REVIEW ARTICLE

CONTINUUM AUDIO
INTERVIEW AVAILABLE
ONLINE
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CITE AS:
CONTINUUM (MINNEAP MINN)
2022;28(1, NEUROLOGY OF
PREGNANCY):72–92.
Address correspondence to
Dr Melissa Rayhill, 1010 Main St,
2nd Floor, Buffalo, NY 14202,
mrayhill@buffalo.edu.
RELATIONSHIP DISCLOSURE:
Dr Rayhill has served as an
associate editor of Headache:
The Journal of Head and
Face Pain.
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Dr Rayhill discusses the use of
various medications for the
treatment of headache in
pregnancy and lactation, none of
which are approved by the US
Food and Drug Administration for
use in pregnancy/lactation.
© 2022 American Academy
of Neurology.
72
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Headache in Pregnancy
and Lactation
By Melissa Rayhill, MD, FAHS
ABSTRACT
PURPOSE OF REVIEW: This article discusses the many tools available for the
treatment of pregnant and postpartum patients with headache. Adequate
treatment of headache is an essential part of good prenatal and
postnatal care.
RECENT FINDINGS: New therapies such as the calcitonin gene-related peptide
monoclonal antibodies, lasmiditan, direct calcitonin gene-related
peptide antagonists, and neuromodulation devices are available for the
treatment of headache. This article contextualizes these new therapies in
practice as they relate to the treatment of migraine in pregnancy and
lactation.
SUMMARY: Headache is common in pregnancy, and neurologists should be
prepared to care for pregnant patients with headache. Preconception
counseling is an important part of providing safe care to patients of
childbearing potential with headache. Identifying potentially dangerous
secondary headache syndromes during pregnancy and the puerperium is
also essential. The repertoire of available acute and preventive headache
treatments is expanding. It is important to discuss the effectiveness and
safety of these therapies in the context of individual patient circumstances
during pregnancy and lactation in coordination with the patient’s
obstetric team.
INTRODUCTION
C
aring for pregnant women who present with headache is often
perceived as a nerve-racking endeavor by many clinicians. As a
result, many women are inappropriately told to forgo treatment for
the safety of their unborn babies. The purpose of this article is to
assure readers that with a better understanding of the tools
available, treating headache well in pregnancy is not only possible but can be a
gratifying part of neurologic practice. This article also reviews potentially
dangerous secondary headache syndromes during pregnancy and the
puerperium, as their risk increases significantly during this time,1 and prompt
identification of these syndromes is essential.
Although tension-type headache may be the most common headache type, it
does not commonly cause patients to seek medical attention. The most common
type of severe headache seen in clinical practice is migraine, which affects
1 billion people worldwide. Migraine is a genetically driven condition in which,
FEBRUARY 2022
under certain circumstances, people can be more prone to activation of the KEY POINTS
trigeminocervical complex, which then produces headache and other associated
● In women between the
symptoms. This process may be modulated by hypothalamic activity and other ages of 30 and 39, the
peripheral and central provocations. prevalence of migraine can
Migraine seems to cause the most disruption during the reproductive years be as high as 27%, which is
and is much more common in women than in men. In women between the ages about 3 times higher than
the prevalence in men in the
of 30 and 39, the prevalence of migraine can be as high as 27%, which is about 3
same age range.
times higher than the prevalence in men in the same age range.2 The prevalence
of migraine in boys and girls is similar until menarche, at which point migraine ● It is prudent to discuss
prevalence starts to increase in girls. The subsequent increase in migraine any potential teratogenicity
prevalence for women over the next few decades of life is thought to be related to of medications at the time
they are prescribed,
fluctuations in estrogen, which might contribute to cellular excitability.3 regardless of the patient’s
current reproductive plan,
PRECONCEPTION PLANNING as plans may unexpectedly
Many pregnancies are unplanned. In the United States in 2008, 51% of change with time.
pregnancies were unplanned. By 2011, the percentage of unintended pregnancies
declined to 45%, although 75% of pregnancies were still unintended among teens
aged 15 to 19 years.4 Preconception planning is valuable to allow patients and
clinicians to minimize risks to the developing baby while also enabling clinicians
to provide anticipatory guidance, reassurance, and hope that patients can still
manage the symptoms of headache if they become pregnant. Unfortunately, 20%
of patients may avoid pregnancy because of their diagnosis of migraine. In a
study by Ishii and colleagues,5 women who avoided pregnancy because of
migraine believed (often erroneously) that migraine would worsen during
pregnancy, make their pregnancy difficult, and have negative effects on
their child.
The fear of worse pregnancy outcomes in patients with migraine is not
completely unsubstantiated, however. In a 2019 Danish population-based study,
more than 20,000 women with migraine were studied with age-matched
controls. Migraine was associated with an increased prevalence ratio of 1.50 for
pregnancy-associated hypertensive disorders, including preeclampsia (95%
confidence interval, 1.39 to 1.61), and a slightly increased risk of miscarriage, low
birth weight, preterm birth, and cesarean delivery (with adjusted prevalence
ratios on the order of 1.10 to 1.20).6 Still, the decision of whether to have children
is highly personal, and clinicians should be prepared to support and treat patients
however they may choose to proceed.
Every woman of reproductive potential should be asked whether they plan to
conceive in the coming months to years, while acknowledging that not all
patients of reproductive age have the desire or ability to conceive. Contraceptives
can often be omitted from patient-reported medication lists. It is prudent to
discuss any potential teratogenicity of medications at the time they are
prescribed, regardless of the patient’s current reproductive plan, as plans may
unexpectedly change with time.
Although no clear guideline has been established for preconception
management of migraine, most oral preventive headache therapies can be
stopped sometime between the patient’s last menstrual period and ovulation,
although more advanced planning may be prudent if a slower taper is warranted.
If ovulation is being tracked in a carefully selected patient, the use of some oral
preventive therapies can be considered at a low dose preovulation, stopped
postovulation, and restarted again preovulation if the patient does not become

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HEADACHE IN PREGNANCY AND LACTATION

pregnant (CASE 4-1). This strategy is based on expert opinion and should not be
used with medications with particularly long half-lives; very-low-dose tricyclics
may work well in this context. In contrast to oral therapies, patients taking
monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) activity
should be advised to stop injections approximately 5 to 6 months before
conception. This recommendation is based on the long half-lives of the
monoclonal antibodies and the lack of sufficient safety data in pregnancy with
theoretical risk of harm.
The use of onabotulinumtoxinA injections in pregnancy remains controversial.
In the absence of high-quality evidence for their use during pregnancy, most
clinicians elect to stop injections before conception. However, some clinicians elect
to continue onabotulinumtoxinA injections up until a positive pregnancy test or
even through the duration of pregnancy. The safety of onabotulinumtoxinA
injections in pregnancy is discussed in more detail later in this article.

