfatal stroke are similar to those recently reported for fatal stroke by the Royal College of General Practitioners (3) and Vessey, McPherson, and Johnson (4), despite the fact that a majority of cases in the current study had a thrombotic origin, whereas a majority of cases in the British studies resulted from hemorrhage. The preponderance of hemorrhagic stroke in the British studies probably reflects the fact that hemorrhagic stroke is often fatal, whereas thrombotic stroke is not (1). The estimate of relative risk for oral contraceptive users derived from the current data is substantially higher than that originally reported by the Collaborative Group for the Study of Stroke in Young Women (CGSS) (1). There are several possible explanations. First, the number of cases in the present study is small, and, therefore, the confidence interval around the estimate is wide. Second, all but one patient in our series had thrombotic stroke and the relative risk estimate (among whites) in the CGSS study was highest for thrombotic patients. Third, we included only those women who were apparently in excellent health before their illness. We excluded patients with treated hypertension or diabetes or with a history of rheumatic heart disease, whereas such women were included in the CGSS study. If, as is likely, these conditions predispose to stroke even in the absence of oral contraceptive use, the inclusion of such women would tend to lead to a lower estimate of relative risk. In our study, as in the report by the CGSS, cigarette smoking was only weakly associated with stroke in healthy young women. Likewise, smoking is not a strong risk factor for venous thromboembolic disease in healthy young women (9). In contrast, smoking is strongly related to the risk of myocardial infarction in such women (10). Although the current results indicate that oral contraceptives markedly increase the risk of stroke in healthy young women, it is worth emphasizing that the illness is rare in this population.
Table 2 . Oral Contraceptive Use among Patients with Stroke and Controls according to Age
Age of Patient
Oral Contraceptive Users
yrs.
