ArticlesIschaemic stroke and combined oral contraceptives: results of an international, multicentre, case-control study
Introduction
The possibility that cerebrovascular accidents (strokes) might be induced by oral contraceptives (OCs) was first raised by Lorentz1 in 1962, shortly after OCs became available. Subsequent case-reports and reviews of temporal changes in clinical experience of stroke among young women2, 3 suggested an association between stroke and OC use, a finding that was consistent with the results of several case-controlβ3 and cohort studies.14, 15, 16, 17, 18 Concern about the cardiovascular side-effects of OCs has limited their use world wide, although an estimated 60Β·70 million women are OC users.19
Most studies of the cardiovascular side-effects of OCs were carried out during the 1960s and 1970s, and there are four reasons to re-examine this association. First, OCs contain lower doses of oestrogen and progestagen than they did in the past, and current recommendations are to restrict use to younger women who do not have other risk factors for cardiovascular disease.20 Although these changes seem appropriate, few data are available to confirm whether there has been a reduction in cardiovascular risk associated with OC use. Second, most previous studies have been done in northern Europe and the USA, and extrapolation of these findings to populations with different incidence rates and prevalence of risk factors for stroke may not be appropriate. Third, although use of OCs seemed to be associated with ischaemic stroke in previous studies, the association with haemorrhagic stroke is less certainβperhaps partly because of inadequate differentiation of stroke type. Finally, previous studies did not have sufficient power to assess effects of duration and past use of OCs, and any interaction between OC-associated risk and other risk factors, such as hypertension and smoking.
This paper reports the association between ischaemic stroke and use of combined OCs, in a multicentre, hospital-based, case-control study of stroke, acute myocardial infarction, and venous thromboembolism, in Africa, Asia, Europe, and Latin America (including the Caribbean). The primary aim of the stroke component of the study was to assess whether current OC use was associated with increased risk of a first stroke in women from Europe and from the other three regions combined (the developing countries). Secondary aims were to evaluate the risk of first stroke in each of the four regions, and assess whether the risk differed among subgroups of womenβsuch as smokers or women with hypertensionβ or according to type, duration, and past use of OCs.
Section snippets
Patients and methods
A detailed description of study methods has been published elsewhere.21, 22 In summary, this hospital-based, case-control study was undertaken in 21 centres in 17 countries subdivided into four regions. Each centre recruited cases and controls from a variable number of collaborating hospitals. Eligible cases were women aged 20Β·44 years (or 15Β·49 years in three centres), who had been admitted to a collaborating hospital between Feb 1, 1989, and Jan 31, 1993, and had, in the opinion of the
Results
703 (31Β·4%) of the 2242 strokes studied were ischaemic. Overall, 456 (20Β·3%) cases were unclassified, although this proportion was more than 80% in Africa because of inadequate diagnostic facilities (table 1). Four cases were excluded from subsequent analyses because their OC status was not known, and two were excluded because no matched controls had been recruited. 1952 controls were matched to the remaining 697 casesβan average of 2Β·6 controls per case in Europe and 2Β·8 per case in the
Discussion
Overall, current use of combined OCs was associated with a significantly increased risk of ischaemic stroke. However, risks were substantially lower among important subgroups of users. The overall odds ratios are similar to those reported from Denmark,13 but lower than those in most earlier studies.5, 8, 9, 12, 16 The only identifiable confounders were number of livebirths and a history of hypertension, in Europe, and a history of hypertension, rheumatic heart disease, or both in the developing
Age, blood pressure, and OC-associated risk
Adjusted odds ratios associated with OC use were greater in older than younger women in Europe and the developing countries. The effect of age on OC-associated risk of ischaemic stroke showed a continuous trend in the developing countries, but this trend was not so clear in Europe. An earlier study reported an effect of age on OC-associated risk for combined circulatory diseases15 but not specifically for ischaemic stroke, which may reflect the limited size of most previous studies of stroke.
Smoking and duration of OC use
Current smoking was not a substantial confounder (ie, did not change risk estimates by β₯5%) of the overall association between OC use and ischaemic stroke in Europe or the developing countries. However, among some subgroups, current smoking was found to increase odds ratios by more than 5%, and hence all risk estimates were adjusted for smoking. In addition, OC-associated odds ratios were higher among current smokers than non-smokers, and the patterns of risk associated with OC use and smoking
Risks by type of OC
In Europe, OC-associated risk of ischaemic stroke was largely confined to the use of higher-oestrogen-dose OCs (table 6). By contrast, in the developing countries, both low-dose and higher-dose preparations were associated overall with about a three-fold increase in odds ratios. However, this difference in risk was affected by women who reported that they had not had their blood pressure measured before they started to use OCs containing second-generation progestagens; among those women use of
Validity and limitations of study
The reference group used in most previous studies of cardiovacular risk associated with OC use was women who had never used OCs. However, in our study the preferred reference group was non-users because risk was almost exclusively associated with current OC use, and never-users, particularly in Europe, represented a small and possibly atypical subset of non-users.
A unique feature of this study was the high proportion of cases that had an accurate diagnosis of ischaemic stroke. Before the
Conclusion
Although this study shows that current OC use was associated with about a three-fold increase in risk of ishaemic stroke, the odds ratios were lower for younger women and those who did not smoke, and less than 2 for those who did not have a history of hypertension and had had their blood pressure checked before the current episode of OC use. Smoking appeared to have a synergistic effect on risk of ischaemic stroke associated with OC use. A history of hypertension among current OC users was
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Writing Committee, study organisation, and participants given at end of article