DIAGNOSIS
The diagnosis of headache is guided by the International Classification of Headache
Disorders, Third Edition (ICHD-3).7 As helpful as the criteria are, a detailed

CASE 4-1 A 27-year-old woman presented for a routine neurologic follow-up visit
for her migraine and expressed a desire to become pregnant soon. She
was taking amitriptyline 10 mg every evening and receiving
fremanezumab-vfrm injections 225 mg monthly and onabotulinumtoxinA
injections every 12 weeks for headache prevention. For acute therapy,
she was using sumatriptan 100 mg as needed for severe headache and
metoclopramide 10 mg as needed for nausea or headache rescue.
After discussion with her neurologist, she elected to immediately stop
fremanezumab-vfrm injections. She continued amitriptyline for another
6 months, but after discontinuing her oral contraceptive pill, she stopped
amitriptyline completely. After a discussion with her obstetrician, she
decided to stop onabotulinumtoxinA injections also, with her last set of
injections just before she stopped taking her oral contraceptive pill.
She returned for another neurologic follow-up visit 8 weeks after two
consecutive negative pregnancy tests, and her headaches were much
more frequent and severe. She restarted amitriptyline, but only took it
before ovulation for two menstrual cycles. During this time, she needed
to use her acute therapies a little more often than usual. After these two
cycles, she became pregnant and stopped sumatriptan use as well. She
started to use metoclopramide as needed for headache acutely with
good effect when acetaminophen was unhelpful, and her headache
frequency and intensity gradually improved by week 10 of her pregnancy.

COMMENT Preconception counseling is imperative, especially when patients are using

long-acting preventive therapies for headache. Additional acute therapies
and other preventive therapies could have been considered once this
patient became pregnant had her headache pattern not improved.

74 FEBRUARY 2022

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history of the course of headache is essential, including eliciting the susceptibility KEY POINTS
to headache in childhood and before pregnancy. One of the first clinical decisions
● Patients taking
during a consultation for headache is determining whether the headache is monoclonal antibodies
secondary to another underlying cause (eg, dissection, preeclampsia, intracranial targeting calcitonin gene-
hypertension) or a primary headache disorder (presumably an inherited related peptide (CGRP)
condition without another underlying cause, eg, tension-type headache or activity should be advised to
stop injections
migraine). A history of hormonally influenced headache (eg, menstrual
approximately 5 to 6 months
association, effect of hormonal contraceptives on headache) may suggest a before conception.
degree of an underlying primary headache disorder and may provide some clues
about how headache could behave in pregnancy. However, even in the same ● The diagnosis of
patient, every pregnancy is different. headache is guided by the
International Classification
of Headache Disorders,
Primary Headache Third Edition.
The most common severe headache disorder is migraine. Although tension-type
headache is the most common headache type worldwide, it is usually mild to ● Women with migraine
with aura may be less likely
moderate in intensity (some headache specialists question whether tension-type to improve in pregnancy,
headache is even mechanistically distinct from migraine at a lower pain intensity). and aura can present for the
The diagnosis of migraine is often missed because of an incorrect notion that all first time during pregnancy.
patients with migraine will be vomiting in a dark room at some point for the
● One study showed that
diagnosis to be correct, but photophobia and phonophobia can be much subtler in
the most common
description (eg, a preference to avoid screaming children or parties when secondary headache
headache is present, a preference to avoid fluorescent lighting, reluctance to go to syndromes in patients who
the gym or grocery store when headache is present). A careful review of the presented to acute care with
ICHD-3 criteria shows that migraine may be much more common than expected severe headache were
caused by hypertensive
in clinical practice (TABLE 4-1); tension-type headache and true cervicogenic disorders of pregnancy. In
headache are actually much less common in most headache medicine practices. this study, a lack of
Cluster headache is characterized by very severe short-duration attacks of headache history was
unilateral side-locked headache with autonomic features. The condition is associated with a nearly
fivefold risk of secondary
uncommon (approximately 1 in 500 people) and affects mostly men.8 As such, it headache, and elevated
is not very common during pregnancy, and data about changes in its frequency blood pressure was
during pregnancy are limited. associated with a 17-fold risk
When discussing the course of primary headache disorders in pregnancy, it is of secondary headache.
crucial to remember that not all patients will have a similar course. Although 50%
of women improve by the end of the first trimester and more than 80% improve
by the end of the second trimester,9 women with aura may be less likely to
improve in pregnancy and aura can present for the first time during pregnancy.10
Still, given the natural improvement that occurs for most pregnant women, some
optimism is warranted.
The challenge in headache diagnosis during pregnancy is determining when to
initiate further testing for secondary headache syndromes. Although most
headache in pregnancy is due to a primary headache disorder, the incidence of
dangerous secondary causes of headache is high, especially at the later stages of
pregnancy. For example, preeclampsia does not occur until after 20 weeks of
gestation, and the risks of venous sinus thrombosis and dissection are highest in
the third trimester and postpartum. Robbins and colleagues11 found that 35% of
140 women presenting to acute care with severe headache who required
inpatient neurologic consultation ended up being diagnosed with a secondary
headache syndrome. The most common secondary headache syndromes in this
group were caused by hypertensive disorders of pregnancy. Preeclampsia was
the most commonly diagnosed disorder, but other related conditions included

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HEADACHE IN PREGNANCY AND LACTATION

posterior reversible encephalopathy syndrome (PRES, which is the radiographic

correlate of preeclampsia), eclampsia, acute arterial hypertension, and reversible
cerebral vasoconstriction syndrome (RCVS, which has a pathophysiologic
mechanism similar to that of preeclampsia). A lack of headache history was
associated with a nearly fivefold risk of secondary headache, and elevated blood
pressure was associated with a 17-fold risk of secondary headache.11 Other
warning signs for secondary headache include fever, papilledema or other
abnormal neurologic examination findings, thunderclap headache onset,
postural provocation, and a history of immunosuppression (TABLE 4-2).
A history of primary headache or migraine is not necessarily reassuring when a
pregnant woman presents with headache. In fact, compared to women without a
history of migraine, women with a history of migraine are more likely to have a
secondary cause of headache, such as cerebral venous thrombosis, pregnancy-
associated stroke, or preeclampsia.12 Therefore, clinicians should have a low
threshold to test for secondary headache syndromes in their pregnant patients
with headache.

