The Risks of Oral Contraceptive Pills

Helen C. Pymar, M.D., Mitchell D. Creinin, M.D.; Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine and Magee-Women's Research Institute, Pittsburgh, Pennsylvania.

Semin Reprod Med. 2001;19(4) 

In This Article

The Risk of Stroke Associated With the Use of Oral Contraceptive Pills

The association of oral contraceptive pills and stroke was first described in the literature of the 1960s and 1970s with pills containing at least 50 mg of ethinyl estradiol.[6,7] A nested case-control study of women recruited in 1968 to 1969 and followed to 1990 showed a small but significant increased risk of stroke among women who had ever used oral contraceptives.[8] However, in the year 2000, most women were using oral contraceptive pills containing 20 to 35 mg of ethinyl estradiol. Thus, the early studies are no longer directly applicable to the current population. Over the past decade, numerous studies have shown no or minimal increase in stroke risk for women taking oral contraceptive pills.

In 1992, Thorogood et al[9] described a case-control study of fatal stroke in women less than 40 years of age living in England and Wales. Women aged 16 to 39 years with a death due to stroke between January 1986 and December 1988 were identified from a national registry. The general practitioner for these cases was identified and interviewed, and additionally provided two age- and marital status-matched control subjects. The authors discussed the trends toward lower-dose estrogen oral contraceptive pills in England and Wales during the time of the study, but did not specifically identify the estrogen dose used by subjects. The cases died from subarachnoid hemorrhage (n = 296), intracerebral hemorrhage (n = 100), unspecified intracranial hemorrhage (n = 5), or occlusive stroke (n = 21). Given the small number of cases with occlusive stroke, it is difficult to form any conclusions with respect to this group of women. Women were considered current users if they used oral contraceptives during the month of their death, past users if they used them between 1 month and 10 years of their death, and never users if they did not use them for more than 10 years before their death. They were asked about smoking and hypertension history, but not about the quantity of cigarette use per day or severity of hypertension. Based on this study, the adjusted risk of death from subarachnoid hemorrhage associated with current use and past use of oral contraceptives was 1.1 (95% CI, 0.7 to 1.9) and 1.2 (95% CI, 0.8 to 1.7), respectively. Likewise, the adjusted risk of death associated with current or past use of oral contraceptives from a hemorrhagic stroke other than a subarachnoid hemorrhage was not significantly greater than 1. Of note, the mortality rate from subarachnoid hemorrhage in England and Wales for women aged 35 to 39 years was 3.2 per 100,000 in 1986. Thus, oral contraceptive use is very unlikely to produce any major changes in attributable risk of subarachnoid hemorrhage.

One of the largest studies of hemorrhagic stroke associated with the use of oral contraceptive pills was the World Health Organization collaborative study of cardiovascular disease and steroid hormone contraception.[2] Women were chosen from 21 centers in 17 countries in Africa, Asia, Europe, and Latin America between 1989 and 1993. The data calculations were determined for European and developing countries separately. The majority of the cases were from the developing countries and likely have less applicability to the U.S. population. Of the 1068 cases of hemorrhagic stroke in women aged 20 to 44 years, only 247 were from Europe. Controls were recruited from a hospital population and matched by age, hospital, and time of admission. There was a nonsignificant increased risk of hemorrhagic stroke in European women currently using oral contraceptives (adjusted OR 1.38; 95% CI, 0.84 to 2.25), but a significantly increased risk for women in developing countries (adjusted OR 1.76; 95% CI, 1.34 to 2.3). In women using oral contraceptives containing less than 50 mg of estrogen, no statistically significant increase in risk of hemorrhagic stroke was seen in nonsmokers, but the increase in risk reached significance if those women were also smokers in both Europe and developing countries.[2]

The same study group also reviewed ischemic stroke in the same study locations and found 697 cases in the 20 to 44 year age group.[1] About 31% of the 2242 stroke cases studied were known to be ischemic in origin. However, about 20% of all stroke subjects were unclassified, with the majority of these cases coming from the African centers. Overall, the odds ratio for risk of ischemic stroke with current oral contraceptive use was 2.99 (95% CI, 1.65 to 5.4) in Europe and 2.93 (95% CI, 2.15 to 4.00) after adjustment for history of hypertension and smoking status. However, when reviewing the 20 cases in Europe using less than 50 mg of estrogen, the adjusted odds ratio was no longer significant.[1]

