Elsevier

The Lancet

Volume 348, Issue 9026, 24 August 1996, Pages 505-510
The Lancet

Articles
Haemorrhagic stroke, overall stroke risk, and combined oral contraceptives: results of an international, multicentre, case-control study

https://doi.org/10.1016/S0140-6736(95)12394-6Get rights and content

Summary

Background

The risk of haemorrhagic stroke associated with use of oral contraceptives (OCs) is less well-established than that for ischaemic stroke. We assessed the risk of haemorrhagic stroke associated with current use of modern OCs as now used throughout the world.

Methods

In this WHO collaborative, case-control study, we assessed the association between risk of haemorrhagic stroke and use of combined OCs in 1068 cases, aged 20·44 years, and 2910 age-matched controls. We also assessed risks for all strokes combined (haemorrhagic, ischaemic, and unclassified) based on 2198 cases and 6086 controls.

Findings

Overall, current use of combined OCs was associated with slightly increased risk of haemorrhagic stroke; the increase was significant in the developing countries (odds ratio 1·76 [95% CI 1·34–2·30]) but not in Europe (1·38 [0·84–2·25]). Use of OCs in women younger than 35 years did not affect risk of haemorrhagic stroke in either group of countries, whereas in women aged older than 35 years, odds ratios were greater than 2. Women who were current users of OCs and had a history of hypertension (detected before current episode of OC use, but not during pregnancy) had a substantially increased risk (ten-fold to 15-fold) of haemorrhagic stroke compared with women who did not use OCs and had no history of hypertension. Odds ratios among current OC users who were also current cigarette smokers were greater than 3. In both groups of countries, past use of OCs, dose of oestrogen, and dose and type of progestagen had no effect on risk, and risks were similar for subarachnoid and intracerebral haemorrhage.

The odds ratios for any type of stroke associated with current use of low-dose (<50 ug oestrogen) and higher-dose OCs were 1·41 (0·90–2·20) and 2 71 (1·70–4·32), respectively, in Europe and 1·86 (1·49–2·33) and 1·92 (1·48–2·50) in the developing countries. From these data we estimated that about 13% and 8% of all strokes in women aged 20·44 in Europe and the developing countries, respectively, are attributable to the use of OCs.

Interpretation

The risk of haemorrhagic stroke attributable to OC use is not increased in younger women and is only slightly increased in older women. The estimated excess risk of all stroke types associated with use of low-oestrogen and higher-oestrogen dose OCs in Europe was about two and eight, respectively, per 100 000 woman-years of OC use. However, findings need to be considered in the context of other risks and benefits associated with OC use, as well as those associated with the use of other forms of contraception.

Introduction

Although the association between use of oral contraceptives (OCs) and cerebral infarction was established in case-control1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and cohort studies11, 12, 13, 14, 15 during the 1960s and 1970s, the effect of OC use on risk of haemorrhagic stroke—the most common type of stroke in women of reproductive age—was less well established in these studies. Most studies of haemorrhagic stroke have focused on subarachnoid haemorrhage (the most common type of haemorrhagic stroke in these women), but these data are controversial9, 12, 16, 17 and there is no consensus about the association between risks of fatal and non-fatal subarachnoid haemorrhage and current and past use of OCs.

The findings of previous studies of the effect of OC use on risks of haemorrhagic stroke are limited because of the small numbers of participants and inadequate differentiation of stroke type. The aim of the WHO collaborative, case-control study was to assess the association between current use of combined OCs and haemorrhagic stroke and to provide an overall assessment of current OC use and risk of all types of stroke.18

Section snippets

Patients and methods

Details of study methods have been published elsewhere.18, 19, 20 Haemorrhagic strokes were classified as subarachnoid, intracerebral, or undifferentiated. A diagnosis of subarachnoid haemorrhage was made when computed tomography (CT) or magnetic resonance imaging (MRI) showed blood in the subarachnoid space. When a CT or MRI scan was not done or reported as normal, the diagnosis could be made if the clinical presentation was compatible with a diffuse neurological disorder with typical signs of

Results

1083 (48·3%) of the 2242 strokes studied were haemorrhagic (table 1). One case from Europe and nine from the developing countries were excluded from all subsequent analyses, because their OC status was not known. Five further cases were excluded because no matched controls had been recruited. 2910 controls were matched to the 1068 cases—an average of 2·6 controls per case in Europe and 2·8 controls per case in the developing countries.