TABLE 4-1 ICHD-3 Diagnostic Criteria for Migraine Without Auraa

Description
Recurrent headache disorder manifesting in attacks lasting 4-72 hours. Typical characteristics
of the headache are unilateral location, pulsating quality, moderate or severe intensity,
aggravation by routine physical activity, and association with nausea and/or photophobia and
phonophobia.
Diagnostic criteria
A At least five attacksb fulfilling criteria B-D
B Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated)c,d
C Headache has at least two of the following four characteristics:
1 Unilateral location
2 Pulsating quality
3 Moderate or severe pain intensity
4 Aggravation by or causing avoidance of routine physical activity (eg, walking or climbing
stairs)
D During headache at least one of the following:
1 Nausea and/or vomiting
2 Photophobia and phonophobia
E Not better accounted for by another ICHD-3 diagnosis

ICHD-3 = International Classification of Headache Disorders, Third Edition.

a
Reprinted with permission from Headache Classification Committee of the International Headache
Society, Cephalalgia.7 © 2018 International Headache Society.
b
One or a few migraine attacks may be difficult to distinguish from symptomatic migrainelike attacks.
Furthermore, the nature of a single or a few attacks may be difficult to understand. Therefore, at least five
attacks are required. Individuals who otherwise meet criteria for migraine without aura but have had fewer
than five attacks should be coded probable migraine without aura.
c
When the patient falls asleep during migraine and wakes up without it, duration of the attack is reckoned
until the time of awakening.
d
In children and adolescents (aged under 18 years), attacks may last 2-72 hours (the evidence for untreated
durations of less than 2 hours in children has not been substantiated).

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 The use of MRI is strongly preferred over CT as it avoids ionizing radiation
exposure to the developing fetus. However, during emergency situations and
when CT is diagnostically advantageous over MRI, the benefits of CT and CT
angiography may outweigh the potential risks to the fetus. No known adverse
effects to human fetuses have been reported when clinically recommended
dosages of gadolinium-based contrast have been given to pregnant women.
However, good quality data studying the teratogenic effects of gadolinium in
pregnant patients are lacking. The American College of Radiology recommends
that gadolinium only be used if it is considered critical and the potential benefits
justify the potential unknown risk to the fetus.13

Secondary Headache
A variety of secondary headache syndromes should be considered when
evaluating pregnant patients. Possibilities include several important
vascular and hypertensive disorders, CSF pressure disorders (intracranial
hypertension and hypotension), infection, endocrine dysfunction (including
hypothyroidism and pituitary apoplexy), anemia, and sleep apnea. Clinicians
should be especially wary of headache with a thunderclap onset in which the
maximum intensity of headache occurs within seconds. The secondary
headache syndromes that are not to be missed during pregnancy and the
puerperium are discussed below.
Cerebral venous thrombosis occurs in 1 in 2500 to 1 in 10,000 pregnancies and
is more likely to occur in patients with a comorbid hypercoagulable disorder. It is
most likely to occur during the third trimester or the postpartum period. In
nonpregnant patients, cerebral venous thrombosis is also associated with the use
of combined hormonal contraceptives. It is thought that the rising levels of
estrogen in late pregnancy may create a relative hypercoagulable state. Shifting
coagulation dynamics in the puerperium may also play a role.14 Patients can
present with headache, seizures, focal neurologic deficits, and signs and
symptoms of increased intracranial pressure such as papilledema and cranial
neuropathies. In one study, almost 90% of patients had associated headache, and
the headache tended to be acute in onset with progressive worsening.15 Venous
hemorrhage may occur in up to 39% of patients.15 Magnetic resonance
venography (MRV) is preferred in pregnancy to avoid the radiation exposure of
CT venography, and treatment usually requires anticoagulation with enoxaparin
sodium injection since it is preferred in pregnancy.16

Characteristics Concerning for Secondary Headache TABLE 4-2

◆ Thunderclap headache onset

◆ Papilledema
◆ Postural provocation/time of day preference
◆ Fever
◆ Systemic hypertension
◆ Cranial neuropathies or other examination abnormalities
◆ History of immunosuppression

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HEADACHE IN PREGNANCY AND LACTATION

Preeclampsia is a condition of widespread endothelial dysfunction during

pregnancy that can impact multiple organ systems. Although the exact
mechanism is still somewhat in question, chronic placental ischemia and
immunologic changes may impact this process. The diagnosis of preeclampsia
should be highly suspected with development of an acute headache in
pregnancy, especially when it occurs with hypertension and proteinuria. In the
absence of proteinuria, women should be diagnosed with preeclampsia if they
present with any of the following severe features: thrombocytopenia, transaminitis,
otherwise unexplained severe persistent right upper quadrant or epigastric
pain, renal insufficiency, pulmonary edema, new-onset headache, or visual
disturbances.17 Preeclampsia is quite common, occurring in 3% to 5% of
pregnancies.18 It most often occurs in the second half of pregnancy, but it can also
first present in the postpartum period. A progressively worsening severe headache
can signal an impending seizure (eclampsia). Treatment includes magnesium
sulfate infusion and blood pressure control. The definitive treatment is delivery;
however, preeclampsia can occur postpartum due to the major endothelial and
physiologic changes that have begun before delivery.
PRES is the radiographic correlate to preeclampsia, and the imaging findings
are a result of failed cerebral autoregulation in the setting of increased
hydrostatic pressure and endothelial cell dysfunction.19 Patients with these
imaging findings can present with headache, confusion, seizures, and cortical
blindness. It is not fully understood why PRES preferentially affects the occipital
lobes; one hypothesis invokes a relatively poor adrenergic innervation in the
posterior circulation territory.20 PRES is best visualized with MRI. It can be seen
in other medical conditions outside of pregnancy, such as malignant
hypertension, and can also be provoked by some medications.
RCVS (also sometimes referred to as postpartum angiopathy) can often
present with focal deficits and a thunderclap headache onset. The majority of
patients have a good outcome, but complications can include ischemic stroke,
subarachnoid hemorrhage, and intraparenchymal hemorrhage.21 RCVS may
have some overlapping pathophysiology and may co-occur with preeclampsia.
Hemorrhagic stroke has an increased frequency during pregnancy, and headache
is often a prominent presenting symptom. Using data from the Canadian Institute
of Health Information, a 2019 study evaluated all antepartum, peripartum, and
postpartum hospitalizations in Canada (excluding Quebec) from 2003 to 2016. The
authors identified 524 cases of stroke among 3,907,262 deliveries (13.4 per 100,000),
and hemorrhagic strokes made up 58.6% of these cases. Furthermore, just over half
of hemorrhagic strokes occurred in the postpartum period. A significant increase in
stroke was associated with hypertensive disorders of pregnancy, emphasizing the
importance of close monitoring of these patients with headache.22 Ischemic stroke is
a less common cause of headache in pregnancy. For more information on stroke in
pregnancy, refer to the article “Maternal Stroke Associated With Pregnancy” by
Eliza C. Miller, MD, MS,23 in this issue of Continuum.
Cervical artery dissection can present with acute headache or neck pain as well
as other neurologic signs (CASE 4-2). In carotid artery dissection, patients may
present with Horner syndrome because of disruption of sympathetic fibers
wrapped around the carotid artery, and patients with vertebral artery dissection
may present with neck pain and other sequelae of posterior circulation ischemia.
Pituitary apoplexy is the result of hemorrhagic infarction of the pituitary
gland. Although it is a rare cause of headache, pregnant women are most

