601

Migraine in Women
Susan W. Broner, MD1 Sarah Bobker, MD1 Louise Klebanoff, MD1

1 Department of Neurology, Weill Cornell Medical College, Address for correspondence Susan W. Broner, MD, Department of
New York, New York Neurology, Weill Cornell Medical Center and Weill Cornell Medical
College, 520 East 70th Street, Starr-607, New York, NY 10021
Semin Neurol 2017;37:601–610. (e-mail: sub9064@med.cornell.edu).

Abstract Migraine is one of the most common neurological disorders, affecting women
disproportionally at a rate of 3:1. Prior to puberty, boys and girls are equally affected,
but the female preponderance emerges after puberty. Migraine pathophysiology is not
fully understood, and although the hormonal effect of estrogen is significant, other
factors are at play. This article will focus on the hormonal influence on migraine in
women. Here we review our most recent understanding of migraine and menstrual
migraine, including epidemiology, pathophysiology, and treatment strategies for this
Keywords challenging disorder, as well as migraine during pregnancy, postpartum period,

Downloaded by: University of Utrecht. Copyrighted material.

► hormones breastfeeding, perimenopause, and menopause. We also review the risks and benefits
► menstrual migraine of exogenous hormone use in this population and discuss stroke risk in women with
► pregnancy migraine aura. By understanding these aspects of migraine in women, we hope to arm
► contraceptives practitioners with the knowledge and tools to help guide treatment of this debilitating
► stroke disorder in this large population.

Epidemiology of Migraine the American Migraine Prevalence and Prevention (AMPP)

Migraine is among the most common patient complaints
seen in a neurology practice, accounting for up to 20% of all
outpatient neurology consultations.1 Migraine is one of the
most prevalent health conditions worldwide and the most
frequent cause of headache consultation in the Americas,
Europe, South-East Asia, and the Western Pacific.2 In the
United States, as many as 32 million Americans will be
affected by migraine at some point in their lives, with the
significantly greater proportion of the patients being
females.3
The global prevalence of migraine is 18.5%; 11.5% of these
patients have definitive migraine and 7.5% have probable
migraine (patients who meet all but one of the diagnostic
criteria for migraine). The prevalence of migraine with aura
ranges from 1.2 to 5.8%, approximately one-quarter of adults
with migraine. Chronic migraine is less common, with the
average cross-study estimate of chronic migraine at 0.5% (range:
0.2–2.7%).4 Prevalence estimates are comparable around the
world and have been consistent for several decades.5
Migraine prevalence varies with age, with women con-
sistently shown to have higher rates of migraine at all ages. In
study, migraine prevalence was found to be highest among
adults 30 to 39 years where prevalence among women
(24.4%) was more than three times that in men (7.4%).
Prevalence was found to be lowest in those older than
60 years (5.0% women, 1.6% men). Even among those aged
12 to 17 years, females had a higher prevalence of migraine at
6.4% compared with males at 4.0%.6
It is well established that sex hormones play an important
role in the epidemiology of migraine. Before puberty, girls
are afflicted with migraine at approximately the same rates
as boys. It has been noted that migraine tends to occur earlier
in boys. The incidence of migraine with aura peaks at around
age 5 in boys and age 12 to 13 in girls. Migraine without aura
peaks at age 10 to 11 in boys and age 14 to 17 in girls.7 The
incidence of migraine peaks between the age of 15 and
19 years in men (6.2/1,000 person-years) and between the
age of 20 and 24 years in women (18.2/1,000 person-years).
By adulthood, up to three times as many women as men
suffer with migraine, with a cumulative incidence of 43% in
women and 18% in men. Four of every 10 women and 2 of
every 10 men will contract migraine in their lifetime, most
before the age of 35 years.7

Issue Theme Women’s Issues in Copyright © 2017 by Thieme Medical DOI https://doi.org/
Neurology; Guest Editor, Steven K. Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0037-1607393.
Feske, MD New York, NY 10001, USA. ISSN 0271-8235.
Tel: +1(212) 584-4662.
602 Migraine in Women Broner et al.
Many women migraineurs note an increase in attacks
during the perimenstrual period. The International Criteria
for Headache Diagnosis 3-β version Appendix divided men-
strual migraine (MM) into pure menstrual migraine (PMM)
and menstrually-related migraine (MRM). PMM is defined by
migraine without aura that occurs during menstruation over
at least three consecutive cycles, exclusively on day 1 þ/ 2
of menstruation (i.e., days  2 to þ3 where day 1 reflects the
onset of bleeding in at least two of three menstrual cycles).
The term MRM uses the same menstrual associated criteria,
but refers to women who are also having migraines outside
of this.8
MM develops most frequently around the onset of
menarche with prevalence peaking around the age of
40 years and declining as menopause approaches.9 The
AAMP study found that nearly 60% of women with migraine
reported an association between migraine and menses.
PMM was seen in 5.5% of the women surveyed and MRM
was seen in 53.8%. Women with MM had an older age of
migraine onset.10 Compared with nonmenstrual migraines,
MM were more likely to cause impairment, were longer,
and were more likely to relapse within 24 hours, increasing
the burden of MM.11
In addition to the higher prevalence of migraine in
women, the burden of the disease is likely to be greater in
women. As described above, MM is more likely to cause
disability when compared with non-MM. Gender is also a
risk factor for chronification of headache, likely due to
hormonal differences; women have a higher prevalence of
chronic daily headache than men. In addition, several studies
have suggested that women have more frequent, more
severe, and more long-lasting headaches when compared
with men and experience more of the associated symptoms
of photophobia, phonophobia, and nausea.12,13
Migraine is comorbid with several medical disorders,
including arterial disease, hypothyroidism, asthma, endo-
metriosis, depression, anxiety, and somatic complaints,
including fibromyalgia, chronic fatigue, irritable bowel syn-
drome, and interstitial cystitis.14 The underlying pathophy-
siology of these comorbidities has not yet been adequately
elucidated.
Migraine poses an enormous personal and social burden
in terms of direct and indirect costs. The Global Burden of
Disease Study 2013 found that migraine is the sixth highest
cause of disability worldwide.15,16 Over 80% of patients with
migraine report some degree of disability. Migraine is the
third cause of disability in those under 50 years of age.17
Despite the magnitude of disability associated with migraine,
only approximately one-half of the patients with debilitating
migraine seek professional help.18 With advances in treat-
ment options, improved awareness of migraine and better
delivery of interventions are essential.
Pathophysiology of Migraine
Our understanding of the pathophysiology of migraine has
advanced significantly over the past several decades. Migraine
is no longer considered as a disease of extracranial vascular
Seminars in Neurology Vol. 37 No. 6/2017
dilatation.19 We now know migraine is an inherited disorder
that involves central pain modulating dysfunction via a com-
plex interplay between neurotransmitters, inflammatory pep-
tides, and vasculature modulated by the trigeminovascular
system involving both the peripheral and central nervous
systems.
Initiating processes in migraine include activation and
sensitization of the trigeminovascular pain pathway as
well as cortical spreading depression in migraine aura.
This activation of the trigeminovascular system results in
neurotransmission to the trigeminal nociceptors that in-
nervate the large blood vessels in the meninges. In turn,
there is a release of calcitonin gene-related peptide (CGRP)
and other vasoactive inflammatory peptides that trigger
vasodilatation, plasma extravagation, and further release
of cytokines and proinflammatory molecules. This com-
plex stimulates second- and third-order sensitization of
the trigeminovascular system neurons, leading to the pain
and allodynia of migraine. This is accompanied by baseline
hyperexcitability of the cortex in people with migraine,
Downloaded by: University of Utrecht. Copyrighted material.
which is likely due to dysfunction of central pain mod-
ulatory processes.20 In addition to the trigeminovascular
complex, the periaqueductal gray, thalamus, hypothala-
mus, and cortex are brought into play. Other putative
players in the production of migraine include nitric oxide
(NO), vasoactive intestinal peptide (VIP), Fos expression,
N-methyl-D-aspartate (NMDA) receptors, glutamate recep-
tors, serotonin, gamma-aminobutyric acid (GABA), and
prostaglandins, among others.21–23
Estrogens have a profound effect on migraine, contributing
to the larger percentage of women with migraine than men.
Hormonal effect is also seen clinically in MM as well as migraine
during pregnancy and postpartum and during perimenopause
and menopause. Early studies revealed that the drop of estrogen
(rather than progesterone) in the luteal phase of the menstrual
cycle is an important trigger for MM. Further, implanted long-
acting estrogen that delivered fluctuating estrogen levels was
shown to lead to menstrual irregularity and triggered more
migraines in some female patients.24 The literature does not
offer a clear reason for this drop in estrogen to serve as a trigger
for many female migraineurs. However, other findings involving
estrogen have added to our understanding. Estradiol appears to
have a direct effect on gene expression. In women with MM,
17β-estradiol at physiological doses appears to significantly
reduce inflammation by reducing mRNA expression and there-
fore levels of CGRP, interleukin (IL)-1β, and inducible nitric oxide
synthase (iNOS). However, pharmacological doses appear to
significantly increase mRNA expression of CGRP in both
patients with MM and controls, highlighting the differences
between estrogen dose and response.25 Migraineurs have faster
late luteal phase-conjugated urinary estrogen decline (greater
absolute rate of decline and greater percent of change) com-
pared with controls, whether the migraineur has MM or MRM.
This suggests an innate neuroendocrine vulnerability to estro-
gen withdrawal in women with migraine.26
The role of genetics in migraine is under investigation.
Functional polymorphisms in estrogen metabolism genes
COMT, CYP1A1, or CYP19A1 have not been found to be

