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m e dic i n e
Cl inic a l Decisions
Interactive at nejm.org
Oral Contraceptives for Menstrual Migraine with Aura
This interactive feature addresses the approach to a clinical issue. A case vignette is followed by specific options, neither of which
can be considered either correct or incorrect. In short essays, experts in the field then argue for each of the options as assigned.
Readers can participate in forming community opinion by choosing one of the options.
C a s e V igne t t e
The patient’s physician consults with you and
you to advise whether combined (estrogen–
A Patient with Chronic Migraines
progestin) oral contraceptive pills should be
Clement D. Lee, M.D.
prescribed for this patient with mainly catameA 30-year-old woman who has chronic migraines nial migraine with aura to reduce the frequency
comes to the clinic to discuss her headaches. of migraine attacks.
Since adolescence, she has had migraine headaches, marked by unilateral throbbing cranial T r e atment O p t i ons
pain with nausea and photophobia, that have oc- Which one of the following approaches would
curred 10 to 12 times a year. The headaches are you take? Base your choice on the literature, your
usually preceded by the sensation of shimmering own experience, published guidelines, and other
lights that migrate across her visual field. Her information.
current medications include topiramate (once
daily), propranolol (twice daily), and oral suma- 1. Recommend prescription of combined oral
triptan to abort acute attacks. She does not smoke
contraceptive pills.
tobacco or use electronic cigarettes. There is no 2. Do not recommend prescription of combined
history of cardiovascular disease in her family.
oral contraceptive pills.
The patient’s vital signs are normal, and the
results of the physical examination are unreTo aid in your decision making, we asked two
markable. She has previously been instructed to experts in the field to summarize the evidence
document her headaches in a journal, and she in favor of approaches assigned by the editors.
has noticed that they frequently occur around Given your knowledge of the issue and the points
the time of her menses. She has no desire for made by the experts, which approach would you
pregnancy and inquires about the use of a com- choose?
bined oral contraceptive pill for the management From the Departments of Medicine and Pediatrics, Tufts Uniof her migraines and for contraception.
versity School of Medicine, Boston.
O p t i on 1
Recommend Prescription
of Combined Oral
Contraceptive Pills
Rossella E. Nappi, M.D., Ph.D.
Both the U.S. and World Health Organization
medical eligibility criteria for contraceptive use
list migraine with aura as an absolute contraindication to combined oral contraceptives.1 The
estrogen component of modern combined oral
contraceptives has been implicated in augment2102
n engl j med 389;22
ing the risk of ischemic stroke associated with
migraine with aura. Women who have migraines
with aura have twice the risk of stroke as women
without migraines (5.9 vs. 2.5 events per 100,000
persons annually), and the risk is nearly six times
as great with contraceptive use (14.5 events per
100,000 persons).2 Even though the overall absolute risk of stroke is low, stroke can cause serious complications, and other hormonal options
(e.g., progestogen-only contraception) are available. Both the American Headache Society and
the International Headache Society are less definitive about the contraindication of oral con-
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The New England Journal of Medicine
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Clinical Decisions
traceptives and recommend an individualized
decision with respect to oral contraceptives that
is based on benefits and risks, especially in the
absence of other risks factors for stroke, such as
an age older than 35 years, tobacco use, hypertension, obesity, diabetes, or hyperlipidemia.3
Providing effective contraception in a woman
such as the one described here requires obtaining a detailed clinical history. The woman in the
vignette is taking two prophylactic migraine
medications (an antiepileptic drug and a betablocker) and reports menstrually related migraine
(i.e., migraine broadly related to menstruation
but not limited to the days during menstruation)
with visual aura that responds to sumatriptan,
which belongs to a third class of antimigraine
medications. Although aura associated with menstruation is not common, it does occur and,
when present, is usually associated with severe,
prolonged migraines that are refractory to both