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susceptible in the peripartum period given the physiologic enlargement and KEY POINTS
hyperemia of the gland that occurs during pregnancy; not surprisingly, having a
● Warning signs for
pituitary macroadenoma also increases the risk of apoplexy. It can be best secondary headache include
detected using MRI with thin cuts through the pituitary. Pituitary apoplexy fever, papilledema or other
characteristically presents with acute or thunderclap headache, and it can lead to abnormal neurologic
bitemporal hemianopia and hypotension. In addition to neurosurgical examination findings,
thunderclap headache
consultation, patients may need to be supported with hydrocortisone and thyroid
onset, postural provocation,
hormone and other hormonal therapy as appropriate.24 and a history of
CSF pressure disorders are secondary headache disorders that commonly immunosuppression.
occur in pregnant and postpartum women. Post–dural puncture headache and
spontaneous intracranial hypotension can be quite disabling as they often limit ● Compared to women
without a history of
the ability to even sit upright. Intracranial hypotension usually presents with migraine, women with a
postpartum headache that progressively worsens throughout the day and usually history of migraine are more
worsens with upright posture as gravity exerts downward traction on the likely to have a secondary
well-innervated meninges that remain attached to the skull. Most patients cause of headache, such as
cerebral venous thrombosis,
improve with conservative therapy and rest over a few days. Some with pregnancy-associated
protracted or particularly severe symptoms may be helped with an autologous stroke, or preeclampsia.
blood patch. Although many patients can still have normal imaging, some may
show diffuse pachymeningeal enhancement and other signs of intracranial ● Preeclampsia is quite
common, occurring in 3% to
hypotension, such as acquired cerebellar tonsillar ectopia, decreased
5% of pregnancies.
mamillopontine distance, and, rarely, subdural hematomas. For more
information on post–dural puncture headache, refer to the article “Neurologic ● Pituitary apoplexy
Complications of Obstetric Anesthesia” by Janet F. R. Waters, MD, MBA, characteristically presents
FAAN,25 in this issue of Continuum. with acute or thunderclap
headache, and it can lead to
Idiopathic intracranial hypertension is an important condition to identify in bitemporal hemianopia and
pregnancy as it can lead to potentially permanent visual loss from malignant hypotension.
papilledema if left unchecked. Idiopathic intracranial hypertension can present
with intractable headache, pulsatile tinnitus, and, sometimes, abducens palsy. ● Intracranial hypotension
usually presents with
Lumbar puncture shows increased intracranial pressure (usually above 25 cm postpartum headache that
H2O), but CSF studies are otherwise normal. Optimization of nutrition should be progressively worsens
prioritized, and medical management with acetazolamide can be considered in throughout the day and
consultation with the patient’s obstetrician.26 Surgical interventions such as optic usually worsens with upright
posture.
nerve sheath fenestration and shunt placement are sometimes required. Given
the possibility of permanent visual loss, it is imperative that patients with this
condition be followed by a neuro-ophthalmologist or ophthalmologist in addition
to a neurologist. For more information on idiopathic intracranial hypertension,
refer to the article “Neuro-ophthalmology and Pregnancy” by Heather E. Moss,
MD, PhD, FAAN,27 in this issue of Continuum. The increased intracranial
pressure that occurs during labor is transient and unlikely to affect the safety of
the mother or baby. Therefore, a cesarean delivery is not routinely required,
neuraxial anesthesia can be offered, and the mode of delivery should be
determined by obstetric factors only.28

TREATMENT OF MIGRAINE DURING PREGNANCY

The treatment of migraine during pregnancy seemed more straightforward
several years ago. The US Food and Drug Administration (FDA) previously
categorized medications based on a hierarchical scale from A (safest) to X
(contraindicated in pregnancy), but these categories were discontinued in 2015.
The previous safety categories provided a simple way to stratify the potential
risks of medications during pregnancy; this stratification helped to facilitate

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HEADACHE IN PREGNANCY AND LACTATION

otherwise more complex patient discussions and medical decision making.

However, the convenience of categorization could lead to oversimplification and an
inadequate understanding of why each medication carried risk. Since then,
clinicians and patients have had to wade through the available data themselves to
make informed decisions about medication use in pregnancy. Although the previous
categories are still sometimes used for the sake of simplicity, they are increasingly
outdated. Other sources available for use include the ReproTox and IBM
Micromedex websites, although these services usually require subscriptions.
The United States Department of Health and Human Services Agency for
Healthcare Research and Quality recently performed a systematic review on the

CASE 4-2 A 36-year-old woman developed a headache that started 2 days after a
normal spontaneous vaginal delivery of her third child with epidural
anesthesia. In her late teenage years, she had experienced headaches
that could sometimes be severe about once per month. She had
experienced no headaches during any of her three pregnancies; however,
2 days after the birth of her third child, she developed daily headache.
She did not remember the headache as starting abruptly, and the pain
was constant. She was seen in the emergency department after she
noticed that she had swelling around her right eye to the point that it was
difficult to see. A lumbar puncture showed a normal opening pressure of
14 cm H2O, and brain MRI and magnetic resonance venography (MRV)
were also normal. On examination in the emergency department, her
systolic blood pressure was between 140 mm Hg and 160 mm Hg, and her
diastolic blood pressure was between 80 mm Hg and 98 mm Hg. She was
then discharged home. She was also treated for a urinary tract infection,
but her headaches did not improve.
Three weeks later, she was seen in clinic for outpatient neurologic
headache consultation. Her headache was located around the right eye,
with pain radiation that was holocephalic and into the neck. The pain was
throbbing and associated with photophobia, phonophobia, osmophobia,
and cutaneous allodynia but not nausea. She had no history of aura. The
headache was associated with rhinorrhea and nasal congestion on the
right and ocular injection of the right eye as well as periorbital swelling on
the right. The headache was not positional, and she had no clear history
of trauma.
On physical examination, she had no ptosis or periorbital edema. She
had right miosis in dim lighting at rest. Her pupils were both reactive in
dim light from 5 mm to 3 mm in the left eye and 4 mm to 3 mm in the right
eye. She had no papilledema, and her visual fields were full. The
remainder of her cranial nerve findings were normal, including facial
sensation to light touch and pinprick. Her mental status, motor, sensory,
gait, and reflex examinations were normal. On magnetic resonance
angiography (MRA), she was found to have a right carotid dissection
(FIGURE 4-1). She was sent back to the emergency department, where she
was started on antiplatelet therapy.