associated with MM.27 However, several other hormone-re-
lated genes have been identified to be associated with predis-
position to migraine and, in particular, MM. These include
ESR1, PR PROGINS insert, and possibly, ESR2 and FSHR, as well as
genetic variants in the SYNE1 and TNF genes.28,29
Other factors have been proposed over the years as con-
tributory to MM. Prostaglandins (PGs) have long been identi-
fied as possible factors in MM. PGs are fatty acid derivatives of
arachidonic acid and are believed to promote neurogenic
inflammation and inhibit norepinephrine release. It appears
that PG levels significantly increase in the luteal phase and
menstruation.30,31 Platelet abnormalities or alterations in
platelet homeostasis have also been observed.32,33
Central processing of the trigeminocervical reflex in
women with MM appears to be different from controls.
Women with MM appear to have different trigeminal ex-
citability compared with controls, with significantly shorter
latencies, when the supraorbital nerve is stimulated during
perimenstruation compared with during the follicular
phase.34 Women with and without migraine seem to have
reduced habituation and increased pain perception to per-
ipheral stimuli during the estrogen withdrawal phase of
migraine.35 This may partly explain why MM is more
painful and debilitating than migraine outside the men-
strual cycle.
Animal models have shed some light on the pathophy-
siology of MM. In one animal model of MM, high estrogen
levels in the estrous cycle were seen to induce increased
neuronal excitability and peripheral sensitization of trigem-
inal ganglia neurons.36 In another experiment, exogenous
estrogen and progesterone exposure in mice with an ovar-
iectomy led to increased cortical spreading depression
(CSD), which may be why aura may worsen in pregnancy
or with combined oral contraceptive (COC) use.37 In the
mouse model of familial hemiplegic migraine-1 (FHM1),
hormonal influence on CSD was clear: female mice showed
reduced susceptibility to and higher velocity and frequency
of CSD compared with male mice. Ovariectomy reversed
this.38
Serotonin has also been implicated in both migraine and
MM. Migraine is thought to be a low 5-hydroxytryptophan
(5-HTP) condition. A recent study looking at the effect of
hormones, 5-HTP (a precursor to serotonin), and cortical
excitability in a mouse model of migraine found that
(1) 5-HTP decreased CSD occurrence in the presence of
ovarian hormones, particularly during estrous, suggesting its
potential benefit as prophylaxis in women with migraine
with aura, (2) elevated estradiol levels increased CSD sus-
ceptibility, while estrogen withdrawal decreased CSD, and
(3) mice with oöphorectomy who then received estradiol
replacement showed increased CSD, decreasing after estra-
diol was removed. These findings may explain why migraine
aura can emerge with pregnancy as estrogen levels rise and
why MRM is rarely associated with MA.39 This study built
upon work which had demonstrated that enzymes involved
in the synthesis of serotonin are expressed in mouse trigem-
inal ganglion, and the level of these enzymes is dependent on
the gender and estrus cycle stage, suggesting that ovarian
Migraine in Women Broner et al. 603
steroids might play a role in the regulation of serotonin
synthesis.40
Treatment of Menstrual Migraine
Because MM is more severe, lasts longer, and causes asso-
ciated nausea and disability more than migraine outside the
menstrual cycle, special treatment strategies are often ne-
cessary. The first step is to have the patient keep a headache
diary over a 3-month period to determine the link to
menstruation as well as total migraine frequency and any
other patterns. Once this is determined, diagnosis and treat-
ment options should be discussed and implemented. Both
pharmacological and nonpharmacologic strategies should be
employed. Pharmacological approaches include acute treat-
ments, daily prophylaxis, and short-term prophylaxis lead-
ing up to and during menses. Nonpharmacological strategies
include trigger avoidance, consistent sleep hygiene, hydra-
tion, exercise, and complementary treatment approaches.
Acute treatments: Many women will respond well to
Downloaded by: University of Utrecht. Copyrighted material.
typical non-MM acute treatment approaches using triptans
or nonsteroidal anti-inflammatory drugs (NSAIDs). How-
ever, because of the high prevalence of associated nausea
during MM compared with non-MM, antiemetics and pro-
kinetics, such a metoclopramide, may be required. There are
seven triptans on the market, and the choice of a particular
agent should take into account the patient’s prior success or
failure and personal preferences, as well as speed of onset,
associated features, such as nausea or vomiting, and recur-
rence. Although any triptan can be used for MM on an as-
needed basis, published data for acute treatment in MM are
available on frovatriptan 2.5 mg,41 almotriptan 12.5 mg,42,43
naratriptan 2.5 mg,44 sumatriptan 6 mg injectable,45 suma-
triptan 50 and 100 mg tablets (with the 100 mg tablet
showing a slight trend in better efficacy than the 50 mg
dose in one study),46–48 rizatriptan 10 mg,49,50 and zolmi-
triptan 2.5 mg and 5 mg.51,52 Although frovatriptan has been
shown to be as effective as almotriptan and zolmitriptan,
there appears to be a lower rate of recurrence with frova-
triptan due to its long half-life and duration of action, making
it a particularly appealing choice for MM.53,54
A variety of NSAIDs can be used in the treatment of MM.
Since elevated prostaglandins have been observed in women
with MM30 use of NSAIDs, which interfere with the production
of PGs and other inflammatory molecules seen in the patho-
physiology of migraine, seems to make sense, and some data
support their use for “miniprophylaxis” (see below). Studies
combining NSAIDs with triptans have also been positive.
Frovatriptan 2.5 mg taken with dexketoprofen 25 or 37.5 mg
showed higher pain free rate at two hours compared with
frovatriptan 2.5 mg alone while retaining the benefit of low
recurrence.55 Sumatriptan–naproxen sodium for women with
MM also suffering from dysmenorrhea has also been shown to
be efficacious.56
Short-Term Prophylaxis: For many women, however, the
above treatments are insufficient, and short-term prophylaxis
may be desirable. In this approach, treatment is initiated prior
to the onset of menstruation or MM itself and is continued for
Seminars in Neurology Vol. 37 No. 6/2017
604 Migraine in Women Broner et al.

