Abstract
We suggest strategies for the use of combined oral contraceptives (COCs) and hormone replacement therapy (HRT) in women with migraine, based on available evidence, when it exists, and expert opinion. They do not set a standard, since migraine management and stroke prevention require a flexible and individualized approach, the evidence is low grade (expert appraisal of the literature with peer review (Grade C, see notes)), and no randomized controlled clinical trials exist. They do not replace general guidelines for the safe use of COCs and national recommendations that relate to migraine and COCs, where they exist.
It is assumed that a diagnosis of migraine has been made and symptoms of transient ischaemic attacks, stroke or other conditions that are contraindications to the use of COCs have been ascertained.
Combined oral contraceptives
Combined oral contraceptives contain synthetic oestrogens and progestogens in doses sufficient to inhibit ovulation.
For most women, COCs are a safe and highly effective method of contraception with added non-contraceptive health benefits.
High-dose COCs (> 50 μg ethinyloestradiol), particularly those containing first generation progestogens, are no longer recommended for routine use.
Low-dose formulations (< 50 μg ethinyloestradiol) containing either second or third generation progestogens should be used when possible. Second generation progestogens include ethynodiol diacetate, levonorgestrel and norethisterone. Third generation progestogens include desogestrel, gestodene and norgestimate.
Risk of ischaemic stroke in young women
In relation to cerebrovascular disease, the term ‘young women’ generally means less than 45 years of age. However, it should be borne in mind that this age limit is only by convention.
The absolute risk of ischaemic stroke is low, estimated to be between 5 and 10 per 100 000 woman-years.
COCs are a risk factor for ischaemic stroke, with the risk being dependent on the dose of oestrogen and the age of the woman. There is no difference in the ischaemic stroke risk between COCs that contain second generation progestogens with a low oestrogen content and those that contain third generation progestogens with a low oestrogen content.
Smoking is the most prevalent modifiable risk factor for ischaemic stroke and carries an odds ratio (OR) of around 2. The OR for smoking combined with oral contraceptives is around 6.
Valid data suggest that migraine in general is a risk factor for ischaemic stroke, with an OR of around 3. It is uncertain whether migraine without aura is a risk factor. There is more evidence for migraine with aura, which has an OR of around 6. However, the absolute risk of stroke in migraineurs remains low. It has been estimated at 17–19 per 100 000 woman-years.
There is an apparent synergism of migraine and COCs for ischaemic stroke with reported ORs of 5–17. The addition of other factors further increases the risk with an OR of 34 reported for the combination of migraine, smoking and COCs. However, this risk has been estimated in only one study and was based on very few subjects.
Use of COCs in women with migraine
There is no contraindication to the use of COCs in women with migraine in the absence of migraine aura or other risk factors. Women should be counselled and regularly assessed for the development of additional risk factors (Box 1).
There is a potentially increased risk of ischaemic stroke in women with migraine who are using COCs and have additional risk factors which cannot easily be controlled, including migraine with aura. One must individually assess and evaluate these risks. Combined oral contraceptive use may be contraindicated. Identify and evaluate risk factors.
Identify and evaluate risk factors.
Diagnose migraine type, particularly the presence of aura.
Women with migraine who smoke should stop smoking before starting COCs.
Other risk factors, such as hypertension and hyperlipidaemia, should be treated.
Consider non-ethinyloestradiol methods in women who are at increased risk of ischaemic stroke, particularly those who have multiple risk factors. Some of these contraceptives are as or more effective in preventing pregnancy than COCs and include progestogen-only hormonal contraception. Observational studies suggest that progestogen-only hormonal contraceptive use is not associated with an increased risk of ischaemic stroke, although quantifiable data are limited.
Screening tests in women with migraine prior to use of COCs
No specific tests need to be undertaken other than those routinely performed or indicated by the patient's history or the presence of specific symptoms, e.g. whose relatives experienced arterial disease when aged 45 years or under.
Migraine-related symptoms that may necessitate further evaluation and/or cessation of COCs
New persisting headache.
New onset of migraine aura.
Increased headache frequency or intensity.
Development of unusual aura symptoms, particularly prolonged aura.
Hormone replacement therapy
Hormone replacement therapy (HRT) aims to restore physiological levels of oestrogen, usually with natural oestrogens, in order to prevent oestrogen deficiency symptoms and diseases resulting from the menopause. The benefits of oestrogen replacement may be modified by the addition of progestogens, which are necessary to protect the endometrium in a woman with an intact uterus.
Age >35 years
Ischaemic heart disease or cardiac disease with embolic potential
Diabetes mellitus
Family history of arterial disease <45 years
Hyperlipidaemia
Hypertension
Migraine aura
Obesity (body mass index >30)
Smoking
Systemic diseases associated with stroke, including sickle
cell disease and connective tissue disorders
Notes:
Absolute risk: the incidence rate of the targeted disorder amongst those exposed.
Relative risk: the ratio of the incidence rate in the exposed group to the incidence rate in the non-exposed group.
Odds ratio: the relative risk approximated from casecontrol studies.
Grading of recommendations:
A: Evidence based on the results of randomized controlled clinical trials with strong methodology and consistent results.
B: Evidence based on the results of randomized controlled clinical trials with strong methodology but inconsistent results.
C: Evidence based on observational studies.
Indications and contraindications in women with migraine
There is no evidence that migraine is a risk factor for ischaemic stroke in women over age 45 years. There are insufficient data to support an increased risk of ischaemic stroke in women with any type of migraine who are using HRT. Consequently, the usual indications and contraindications for HRT should be applied.
Footnotes
Acknowledgements%
The members of the Task Force are grateful to AstraZeneca (France) for financial support for their meetings.