Cases and controls had similar mean body-mass index, number

Discussion

Overall, current use of combined OCs was associated with a slightly increased risk of haemorrhagic stroke; this increased risk was significant in the developing countries but not in Europe. There was no increase in risk of haemorrhagic stroke in younger women in either group of countries, whereas for older women the odds ratios were above 2. The major risk factors for haemorrhagic stroke were a history of high blood pressure (detected outside pregnancy), hypertension during pregnancy, a family

Overall risk of stroke

The separate assessment of the risks of haemorrhagic and ischaemic strokes associated with use of combined OCs is of scientific and clinical importance. However, for women using or contemplating the use of OCs, the overall risk of stroke of any type is a more important consideration. Based on analyses of 2198 cases of any kind of stroke and 6086 matched controls whose OC use was known, and for whom complete information was available on confounding variables (a history of hypertension and

References (31)

  • KK Chang et al.

    Oral contraceptives and stroke: a preliminary report on an epidemiologic study in Taiwan, China

    Int J Gynecol Obstet

    (1986)
  • R Bonita

    Epidemiology of stroke

    Lancet

    (1992)
  • WHW Inman et al.

    Investigation of deaths from pulmonary, coronary and cerebral thrombosis and embolism in women of child-bearing age

    BMJ

    (1968)
  • MP Vessey et al.

    Investigation of relation between use of oral contraceptives and thromboembolic disease: a further report

    BMJ

    (1969)
  • PE Sartwell et al.

    Thromboembolism and oral contraceptives: an epidemiological case control study

    Am J Epidemiol

    (1969)
  • R Fogelholm et al.

    Ischaemic cerebrovascular disease in young adults

    Acta Neurol Scand

    (1973)
  • Oral contraceptives and stroke in young women

    JAMA

    (1975)
  • H Jick et al.

    Oral contraceptives and non-fatal stroke in healthy young women

    Ann Intern Med

    (1978)
  • KL Mettinger et al.

    Stroke before 55 years of age at Karolinska Hospital 1973–77: a study of 388 well-defined cases

    Acta Neurol Scand

    (1984)
  • M Thorogood et al.

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

    Am J Epidemiol

    (1992)
  • O Lidegaard

    Oral contraception and risk of a cerebral thromboembolic attack: results of a case-control study

    BMJ

    (1993)
  • S Ramcharan et al.

    The Walnut Creek contraceptive study. Centre for Population Research Monograph Number 81–564

    (1981)
  • Further analysis of mortality in oral contraceptive users

    Lancet

    (1981)
  • PM Layde et al.

    Incidence of arterial disease among oral contraceptive users

    J R Coll Gen Practitioners

    (1983)
  • MP Vessey et al.

    Oral contraceptives and stroke: findings in a large prospective study

    BMJ

    (1984)
  • Cited by (233)

    • Risk Factors and Prevention

      2021, Stroke: Pathophysiology, Diagnosis, and Management
    • The effects of inhaled respiratory drugs on the risk of stroke: A nested case-control study

      2016, Pulmonary Pharmacology and Therapeutics
      Citation Excerpt :

      We could not find any plausible explanation for the link between ICSs and hemorrhagic stroke. It might be due to type I error by multiple comparisons [21], although a few studies have reported the association between the use of systemic corticosteroids and hemorrhagic stroke [22,23]. The advantages of this study include that it was based on a nationwide claims database, which minimized the likelihood of selection bias [24].

    • Modifiable Risk Factors and Determinants of Stroke

      2016, Stroke: Pathophysiology, Diagnosis, and Management
    • Migraine and contraception

      2015, Gynecologie Obstetrique et Fertilite
    • Cerebrovascular Stroke: Sex Differences and the Impact of Estrogens. Sex Differences and the Impact of Estrogens.

      2015, Estrogen Effects on Traumatic Brain Injury: Mechanisms of Neuroprotection and Repair
    View all citing articles on Scopus

    Writing committee given at end of article

    View full text