several days into menses. To be effective, a woman must have a
regular and predictable menstrual cycle. Level 1 Evidence
(effective) supports frovatriptan for the preventive treatment
of MRM.57 For prophylaxis, 2.5 mg is used once or twice a day
for 6 days starting 2 days prior to the onset of the expected MM.
Studies have shown a statistically significant benefit compared
with placebo for headache reduction, increase in headache-
free time, and a reduction in severity. Although once daily
dosing was beneficial, twice daily dosing appeared to provide
even greater benefit.58 Level 2 Evidence (probably effective)
supports zolmitriptan and naratriptan for MM prevention.
Zolmitriptan 2.5 mg has been shown to be effective when
used two to three times a day for 7 days starting 2 days prior to
onset of expected menses, resulting in reduced frequency and
breakthrough pain.59 Naratriptan 1 mg taken twice daily for
5 days starting 2 days prior to the expected onset of menses
across four perimenstrual periods showed benefit over pla-
cebo, although 2.5 mg was not seen to be efficacious.60 In one
study, eletriptan (20 mg three times daily starting 2 days prior
to the expected onset of menstruation and continued for a total
NSAIDs are also used for short-term prophylaxis of MM.
Naproxen sodium 550 mg twice daily or mefenamic acid
500 mg three times daily, used 2 to 4 days prior to the onset
of the MM and continued through day 3 of menstrual flow,
can be an effective method and may address coexisting
dysmenorrhea.65,66 The lack of response to one NSAID does
not reflect a global lack of responsiveness to the class, and
others NSAIDs may be tried.
For those without vascular contraindications, ergotamines
have also been shown to be useful in MM miniprophylaxis.
Given the relatively short duration of use, the risk of toxicity
and dependence is low.67 Time-released dihydroergotamine
(not available in the United States) has been shown to be
beneficial in reducing MM intensity and duration, used daily
starting 2 days prior to menses onset and taken for 7 days.68 In
one study of DHE-45 nasal spray (2 mg per spray, used one
spray every 8 hours) for MM prophylaxis, patients experienced
significant benefit with good tolerability69 (►Table 1).
Long-Term Migraine Prevention: Migraine prevention is
indicated for any patient who reports frequent migraines, has

Downloaded by: University of Utrecht. Copyrighted material.

of 6 days) significantly reduced headache activity compared
with placebo; however, 9% may experience migraine in the
3 days immediately after discontinuing eletriptan.61 A follow-
up study of eletriptan, comparing its use during MM with non-
MM, showed similar 2-hour headache outcome measures
between the two groups but a higher recurrence rate and a
lower sustained response rate for nausea in the MM group.62
Sumatriptan 25 mg can also be effective; dosing is three times
daily starting 2 to 3 days before the expected day of headache
onset and continued for a total of 5 days.63 Short-term pro-
phylaxis with triptans appears to be safe. In one study,
frovatriptan for 6 days a month as “miniprophylaxis” was
safe and well tolerated over a 12- to 15-month period. There
was no evidence of increased cardiovascular risk, and rebound
headache was not evident.64
inadequate response to acute treatments, or makes frequent
use of abortive agents. Often, acute treatment strategies and
even short-term prophylaxis are more effective when mi-
graine prevention is in place. Trials of at least 2 months of a
drug are needed to see full effect. For women already using a
daily preventative medication, transiently increasing the dose
prior to the onset of the MM can be beneficial.70 Preventive
agents include β-blockers, antidepressants, antiepileptic med-
ications, calcium channel blockers, among others, including
botulinum toxin for those with chronic migraine.
Hormonal Manipulation in the treatment of MM: For
women who have failed the above treatments, hormonal
manipulation may be considered, provided there are no
contraindications, such as diabetes, hyperlipidemia, hyper-
tension, clotting disorders, or tobacco use. The use of

Table 1 Studied short-term prophylaxis regimens for menstrual migraine

Medication Regimen FDA Primary contraindications

approved
Frovatriptan57,58 2.5 mg BID  6 d, starting 2 d prior to MM onset No History of stroke or MI,
uncontrolled vascular risk
factors, hypercoaguable state
among others Presence of
aura may be a contraindication
Zolmitriptan59 2.5 mg BID to TID  7 d, starting No As above
2 d prior to onset of menses
Naratriptan60 1 mg BID  5 d, starting 2 d prior to onset of menses No As above
Eletriptan61,62 20 mg BID  6 d, starting 2 d prior to onset of menses No As above
Sumatriptan63 25 mg TID  5 d, starting 2–3 d prior to onset of MM No As above
65
Naproxen 550 mg BID  5–7 days starting 2–4 d prior to MM No Renal disease,
gastrointestinal bleeding
Mefenamic Acid66 500 mg TID  5–7 days starting 2–4 d prior to MM No Renal disease,
gastrointestinal bleeding
Dihydroergotamine 2 mg spray used one spray every 8 h for No As for triptans
nasal spray69 6 d starting 2 d prior to onset of MM

Abbreviations: FDA, food and drug administration; MM, menstrual migraine.