prophylactic medications and medications to treat
symptoms.4
Therefore, the patient’s request for a combined oral contraceptive pill, the most common
form of hormonal contraception, to control her
migraines is legitimate and should not be automatically discounted on the basis of presumed
stroke risk in the absence of substantial risk
factors. Available data do not support the use of
these agents to prevent general migraines, but
avoidance of fluctuations in estrogen levels may
help manage menstrually related migraines effectively; estrogen-containing pills are also useful in many menstrually regulated reproductive
conditions (e.g., heavy menstrual bleeding or
dysmenorrhea).4,5 It would be pertinent to determine the dose of topiramate prescribed to this
patient, since daily doses higher than 200 mg
may reduce contraceptive potency.6
Combined oral contraceptives with continuous,
extended, or flexible regimens; short hormonefree intervals; or supplementation with estrogen
alone during the hormone-free interval may reduce menstrual bleeding and make migraines
more predictable in women with menstrually
related migraines.4,5 Low-dose estrogen can be
used even in women who have simple visual
aura, with careful monitoring and discontinuation if the auras worsen. Preparations containing very low doses of estrogen (e.g., 10 to 20 µg
of ethinyl estradiol) are not clearly linked to the
risk of stroke, as compared with the higher
n engl j med 389;22
doses (e.g., 30 to 50 µg) investigated in earlier
studies.5 New formulations with alternative routes
of administration (e.g., intravaginal) may expose
a woman to low stable doses of ethinyl estradiol
that have less effect on the body but still deliver
levels of hormones that can block ovulation.4,5
Finally, a new era of contraception is being
heralded by natural estrogens, including
17?-estradiol, estradiol valerate, and estetrol (a
native estrogen of fetal origin). These show
promise for conferring a lower risk of cardiovascular complications than that associated with
ethinyl estradiol and thus may become the most
suitable options in women with migraine who
need or want combined hormonal contraception.4
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
From the University of Pavia Medical School, Unit of Reproductive Medicine, IRCCS San Matteo Hospital, Pavia, Italy.
O p t i on 2
Do Not Recommend
Prescription of Combined
Oral Contraceptive Pills
Carrie Cwiak, M.D., M.P.H.
Combined oral contraceptives are the most common method of reversible contraception in the
United States.7 However, there are several alternative hormonal and nonhormonal contraceptive
methods available. Patient-centered contraceptive counseling requires ensuring that each patient is aware of all contraceptive options, including the characteristics, benefits, and risks of
each method in the context of needs, values, and
preferences, so that the patient can make an
informed decision. In this situation, the clinician should ask the patient whether her utmost
priority is to decrease the frequency of migraine
headaches or to avoid pregnancy. Are her current
migraine medications suboptimal owing to side
effects or limited access? Does she desire pregnancy at any time in the future? What are her
preferences for contraceptive use requirements
or expected bleeding patterns? The relevant benefits and risks of the various options are important for the patient to consider.
Attention to the timing of migraines that occur around the time of menses may elucidate
whether they are related to estrogen withdrawal
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November 30, 2023
The New England Journal of Medicine
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Clinical Decisions
before menses, prostaglandin release during
menses, or both.8 Since all systemic hormonal
contraceptive methods inhibit ovulation and
suppress menses, their use may decrease the
frequency or severity of menstrual migraines.
The progestogenic component in all systemic
hormonal contraceptive methods is responsible
primarily for inhibiting the luteinizing hormone
surge, ovulation, and menstrual bleeding. Systemic progestin-only contraceptives include the
subdermal implant, injectable contraceptives, and
progestin-only oral contraceptives. The estrogenic component added to combined agents
provides the option for cyclic bleeding that mimics a menstrual pattern; this component is also
found in transdermal patches and vaginal rings.8
It is the estrogenic component that increases the
risk of cardiovascular events (e.g., venous thromboembolism, myocardial infarction, or stroke)
in users of combined hormonal contraceptives.