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management of primary headache disorders in pregnancy.29 Based on limited
available evidence, this review surprisingly concluded that calcium channel blockers
and antihistamines might be considered first-line preventive therapies for headache
in pregnancy, and that metoclopramide, diphenhydramine, and triptans might
actually be better first-line acute options than acetaminophen. In clinical practice,
however, calcium channel blockers and antihistamines are not considered to be the
most efficacious in treating headache.30 The discussion in this article aims to provide
some guidance and clarity on which therapies should be considered first, which
therapies can possibly be considered when initial therapies have failed, and which
therapies should be avoided in pregnant patients with migraine.

FIGURE 4-1
Imaging of the patient in CASE 4-2. Axial T1-weighted MRI with fat saturation shows a
hyperintense crescent (A, arrow; B) representing subacute thrombus in the false lumen of
the dissected internal carotid artery. The true lumen, which appears hypointense, is
posterior to the thrombus and is compressed by the false lumen. Coronal time-of-flight
magnetic resonance angiography (MRA) shows a filling defect of the cervical segment of
the right internal carotid artery extending just inferior to the petrous segment (C, arrows).

Secondary headache syndromes commonly present in the puerperium, and COMMENT

detailed testing is often warranted. Pupillary examination should be
performed in both dim and bright lighting; dim lighting will make any
disruption to sympathetic function more obvious. This patient was found to
have a carotid artery dissection, with symptoms likely starting 2 days after
her delivery. Arterial dissection risk increases in the puerperium, and
arterial imaging should be considered in postpartum patients presenting
with headache.

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HEADACHE IN PREGNANCY AND LACTATION

Preventive Therapy
Preventive therapies for primary headache disorders aim to decrease the overall
frequency and intensity of headache over time. These therapies often take at least
several weeks to start impacting the headache pattern, and anticipatory guidance
with discussion of expectations of treatment is essential from the beginning.
Many patients (pregnant or not) choose to forgo preventive therapy if headache
frequency is generally low (usually less than 1 to 2 headache days per week), but
preventive therapy can still be considered to reduce the frequency of particularly
disabling attacks. To make an accurate assessment of headache burden, it is
essential to ask patients about days of complete headache freedom. Many patients
prioritize discussion of their most severe attacks and minimize days with mild
headache. Particularly in pregnant patients, the choice to pursue preventive
therapy should be tailored to individual patient circumstances and values. The
discussion is important because of the inherent dissonance between selecting
treatment that is safe and simultaneously selecting treatment that will actually work.
Given the natural improvement in headache that many patients experience
with pregnancy, it may be reasonable to monitor their headaches without

TABLE 4-3 Safety and Effectiveness of Preventive Treatments in Pregnancy

Medication Safetya Effectivenessa

Propranolol More safe Most effective

Magnesium More safe Least effective

Memantine More safe Moderately effective

Coenzyme Q10 More safe Least effective

Venlafaxine Moderate safety Moderately effective

OnabotulinumtoxinA Moderate safety Most effective

Amitriptyline/nortriptyline Moderate safety Most effective

Riboflavin Moderate safety Least effective

Verapamil Moderate safety Least effectiveb

Gabapentin Moderate safety Least effective

Calcitonin gene-related peptide targeting treatments (erenumab, Least safe Most effective
fremanezumab, galcanezumab, eptinezumab, rimegepant, atogepant)

Topiramate Least safe Most effective

Lisinopril Least safe Moderately effective

Candesartan Least safe Moderately effective

Valproic acid Least safe Most effective

Feverfew Least safe Least effective

a
Relative safety and effectiveness judged by the opinion of the author of this article combining tolerability in clinical practice and review of the
available evidence29,33 and expert consensus,34 not based on direct comparisons among therapies in clinical trials.
b
May have a specific role in the prevention of migraine with aura.

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preventive therapy early on to see if preventive therapy is indeed required. All KEY POINTS
patients with primary headache disorders may benefit from a discussion of
● The US Food and Drug
lifestyle modifications, such as sleep optimization, stress management, adequate Administration previously
hydration, and regular healthy meals. Patients should also be screened for categorized medications
medication-overuse headache. It is reasonable to consider physical therapy, based on a hierarchical scale
medical massage, cognitive-behavioral therapy, and relaxation techniques in the from A (safest) to X
(contraindicated in
interested patient as well, although the evidence for these nonpharmacologic
pregnancy), but these
interventions is mixed and limitations may include cost and time.29,31 In addition, categories were
intermittent peripheral (usually occipital) nerve blocks can be used safely for the discontinued in 2015.
treatment of severe headache during pregnancy.32
Preventive therapies graded by relative safety and relative effectiveness by the ● To make an accurate
assessment of headache
author of this article are listed in TABLE 4-3.33,34 Effectiveness was judged by the burden, it is essential to ask
opinion of the author of this article, combining tolerability in clinical practice and patients about days of
review of the available evidence29,33,34; it was not based on direct comparisons complete headache
among therapies in clinical trials. If pharmacotherapy is indicated for headache freedom.
prevention, it may be most prudent to start with one of the following preferred ● Given the natural
medications: propranolol (effective; long history of use in pregnancy, although improvement in headache
observational studies show some concern with intrauterine growth restriction, that many patients
neonatal bradycardia, hypoglycemia, and possible multicystic renal dysplasia experience with pregnancy,
it may be reasonable to
risk),35 cyclobenzaprine36 or memantine37 (both less effective than propranolol
monitor their headaches
but likely safe based on animal studies), or oral magnesium (less effective than without preventive therapy
propranolol; safety is likely good, but this is controversial, as discussed below). early on to see if preventive
Cyclobenzaprine can also be used as a sedating rescue therapy.33 therapy is indeed required.
Magnesium therapy was long thought to be one of the safest available options
● All patients with
for migraine prevention in pregnancy. Today, IV magnesium therapy is still headache may benefit from
standard care for the treatment of eclampsia and preeclampsia, in which the a discussion of lifestyle
benefits of treatment clearly outweigh the risks. However, 1 year before the modifications, such as sleep
discontinuation of the FDA safety categories, IV magnesium sulfate was demoted optimization, stress
management, adequate
from Category A to Category D for tocolytic therapy.38 This change was in hydration, and regular
response to concerns about fetal skeletal abnormalities after more than 5 days of healthy meals.
treatment, theoretically from altered calcium physiology during bone
development. Therefore, single doses of IV magnesium sulfate are still used by
many clinicians for status migrainosus, although this remains an area of
controversy. After the FDA’s change, clinicians were left to wonder whether oral
magnesium therapy still remained safe at the previous Category A/B or if this
new warning about IV magnesium should be extrapolated to oral doses as well.
When a physician contacted the FDA for clarification on this point years later,
the FDA simply said that the categories were no longer in use and provided no
further comment.33 Still, most headache specialists continue to believe that oral
magnesium remains one of the safer available preventive options in pregnancy.
Whatever the correct interpretation of the category change may be, it is clear that
a detailed informed consent is warranted when recommending magnesium
therapies to pregnant patients.
If other options are needed, the benefits of some second-line therapies may
outweigh the potential risks in some patients. Consultation with the patient’s
obstetrician is imperative. Second-line therapies that could be considered include
onabotulinumtoxinA injections (effective, although safety is not established;
because it takes a long time to provide any benefit, it is difficult to measure its
effect over natural improvements during pregnancy), CoQ10 (less effective;
likely safe based on a single randomized trial),39 venlafaxine (moderate