Seminars in Neurology Vol. 37 No. 6/2017


exogenous hormones in women with aura may increase the
risk of stroke, so their use in such patients must be evaluated
on a case-by-case basis (see below). The concept behind
hormonal intervention is to counterbalance the natural,
steep decline of estrogen in the luteal phase that appears
to be the main driving force for MM. Strategies include (1)
supplementing estrogen when levels are dropping in the
luteal phase or (2) using a noncycling combined oral contra-
ceptive agent (COC) or progestin-only pill (POP) to inhibit
follicular development and ovulation, and thereby reduce the
large estrogen fluctuations that trigger migraine. Although
many women do respond to exogenous hormones, it is
important to alert the patient that some may experience
more frequent migraines. Development of an aura for the
first time during hormone use is an indication for immediate
cessation of the hormone due to perceived stroke risk.
Estrogen Supplementation: Supplementation of falling
estrogen levels near the onset of menstruation may provide
relief. In one study, women who used 1.5 mg estradiol gel for
7 days starting 2 days prior to onset of expected MM
experienced a statistically significant reduction in frequency
and the use of acute treatments.71 Another study showed
that a 0.1 mg per day estrogen patch starting just prior to
onset of menses for a total of 7 days was effective in reducing
MM, but lower doses were not.72 Patches and gels are
believed to be more effective, because these have a steady
state of absorption compared with the fluctuations seen in
oral supplementation.
Daily Hormonal Use: There are many formulations of
COCs, and the lower dose (35 µg or less) monophasic COCs
may be safer and less disruptive to migraineurs than higher
dose and triphasic formulations. Minimizing the number of
placebo days by noncycling (elimination of the placebo week)
may be beneficial in reducing MM. Elimination of the men-
strual cycle with the use of hormonal preventatives has been
correlated with a transformation from chronic to episodic
migraine as well as a significant reduction in acute treatment
use.73 Noncycling COC may lead to a decrease in headache
severity along with improvement in work productivity and
involvement in activities74 Additionally, formulations, such
as the patch or the vaginal ring, deliver a steady state of
hormones compared with the peaks and troughs found in
oral counterparts. This steady state may help minimize
migraine vulnerability by reducing estrogen fluctuations.
One study looking at the effect of noncycling use of the
vaginal ring in women with migraine with aura and MRM
showed an association with reduction in frequency of
migraine aura with resolution of MRM. The stroke risk could
not be assessed or extrapolated from this study.75
The progestin-only pill (POP) may be beneficial for women
with MM, reducing migraine frequency in women without
aura and, in one study, addressing comorbid endometriosis
pain.76 In a pooled analysis of four studies from 1980 to 2016,
the effect of POP use on migraine in general showed that
desogestrel 75 µg/day significantly reduced migraine fre-
quency, intensity, duration, and acute treatment use.77 More
studies are needed on the use of the POP pill for MM, but this
may turn out to be a better option for women with aura.
Migraine in Women Broner et al. 605
Few data are available on induced menopause (hyster-
ectomy or oöphorectomy) for treatment of MM. In one study,
two-thirds of patients who underwent surgical menopause
reported a worsening of their headaches, but postoperative
use of daily estrogen replacement confounds these results.
There is no current role for these procedures for the manage-
ment of MM.78
Complementary Approaches: Although many patients ex-
perience benefit from the pharmacological approaches to MM,
some have intolerable side effects or are looking for nonphar-
macological approaches. Probably through its antiprostaglan-
din effect, vitamin E, 400 units taken daily for 5 days starting
2 days prior to menstruation, has been shown to reduce pain
severity and disability and associated features compared with
placebo.79 This regimen has also been found to improve the
pain of dysmenorrheal significantly.80 Magnesium has been
shown to reduce the pain of MM and premenstrual symp-
toms.81 There are no completed studies on the role of acupunc-
ture in MM prevention; however, one study is underway.82
Downloaded by: University of Utrecht. Copyrighted material.
Migraine in Pregnancy, Postpartum, and
Breastfeeding
Migraine affects a significant number of women during
childbearing years. Given that almost half of all pregnancies
are unintended, practitioners should counsel their female
patients about potential teratogenicity or other adverse fetal
outcomes with migraine treatments, stressing the importance
of adequate birth control.83 Several preventive agents are
Category D in pregnancy, including valproic acid, topiramate,
candesartan, nortriptyline, imipramine, and magnesium.
When planning pregnancy, it is recommended that practi-
tioners develop a plan for the woman to taper off medications
in advance of conception, taking into consideration the half-life
of the particular medication.
For some women, a worsening of migraine may be the first
indication of pregnancy. However, 60 to 87% of women with
MRM improve in the second or third trimester.84 Four to 8% of
women may worsen, with a disproportionate number of
women with aura in this group. Migraine may start for the
first time in pregnancy (1.3–16.5%), often in the first trimester,
and a significant portion of such women present with migraine
with aura.85 Factors contributing to this de novo onset or
worsening include the hormonal changes of pregnancy and,
likely, nausea, dehydration, lack of sleep, and stress.
For new onset or worsening headaches in pregnancy, the
initial step in management is to ensure that there is no
underlying pathology. Once this has been done, choosing
treatment options that minimize risk to the developing fetus
while reducing pain and disability in the mother should be the
focus. Nonmedication approaches are the cornerstone of treat-
ment. These include lifestyle factors, such as a healthy diet and
regular sleep, maintaining good hydration, minimizing caf-
feine, and avoiding triggers as well as biofeedback, acupunc-
ture, meditation, icepacks or heat, and moderate exercise
as tolerated. These measures may be sufficient to get the
patient through the first trimester, after which migraines
tend to improve.
Seminars in Neurology Vol. 37 No. 6/2017
606 Migraine in Women Broner et al.
When these strategies are not sufficient, some acute treat-
ments are considered safe in moderation. Although treatment
options are limited, several strategies can be employed work-
ing in coordination with the patient’s obstetrician. Limited use
of acetaminophen (category B) may be helpful, especially
when combined with caffeine. Although causality has not
been determined, two studies have observed an association
between acetaminophen use in pregnancy and ADHD and
other hyperactive kinetic disorders in children.86,87 One study
has suggested an association of acetaminophen with autism
spectrum symptoms in males.88 More research needs to be
done to better understand these relationships given how
widespread acetaminophen use is. Meanwhile, women should
be advised to limit use of acetaminophen during pregnancy.
All NSAIDs are category D in the third trimester, but a few,
including ibuprofen, naproxen, indomethacin, and ketorolac,
are category B in the first and second trimester. Several opioids,
such as meperidine and morphine, are category B until the third
trimester when these should be used with caution. Codeine,
hydrocodone, and oxycodone have been associated with major
birth defects, including cardiac malformations, but it is not clear
if this relationship is causal.89 Antiemetics are often used in
migraine management. Pyridoxine and doxylamine are cate-
gory A, while diphenhydramine, dimenhydrinate, cyprohepta-
dine, ondansetron, and metoclopromide are category B.
Ondansetron may confer a small risk of cardiovascular mal-
formations.90 Ginger may be a safe alternative for nausea. If
steroids are indicated, prednisone (category C) is preferred to
dexamethasone, because prednisone is more efficiently meta-
bolized by the placenta and excluded in its active form from the
fetal circulation. Ergotamines and aspirin should be avoided
during pregnancy. Triptans are category C during pregnancy
carrying the risk of vasoconstriction and should be avoided.
However, a meta-analysis looking at over 4,000 women who
took triptans during pregnancy did not show an association
with developmental issues, an increased rate of major con-
genital malformations, or prematurity; triptans may confer an
increased risk of spontaneous abortions.91,92 More research
needs to be done on agents in this class given their efficacy and
the great disability of the disorder.
For severe attacks, IV fluids and IV antiemetic agents are
often helpful. Lidocaine-only blocks nerves to interrupt status
migrainous as well as intranasal lidocaine (category B) can be
beneficial acutely. Daily oral preventive agents are reserved for
women with frequent, severe attacks or significant vomiting,
where the benefit might outweigh the potential risks to the
developing fetus. Because most preventive agents are category
C or higher, a decision to use these agents should follow a full
discussion with the patient, her partner, and her obstetrician,
and full consent should be obtained from all parties. Com-
monly used treatments include labetalol, propranolol, sertra-
line, and occasionally amitriptyline. Memantine is category B;
however, this designation is based on animal studies, and
therefore the full risks to humans are not known. Acupuncture,
biofeedback, and the transcutaneous nerve stimulator device
are considered safe preventive therapies during pregnancy.
Although historically migraine has not been felt to confer a
greater risk of complications of pregnancy, several new studies
Seminars in Neurology Vol. 37 No. 6/2017
bring this judgment into question. Recent studies of pregnant
women with migraine have shown an increased risk of adverse
delivery outcomes. These include increase risk of low birth
weight, preterm delivery, preeclampsia, cesarean section, and
severe nausea and vomiting.93–95 Given these studies, it is
important that gynecologists and obstetricians screen their
patients for migraine.
Migraine symptoms often emerge in the postpartum
period as estrogen levels rapidly fall. Breastfeeding may
delay the return of migraines by keeping estrogen levels
elevated. Treatment principles in breastfeeding are similar to
those in pregnancy. Ibuprofen, ketoprofen, and sumatriptan
are generally regarded as safe, though some physicians
recommend the pump and dump method several hours after
treating. Working with the patient’s pediatrician to find the
safest approach for both mother and infant is recommended.
Migraine during Perimenopause and
Menopause
Downloaded by: University of Utrecht. Copyrighted material.
For many women, the perimenopausal time brings worsening
migraines. While the average age of menopause in the
United States is 51 years, perimenopause starts in the preced-
ing decade (in some as early as the mid to late 30s) and marks
the end of the reproductive years. This transition is caused by
fluctuating ovarian function with fluctuating hormone levels
resulting in irregular periods, hot flashes, insomnia, difficulty
concentrating, and a reduction in libido. This chaotic hormonal
variation can lead to higher migraine frequency and worsening
severity, and some women with prior quiescent disease may
see a return of migraine attacks. For women with MRM,
irregular cycles set in making migraine attacks unpredictable
and treatment more challenging. In particular, women with a
history of premenstrual syndrome appear to have a significant
increased risk for high frequency headache during this time
period.96 Although tests may confirm perimenopause, these
are unlikely to alter diagnosis or management.
Approaches to management include typical migraine
preventive agents and acute treatments. When these fail
and there are significant vasomotor symptoms and no con-
traindications, the use of hormone replacement therapy
(HRT) may be helpful to some. HRT doses are typically lower
than COC doses but do help stabilize estrogen withdrawal,
thereby minimizing migraine induction. Patches and gels are
less likely to aggravate migraine frequency compared with
oral formulations because of their steady state.97 For women
with an intact uterus using estrogen, the addition of proges-
tin for endometrial protection is typically employed. Con-
tinuous progestin use rather than cycling of progestin may be
less provocative for women with migraine.98 If migraine
worsens with HRT, reducing the dose, utilizing a noncycling
method, or switching from conjugated estrogens to pure
estradiol may be beneficial.99
For women who have contraindications to HRT or who
otherwise do not wish to use or have failed HRT, venlafaxine,
paroxetine, fluoxetine, and gabapentin have been shown to
help reduce the vasomotor symptoms of perimenopause.100
These four agents have some efficacy in migraine prevention,