The baseline risk of stroke in women of reproductive age is only 5 to 10 cases per 100,000
woman-years.8 The risk of ischemic stroke is
increased in patients with migraines, and more
so if aura is present. A systematic review of studies involving users of combined oral contraceptives who have migraines showed that the risk of
stroke was two to four times that in nonusers
with migraines.9 Included was a study that evaluated the association of the use of these drugs
with the risk of stroke according to migraine
type, which showed an increased risk of stroke
only among users with migraine with aura as
compared with users without migraine (odds
ratio, 1.5; 95% confidence interval, 1.1 to 2.0).10
This prompted the Centers for Disease Control
and Prevention to assert that combined hormonal contraceptives may be used by patients
who have migraines without aura, but among
those who have migraines with aura, their use
presents an unacceptable health risk.1 In contrast, patients who have migraines with aura can
safely use progestin-only and nonhormonal contraceptive methods.1 Although data are lacking
from studies on progestin-only contraceptive use
in patients with migraines, in an international
case–control study, no increased risk of cardiovascular events was observed among healthy
users of progestin-only oral or injectable contraceptives.11 With the availability of lower-risk alternatives for menstrual suppression, there is no
n engl j med 389;22
compelling reason to offer a combined hormonal contraceptive pill to this patient.
Finally, although hormonal contraception has
benefits related to ovulation inhibition and menstrual suppression, it is not a first-line therapy
for control of migraines regardless of whether
they are related to menses. Other migraine therapies, including newer agents such as calcitonin
gene-related peptide receptor antagonists (gepants), should be considered, and separately,
locally acting intrauterine devices and barrier
methods should still be considered for their
contraceptive attributes, especially since their
use will not affect this patient’s risk of cardiovascular or stroke events, nor, contrary to popular belief, will it worsen migraines.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
From the Department of Gynecology and Obstetrics, Emory
University School of Medicine, Atlanta.
1. Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. medical eligi-
bility criteria for contraceptive use, 2016. MMWR Recomm Rep
2016;65:1-103.
2. Sacco S, Merki-Feld GS, Ægidius KL, et al. Hormonal contraceptives and risk of ischemic stroke in women with migraine:
a consensus statement from the European Headache Federation
(EHF) and the European Society of Contraception and Reproductive Health (ESC). J Headache Pain 2017;18:108.
3. Sheikh HU, Pavlovic J, Loder E, Burch R. Risk of stroke associated with use of estrogen containing contraceptives in women with migraine: a systematic review. Headache 2018;58:5-21.
4. Nappi RE, Tiranini L, Sacco S, De Matteis E, De Icco R, Tassorelli C. Role of estrogens in menstrual migraine. Cells 2022;
11:1355.
5. Calhoun AH. Hormonal contraceptives and migraine with
aura — is there still a risk? Headache 2017;57:184-93.
6. Viana M, Terreno E, Goadsby PJ, Nappi RE. Topiramate for
migraine prevention in fertile women: reproductive counseling
is warranted. Cephalalgia 2014;34:1097-9.
7. Daniels K, Daugherty J, Jones J, Mosher W. Current contraceptive use and variation by selected characteristics among
women aged 15–44: United States, 2011–2013. Natl Health Stat
Report 2015;86:1-14.
8. Cwiak C, Edelman AB. Combined oral contraceptives. In:
Hatcher RA, ed. Contraceptive technology. 21st ed. Ayer Company Publishers, 2018:265-316.
9. Tepper NK, Whiteman MK, Zapata LB, Marchbanks PA, Curtis KM. Safety of hormonal contraceptives among women with
migraine: a systematic review. Contraception 2016;94:630-40.
10. MacClellan LR, Giles W, Cole J, et al. Probable migraine with
visual aura and risk of ischemic stroke: the Stroke Prevention in
Young Women study. Stroke 2007;38:2438-45.
11. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Cardiovascular disease and use of oral and injectable progestogen-only
contraceptives and combined injectable contraceptives: results
of an international, multicenter, case-control study. Contraception 1998;57:315-24.
Copyright © 2023 Massachusetts Medical Society.
nejm.org
November 30, 2023
The New England Journal of Medicine
Downloaded from nejm.org by rossella nappi on November 29, 2023. For personal use only. No other uses without permission.
Copyright © 2023 Massachusetts Medical Society. All rights reserved.