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HEADACHE IN PREGNANCY AND LACTATION

effectiveness; possible increased risk of pregnancy loss, neonatal seizures/

abstinence syndrome with use late in pregnancy),40 riboflavin (less effective;
unknown safety of supraphysiologic doses),41 amitriptyline/nortriptyline
(effective; possible increased risk of pregnancy loss, neonatal seizures/abstinence
syndrome with use in late pregnancy, cardiac malformations),42,43 verapamil
(low to moderate effectiveness for migraine; risk of fetal bradycardia, heart
block),44 and gabapentin (less effective; possible cardiac malformations, preterm
birth, small for gestational age).45
The FDA’s official stance is that administration of onabotulinumtoxinA is not
recommended during pregnancy given the absence of well-controlled studies.
When pregnant mice and rats were injected intramuscularly during the period of
organogenesis, the developmental no observed effect level (NOEL) was 4 U/kg.
Higher doses (8 U/kg or 16 U/kg) were associated with reductions in fetal body
weight or delayed ossification, or both. More serious concerns were seen when
onabotulinumtoxinA was given to rabbits, although the FDA noted that rabbits
appear to be very sensitive to onabotulinumtoxinA.46 In humans, a very limited
amount of data from just over 200 pregnancies reported no increased
teratogenicity and no increased risk of pregnancy loss compared to the general
population, but the amount of available data is insufficient to make any solid
conclusions about the safety of onabotulinumtoxinA.47
Despite this, wide variability exists in clinical practice regarding the use of
onabotulinumtoxinA in pregnancy. Some clinicians continue to inject
throughout pregnancy, some continue to inject up until a positive pregnancy test,
and some avoid injections entirely before conception. More than a dozen cases of
systemic botulism in pregnant women have been reported, and all suggest
onabotulinumtoxinA may be too large to cross the placental circulation but may
have led to preterm delivery in at least six cases.48 Being mindful of these
concerns, this therapeutic option can occasionally be considered during
pregnancy for women with particularly intractable and disabling chronic
migraine. In these cases, it may be prudent to avoid starting onabotulinumtoxinA
injections in toxin-naïve patients during pregnancy and only consider restarting
the therapy in patients with significant worsening of primary headache after
stopping injections at the start of pregnancy.
More consensus exists on what to avoid in pregnancy, although some newer
available therapies are largely avoided because of theoretical risks in the absence
of good data. Although human data on the use of CGRP monoclonal antibodies in
pregnancy are lacking, animal studies did not show evidence of teratogenicity.49-51
However, given the lower levels of CGRP in patients with preeclampsia compared
to normotensive individuals, most headache specialists believe avoidance of
CGRP monoclonal antibodies in pregnancy is warranted.52 Consequently, it
bears repeating that clinicians should be mindful of the long half-life of these
medications that are dosed once monthly or quarterly. Despite its efficacy,
topiramate should be avoided given the known risks of cleft palate and lip,
intrauterine growth restriction, and metabolic acidosis.53 Angiotensin-converting
enzyme inhibitors and angiotensin II receptor blockers, such as lisinopril and
candesartan, have low to moderate effectiveness but are associated with fetal and
neonatal death with second- and third-trimester exposure, oligohydramnios, fetal
lung hypoplasia, renal failure, skeletal deformations, and hyperkalemia.54
Some preventive headache treatments are absolutely contraindicated in
pregnancy. Valproic acid was previously in FDA Category X as a contraindication

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for migraine prevention. Valproic acid should always be avoided given the risk of KEY POINTS
neural tube defects, craniofacial defects, cardiovascular malformations, autism,
● Given the lower levels of
and decreased IQ.55 Similarly, feverfew is contraindicated for migraine CGRP in patients with
prevention in pregnancy; although it is an over-the-counter supplement that preeclampsia compared to
may be perceived as benign, it can have dangerous consequences, such as uterine normotensive individuals,
contractions and spontaneous miscarriage.33 Reviewing prescription medications most headache specialists
believe avoidance of CGRP
for safety in pregnancy is routine, but clinicians must not forget to specifically
monoclonal antibodies in
ask about over-the-counter medication and supplement use. pregnancy is warranted.

Acute Therapy ● Despite its efficacy,

Regardless of headache frequency, everyone deserves to have a reliable acute topiramate should be
avoided during pregnancy
therapy for an exacerbation of headache. The goal of acute therapy is to restore given the known risks of
function and resolve pain and other associated symptoms within 2 hours. If a cleft palate and lip,
treatment does not reliably help within 2 hours, other options should be explored. intrauterine growth
No medication is totally devoid of risk to the developing fetus, and risks should restriction, and metabolic
acidosis.
be discussed thoroughly among the patient, the patient’s neurologist, and
the patient’s obstetrician. Still, for particularly severe or disabling attacks, ● Feverfew is
infrequent use of some therapies may result in more benefit than risk. contraindicated for migraine
Inadequate treatment of headache in pregnant women results in work prevention in pregnancy as it
can provoke uterine
absenteeism and presenteeism (still present at work, but with decreased
contractions and
productivity), and pregnant women already face personal and career challenges. spontaneous miscarriage.
Similar to the preventive therapies in TABLE 4-3, the acute therapies listed in
TABLE 4-4 are graded by relative safety and relative effectiveness. Effectiveness was ● Reviewing prescription
judged by the opinion of the author of this article, combining tolerability in clinical medications for safety in
pregnancy is routine, but
practice and review of the available evidence29,33,34 and was not based on direct clinicians must not forget to
comparisons among therapies in clinical trials. specifically ask about over-
Acute medications historically viewed as preferred first-line agents include the-counter medication and
acetaminophen (moderate effectiveness; long history of use but safety is supplement use.
controversial after Agency for Healthcare Research and Quality [AHRQ] ● The goal of acute therapy
systematic review,29 as discussed below), metoclopramide (effective; many for headache is to restore
studies demonstrate good safety; caution with use around delivery given function and resolve pain
extrapyramidal side effects),56 and lidocaine (effective and can be used and other associated
symptoms within 2 hours. If
subcutaneously or with intranasal instillation for nerve blocks; limited data in
a treatment does not
humans but frequently used; no teratogenicity in animal studies).57,58 reliably help within 2 hours,
Certainly, acetaminophen has been considered first-line therapy for the other options should be
acute treatment of headache and pain in pregnancy for many years. Most explored.
headache specialists believe it is likely safe. However, given reports of premature
closure of the ductus arteriosus with use in the third trimester, increased risk of
early childhood respiratory disorders with frequent use, and reports of prolonged
use and third-trimester use leading to an association with attention-deficit/
hyperactivity disorder (ADHD) based on the AHRQ review,29 a more thoughtful
discussion of benefits and risks may be warranted. The data suggest that more
frequent use may increase these associated risks, so it would be reasonable to
continue occasional use when needed during pregnancy.
Along with the first-line agents mentioned above, diphenhydramine and
ondansetron are safe adjunct therapies that may be useful in treating pregnant
patients with migraine. Although neither of these medications is particularly
good at decreasing the pain of headache, diphenhydramine may play a useful
indirect role via its sedating properties, and ondansetron may be useful in
preventing severe nausea and vomiting if other therapies are insufficient