with venlafaxine rated as probably effective (level B) and
fluoxetine and gabapentin rated as level U, with insufficient
or conflicting evidence.57
The effect of menopause on migraine is still not clearly
understood. It has been observed that migraine typically
improves after menopause in general population studies, but
worsens in women in headache clinic studies.101,102 Overall,
it appears that women with a history of premenstrual
syndrome do better after menopause.103
Vascular Risk in Women with Migraine
It has long been recognized that there is an association
between migraine and ischemic stroke.104 This risk is pri-
marily attributed to migraine with aura most typically in
younger women, and it appears to be independent of other
risk factors. 105–107 A meta-analysis reported that the risk of
stroke was doubled in those with migraine with aura and
tripled in the female cohort.108 It also appears that aura
frequency of more than once a month as well as a life-time
duration of less than a year is associated with an even higher
stroke risk.104,105 There are no data to date that suggest that
effective treatment of migraine with aura to reduce fre-
quency actually reduces this risk.106 Hemorrhagic stroke
appears to be consistently increased in MA, MO, and un-
categorized migraine.109
The mechanisms of the relationship between migraine with
aura and stroke are complex; hormonal influences are thought
to contribute. Increased estrogen levels may increase the risk
of ischemic stroke via their effect on endothelial function,
coagulation factors, and inflammation.110 The stroke risk
appears to be greater in women, and the magnitude of the
increase is greater in women who take higher dose COCs.111,112
As for many vascular risk factors, the risk appears to be
compounded in the presence of other known risk factors.106
COCs alone pose a stroke risk, so there is much concern about
women with aura using COC and increasing their stroke risk.
Guidelines of the American College of Obstetricians and
Gynecologists state that the risks of COCs are unacceptable
in this group, whereas COCs are not contraindicated in
migraine without aura in healthy, nonsmoking women
35 years of age or under.113 However, controversies remain
around the interpretation of the data. In particular, it appears
that estrogen dose matters when speaking of stroke risk as well
as thrombotic risk. A meta-analysis shows that the risk of
ischemic stroke among COC users decreases significantly with
decreasing estrogen dose. Estrogen doses less than 50 µg
confer a lower risk than higher doses of estrogen above
50 µg. Risk continues to go down as estrogen dose goes
down to 35, 30, and 20 µg.114 Thrombotic risk may also
correlate with dose and duration of exposure.115
This controversy highlights the need for more studies, so we
can better advise our patients. It is generally agreed, however,
that any form of hormonal therapy should be avoided in patients
with prolonged aura (lasting longer than 60 minutes) or aura
with multiple neurological symptoms, including migraine with
brainstem aura and hemiplegic migraine. Women who do not
have aura but are contemplating hormonal contraception
Migraine in Women Broner et al. 607
should be carefully counseled to report new onset aura symp-
toms or any changes in cardiovascular risk status, and they
should be evaluated on a case-by-case basis for safety. Discon-
tinuation of COCs should be immediate if migraines worsen
after the first few months of treatment or if an aura develops for
the first time.116
For the large number of women with simple aura, an
individualized rather than a one-size-fits-all approach appears
to be more appropriate. Developing a risk–benefit assessment
in coordination with the patient and her gynecologist that
includes the circumstances of the need for hormonal use, age,
the subtype of migraine, smoking status, and any other
vascular risk factors allows practitioners to approach the
problem systematically as we wait for more data to guide us.
Conclusion
Migraine is one of the most common neurological conditions
and is the third most common disabling disorder globally;
yet, up to 50% of sufferers do not receive medical care.
Downloaded by: University of Utrecht. Copyrighted material.
Women are disproportionately affected by a ratio of 3:1, in
part due to hormonal differences with changes in estrogen
appearing to be the main driver. Many other factors, includ-
ing serotonin, prostaglandins, and central processing, appear
to play an important role in the pathophysiology of migraine.
Many treatment options exist for hormonally related mi-
graine, including acute treatments, short- and long-term
prophylaxis, and hormonal manipulation. Fewer options are
available during pregnancy and breastfeeding, but by working
with patients’ obstetricians and pediatricians, solutions can be
found. Understanding and discussing risks and benefits with
patients are essential parts of pharmacological treatment.
Stroke is associated with migraine, particularly in women
with migraine with aura, and hormone use is currently not
recommended in this subtype. To improve our care of patients,
more studies need to be done to expand our knowledge of
migraine in women, including hormonal effects on the patho-
genesis of migraine and stroke.
Conflict of Interest
Dr Broner reports personal fees from Allergan, outside the
submitted work.
References
1 Stone J, Carson A, Duncan R, et al. Who is referred to neurology
clinics?–the diagnoses made in 3781 new patients Clin Neurol
Neurosurg 2010;112(09):747–751
2 World Health Organization. Atlas of Headache Disorders and
Resources in the World 2011. Geneva, Switzerland: World Health
Organization; 2011
3 Pavlovic JM, Akcali D, Bolay H, Bernstein C, Maleki N. Sex-related
influences in migraine. J Neurosci Res 2017;95(1–2):587–593
4 Merikangas KR. Contributions of epidemiology to our under-
standing of migraine. Headache 2013;53(02):230–246
5 Linet MS, Stewart WF. Migraine headache: epidemiologic per-
spectives. Epidemiol Rev 1984;6:107–139
6 Lipton RB, Bigal ME, Diamond M, Freitag DO, Reed ML, Stewart WF;
AMPP Advisory Group. Migraine prevalence, disease burden, and
the need for preventive therapy. Neurology 2007;68(05):343–349
Seminars in Neurology Vol. 37 No. 6/2017
608 Migraine in Women Broner et al.
7 Stewart WF, Wood C, Reed ML, Roy J, Lipton RB; AMPP Advisory
Group. Cumulative lifetime migraine incidence in women and
men. Cephalalgia 2008;28(11):1170–8
8 Headache Classification Committee of the International Head-
ache Society. The International Classification of Headache Dis-
orders, 3rd edition (beta version). Cephalalgia 2013;33(09):
629–880
9 Epstein MT, Hockaday JM, Hockaday TD. Migraine and repor-
oductive hormones throughout the menstrual cycle. Lancet
1975;1(7906):543–548
10 Pavlović JM, Stewart WF, Bruce CA, et al. Burden of migraine
related to menses: results from the AMPP study. J Headache Pain