When the same study group reviewed all types of strokes, the adjusted odds ratio for low-dose estrogen use in European countries was 1.41 (95% CI, 0.90 to 2.20).[2] Additionally, for both ischemic and hemorrhagic strokes, a history of hypertension or smoking combined with current use of oral contraceptive pills was associated with a significantly increased risk of stroke.[1,2]

Two low-dose estrogen population-based case-control studies have been performed on women in the United States, and their results have been published individually and with pooled data from both studies.[10,11,12] Petitti et al[10] reviewed fatal and nonfatal strokes in female members aged 15 through 44 years of the California Kaiser Permanente Medical Care Program. Cases were identified between 1991 and 1994 using hospital admission and discharge, emergency department, and out-of-plan hospitalization payment records. Three randomly selected control subjects were paired with each case based on age and care facility used. There were 395 eligible subjects for interview, of whom 357 (90%) had completed interview information. Of these, 295 cases were considered for the analysis; 151 had a hemorrhagic stroke and 144 had an ischemic stroke. Odds ratios for ischemic stroke and hemorrhagic stroke in users of low-dose oral contraceptives (adjusted for treated hypertension, treated diabetes, smoking status, race or ethnic group, and body mass index) approached 1 and were not significant. Unfortunately, this study did not determine the severity of hypertension or account for untreated hypertension. Likewise, there was no assessment as to the number of cigarettes smoked daily. Therefore, a possible dose-response effect of these variables could not be assessed. The incidence of ischemic and hemorrhagic stroke in females aged 15 through 44 years was also calculated. In 3.6 million woman-years of observation, there were 195 ischemic and 201 hemorrhagic strokes, which translates to an incidence of 5.4 per 100,000 and 5.6 per 100,000 woman-years, respectively. Thus, even slight increases in relative risk should make little difference in attributable risk due to oral contraceptive use for this population.

The second population-based case-control study was completed by Schwartz et al[11] in 1997. This study involved women aged 18 to 44 years living in western Washington state between 1991 and 1995. Cases were women with a first diagnosis of fatal or nonfatal stroke who were identified through medical records at 34 acute care hospitals in the region and death certificates. Eligible controls were women who had no history of major coronary or cardiovascular disease selected by random digit dialing in the appropriate counties. There were 173 cases of stroke included in the analysis and 102 were hemorrhagic, 60 were ischemic, and 11 were classified as "other." Women using low-dose oral contraceptives within a month of their event had a stroke risk similar to women who had never used them (OR 0.89; 95% CI, 0.42 to 1.90). In this study, the overall incidence of total stroke among 18 to 44 year old women was 11.3 per 100,000 woman-years, and the overall incidence of hemorrhagic and ischemic stroke was 6.4 and 4.3 per 100,000 woman-years, respectively.

When these studies were combined, there were still no statistically significant increased risks for women using oral contraceptive pills after adjustment for stroke risk factors.[12] This is different from the results obtained by the WHO study,[1,2] most likely because of different prescribing practices in the United States (consistent use of low-dose rather than high-dose oral contraceptive pills, more consistent blood pressure assessments, or avoidance of use in smoking women over the age of 35 years). Women reporting a history of migraine and using low-dose oral contraceptive pills had significantly increased risks of ischemic stroke (OR 2.08; 95% CI, 1.19 to 3.65) but not hemorrhagic stroke (OR 2.15; 95% CI, 0.85 to 5.45). However, this is based on only four current oral contraceptive users in the cases with a history of migraine, and there is no information on a history of focal neurologic signs in these migraineurs. Therefore, this finding needs to be interpreted with caution.

In summary, stroke is a very uncommon event in childbearing women, occurring in approximately 11 per 100,000 women over 1 year. Women with a history of hypertension and smoking are at higher risk for these conditions. However, the use of low-dose oral contraceptives in women at low risk for stroke appears to have minimal effects on the attributable risk and should be considered safe in that population.


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