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HEADACHE IN PREGNANCY AND LACTATION

(although safety data are mixed, with some concern for cleft palate and
renal agenesis/dysgenesis).59
Second-line agents to consider for acute treatment of migraine include
triptans (effective; accumulating evidence that they are relatively safe),
ibuprofen (effective; avoid in the first trimester because of a risk of spontaneous
miscarriage and avoid in the third trimester given risk of premature closure of
the ductus arteriosus), prednisone/methylprednisolone (variable effectiveness
but often used clinically for status migrainosus; increased risk of cleft lip/palate
and possibly low birth weight more with chronic use),60 and prochlorperazine
(moderately effective; no known risks aside from neonatal extrapyramidal
symptoms, although metoclopramide preferred).33
Traditionally, triptans have been avoided during pregnancy because of
concern for potential impacts to placental circulation. However, given how
commonly these medications are used and given the accumulated information on
exposures during pregnancy over the years,29,61,62 more and more headache
specialists are adding triptans back to the list of possible therapies offered to
pregnant patients with migraine. With that being said, most headache specialists

TABLE 4-4 Safety and Effectiveness of Acute Medications in Pregnancy

Medication Safetya Effectivenessa

Metoclopramide More safe Moderately effective

Lidocaine (subcutaneous, intranasal) More safe Moderately effective

Acetaminophen More safe Moderately effective

Cyclobenzaprine More safe Moderately effective

Diphenhydramine (adjunct for sedation) More safe Least effective

Ondansetron (adjunct for nausea) Between safest and moderate Most effective
safety categories

Triptans Between safest and moderate Most effective

safety categories

Ibuprofen (only for use during second trimester) Moderate safety Moderately effective

Prednisone Moderate safety Moderately effective

Prochlorperazine Moderate safety Moderately effective

Oxycodone (generally not recommended for migraine) Moderate safety Least effective

Butalbital (generally not recommended for migraine) Moderate safety Least effective

Lasmiditan Least safe Most effective

Gepants (rimegepant, ubrogepant) Least safe Most effective

Magnesium sulfate (IV) Least safe Least effective

Ergots Least safe Moderately effective

a
Relative safety and effectiveness judged by the opinion of the author of this article combining tolerability in clinical practice and review of the
available evidence29,33 and expert consensus,34 not based on direct comparisons among therapies in clinical trials.

86 FEBRUARY 2022

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would agree that triptans should still probably not be used as first-line therapy. KEY POINTS
Butalbital-containing medications and opiates are not recommended for the
● Butalbital-containing
treatment of migraine in general, and the same applies to pregnant patients.63 medications and opiates are
Given the relative limitation in acute therapy options during pregnancy, it is not recommended for the
reasonable to consider using these medications sparingly in pregnant patients, treatment of migraine in the
although triptans are likely a safer option. Butalbital and opiates should only be general population; this
applies to both pregnant
used as a last resort, and clinicians should be mindful of neonatal withdrawal
and nonpregnant patients.
syndromes with more frequent use.
The new direct CGRP receptor antagonists ubrogepant and rimegepant and ● The new direct CGRP
the new serotonin-1F agonist lasmiditan should be avoided in pregnancy given receptor antagonists
the paucity of available evidence about their safety in pregnancy. Aspirin is often ubrogepant and rimegepant
and the new serotonin-1F
used for the prevention of preeclampsia in patients who are at high risk,64 agonist lasmiditan should be
although most headache specialists avoid this, if possible, when the indication is avoided in pregnancy given
for treatment of migraine given the risk of premature closure of the ductus the paucity of available
arteriosus in late pregnancy, fetal/neonatal hemorrhage, perinatal mortality, and evidence about their safety
in pregnancy.
intrauterine growth restriction with chronic higher doses.33 Ergot derivatives,
including dihydroergotamine, are absolutely contraindicated for use during ● Neuromodulation devices
pregnancy given the oxytocic effects and intrauterine growth restriction.65 should be theoretically safe
to use in pregnant women
with migraine or cluster
Medical Devices
headache, but data are
Neuromodulation devices should be theoretically safe to use in pregnant women limited.
with migraine or cluster headache, but data are limited. Options include single-
pulse transcranial magnetic stimulation, vagus nerve stimulation, trigeminal ● If headache improved
nerve stimulation, remote electrical neuromodulation, and occipital nerve during pregnancy, some
women enjoy a continued
stimulation. Many headache specialists feel the use of these devices during improvement during
pregnancy may be preferable to oral medications with established or unknown lactation and may not
teratogenic potential. However, adequately sham-controlled trials are difficult to require immediate
implement, device effectiveness in clinical practice is moderate at best, and— resumption of their prior
preventive therapies.
perhaps most important—cost continues to be a major barrier to these treatments
for many patients. Still, neuromodulation remains an important tool in the
toolbox when options may otherwise be limited.