2015;16:24
11 MacGregor EA, Victor TW, Hu X, et al. Characteristics of men-
strual vs nonmenstrual migraine: a post hoc, within-woman
analysis of the usual-care phase of a nonrandomized menstrual
migraine clinical trial. Headache 2010;50(04):528–538
12 Boardman HF, Thomas E, Croft PR, Millson DS. Epidemiology of
headache in an English district. Cephalalgia 2003;23(02):129–137
13 Celentano DD, Linet MS, Stewart WF. Gender differences in the
experience of headache. Soc Sci Med 1990;30(12):1289–1295
14 Macgregor EA, Rosenberg JD, Kurth T. Sex-related differences in
epidemiological and clinic-based headache studies. Headache
2011;51(06):843–859
15 Global Burden of Disease Study 2013 Collaborators. Global,
regional, and national incidence, prevalence, and years lived
with disability for 301 acute and chronic diseases and injuries in
188 countries, 1990–2013:a systematic analysis for the Global
Burden of Disease Study 2013. Lancet 2015;386(9995):743–800
16 Steiner TJ, Birbeck GL, Jensen RH, Katsarava Z, Stovner LJ,
Martelletti P. Headache disorders are third cause of disability
worldwide. J Headache Pain 2015;16:58
17 Steiner TJ, Stovner LJ, Vos T. GBD 2015: migraine is the third cause
of disability in under 50s. J Headache Pain 2016;17(01):104
18 Merikangas KR, Cui L, Richardson AK, et al. Magnitude, impact,
and stability of primary headache subtypes: 30 year prospective
Swiss cohort study. BMJ 2011;343:d5076
19 Wolff HG. Headache and Other Head Pain. 2nd ed. New York, NY:
Oxford University Press; 1963
20 Pietrobon D, Moskowitz MA. Pathophysiology of migraine. Annu
Rev Physiol 2013;75:365–391
21 Goadsby PJ. Pathophysiology of migraine. Neurol Clin 2009;27
(02):335–360
22 Puledda F, Messina R, Goadsby PJ. An update on migraine:
current understanding and future directions. J Neurol 2017;
264(09):2031–2039
23 Parantainen J, Vapaatalo H, Hokkanen E. Relevance of prosta-
glandins in migraine. Cephalalgia 1985;5(Suppl 2):93–97
24 Somerville BW. Estrogen-withdrawal migraine II. Attempted
prophylaxis by continuous estradiol administration. Neurology
1975;25(03):245
25 Karkhaneh A, Ansari M, Emamgholipour S, Rafiee MH. The effect
of 17β-estradiol on gene expression of calcitonin gene-related
peptide and some pro-inflammatory mediators in peripheral
blood mononuclear cells from patients with pure menstrual
migraine. Iran J Basic Med Sci 2015;18(09):894–901
26 Pavlović JM, Allshouse AA, Santoro NF, et al. Sex hormones in
women with and without migraine: Evidence of migraine-spe-
cific hormone profiles. Neurology 2016;87(01):49–56
27 Sutherland HG, Champion M, Plays A, et al. Investigation of
polymorphisms in genes involved in estrogen metabolism in
menstrual migraine. Gene 2017;607:36–40
28 Colson N, Fernandez F, Griffiths L. Genetics of menstrual migraine: the
molecular evidence. Curr Pain Headache Rep 2010;14(05):389–395
29 Rodriguez-Acevedo AJ, Smith RA, Roy B, et al. Genetic association
and gene expression studies suggest that genetic variants in the
SYNE1 and TNF genes are related to menstrual migraine. J Headache
Pain 2014;15:62
Seminars in Neurology Vol. 37 No. 6/2017
30 Nattero G, Allais G, De Lorenzo C, et al. Relevance of prostaglandins
in true menstrual migraine. Headache 1989;29(04):233–238
31 Silberstein SD, Merriam GR. Sex hormones and headache. J Pain
Symptom Manage 1993;8(02):98–114
32 Benedetto C, Allais G, Ciochetto D, De Lorenzo C. Pathophysio-
logical aspects of menstrual migraine. Cephalalgia 1997;17
(Suppl 20):32–34
33 Allais G, Facco G, Ciochetto D, De Lorenzo C, Fiore M, Benedetto C.
Patterns of platelet aggregation in menstrual migraine. Cepha-
lalgia 1997;17(Suppl 20):39–41
34 Varlibas A, Erdemoglu AK. Altered trigeminal system excitability in
menstrual migraine patients. J Headache Pain 2009;10(04):277–282
35 de Tommaso M, Valeriani M, Sardaro M, et al. Pain perception and
laser evoked potentials during menstrual cycle in migraine.
J Headache Pain 2009;10(06):423–429
36 Saleeon W, Jansri U, Srikiatkhachorn A, Bongsebandhu-phub-
hakdi S. Estrous cycle induces peripheral sensitization in tri-
geminal ganglion neurons: an animal model of menstrual
migraine. J Med Assoc Thai 2016;99(02):206–212
37 Chauvel V, Schoenen J, Multon S. Influence of ovarian hormones on
cortical spreading depression and its suppression by L-kynurenine
in rat. PLoS One 2013;8(12):e82279
38 Ferrari MD, Klever RR, Terwindt GM, Ayata C, van den Maag-
Downloaded by: University of Utrecht. Copyrighted material.
denberg AM. Migraine pathophysiology: lessons from mouse
models and human genetics. Lancet Neurol 2015;14(01):
65–80
39 Chauvel V, Multon S, Schoenen J. Estrogen-dependent effects of
5-hydroxytryptophan on cortical spreading depression in rat:
Modelling the serotonin-ovarian hormone interaction in migraine
aura. Cephalalgia 2017 (Epub ahead of print). Doi: 10.1177/
0333102417690891
40 Asghari R, Lung MS, Pilowsky PM, Connor M. Sex differences in
the expression of serotonin-synthesizing enzymes in mouse
trigeminal ganglia. Neuroscience 2011;199:429–437
41 MacGregor EA. A review of frovatriptan for the treatment of
menstrual migraine. Int J Womens Health 2014;6:523–535
42 Bussone G, Allais G, Castagnoli Gabellari I, Benedetto C. Almo-
triptan for menstrually related migraine. Expert Opin Pharmac-
other 2011;12(12):1933–1943
43 Allais G, Bussone G, D’Andrea G, et al. Almotriptan 12.5 mg in
menstrually related migraine: a randomized, double-blind, pla-
cebo-controlled study. Cephalalgia 2011;31(02):144–151
44 Massiou H, Jamin C, Hinzelin G, Bidaut-Mazel C; French Naramig
Collaborative Study Group. Efficacy of oral naratriptan in the
treatment of menstrually related migraine. Eur J Neurol 2005;12
(10):774–781
45 Solbach MP, Waymer RS. Treatment of menstruation-associated
migraine headache with subcutaneous sumatriptan. Obstet Gy-
necol 1993;82(05):769–772
46 Schreiber CP, Cady RK. Diagnosis of menstrual headache and an
open-label study among those with previously undiagnosed
menstrually related migraine to evaluate the efficacy of suma-
triptan 100 mg. Clin Ther 2007;29(Suppl):2511–2519
47 Landy S, Savani N, Shackelford S, Loftus J, Jones M. Efficacy and
tolerability of sumatriptan tablets administered during the
mild-pain phase of menstrually associated migraine. Int J Clin
Pract 2004;58(10):913–919
48 Nett R, Landy S, Shackelford S, Richardson MS, Ames M, Lener M.
Pain-free efficacy after treatment with sumatriptan in the mild
pain phase of menstrually associated migraine. Obstet Gynecol
2003;102(04):835–842
49 Silberstein SD, Massiou H, Le Jeunne C, Johnson-Pratt L, McCar-
roll KA, Lines CR. Rizatriptan in the treatment of menstrual
migraine. Obstet Gynecol 2000;96(02):237–242
50 Mannix LK, Loder E, Nett R, et al. Rizatriptan for the acute
treatment of ICHD-II proposed menstrual migraine: two pro-
spective, randomized, placebo-controlled, double-blind studies.
Cephalalgia 2007;27(05):414–421

