Combined Hormonal Contraceptives and Migraine: An Update on the Evidence

By Pelin Batur, MD, FACP, NCMP

Combined hormonal contraceptives are contraindicated in women who have migraine with aura because they pose a risk of stroke. But how great is the risk, and how strong is the evidence, particularly with today’s low-dose contraceptives?

What the guidelines say

Current guidelines restrict the use of combined hormonal contraceptives in the setting of migraine with aura, but not in migraine without aura.

In 2016, the US Centers for Disease Control and Prevention published updates to its medical eligibility criteria for contraceptive use in various medical conditions. In the case of migraine without aura, the guidelines note no limitation to the use of combined hormonal contraceptives, regardless of the patient’s age. In the case of migraine with aura, the consensus was that the risk associated with combined hormonal contraception typically outweighs its benefits, noting “an unacceptable health risk if the contraceptive method is used.”

We believe a fresh look at the data is warranted.

Early oral contraceptives were all high-dose

This issue first surfaced in the decade and a half after the initial launch of oral contraceptives in 1960. The products then were all high-dose pills, containing up to 150 µg of mes­tranol. In subsequent decades, the dose of estrogen was successively reduced, so that now some pills contain only 10 µg of ethinyl estradiol. High-dose pills—which today contain 50 µg of ethinyl estradiol—account for less than 1 percent of pills currently sold in the United States and have been eliminated in many countries.

Stroke risk: estrogen dose matters

Shortly after the first combined oral contraceptives were released, reports of adverse events began to appear, although serious events were relatively rare. In response, prescribing guidelines advised against giving oral contraceptives to women with a history of deep vein thrombosis, myocardial infarction, stroke, or hypertension. Current low-dose formulations are considerably safer than high-dose options but are not entirely without risk.

Stroke risk with combined oral contraceptives was first highlighted in a landmark article in 1975. By today’s standards, they were all taking high-dose pills. The risk of thrombotic stroke was four to five times higher in users than in nonusers.

In 1996, a study from the World Health Organization reported an increased risk of stroke with high-dose combined oral contraceptives. With preparations containing less than 50 μg of ethinyl estradiol, the risk was not statistically significant.

In 2002, a five-year case-control study in Denmark found that the risk of stroke with combined oral contraceptives correlated directly with the estrogen content. Reassuringly, a 2012 retrospective review of the Danish national registry revealed a low absolute risk of arterial events in users of combined oral contraceptives; risks were substantially lower with 20-μg ethinyl estradiol products than with those containing 30 to 40 μg.

Stroke risk increases with frequency of migraine aura

Use of combined hormonal contraceptives in women who have migraine with aura remains controversial, based on good evidence that aura increases stroke risk and good evidence that high-dose oral contraceptives increase stroke risk.

A cohort study encompassing more than 470,000 person-years with a median follow-up of 26 years found that while migraine without aura conferred no increase in risk of all-cause mortality, migraine with aura did.

Several other studies have confirmed that migraine with aura can increase risk, including the longitudinal Women’s Health Study and an analysis of the World Health Organization study of stroke in young women.

In a pilot study, 28 women referred to a tertiary headache clinic who had migraine with aura and intractable menstrual-related migraine were offered combined hormonal contraception in the form of a vaginal ring that releases only 15 μg ethinyl estradiol per 24 hours, thereby reducing peak estrogen exposure to a level lower than those encountered with the native menstrual cycle (with the suppression of ovulation). The women used this continuous ultra-low-dose hormonal contraception without placebo days. After a mean follow-up of 8 months, this regimen reduced aura frequency from a baseline average of 3.2 per month to only 0.2 per month. No woman had an increase in aura frequency, and menstrual-related migraine was eliminated in 21 of the 23 evaluable patients.

Choosing the optimal contraceptive formulation

Today, ultra-low-dose combined oral contraceptives (containing 10–15 µg of ethinyl estradiol) inhibit ovulation with doses of estrogen that are in a midphysiologic range. Consequently, they expose women to lower peak concentrations of estrogen than they would experience in their natural menstrual cycle. If a combined oral contraceptive is used in women with migraine with aura, lower estrogen doses (≤ 20 µg ethinyl estradiol) are preferred to decrease aura frequency and minimize the risk of stroke associated with high-dose ethinyl estradiol formulations.

Advising patients

It is important to remember that the risks of unintended pregnancy are always greater than the risks of any contraceptive, especially in women with chronic medical conditions, including those who have migraine with aura.

For a patient who has a history of migraine with aura, if the goal is only to prevent pregnancy, we would recommend another contraceptive option that does not involve estrogen. However, we would consider prescribing a combined hormonal contraceptive in a low-dose regimen if the patient prefers this regimen for other health benefits (e.g., acne control), if she has no other risk factors for stroke, and if she gives her informed consent after a discussion of the risks and benefits. Women who have menstrual-related migraine refractory to or who cannot tolerate other migraine therapies are often willing to try a low-dose estrogen-containing contraceptive for control of their migraine, especially if they have tried it in the past and believe that it helped prevent migraine. Patients should have follow-up within three months to discuss whether they have benefited from the regimen in terms of headache frequency or severity.

Dr. Batur is Education Director for the Primary Care Women’s Health Program in Cleveland Clinic’s Medicine Institute.

Read the full version of this abridged article in Cleveland Clinic Journal of Medicine