Ischaemic Stroke

Strokes are of two main kinds: obstruction of a blood vessel in the brain (ischaemic stroke) and bleeding in the brain from a blood vessel (haemorrhagic stroke). Since the risk factors for each category of stroke might be different, researchers have often tried to distinguish between ischaemic and haemorrhagic stroke. The relationship between use of combined oral contraceptives and ischaemic stroke has been demonstrated in a number of epidemiological studies (1). Most found current use of combined oral contraceptives to be associated with an overall increased risk of ischaemic stroke which was roughly 3 times that of non-users.

Studies that have looked for a relationship between increased risk and duration of use have found little evidence of one. Some studies reported no significantly elevated risk of ischaemic stroke among past users of combined oral contraceptives compared with women who had never used them (2,3,4), while certain others (5,6) found that the relative risk of ischaemic stroke among former users was lower than that among women who had never been users.

Various studies have observed that age, smoking, hypertension and migraine are independently associated with the risk of ischaemic stroke in women. This is consistent with evidence of two meta-analyses. It is likely, therefore, that the risk of ischaemic stroke varies among users of combined oral contraceptives, depending on their characteristics.

The WHO study (4) reported higher relative risks among users of combined oral contraceptives who were aged 35 years or more than among those who were under 35, but this difference was attenuated among women who had their blood pressure checked. Substantially higher relative risks among older users were also reported in a case–control study in Italy. The age-related effects may have been due to changes in the prevalence of hypertension among older women.

In the WHO study(4) and a study in the USA (7) in the 1970s, users of oral contraceptives with a history of hypertension had a substantially greater relative risk of ischaemic stroke than users without hypertension. Compared with women without a history of hypertension who were not using combined oral contraceptives, the relative risk among women in the WHO study(4) who were current users and who had a history of hypertension was 14.5 in developing countries and 10.7 in Europe; the relative risk associated with current use of oral contraception by women without hypertension was 2.7 in developing countries and 2.7 in Europe. In the WHO study (4), differences in relative risk between older and younger women were attenuated among women who reported having their blood pressure checked before they started oral contraceptive use. The Transnational Study (8) also found smaller relative risks among women who reported having had their blood pressure checked prior to their current episode of oral contraceptive use. Taken together, these findings suggest that blood pressure may have an important role in the risk of ischaemic stroke associated with use of oral contraceptives.

In the WHO study (4), use of oral contraceptives containing less than 50 µg of estrogen was associated with a smaller relative risk than was use of higher-dose preparations in European countries. However, there was no apparent difference between the relative risk in users of low-dose preparations and higher-dose preparations in developing countries. In the Transnational Study (8), users of preparations containing 50 µg or more of estrogen had a slightly higher relative risk of stroke than users of preparations containing less estrogen.

Neither the dose nor the type of progestogen in combined oral contraceptives was found to have a consistent effect on relative risk in women recruited to the WHO study. However, the number of women using the more recently introduced preparations containing desogestrel, gestodene or norgestimate was very small.

The Scientific Group concluded that:

• The incidence of fatal and non-fatal ischaemic stroke is very low in women of reproductive age in both developed and developing countries.

• The reported estimates of relative risk of ischaemic stroke associated with use of combined oral contraceptives have decreased since the earliest epidemiological studies linking use of oral contraceptives with stroke.

• In women who do not smoke, who have their blood pressure checked, and who do not have hypertension, the risk of ischaemic stroke is increased about 1.5-fold in current users of low-dose combined oral contraceptives compared with non-users. There is no further increase in the risk of ischaemic stroke with increasing duration of use of combined oral contraceptives. Women who have stopped taking combined oral contraceptives are at no greater risk of ischaemic stroke than women who have never used oral contraceptives. These conclusions appear to apply equally in developed and developing countries.

• Women with hypertension have an increased absolute risk of ischaemic stroke. The relative risk of ischaemic stroke in current users of combined oral contraceptives with hypertension appears to be at least three times that in current users without hypertension. This conclusion appears to apply equally in developed and developing countries.

• The absolute risk of ischaemic stroke in women who smoke is about 1.5–2 times that in non-smokers; this risk is multiplied by a factor of 2–3 if such women are current users of combined oral contraceptives. This conclusion appears to apply equally in developed and developing countries.

• The risk of ischaemic stroke in users of combined oral contraceptives containing high doses of estrogen is higher than that in users of combined oral contraceptives containing low doses of estrogen.

• There are insufficient data to allow any conclusion to be drawn about whether the risk of ischaemic stroke is related to the type or dose of progestogen contained in low-dose combined oral contraceptives.

References

1. Inman WHW, Vessey MP. Investigation of deaths from pulmonary, coronary, and cerebral thrombosis and embolism in women of child-bearing age. British medical journal, 1968, 2:193–199.

2. Vessey, MP, Lawless M, Yeates D. Oral contraceptives and nonfatal stroke in healthy young women. Annals of internal medicine, 1978, 88:58–60.

3. Hannaford PC, Croft PR, Kay CR. Oral contraception and stroke. Evidence from the Royal College of General Practitioners' Oral Contraceptive Study. Stroke, 1994, 25: 935–942.

4. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Ischaemic stroke and combined oral contraceptives: results of an international multicentre case–control study. Lancet, 1996, 348:498–505.

5. Lidegaard Ř. Oral contraception and risk of a cerebral thromboembolic attack: results of a case–control study. British medical journal, 1993, 306:956–963.

6. Pettiti DB et al. Stroke in users of low-dose oral contraceptives. New England journal of medicine, 1996, 335:8–15.

7. Collaborative Group for the Study of Stroke in Young Women. Oral contraceptives and stroke in young women. Journal of the American Medical Association, 1975, 231:718–722.

8. Heinmann LAJ et al.Oral contraceptives and the risk of thromboembolic stroke. Contraception, 1997, 56:129–140.

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