51 Tuchman M, Hee A, Emeribe U, Silberstein S. Efficacy and
tolerability of zolmitriptan oral tablet in the acute treatment
of menstrual migraine. CNS Drugs 2006;20(12):1019–1026
52 Loder E, Silberstein SD, Abu-Shakra S, Mueller L, Smith T. Efficacy
and tolerability of oral zolmitriptan in menstrually associated
migraine: a randomized, prospective, parallel-group, double-
blind, placebo-controlled study. Headache 2004;44(02):120–130
53 Allais G, Tullo V, Omboni S, et al. Frovatriptan vs. other triptans for
the acute treatment of oral contraceptive-induced menstrual mi-
graine: pooled analysis of three double-blind, randomized, cross-
over, multicenter studies. Neurol Sci 2013;34(Suppl 1):S83–S86
54 Bartolini M, Giamberardino MA, Lisotto C, et al. Frovatriptan versus
almotriptan for acute treatment of menstrual migraine: analysis of
a double-blind, randomized, cross-over, multicenter, Italian, com-
parative study. J Headache Pain 2012;13(05):401–406
55 Allais G, Bussone G, Tullo V, et al. Frovatriptan 2.5 mg plus
dexketoprofen (25 mg or 37.5 mg) in menstrually related
migraine. Subanalysis from a double-blind, randomized trial.
Cephalalgia 2015;35(01):45–50
56 Cady RK, Diamond ML, Diamond MP, et al. Sumatriptan-na-
proxen sodium for menstrual migraine and dysmenorrhea:
satisfaction, productivity, and functional disability outcomes.
Headache 2011;51(05):664–673
57 Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E;
Quality Standards Subcommittee of the American Academy of
Neurology and the American Headache Society. Evidence-based
guideline update: pharmacologic treatment for episodic migraine
prevention in adults: report of the Quality Standards Subcommit-
tee of the American Academy of Neurology and the American
Headache Society. Neurology 2012;78(17):1337–1345
58 Silberstein SD, Elkind AH, Schreiber C, Keywood C. A randomized
trial of frovatriptan for the intermittent prevention of menstrual
migraine. Neurology 2004;63(02):261–269
59 Tuchman MM, Hee A, Emeribe U, Silberstein S. Oral zolmitriptan in
the short-term prevention of menstrual migraine: a randomized,
placebo-controlled study. CNS Drugs 2008;22(10):877–886
60 Newman L, Mannix LK, Landy S, et al. Naratriptan as short-term
prophylaxis of menstrually associated migraine: a randomized,
double-blind, placebo-controlled study. Headache 2001;41(03):
248–256
61 Marcus DA, Bernstein CD, Sullivan EA, Rudy TE. Perimenstrual
eletriptan prevents menstrual migraine: an open-label study.
Headache 2010;50(04):551–562
62 Bhambri R, Martin VT, Abdulsattar Y, et al. Comparing the
efficacy of eletriptan for migraine in women during menstrual
and non-menstrual time periods: a pooled analysis of rando-
mized controlled trials. Headache 2014;54(02):343–354
63 Newman LC, Lipton RB, Lay CL, Solomon S. A pilot study of oral
sumatriptan as intermittent prophylaxis of menstruation-re-
lated migraine. Neurology 1998;51(01):307–309
64 MacGregor EA, Brandes JL, Silberstein S, et al. Safety and toler-
ability of short-term preventive frovatriptan: a combined ana-
lysis. Headache 2009;49(09):1298–1314
65 Al-Waili NS. Treatment of menstrual migraine with prostaglan-
din synthesis inhibitor mefenamic acid: double-blind study with
placebo. Eur J Med Res 2000;5(04):176–182
66 Sances G, Martignoni E, Fioroni L, Blandini F, Facchinetti F, Nappi
G. Naproxen sodium in menstrual migraine prophylaxis: a
double-blind placebo controlled study. Headache 1990;30(11):
705–709
67 Edelson RN. Menstrual migraine and other hormonal aspects of
migraine. Headache 1985;25(07):376–379
68 D’Alessandro R, Gamberini G, Lozito A, Sacquegna T. Menstrual
migraine: intermittent prophylaxis with a timed-release phar-
macological formulation of dihydroergotamine. Cephalalgia
1983;3(Suppl 1):156–158
69 Silberstein S, Bradley K. DHE-45® in the prophylaxis of menstru-
ally related migraine. Platform presentation at the IX Migraine
Migraine in Women Broner et al. 609
Trust International Symposium, London, UK, September 1996.
Cephalalgia 1996;16:371
70 Silberstein SD, Frietag FG, Bigal ME. Migraine treatment. In:
Stephen D. Silberstein, Richard B. Lipton, and David W. Dodick,
eds. Wolff’s Headache and Other Head Pain, 8th ed. New York,
NY: Oxford University Press; 2008:177–192
71 Dennerstein L, Morse C, Burrows G, Oats J, Brown J, Smith M.
Menstrual migraine: a double-blind trial of percutaneous estra-
diol. Gynecol Endocrinol 1988;2(02):113–120
72 de Lignières B, Vincens M, Mauvais-Jarvis P, Mas JL, Touboul PJ,
Bousser MG. Prevention of menstrual migraine by percutaneous
oestradiol. Br Med J (Clin Res Ed) 1986;293(6561):1540
73 Calhoun A, Ford S. Elimination of menstrual-related migraine
beneficially impacts chronification and medication overuse.
Headache 2008;48(08):1186–1193
74 Sulak P, Willis S, Kuehl T, Coffee A, Clark J. Headaches and oral
contraceptives: impact of eliminating the standard 7-day pla-
cebo interval. Headache 2007;47(01):27–37
75 Calhoun A, Ford S, Pruitt A. The impact of extended-cycle vaginal
ring contraception on migraine aura: a retrospective case series.
Headache 2012;52(08):1246–1253
76 Morotti M, Remorgida V, Venturini PL, Ferrero S. Progestogen-
only contraceptive pill compared with combined oral contra-
Downloaded by: University of Utrecht. Copyrighted material.
ceptive in the treatment of pain symptoms caused by endome-
triosis in patients with migraine without aura. Eur J Obstet
Gynecol Reprod Biol 2014;179:63–68
77 Warhurst S, Rofe CJ, Brew BJ, et al. Effectiveness of the progestin-
only pill for migraine treatment in women: a systematic review
and meta-analysis. Cephalalgia 2017 (Epub ahead of print]). Doi:
10.1177/0333102417710636
78 Neri I, Granella F, Nappi R, Manzoni GC, Facchinetti F, Genazzani
AR. Characteristics of headache at menopause: a clinico-epide-
miologic study. Maturitas 1993;17(01):31–37
79 Ziaei S, Kazemnejad A, Sedighi A. The effect of vitamin E on the