TREATMENT OF MIGRAINE DURING LACTATION AND THE PUERPERIUM

Once secondary headache has been excluded, many therapeutic options are
available for the treatment of postpartum headache. If headache improved
during pregnancy, some patients enjoy a continued improvement during
lactation and may not require immediate resumption of their prior preventive
therapies. Similarly, the return of the menstrual cycle and cessation of lactation
can sometimes prompt the return of a prepregnancy headache pattern in some
women. Breastfeeding an infant requires significant effort and time, but it can
also be an incredibly gratifying bonding experience. Many treatments pose more
risk to preterm and newborn infants, so some safety concerns may lessen as the
baby grows older. Unfortunately, patients are often routinely told to just “pump
and dump” after medication use. This practice can be incredibly disruptive and
may sometimes lead to the early cessation of breastfeeding altogether, although
occasionally it can be necessary. These hardships should always be considered
when discussing the benefits and risks of treatments during lactation. Clinicians
should familiarize themselves with evidence-based tools to guide discussions
about the safety of medications during lactation, such as LactMed66 and Hale’s
Medications & Mother’s Milk, the latter of which uses a L1 to L5 safety scale with

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HEADACHE IN PREGNANCY AND LACTATION

TABLE 4-5 Safety and Effectiveness of Medications During Lactation

Medication Hale’s risk categorya,66 Safetya Effectivenessa,b

Acute therapies

Acetaminophen/ibuprofen L1 More safe Moderately effective

Triptans (eletriptan/sumatriptan preferred) L2/L3 More safe Most effective

Lidocaine (subcutaneous/intranasal) L2 More safe Moderately effective

Prednisone (short term) L2 More safe Moderately effective

Ondansetron (adjunct for nausea) L2 More safe Most effective

Antiemetics L2/L3 Moderate safety Moderately effective

Lasmiditan Not rated Least safe Most effective

Gepants (ubrogepant, rimegepant) Not rated Least safe Most effective

Ergots L4 Least safe Most effective

Preventive therapiesc

Amitriptyline/nortriptyline L2 More safe Most effective

Candesartan L3 Moderate safety Moderately effective

Gepants (atogepant, rimegepant) Not rated Least safe Most effective

Propranolol L2 More safe Most effective

Topiramate L3 Moderate safety Most effective

OnabotulinumtoxinA L3 Moderate safety Most effective

Riboflavin/magnesium L1 More safe Least effective

Valproic acid L2 Moderate safety Most effective

Venlafaxine L3 Moderate safety Moderately effective

Verapamil L2 More safe Moderately effective

d
Calcitonin gene-related peptide Not rated Least safe Most effective
targeting treatments (erenumab,
fremanezumab, galcanezumab,
eptinezumab)

a
Relative safety and effectiveness judged by the opinion of the author of this article combining tolerability in clinical practice and review of the
available evidence29,33 and expert consensus,34 not based on direct comparisons among therapies in clinical trials.
b
Hale’s risk categories:
L1 Safest: Drug has been taken by many breastfeeding women without evidence of adverse effects in nursing infants OR controlled studies have
failed to show evidence of risk.
L2 Safer: Drug has been studied in a limited number of breastfeeding women without evidence of adverse effects in nursing infants.
L3 Moderately Safe: Studies in breastfeeding have shown evidence for mild nonthreatening adverse effects OR there are no studies in
breastfeeding for a drug with possible adverse effects.
L4 Possibly Hazardous: Studies have shown evidence for risk to a nursing infant, but in some circumstances the drug may be used during
breastfeeding.
L5 Contraindicated: Studies have shown significant risk to nursing infants. The drug should NOT be used during breastfeeding.
c
Lactation for a premature baby may require caution for any preventive treatment that is a central nervous system depressant.
d
The large size of monoclonal antibodies could theoretically reduce the degree that these medications are expressed in breast milk, although this
has not been adequately studied.68

88 FEBRUARY 2022

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L1 being the safest.67 TABLE 4-5 summarizes this author’s opinion about safety KEY POINTS
and effectiveness of common headache treatments when used during lactation.68
● Eletriptan has the lowest
For acute treatments, acetaminophen and ibuprofen are relatively safe first- milk to plasma ratio of the
line options. The triptans are also commonly used. Although it is sometimes triptans, and sumatriptan
difficult to get insurers to cover it, eletriptan has the lowest milk to plasma ratio has the most safety data
of the triptans, and sumatriptan has the most safety data available for breastfeeding. available for breastfeeding.
Antiemetics can be used, although caution should be used because of their sedating
● Ubrogepant, rimegepant,
effects. Metoclopramide has been known to increase milk supply, and promethazine and lasmiditan should be
can interfere with the establishment of lactation. Similar to the recommendations avoided during lactation
for their use in pregnancy, ubrogepant, rimegepant, and lasmiditan should be given the absence of
avoided during lactation given the absence of available data. available data.

Although patients and clinicians should continue to use caution when deciding ● The CGRP monoclonal
on use of preventive therapy during lactation, arguably more therapeutic options antibodies have not been
are available as compared to during pregnancy. Amitriptyline and nortriptyline studied in lactation.
have limited drug excreted in breast milk (although they can cause sedation in However, given their large
size, it is unlikely that they
sleep-deprived parents). Propranolol, riboflavin, and magnesium can also be will pass through into breast
used. Topiramate should be used at lower doses and with caution given the milk, and some headache
possibility of lethargy and diarrhea in the infant, and avoidance of the drug is specialists are now
prudent if the child is preterm or a newborn66; however, levels measured in considering their use when
treating particularly
breast milk were only between 3% to 23% of the mother’s weight-adjusted dose in
disabling and intractable
published studies.69 OnabotulinumtoxinA is probably compatible with migraine.
breastfeeding given its peripheral administration and large molecular size,
although it has not been well studied.24 Verapamil is also likely safe.70 The CGRP
monoclonal antibodies have not been studied in lactation. However, given their
large size, it is unlikely that they will pass through into breast milk, and some
headache specialists are now considering their use when treating particularly
disabling and intractable migraine in patients who are breastfeeding.

CONCLUSION
A variety of treatment options exist for primary headache disorders in pregnancy
and lactation, including oral medications, medical devices, and other
nonpharmacologic therapy. Newer emerging therapies should generally be
avoided until more data are available. A prior history of migraine is not
necessarily reassuring when new headache presents during pregnancy or the
puerperium, and secondary headache is quite common. Close coordination with
the patient’s obstetric team is essential, and preconception planning is ideal.
Neurologists should be prepared to provide evidence-based care for pregnant
and lactating patients with headaches.

USEFUL WEBSITES
REPROTOX
The REPROTOX database includes summaries of the
effects of medications, chemicals, infections, and
physical agents on pregnancy, reproduction, and
development (requires subscription, free for
trainees).
reprotox.org
AGENCY FOR HEALTHCARE RESEARCH AND QUALITY 2020
SYSTEMATIC REVIEW ON MANAGEMENT OF PRIMARY
HEADACHES IN PREGNANCY
This webpage provides the results of a systematic
review of the management of primary headaches in
pregnancy and a summary of the main points of the
review.
effectivehealthcare.ahrq.gov/products/
headaches-pregnancy/research

CONTINUUMJOURNAL.COM 89

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HEADACHE IN PREGNANCY AND LACTATION

DRUGS AND LACTATION DATABASE (LACTMED)

This database contains information on drugs and
other chemicals to which breastfeeding mothers
may be exposed and includes the possible adverse
effects in the nursing infant.
ncbi.nlm.nih.gov/books/NBK501922

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