treatment of menstrual migraine. Med Sci Monit 2009;15(01):
CR16–CR19
80 Kashanian M, Lakeh MM, Ghasemi A, Noori S. Evaluation of
the effect of vitamin E on pelvic pain reduction in women
suffering from primary dysmenorrhea. J Reprod Med 2013;58
(1–2):34–38
81 Facchinetti F, Sances G, Borella P, Genazzani AR, Nappi G.
Magnesium prophylaxis of menstrual migraine: effects on in-
tracellular magnesium. Headache 1991;31(05):298–301
82 Zhang XZ, Zhang L, Guo J, et al. Acupuncture as prophylaxis for
menstrual-related migraine: study protocol for a multicenter
randomized controlled trial. Trials 2013;14:374
83 Finer LB, Zolna MR. Unintended pregnancy in the United States:
incidence and disparities, 2006. Contraception 2011;84(05):
478–485
84 Fox AW, Davis RL. Migraine chronobiology. Headache 1998;38(06):
436–441
85 Aubé M. Migraine in pregnancy. Neurology 1999;53(04, Suppl 1):
S26–S28
86 Liew Z, Ritz B, Rebordosa C, Lee PC, Olsen J. Acetaminophen use
during pregnancy, behavioral problems, and hyperkinetic dis-
orders. JAMA Pediatr 2014;168(04):313–320
87 Brandlistuen RE, Ystrom E, Nulman I, Koren G, Nordeng H.
Prenatal paracetamol exposure and child neurodevelopment: a
sibling-controlled cohort study. Int J Epidemiol 2013;42(06):
1702–1713
88 Avella-Garcia CB, Julvez J, Fortuny J, et al. Acetaminophen use in
pregnancy and neurodevelopment: attention function and autism
spectrum symptoms. Int J Epidemiol 2016;45(06):1987–1996
89 Babb M, Koren G, Einarson A. Treating pain during pregnancy.
Can Fam Physician 2010;56(01):25–27
90 Danielsson B, Wikner BN, Källén B. Use of ondansetron during
pregnancy and congenital malformations in the infant. Reprod
Toxicol 2014;50:134–137
Seminars in Neurology Vol. 37 No. 6/2017
610 Migraine in Women Broner et al.
91 Wood ME, Frazier JA, Nordeng HM, Lapane KL. Prenatal triptan
exposure and parent-reported early childhood neurodevelop-
mental outcomes: an application of propensity score calibration
to adjust for unmeasured confounding by migraine severity.
Pharmacoepidemiol Drug Saf 2016;25(05):493–502
92 Marchenko A, Etwel F, Olutunfese O, Nickel C, Koren G, Nulman I.
Pregnancy outcome following prenatal exposure to triptan
medications: a meta-analysis. Headache 2015;55(04):490–501
93 Chen HM, Chen SF, Chen YH, Lin HC. Increased risk of adverse
pregnancy outcomes for women with migraines: a nationwide
population-based study. Cephalalgia 2010;30(04):433–438
94 Bánhidy F, Acs N, Horváth-Puhó E, Czeizel AE. Pregnancy
complications and delivery outcomes in pregnant women with
severe migraine. Eur J Obstet Gynecol Reprod Biol 2007;134(02):
157–163
95 Marozio L, Facchinetti F, Allais G, et al. Headache and adverse
pregnancy outcomes: a prospective study. Eur J Obstet Gynecol
Reprod Biol 2012;161(02):140–143
96 Martin VT, Pavlovic J, Fanning KM, Buse DC, Reed ML, Lipton RB.
Perimenopause and menopause are associated with high fre-
quency headache in women with migraine: results of the
American Migraine Prevalence and Prevention Study. Headache
2016;56(02):292–305
97 MacGregor A. Effects of oral and transdermal estrogen replace-
ment on migraine. Cephalalgia 1999;19(02):124–125
98 MacGregor EA. Perimenopausal migraine in women with vaso-
motor symptoms. Maturitas 2012;71(01):79–82
99 Silberstein SD, Merriam GR. Estrogens, progestins, and head-
ache. Neurology 1991;41(06):786–793
100 North American Menopause Society. Treatment of menopause-
associated vasomotor symptoms: position statement of The North
American Menopause Society. Menopause 2004;11(01):11–33
101 Ripa P, Ornello R, Degan D, et al. Migraine in menopausal women:
a systematic review. Int J Womens Health 2015;7:773–782
102 Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M.
Prevalence and burden of migraine in the United States: data
from the American Migraine Study II. Headache 2001;41(07):
646–657
Seminars in Neurology Vol. 37 No. 6/2017
103 Wang SJ, Fuh JL, Lu SR, Juang KD, Wang PH. Migraine prevalence
during menopausal transition. Headache 2003;43(05):470–478
104 Kurth T. Migraine with aura and ischemic stroke: which addi-
tional factors matter? Stroke 2007;38(09):2407–2408
105 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(09):2438–2445
106 Abanoz Y, Gülen Abanoz Y, Gündüz A, et al. Migraine as a risk
factor for young patients with ischemic stroke: a case-control
study. Neurol Sci 2017;38(04):611–617
107 Collaborative Group for the Study of Stroke in Young Women.
Oral contraceptives and stroke in young women. Associated risk
factors. JAMA 1975;231(07):718–722
108 Spector JT, Kahn SR, Jones MR, Jayakumar M, Dalal D, Nazarian S.
Migraine headache and ischemic stroke risk: an updated meta-
analysis. Am J Med 2010;123(07):612–624
109 Chang CL, Donaghy M, Poulter N; The World Health Organisation
Collaborative Study of Cardiovascular Disease and Steroid Hor-
mone Contraception. Migraine and stroke in young women:
case-control study. BMJ 1999;318(7175):13–18
110 Davis PH. Use of oral contraceptives and postmenopausal hor-
mone replacement: evidence on risk of stroke. Curr Treat Options
Neurol 2008;10(06):468–474
Downloaded by: University of Utrecht. Copyrighted material.
111 Sacco S, Ricci S, Degan D, Carolei A. Migraine in women: the role
of hormones and their impact on vascular diseases. J Headache
Pain 2012;13(03):177–189
112 Fazio G, Ferrara F, Barbaro G, et al. Protrhombotic effects of
contraceptives. Curr Pharm Des 2010;16(31):3490–3496
113 Edlow AG, Bartz D. Hormonal contraceptive options for women
with headache: a review of the evidence. Rev Obstet Gynecol
2010;3(02):55–65
114 Xu Z, Li Y, Tang S, Huang X, Chen T. Current use of oral contra-
ceptives and the risk of first-ever ischemic stroke: a meta-analysis
of observational studies. Thromb Res 2015;136(01):52–60
115 Calhoun A. Combined hormonal contraceptives: is it time
to reassess their role in migraine? Headache 2012;52(04):
648–660
116 Tepper D. Aura with headache. Headache 2014;54(06):115–116